Protocol Template



CLINICAL STUDY PROTOCOL FORMTEXT Study Title.WORKING INSTRUCTIONSInstructions given in hidden text.To show hidden text: Office button > Word options > Display > check hidden text.Delete on finalisation.Short Title:Short Study Title or Study Acronym, maximum 40 charactersVersion: FORMTEXT 1 SET \* MERGEFORMAT ASK VersionNumber " " Date:06-Sep-2018CHDR number:CHDR FORMTEXT 9999 FILLIN "CHDR Number" Sponsor number:Z12Y34-32X6 or delete row if NAEthics Committee number:PYY.123 or delete row if NAToetsing Online number:NL3423456634-54EudraCT number:YYYY-123456-78 or delete row if NATITLE PAGEStudy title and acronym, if anyDescribe the purpose and key design features of the study.Use the following elements in the proposed order, as applicable:Treatment assignment: e.g., randomized.Blinding: e.g., open-label, single-blind, double-blind.Reference treatment: e.g., placebo-controlled, active-controlled, non-comparative.If a placebo is being used for blinding purposes only, it is a non-comparative study and not a placebo-controlled study.Design: e.g., parallel group, crossover, etc.Study type: efficacy, safety and tolerability, pharmacokinetic, pharmacodynamic, single-ascending dose, multiple-ascending dose, dose-escalating, dose-ranging, dose-finding, long-term tolerability, extension, etc.Statistical hypothesis (or lack of): exploratory, superiority, non-inferiority, equivalence study. Investigational drug: drug name (INN) and/or drug-specific number Subject/patient population: e.g., adults, children, women, elderly, hospitalized, Japanese, renal or liver dysfunction, etc.Example: Randomized, double-blind, placebo-controlled single ascending dose study to assess the efficacy, safety and tolerability of paracetamol in healthy male subjects.Make sure to use the same (or very similar) ‘short title’ for protocol, Promasys (max 40 characters inc spaces), and ABR form (max 70 characters inc spaces) is used.Example: Single ascending dose study of paracetamol.Fields to fill in are in CHDR Complementary Green (R13 G126 B11). Fill these in once, select all (Ctrl+A) then F9.HEADER & FOOTEROther protocol numbers can be added to the header at the sponsor's request.Check protocol version number is consistent throughout document.The word 'confidential' is optional.GENERAL PROTOCOL WRITING INSTRUCTIONSWriting instructions or examples are given in CHDR Secondary Blue (R0 G0 B255) italics and are to be deleted/hidden before finalizing the protocol. Optional words and sentences are given in CHDR Magenta (R230 G0 B126) and should be converted to normal black or deleted if not applicable.Hyperlinks to internet guidelines are given in CHDR Secondary Purple (R128 G0 B255).Do not alter or delete sections or mandatory text, unless this is specifically indicated. Rather mention “Not applicable”.Use UK spelling throughout and spell check the document before release (NB the spelling of the word ‘Centre’ in our name), unless sponsor specifically requests otherwise.Ensure that hyphenation (e.g., double-blind) and capitalisation (e.g., investigator or investigator) are consistent throughout.Write “must” rather than “should” if the instruction is mandatory. The word “should” can be misinterpreted as “could be done” or "not need be done”.Always specify units, preferentially using the International System of Units whenever applicable.Number any tables or figures in sequence. Do not use the section number in which they appear. USE the caption/cross-reference function under the References tab.To increase the readability of protocols use < for inferior to (not ), and for superior or equal to (not >), whenever there is a choice.When writing 'plasma drug concentration' NEVER interchange the words 'plasma' and 'drug'. By writing 'drug plasma concentration' it is implying that the concentration of plasma in drug is being measured (?!). Consider 'breath alcohol concentration' vs. 'alcohol breath concentration' - these do not have the same meaning. ALWAYS 'matrix-drug-concentration'Alternately write 'drug concentration in plasma'. Be consistent with using 'levels' or 'concentrations' (preference to the latter)Use the future tense when appropriate (except for amendment section).Style (Black, unless a hyperlink/cross-reference then blue: RGB0 0 255):Font: Arial Chapters HEADING 1Heading 2, 12 ptHeading 3, 11 pt, numbering, sentence caseHeading 4, 11 pt, no numbering, italics, bold, no-indentNo levels beyond heading 4.Cross-reference/Hyperlink (in text cross-reference to a Table, Figure, or Section)Turn on gridlines: click on ‘short title’ on the title page >Layout > Table > View GridlinesTable Style:Top & bottom border 1.5 pt solid line. Inside Horizontal Border, 0.5 pt, broken line.Avoid vertical lines where possible.If there is doubt whether to include or delete a section then check pg 31-34 of ICH E6(R1).While providing documents in Electronic Common Technical Document (eCTD) format is not a standard CHDR service, recognise that some sponsors request this service. For protocols (and reports) the most pertinent information regarding eCTD can be found in Appendix 7 of the ICH eCTD Specification V 3.2.2. Many of these issues are dealt with by following the following instructions:Cross-referencingTable and figures should be labelled by going to References tab > Captions > Insert Caption > select the appropriate label and use Roman numerals. The citation should be made blue (use the Cross-reference style) to indicate it is a hyperlink. When referring to another part of the document (section, table, or figure) go to either References tab > Captions or Insert tab > Links then > Cross-reference. Insert the appropriate reference type and ensure reference is to 'only label and number' and the' insert as hyperlink' checkbox is ticked.To make Refman citations eCTD compliant:Create bibliography (see reference section)Find citation in text e.g.[1], select and use blue Cross-Reference style.While selected, go to Insert > Links > Hyperlinks > Place in this document > REFERENCE > OKPrinting/saving as pdf: Make sure 'Print hidden text' is not checked under Office button > Word options > Display.Go to Acrobat tab > Create Adobe PDF > Preference. Under Setting tab:Tick 'create bookmarks' and 'add links' 'PDFA/1-a: 2005 compliant file' should be unchecked.Under the Setting tab Go to advanced settings…: Compatibility set to Adobe 5.0 (PDF 1.4)Tick 'optimize for fast web viewingUnder Fonts > tick 'embed all fonts'Under Bookmarks tab: tick 'Convert Word Headings to Bookmarks'Check the element 'Cross-reference' in the scroll-list.To print:Adobe tab > Create PDF > Save (remember CCMO file naming guidelines: 'C1. CHDRxxxx Clinical Study Protocol_versiondate')SUMMARY OF CHANGES [Delete ON INITIAL, COPY FOR AMENDMENTS]Study Title StudyTitle \* MERGEFORMAT Study Title.The following revisions were made to the protocol, which are also reflected in the synopsis, and other documents:This section contains a summary of general changes and their rationale made to the protocol and other documents.Copy text from the amendment document.It should be in chronological order (amd1, amd2, etc). Within an amendment summary give precedence to substantial amendments and try to maintain the order of the changes as they occur in the document. Changes to the synopsis do not need to be mentioned, as they are a reflection of the protocol change.Guidance for justification and classification can be found in section 3.3 of this document . PROTOCOL VERSION 2, AMENDMENT 1,10-DEC-2012ChangeRationaleJustification & ClassificationChanged Document(s), SectionUpper limit of inclusion criterion age was changed from 35 years to 85 years.No rationale for previous limit. Change of age range and inclusion criterion: substantial- Protocol, Section 4.1.2- SIS & ICF, Introduction Monitor detailsNew study monitorChange of name: non-substantial- Protocol, Contact DetailsThe font was changed from Times New Roman to Arial.Consistency with house style.Stylistic change: non-substantial- Protocol, Whole DocumentCONTACT DETAILS [Delete SPONSOR section if internal study]SPONSOR Move as appropriate e.g. CHDR acting as EU rep.: (EU legal representative) FORMTEXT Full Sponsor NameStreetPostcode, CityCountryClinical Trial Leader Name / Qualification(s)Telephone: + inserte-mail: insert@Head of Clinical PharmacologyName / Qualification(s)Telephone: + inserte-mail: insert@Clinical PharmacologistName / Qualification(s)Telephone: + inserte-mail: insert@Monitor[Delete if 3rd party i.e. independent from sponsor and add next page]Name / Qualification(s)Telephone: + inserte-mail: insert@Medical Expert or Drug Safety Physician[Mandatory] Name / Qualification(s)Telephone: + inserte-mail: insert@Trial Site(visit & delivery address)Centre for Human Drug ResearchZernikedreef 82333 CL LeidenThe NetherlandsTelephone: + 31 71 5246 400Fax: + 31 71 5246 499Emergency: + 31 71 5246 444Principal investigator[Mandatory] FORMDROPDOWN Telephone: + inserte-mail: insert@Co-investigator FORMTEXT Name / Qualification(s)Telephone: + inserte-mail: insert@Co-investigator FORMTEXT Name / Qualification(s)Telephone: + inserte-mail: insert@Manager Operations UnitJ. M. (Ria) Kroon, BScTelephone: + 31 71 5246 498e-mail: rk@chdr.nlManager Clinical UnitC. E. (Emilie) Jonxis, MANPTelephone +31 71 5246433e-mail: ejonxis@chdr.nlStatisticianM. L. (Marieke) de Kam, MScTelephone: + 31 71 5246 458e-mail: mdekam@chdr.nlINDEPENDENT PHYSICIANProf. Dr G.J. Blauw, MD, PhDDepartment of Gerontology and Geriatrics LUMCPostbus 96002300 RC LeidenTelephone: + 31 71 5266 640MONITOR(visit & delivery address)[Delete section if internal study or sponsor monitor]Full Company NameStreetPostcode, CityCountryContact personName / Qualification(s)Telephone: + inserte-mail: insert@LABORATORY – CHEMISTRY AND HAEMATOLOGYC.M. Cobbaert, PhDAKCL LUMC, E2-PAlbinusdreef 22333 ZA LeidenThe NetherlandsContact personR.N. Malhoe Mishre-LalaiLABORATORY – MICROBIOLOGYA.C.M. Kroes, MD, PhDKML LUMC, E4-PAlbinusdreef 22333 ZA LeidenThe Netherlands Contact personA.C.M. KroesLABORATORY – PK BIOANALYTICAL[Duplicate if more than one lab, medical and/or technical department]Full Laboratory NameStreetPostcode, CityCountryContact personName / Qualification(s)Telephone: + inserte-mail: insert@PHARMACY(visit & delivery address)Apotheek LUMC, L0-P30Goederenontvangst apotheek attn. trialsEinthovenweg 62333 ZC LeidenThe NetherlandsTelephone:+ 31 71 5269111Fax+ 31 71 5262611Pharmacist / Trial ManagerMarieke Tio, PharmD / Linda van der HulstCHDR template v2018.9SIGNATURE PAGE - PRINCIPAL INVESTIGATORStudy Title StudyTitle \* MERGEFORMAT Study Title.I acknowledge accountability for this protocol in accordance with CHDR’s current procedures. FORMDROPDOWN Principal investigatorSignatureDate (dd Mmm yyyy)[For CHDR sponsored studies, add the following text]This is an investigator-initiated trial, CHDR acts as both the investigator as well as the sponsor of the study, with all applicable responsibilities. SIGNATURE PAGE - TRIAL SITE STAFFCentre for Human Drug ResearchStudy Title StudyTitle \* MERGEFORMAT Study Title.I acknowledge responsibility for this protocol in accordance with CHDR’s current procedures.CoInvestigator1Name / Qualification(s)Co-investigatorSignatureDate (dd Mmm yyyy)CoInvestigator2Name / Qualification(s)Co-investigatorSignatureDate (dd Mmm yyyy)J. M. (Ria) Kroon, BScManager Operations UnitSignatureDate (dd Mmm yyyy)C.E. (Emilie) Jonxis, MANPManager Clinical UnitSignatureDate (dd Mmm yyyy)M. L. (Marieke) de Kam, MScStatisticianSignatureDate (dd Mmm yyyy)SIGNATURE PAGE - SPONSOR FullSponsorName \* MERGEFORMAT Full Sponsor NameStudy Title StudyTitle \* MERGEFORMAT Study Title.I approve this protocol on behalf of the sponsor.Name / Qualification(s)Sponsor’s representative / TitleSignatureDate (dd Mmm yyyy)TABLE OF CONTENTSTo update the table of contents or the lists of tables/figures/appendices, place the cursor in the table of contents or list and press F9 (NB this may protect the document - unprotect by going to review > Protect > Protect Document > Restrict Formatting and Editing > Stop Protection.Ensure settings are correct: Right click > edit field > select TOC > Tick 'show page numbers'Tick 'Right align page numbers'Show levels: 3Tick 'Use hyperlinks instead of page numbers'This TOC will remain blue as it is a hyperlink in the pdf version.Add TOC for tables/figures/appendices if applicable. TOC \o "1-3" \h \z \u SUMMARY OF CHANGES PAGEREF _Toc443568416 \h 2CONTACT DETAILS PAGEREF _Toc443568417 \h 3SIGNATURE PAGE - PRINCIPAL INVESTIGATOR PAGEREF _Toc443568418 \h 5SIGNATURE PAGE - TRIAL SITE STAFF PAGEREF _Toc443568419 \h 6SIGNATURE PAGE - SPONSOR PAGEREF _Toc443568420 \h 7TABLE OF CONTENTS PAGEREF _Toc443568421 \h 7LIST OF ABBREVIATIONS PAGEREF _Toc443568422 \h 7PROTOCOL SYNOPSIS PAGEREF _Toc443568423 \h 71BACKGROUND AND RATIONALE PAGEREF _Toc443568424 \h 71.1Context PAGEREF _Toc443568425 \h 71.2Non-clinical information PAGEREF _Toc443568426 \h 71.2.1Non-clinical pharmacology PAGEREF _Toc443568427 \h 71.2.2Non-clinical pharmacokinetics and metabolism PAGEREF _Toc443568428 \h 71.2.3Non-clinical toxicology and safety pharmacology PAGEREF _Toc443568429 \h 71.3Clinical information PAGEREF _Toc443568430 \h 71.3.1Clinical pharmacology PAGEREF _Toc443568431 \h 71.3.2Clinical pharmacokinetics and metabolism PAGEREF _Toc443568432 \h 71.3.3Clinical toxicology and safety pharmacology PAGEREF _Toc443568433 \h 71.4Study rationale PAGEREF _Toc443568434 \h 71.4.1Benefit and risk assessment PAGEREF _Toc443568435 \h 71.4.2Medical and regulatory background PAGEREF _Toc443568436 \h 71.4.3Study population PAGEREF _Toc443568437 \h 71.4.4Study design PAGEREF _Toc443568438 \h 71.4.5Comparative drug(s) and/or placebo PAGEREF _Toc443568439 \h 71.4.6Safety margin calculations, dose selection, dose escalation, and stopping criteria PAGEREF _Toc443568440 \h 71.4.7Treatment duration PAGEREF _Toc443568441 \h 71.4.8Primary endpoint PAGEREF _Toc443568442 \h 71.4.9Statistical hypotheses and sample size PAGEREF _Toc443568443 \h 72STUDY OBJECTIVES PAGEREF _Toc443568444 \h 72.1Primary objective PAGEREF _Toc443568445 \h 72.2Secondary objectives PAGEREF _Toc443568446 \h 73STUDY DESIGN PAGEREF _Toc443568447 \h 73.1Overall study design and plan PAGEREF _Toc443568448 \h 73.1.1Screening PAGEREF _Toc443568449 \h 73.1.2Treatment and observation period PAGEREF _Toc443568450 \h 73.1.3Follow-up PAGEREF _Toc443568451 \h 74STUDY POPULATION PAGEREF _Toc443568452 \h 74.1Subject population PAGEREF _Toc443568453 \h 74.2Inclusion criteria PAGEREF _Toc443568454 \h 74.3Exclusion criteria PAGEREF _Toc443568455 \h 74.4Concomitant medications PAGEREF _Toc443568456 \h 74.4.1Allowed concomitant medications PAGEREF _Toc443568457 \h 74.4.2Prohibited concomitant medications PAGEREF _Toc443568458 \h 74.4.3Escape/rescue medications PAGEREF _Toc443568459 \h 74.5Lifestyle restrictions PAGEREF _Toc443568460 \h 74.5.1Contraception requirements PAGEREF _Toc443568461 \h 74.6Study drug discontinuation and withdrawal PAGEREF _Toc443568462 \h 74.6.1Study drug interruption or discontinuation PAGEREF _Toc443568463 \h 74.6.2Subject withdrawal PAGEREF _Toc443568464 \h 74.6.3Replacement policy PAGEREF _Toc443568465 \h 75INVESTIGATIONAL MEDICINAL PRODUCT PAGEREF _Toc443568466 \h 75.1Investigational drug and matching placebo PAGEREF _Toc443568467 \h 75.2Comparative drug PAGEREF _Toc443568468 \h 75.3Study drug dosing scheme PAGEREF _Toc443568469 \h 75.4Study drug up- and down-titration PAGEREF _Toc443568470 \h 75.5Study drug packaging and labelling PAGEREF _Toc443568471 \h 75.6Study drug preparation PAGEREF _Toc443568472 \h 75.7Drug accountability PAGEREF _Toc443568473 \h 75.8Treatment assignment and blinding PAGEREF _Toc443568474 \h 75.8.1Treatment assignment PAGEREF _Toc443568475 \h 75.8.2Blinding PAGEREF _Toc443568476 \h 76STUDY ENDPOINTS PAGEREF _Toc443568477 \h 76.1Efficacy endpoints PAGEREF _Toc443568478 \h 76.2Safety and tolerability endpoints PAGEREF _Toc443568479 \h 76.3Pharmacokinetic endpoints PAGEREF _Toc443568480 \h 76.4Pharmacodynamic endpoints PAGEREF _Toc443568481 \h 77STUDY ASSESSMENTS PAGEREF _Toc443568482 \h 77.1Efficacy assessments PAGEREF _Toc443568483 \h 77.2Safety and tolerability assessments PAGEREF _Toc443568484 \h 77.2.1Specific safety and tolerability assessments PAGEREF _Toc443568485 \h 77.2.2Vital signs PAGEREF _Toc443568486 \h 77.2.3Weight and height PAGEREF _Toc443568487 \h 77.2.4Physical examination PAGEREF _Toc443568488 \h 77.2.5Electrocardiography PAGEREF _Toc443568489 \h 77.2.6Laboratory assessments PAGEREF _Toc443568490 \h 77.3Pharmacokinetic and pharmacodynamic assessments PAGEREF _Toc443568491 \h 77.3.1Labelling PAGEREF _Toc443568492 \h 77.3.2Shipping Procedures PAGEREF _Toc443568493 \h 77.3.3Bioanalysis PAGEREF _Toc443568494 \h 77.4Pharmacodynamic assessments and questionnaires PAGEREF _Toc443568495 \h 77.4.1Concomitant medications PAGEREF _Toc443568496 \h 77.5Sequence of assessments and time windows PAGEREF _Toc443568497 \h 77.6Total blood volume PAGEREF _Toc443568498 \h 78SAFETY REPORTING PAGEREF _Toc443568499 \h 78.1Definitions of adverse events PAGEREF _Toc443568500 \h 78.1.1Intensity of adverse events PAGEREF _Toc443568501 \h 78.1.2Relationship to study drug PAGEREF _Toc443568502 \h 78.1.3Chronicity of adverse events PAGEREF _Toc443568503 \h 78.1.4Action PAGEREF _Toc443568504 \h 78.1.5Serious adverse events PAGEREF _Toc443568505 \h 78.1.6Suspected unexpected serious adverse reactions PAGEREF _Toc443568506 \h 78.1.7Reporting of serious adverse events PAGEREF _Toc443568507 \h 78.1.8Follow-up of adverse events PAGEREF _Toc443568508 \h 78.2Temporary halt for reasons of subject safety PAGEREF _Toc443568509 \h 78.3Annual safety report or development safety update report PAGEREF _Toc443568510 \h 78.4Pregnancy PAGEREF _Toc443568511 \h 78.4.1Teratogenicity PAGEREF _Toc443568512 \h 78.4.2Reporting of pregnancy PAGEREF _Toc443568513 \h 78.5Data safety monitoring board PAGEREF _Toc443568514 \h 79STATISTICAL METHODOLOGY AND ANALYSES PAGEREF _Toc443568515 \h 79.1Statistical analysis plan PAGEREF _Toc443568516 \h 79.2Protocol violations/deviations PAGEREF _Toc443568517 \h 79.3Power calculation PAGEREF _Toc443568518 \h 79.4Missing, unused and spurious data PAGEREF _Toc443568519 \h 79.5Analysis sets PAGEREF _Toc443568520 \h 79.5.1Safety set PAGEREF _Toc443568521 \h 79.5.2Pharmacokinetic analysis set PAGEREF _Toc443568522 \h 79.5.3Pharmacodynamic analysis set PAGEREF _Toc443568523 \h 79.6Subject disposition PAGEREF _Toc443568524 \h 79.7Baseline parameters and concomitant medications PAGEREF _Toc443568525 \h 79.7.1Demographics and baseline variables PAGEREF _Toc443568526 \h 79.7.2Medical history PAGEREF _Toc443568527 \h 79.7.3Concomitant Medications PAGEREF _Toc443568528 \h 79.7.4Treatment compliance/exposure PAGEREF _Toc443568529 \h 79.8Safety and tolerability endpoints PAGEREF _Toc443568530 \h 79.8.1Adverse events PAGEREF _Toc443568531 \h 79.8.2Vital signs PAGEREF _Toc443568532 \h 79.8.3ECG PAGEREF _Toc443568533 \h 79.8.4Clinical laboratory tests PAGEREF _Toc443568534 \h 79.9Pharmacokinetic and pharmacodynamic endpoints PAGEREF _Toc443568535 \h 79.9.1Pharmacokinetics PAGEREF _Toc443568536 \h 79.9.2Pharmacodynamics PAGEREF _Toc443568537 \h 79.9.3Inferential methods PAGEREF _Toc443568538 \h 79.9.4PK/PD modelling PAGEREF _Toc443568539 \h 79.10Exploratory analyses and deviations PAGEREF _Toc443568540 \h 79.11Interim analyses PAGEREF _Toc443568541 \h 710GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES PAGEREF _Toc443568542 \h 710.1Good clinical practice PAGEREF _Toc443568543 \h 710.1.1Ethics and good clinical practice PAGEREF _Toc443568544 \h 710.1.2Ethics Committee / institutional review board PAGEREF _Toc443568545 \h 710.1.3Informed consent PAGEREF _Toc443568546 \h 710.1.4Insurance PAGEREF _Toc443568547 \h 710.2Study funding PAGEREF _Toc443568548 \h 710.3Data handling and record keeping PAGEREF _Toc443568549 \h 710.3.1Data collection PAGEREF _Toc443568550 \h 710.3.2Database management and quality control PAGEREF _Toc443568551 \h 710.4Access to source data and documents PAGEREF _Toc443568552 \h 710.5Quality control and quality assurance PAGEREF _Toc443568553 \h 710.5.1Monitoring PAGEREF _Toc443568554 \h 710.6Protocol amendments PAGEREF _Toc443568555 \h 710.6.1Non-substantial amendment PAGEREF _Toc443568556 \h 710.6.2Substantial amendment PAGEREF _Toc443568557 \h Fout! Bladwijzer niet gedefinieerd.10.7End of study report PAGEREF _Toc443568558 \h 710.8Public disclosure and publication policy PAGEREF _Toc443568559 \h 711STRUCTURED RISK ANALYSIS PAGEREF _Toc443568560 \h 711.1Potential issues of concern PAGEREF _Toc443568561 \h 711.1.1Level of knowledge about mechanism of action PAGEREF _Toc443568562 \h 711.1.2Previous exposure of human beings with the test product(s) and/or products with a similar biological mechanism PAGEREF _Toc443568563 \h 711.1.3Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell material? PAGEREF _Toc443568564 \h 711.1.4Selectivity of the mechanism to target tissue in animals and/or human beings PAGEREF _Toc443568565 \h 711.1.5Analysis of potential effect PAGEREF _Toc443568566 \h 711.1.6Pharmacokinetic considerations PAGEREF _Toc443568567 \h 711.1.7Study population PAGEREF _Toc443568568 \h 711.1.8Interaction with other products PAGEREF _Toc443568569 \h 711.1.9Predictability of effect PAGEREF _Toc443568570 \h 711.1.10Can effects be managed? PAGEREF _Toc443568571 \h 711.2Synthesis PAGEREF _Toc443568572 \h 712REFERENCES PAGEREF _Toc443568573 \h 7APPENDIX PAGEREF _Toc443568574 \h 7LIST OF ABBREVIATIONSCreate a list of abbreviations used in the main text.Give each abbreviation in brackets after the first use in text and thereafter use the abbreviation only.Use, modify the following sample list as appropriate. Do not list units (e.g., mg, cm, dl), common abbreviations (am, pm, etc., i.e., e.g.), common medical terms (e.g., QT interval) or abbreviations not used in text.ABRABR form, General Assessment and Registration form, is the application form that is required for submission to the accredited Ethics Committee; in Dutch, ABR = Algemene Beoordeling en RegistratieAEAdverse EventAeinfCumulative amount of administered dose excreted into the urine from time zero to infinity after single doseAe%infPercentage of administered dose excreted into the urine from time zero to infinity after single doseAelastCumulative amount of administered dose excreted into the urine from time zero to time of last measurable concentrationAe%lastPercentage of administered dose excreted into the urine from time zero to time of last measurable concentrationAetauCumulative amount of administered dose excreted into the urine within the dosing intervalAe%tauPercentage of administered dose excreted into the urine within the dosing intervalALTalanine aminotransferase/serum glutamic pyruvic transaminase (SGPT)ANCOVAAnalysis of CovarianceANOVAAnalysis of VarianceaPTTactivated partial thromboplastin time ASTaspartate aminotransferase/serum glutamic oxaloacetic transaminase (SGOT)ATCAnatomic Therapeutic ChemicalAUCArea under the concentration – time curveAUCinfArea under the concentration – time curve from time zero to infinityAUClastArea under the concentration – time curve from time zero to time of last measurable concentration AUCtauArea under the concentration – time curve between consecutive dosingb.i.d.bis in diem / twice a dayBLQBelow the Limit of QuantificationBMIBody Mass IndexBPBlood Pressurebpmbeats per minuteCACompetent authority (also CCMO)CCMOCentral Committee on Research Involving Human Subjects; in Dutch: Centrale Commissie Mensgebonden OnderzoekCHDRCentre for Human Drug ResearchCIConfidence IntervalCKcreatine kinaseCL/FApparent total clearance following extravascular administrationCLRRenal clearance CmaxMaximum concentrationCtroughConcentration immediately prior to dosing at multiple dosingCRFCase Report FormCVCoefficient of variationDSMBData Safety and Monitoring BoardECEthics Committee (also Medical Research Ethics Committee (MREC); in Dutch: Medisch Ethische Toetsing Commissie (METC).ECGElectrocardiogramEDTAEthylene diamine tetra-acetic acidELISAEnzyme-linked immunosorbant assayEMAEuropean Medicines AgencyEUEuropean UnionFDAFood and Drug AdministrationGCPGood Clinical PracticeICHInternational Conference on HarmonizationIBinvestigator’s BrochureIDMCIndependent Data Monitoring CommitteeIMPDInvestigational Medicinal Product DossierINRInternational Normalized Ratioi.v.Intravenous(ly)IRBInstitutional Review BoardLDHLactate dehydrogenaseMaxMaximumMedDRAMedical Dictionary for Regulatory ActivitiesminMinutesMinMinimumo.d.omnia die/once a dayp.o.per os / orallySAESerious Adverse EventSAPStatistical Analysis PlanSDStandard DeviationSEMStandard Error of the MeanSOCSystem Organ ClassSOPStandard Operating ProcedureSPCSummary of Product CharacteristicsSSTSerum Separator TubeSUSARSuspected Unexpected Serious Adverse Reactiont.i.d. ter in diem / three times a dayt?Terminal Elimination Half-lifetlagAbsorption lag timetmaxTime to attain CmaxULNUpper Limit of NormalVz/FApparent volume of distribution during the terminal elimination phase after extravascular administrationWHOWorld Health OrganizationWBPPersonal Data Protection Act; in Dutch: Wet Bescherming PersoonsgevensWMOMedical Research Involving Human Subjects Act; in Dutch: Wet Medisch-wetenschappelijk Onderzoek met Mensen.PROTOCOL SYNOPSISMaximum 4 pages + 1 Visit and Assessment Schedule, suitable for internal CHDR Scientific Review Council and Scientific Advisory Board Submission.TitleExample: Randomized, double-blind, placebo-controlled single ascending dose study to assess the efficacy, safety and tolerability of paracetamol in healthy male subjects.Short TitleExample: Single ascending dose study of paracetamol.Principal investigator & Trial SiteName / Qualification(s), Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The NetherlandsBackground & RationaleIndicate the research question and rationaleMechanism of action of investigational drugRelevant (pre)clinical data (e.g. pharmacology, pharmacokinetics, toxicology/safety, pharmacodynamics)Justification of dose/treatment duration Objective(s)Use the word “demonstrate”, only if the study is powered for the relevant objective, in most cases the primary objective. Use the words “assess” or “evaluate”, if this is not the case.Each objective must correspond to a pre-defined efficacy, safety, tolerability, pharmacokinetic, pharmacodynamic endpoint. Consider if splitting the objectives into primary and secondary if required. Primary ObjectiveExample: To assess the efficacy, safety and tolerability of paracetamol in healthy male subjects. Secondary ObjectivesExample: To explore the immunogenicity of paracetamol.DesignTypically very similar to the title. Example: Randomized, double-blind, placebo-controlled single ascending dose study.Indicate overall study design (preferable by means of schematic representation)Provide sequence, definition and duration of study periods: screening, washout, run-in, treatment (titration, maintenance), follow-up periods, as applicable.Define, as appropriate:Baseline End-of-Study (or premature discontinuation) for an individual subjectDifferentiate between study and treatment durationInvestigational drugRoute / Dose(s) / Dosage regimen / BlindingTitration and maintenance phases, as parative drugRoute / Dose / Dosage regimen / Blinding/ ReasonFor placebo- and/or active-controlled studies or deleteSubjects / GroupsExample: A total of Z subjects/patients are planned to be enrolled. Y groups of X subjects (W active + N placebo). Mention randomization ratio and any stratification (Williams square design (must be divisible by the number of treatments), male and female subjects, etc).Inclusion criteriaMust match the protocol. Examples are given below.(For SAB synopsis, only mention the most important/relevant criteria)Signed informed consent prior to any study-mandated procedureHealthy <male> or <female> subjects, 18 to 45 years of age, inclusive at screening. Body mass index (BMI) between 18 and 30 kg/m2, inclusive at screening, and with a minimum weight of 50 kg.All women of child bearing potential <and all males> must practice effective contraception during the study and be willing and able to continue contraception for at least 90 days <(females)> or xx days <(males)> after their last dose of study treatment.Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions. Exclusion criteriaMust match the protocol. Examples are given below.(For SAB synopsis, only mention the most important/relevant criteria)Evidence of any active or chronic disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (following a detailed medical history, physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) and12-lead electrocardiogram (ECG)). Minor deviations from the normal range may be accepted, if judged by the Investigator to have no clinical relevance.Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects.Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg at screening/baseline.Abnormal findings in the resting ECG at screening/baseline defined as:QTcF> 450 or < 300 msec Notable resting bradycardia (HR?<?45 bpm) or tachycardia (HR?>?100 bpm)Personal or family history of congenital long QT syndrome or sudden death;ECG with QRS and/or T wave judged to be unfavourable for a consistently accurate QT measurement (e.g., neuromuscular artefact that cannot be readily eliminated, arrhythmias, indistinct QRS onset, low amplitude T wave, merged T- and U-waves, prominent U waves);Evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker Use of any medications (prescription or over-the-counter [OTC]), within 14 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions are paracetamol (up to 4 g/day) and ibuprofen (up to 1g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator.Use of any vitamin, mineral, herbal, and dietary supplements within 7 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions will only be made if the rationale is clearly documented by the investigator.Participation in an investigational drug or device study within 3 months prior to first dosing.History of abuse of addictive substances (alcohol, illegal substances) or current use of more than 21 units alcohol per week, drug abuse, or regular user of sedatives, hypnotics, tranquillisers, or any other addictive agentPositive test for drugs of abuse at screening or pre-dose. Alcohol will not be allowed from at least 24 hours before screening or pre-dose. Smoker of more than 10 cigarettes per day prior to screening or who use tobacco products equivalent to more than 10 cigarettes per day and unable to abstain from smoking whilst in the unit.Is demonstrating excess in xanthine consumption (more than eight cups of coffee or equivalent per dayAny confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable).Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening or intention to donate blood or blood products during the study.If a woman, pregnant, or breast-feeding, or planning to become pregnant during the study.Any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease.Concomitant medicationsMust match the protocol. Examples are given below.(For SAB synopsis, only mention notable medication that is not standard)No prescription medications and OTC medications will be permitted within 14 days prior to study drug administrations, or less than 5 half-lives (whichever is longer, and during the course of the study.No vitamin, mineral, herbal, and dietary supplements will be permitted within 7 days prior to study drug administrations, or less than 5 half-lives (whichever is longer, and during the course of the study.Exceptions are paracetamol (up to 4 g/day) and ibuprofen 1 g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator.Tolerability / safety endpointsDisease or drug-specific tolerability and safety endpoints. For example: (Serious) adverse events ((S)AEs) will be collected throughout the study at every study visit. Laboratory safety and vital signs will be obtained multiple times during the course of the study according to the Visit and Assessment Schedule Pharmacokinetic endpointsDelete if not applicable.Pharmacodynamic endpointsDelete if not applicable.Efficacy endpointsDelete if not applicable, e.g., phase I study.Sample Size JustificationEither (if based on power calculation) modify:The sample size required to achieve a power of at least 80% to detect an expected difference of the primary endpoint of 25% at a two-sided significance level of 0.05, are given in the following table for a range of within subject CV /SD valuesWithin subject CV/SDActual powerSample size.25.8118.30.8022.35.8025Or (if not based on a power calculation)Example: This is an exploratory study; therefore, the sample size is not based on statistical considerations.Statistical methodologyMention any interim analysis, its timing and related statistical methodology.Example:After each cohort an interim analysis will take place by generating summary graphs by treatment and time. No statistical testing will be conductedDescribe analyses and tests as applicable.Example:To establish whether significant treatment effects can be detected on the primary endpoint, the endpoint will be analyzed with a mixed model analysis of variance with treatment, time, and treatment by time as fixed factors and subject, subject by treatment and subject by time as random factors and the average baseline measurement as covariate. Parameters will initially be analyzed without transformation, but if the data suggest otherwise, log-transformation may be applied.Study committee(s)Mention if a Data and Safety Monitoring Board (DSMB) is necessary and will be used otherwise delete if not applicable.VISIT AND ASSESSMENT SCHEDULEUse and modify this sample table as appropriate. Replace randomization visit by enrolment visit for non-randomized studies.Specify when a visit does not need to be face-to-face and could be performed by phone only, e.g., 28-days follow-up visit.Where 10% window becomes too large, provide pragmatic time windows for visits, e.g., Month 12 ( 2?weeks).Limit footnotes (under the References tab) to a minimum to ensure their readability.Mandatory that dosing day is Day 0 (zero) to ensure consistency with statistical tables. When there is a challenge/pre-treatment drug discuss the timetable zero point with statistics (preference for start of treatment) and operations (preference for start of pre-treatments). Consider listing assessments in order of priorityTable SEQ Table \* ARABIC 1 Visit and Assessment ScheduleSCRTreatment days 1, 8, 22, 30, 44, 52, 66, 75FU Time point AssessmentUp to-42 d-2h-1h-30min-15min0h1h2h3h4h5h6h8h12h+14 d± 2 dInformed consentXDemographyXInclusion and exclusion criteriaXMedical history XPhysical examinationXXConcomitant medicationXVirologyXBsHaem, BsChem, UrinalysisXXUrDrug, BrAlcXXTemperatureXXXECGXXXXGeneral symptomsXXXXXXXXXXXVital Signs (Pulse Rate, BP, RR)Meals / snackXXDrug (-placebo) administrationXXXPK sampleXXXXXXXXXPD testsXXXXXDischargeXX(S)AE/Con-meds<----- continuous ----->BP = Blood Pressure, HR = Heart Rate, RR = Respiratory Rate, SCR = Screening, EEG = Electroencephalogram, PK = Pharmacokinetics, AE = Adverse Event, UrDrug = Urine Drug Screen, BsHaem = Blood Sample Haematology, BsChem = Blood Sample Chemistry, BrAlc = Breath Alcohol Test. BACKGROUND AND RATIONALEContextBriefly summarize (? page) what is known or not known about the role played by the system inhibited or activated by the investigational drug in particular in the studied disease.Summarize in vitro, in vivo or ex-vivo data in normal animals and animal models, in human healthy subjects and patients.Non-clinical informationTopic should be included per ICHE6(R1)Refer to the investigator’s Brochure.Summary of the findings from the non-clinical studies that potentially have clinical significance.Non-clinical pharmacologyNon-clinical pharmacokinetics and metabolismNon-clinical toxicology and safety pharmacologyClinical informationTopic should be included per ICHE6(R1)Summary of the findings from the clinical studies that are relevant.Clinical pharmacologyClinical pharmacokinetics and metabolismClinical toxicology and safety pharmacologyStudy rationaleBenefit and risk assessmentTopic should be included per ICHE6(R1)Summary of the known and potential risks and benefits, if any, to human subjects.Examples:The risks associated with the administration of <drug> to humans have not yet been identified, because this compound has not yet been studied in humans. On the basis of data collected from preclinical investigations, the main target organ toxicity of <drug> is considered to be related to the thyroid. Humans are much less sensitive to changes in thyroid hormones because their higher levels of thyroxine-binding proteins lead to slower hormone metabolism. As a safety measure thyroid hormones will be monitored in this study. <drug> is expected to have an analgesic potential. Symptoms such as somnolence, dizziness, fatigue, reduced vigilance, etc., are to be expected following administration. Subjects should not drive a car and should not engage in activities that require operating vehicles or dangerous machinery following administration of <drug>. Thus, the subjects will remain in the clinic under supervision and will be discharged by a physician only if their medical condition allows. The study design has been used previously in many entry-into-man studies, and is accepted by scientists and regulatory authorities. All study drug administrations will be done in the clinic under medical supervision. The subjects receiving any study drug will remain in the clinic for at least 48 hours after each study drug administration. Thus, the subjects can be closely monitored for any adverse signs during the different treatments. Therefore, providing the protocol is adhered to, careful observation and medical management will minimize any associated risk in this study.For a structured risk assessment see Section REF _Ref326941144 \r \h \* MERGEFORMAT 11.Medical and regulatory backgroundGive rationale for current study.Indicate in general terms its role in the overall clinical development program.Refer to any relevant ICH, FDA or EMA regulatory guidelines, e.g. scientific guidelines recommending a certain type of study.Study populationJustify choice of subject population in terms of age, sex, disease class etc.Justify choice of subject population when including subjects who are incapable to giving informed consent, e.g., children, coma patients, patients with psychiatric disorders, etc.Discuss suitability of subject population for achieving the study objectives.Discuss if necessary, how representative the study population is compared to the general population.Study designRefer to any relevant ICH, FDA or EMA regulatory guidelines justifying the study design for the class of drug in this particular disease/ indication.Or: Briefly explain why the specific study design has been chosen:Discuss suitability of the study design for achieving the study objectives, e.g., discuss the reason and adequacy of a crossover design. Mention any known or potential issues related to the design, e.g., justify the assumptions of no period and carry over effects for a crossover design. Justify using a non-randomized, non-comparative, or open-label study design and explain any measures used to reduce parative drug(s) and/or placeboDelete if not applicable.Justify choice and dosage of active comparative drug(s).Justify the use of a placebo, e.g., absence of reference treatment and/or absence of approved/labelled drug in this indication, etc.Discuss the potential risk of using a placebo if patients are to be washed out from a previous treatment, etc.Safety margin calculations, dose selection, dose escalation, and stopping criteriaTopic should be included per ICHE6(R1)Justify the route of administration, dosage, dosage regimen and treatment period of the investigational drug.Use or modify the following text:Safety margin calculationsSafety margins for <drug> were calculated for the planned starting dose of 5?mg and a high dose of 1000 mg based on NOAEL/MABEL human equivalent doses including a safety factor of X as well as modelled exposures (AUC0–24h) in humans.Dose escalationDoses will be administered in an escalating manner following thorough review of the safety, tolerability, and PD data for at least 24 hours post?dose after all subjects have completed the scheduled safety and PD assessments in the preceding dose group. The review of the data and the decision on the next dose level will be made jointly by the investigator and the sponsor.Stopping criteriaDose escalation will be stopped in case of an unacceptable tolerability profile based on the nature, frequency, and intensity of observed AEs judged jointly by the investigator and the sponsor.Treatment durationTopic should be included per ICHE6(R1). Justify the duration of treatment.Discuss suitability of the duration of treatment for achieving the study objectives.Primary endpointJustify the choice of the primary or co-primary endpoint(s) in relation to study primary objective(s), e.g., clinical endpoint, validated surrogate endpoint, intermediate biomarker, etc. Address its clinical relevance, as appropriate.Refer to any relevant ICH, FDA or EMA regulatory guidelines.Justify the absence of a primary endpoint, e.g., exploratory study.Justify why the study is powered for a secondary endpoint, as applicable.Statistical hypotheses and sample sizeEither: Briefly explain why the sample size is not based on a pre-defined hypothesis, e.g., exploratory study.This is an exploratory study; therefore, the sample size is not based on statistical considerations.Or: State the null and alternative hypotheses in relation to the primary objective(s) using a lay vocabulary.Example: The null hypothesis is that of no difference between the effects of paracetamol and placebo for the combined endpoint of death and worsening of liver failure in patients hospitalized for acute liver failure.Example: The alternative hypothesis is that the effects of the two treatments differ. The difference to be detected is a relative risk reduction (treatment difference) of 25%, i.e., decreases the incidence of this combined endpoint from 40% (expected incidence in the placebo group) to 30%. For a superiority study, provide the medical rationale for the treatment difference to be detected and discuss its clinical relevance in view of the minimal clinically relevant difference, as appropriate.For a non-inferiority or equivalence study, provide the medical rationale for the non-inferiority or equivalence margin and discuss its clinical relevance. State the sample size in relation to the statistical hypotheses.Justify any sample size adjustment for dropouts (e.g., during screening, washout, run-in or treatment phase, as applicable) or for non-evaluable subjects.The number of subjects should always be large enough to provide a reliable answer to questions addressed. Also the size of detectable differences should be of clinical relevance.The number of subjects is usually determined by the primary objective of the trial. If the sample size is determined on some other basis, then this should be made clear and justified. There are many formulas to calculate the size of the study population. It should be clear which method is used and the reasons why this method has been chosen. In case of multiple primary objectives, eg evaluation of multiple endpoints, each objective should have its own power calculation and in each of these the multiplicity corrected alpha, if needed, should be taken into account.Also, the calculation itself should be given with a predefined p-value (usually 5%) and power. The power of the study is the probability that the study will have a significant (positive) result – provided a positive effect exists. Ask advice from a statistician to help you with this matter.STUDY OBJECTIVESTopic should be included per ICHE6(R1)State the study primary and secondary objectives. Be as specific as possible.Adapt as appropriate when there are no pre-defined primary or secondary objectives, e.g., exploratory study i.e., delete the headings below.Use the word “demonstrate”, only if the study is powered for the relevant objective, in most cases the primary objective. Use the words “assess”, “evaluate”, or”investigate” if this is not the case.Objectives are different from endpoints.Each objective must correspond to a pre-defined efficacy, safety, tolerability, pharmacokinetic, pharmacodynamic, quality of life or pharmacoeconomic endpoint. The reverse is not always true: one might have more endpoints than objectives.Primary objectiveSecondary objectivesSTUDY DESIGNOverall study design and planTopic should be included per ICHE6(R1)Summarize the study design and plan without repeating the objectives.Add level 3 headings, as appropriate.Use the following elements in the proposed order as applicable:Prospective or retrospective Number of centers: monocenter or multicenterBlinding: e.g., open-label, single-blind, double-blind.Treatment assignment: e.g., randomized.Reference treatment: e.g., placebo-controlled, active-controlled, non-comparative.If a placebo is being used for blinding purposes only, it is a non-comparative study and not a placebo-controlled study.Design: e.g., parallel group, crossover, etc.Study type: e.g., efficacy, safety and tolerability, pharmacokinetic, pharmacodynamic, single-ascending dose, multiple-ascending dose, dose-escalating, dose-ranging, dose-finding, long-term tolerability, extension, etc.Statistical hypothesis (or lack of): exploratory, superiority, non-inferiority, equivalence study Study phase: I, IIa, IIb, IIIa, IIIb, IV or VInvestigational drug: or drug name (INN) and/or drug-specific number, route of administration, dose(s), dose regimen, etc.Subject population: e.g., adults, children, elderly, women, hospitalized, Japanese, renal or liver dysfunction, etc.Disease including classification (e.g., NYHA or WHO class) and grading (e.g., mild, moderate or severe), as appropriate.Provide sequence, definition and duration of study periods: e.g., screening, run-in, washout, treatment (titration, maintenance), follow-up periods, as applicable.State the total study duration for an individual subject. Use, modify or delete the following:The total duration of the study for each subject will be up to xx days divided as follows:Screening: Up to 42 days before dosing;Treatment and study assessments: Days -1 to 99In Clinic period: Days -2 to 3;Follow-up visit: 7 to 10 days after last dose.Subjects will be admitted to the study unit on Day -2 and will be discharged approximately 48 hours after study drug administration.ScreeningTreatment and observation periodDefine baseline as appropriate.Follow-upDefine End-of-Study or premature discontinuation for an individual subject, as appropriate.Define End-of-Study as a whole, as applicable, e.g., event-driven study.STUDY POPULATIONSubject populationTopic should be included per ICHE6(R1)Describe the study subject population.Example: A total of 24 subjects (12 males and 12 females) will be enrolled into the study following satisfactory completion of a screening visit where eligibility for the study will be checked. Males and females will be age–matched within ±5 years. Subjects will be recruited via media advertisement or from the subjects’ database of the Centre for Human Drug Research, Leiden, the Netherlands.Inclusion criteriaTopic should be included per ICHE6(R1). Inclusion criteria must match those in the synopsis.Specify the conditions a subject must meet to be included in the study.Distinguish between screening, washout or run-in criteria, and enrolment or randomization criteria, as appropriate.Be as specific as possible.Use numbering.Exclusion criteriaTopic should be included per ICHE6(R1). Exclusion criteria must match those in the synopsis.Specify the conditions under which a subject cannot be included in the study.Avoid repeating the same item for both the inclusion and exclusion criteria (e.g., inclusion: normal renal function and exclusion: renal dysfunction).Be as specific as possible.Use numbering.Concomitant medicationsTopic should be included per ICHE6(R1). Use, modify or delete the following text:All medications (prescription and over-the-counter [OTC]) taken within 30 days of study screening will be recorded.No prescription medications and OTC medications will be permitted within 14 days prior to study drug administrations, or less than 5 half-lives (whichever is longer, and during the course of the study. In addition, no vitamin, mineral, herbal, and dietary supplements will be permitted within 7 days prior to study drug administrations, or less than 5 half-lives (whichever is longer, and during the course of the study.Exceptions are paracetamol (up to 4 g/day) and ibuprofen 1 g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator.Delete these level 3 headings if not applicable.Allowed concomitant medicationsMention any disease-specific concomitant medications, as applicable.Refer to treatment of disease worsening during study drug administration, as appropriate.Describe any specific rules concerning concomitant medications, e.g., stable disease-specific concomitant medications for at least 3 months.State why the use of concomitant medications is not expected to confound the treatment effect, as applicable.Prohibited concomitant medicationsMention any forbidden concomitant medications or herbal medicines during study drug administration, giving a brief rationale as needed, e.g., disease-specific treatments or known drug-drug interactions.Escape/rescue medicationsEscape medication is medication which can be used, apart from the investigational product, during periods of acute attacks, pain or other complaints.Lifestyle restrictions Consider the in-house time, dietary aspects, alcohol, smoking and allowed physical activities for the study. Not all these restrictions are required for all studies. Only include them if they are necessary.Consider restricting certain drugs/foods known to interact with CYP450s, listed here.Use, modify or delete the following text:Approximate meal times will be according to the study schedule. In-clinic meals will be comparable in composition and time of administration across all cohorts in each study part. For the screening and the follow up visit, subjects will be required to fast for at least 4 hours. Subjects will be required to fast minimally 8 hours overnight (no food and no fluid including water) before study dose administration. Water is allowed as required.Any nutrients known to modulate CYP enzymes activity (e.g., grapefruit or Seville orange containing products or quinine containing drinks (tonic water or bitter lemon)) will not be permitted from 3 days before dosing until <EOS/ collection of the final pharmacokinetic blood sample/ discharge from the study unit >.The use of (illicit) drugs including cannabis can influence the measurements. Therefore, using 'drugs' is not permitted from 3 days before dosing and until <EOS/ collection of the final pharmacokinetic blood sample/ discharge from the study unit >. Since poppy seeds can cause a positive 'drugs' result; these should be avoided. If a positive result occurs without an explanation, the subject cannot participate in the study. However, positive urine drug screen for prescribed medication is allowed at the discretion of the PI.Alcohol will not be allowed from at least 24 hours before screening, dosing, at each scheduled visit, and whilst in the study unit until <EOS/ collection of the final pharmacokinetic blood sample/ discharge from the study unit>. At other times throughout the study, subjects should not consume more than 2 units of alcohol daily on average (one unit is 10 grams of alcohol). Subjects may undergo an alcohol breath test at the discretion of the investigator.Subjects will not be allowed to have excessive caffeine consumption, defined as >800 mg per day from 7 days prior to the first dose of the study drug until 24 hours prior to dosing. Subjects will abstain from caffeine-containing products for 24 hours prior to the start of dosing until <EOS/ collection of the final pharmacokinetic blood sample/ discharge from the study unit>. Caffeine quantities defined as: one cup of coffee contains 100 mg of caffeine; one cup of tea, or one glass of cola, or potion of chocolate (dark:100 g, milk 200 g) contains approximately 40 mg of caffeine; one bottle of Red Bull contains approximately 80 mg of caffeine.Subjects will abstain from the use of tobacco-or nicotine-containing products (including e-cigarettes and patches) for 24 hours prior to dosing until <EOS/ collection of the final pharmacokinetic blood sample/ discharge from the study unit>.Strenuous physical activity (e.g., heavy lifting, weight or fitness training) is not allowed from 48 hours prior to each study day until <EOS/ collection of the final pharmacokinetic blood sample/ discharge from the study unit>. Light ambulatory activities (e.g. walking at normal pace) will be permitted, with the level of activities kept as similar as possible on all days in the study unit. Subjects will be confined to the procedure room for the first <x> hours after dosing during continuous ECG monitoring, except to use the toilet. After this, if the equipment setup allows, subjects may be ambulatory during the ECG monitoring period, but should not engage in strenuous activities.Contraception requirementsFollowing guidance from the BEBO, a minimum 90 days is required for females. If a shorter term is used, provide rationale. If a shorter term for males is used, modify accordingly.Use or modify, or delete the following text: All women of child bearing potential <and all males> must practice effective contraception during the study and be willing and able to continue contraception for at least 90 days after their last dose of study treatment.Women of child bearing potential are defined as all women physiologically capable of becoming pregnant, unless they meet one of the following conditions:Postmenopausal: 12 months of natural (spontaneous) amenorrhea or 6 weeks after surgical bilateral oophorectomy with or without hysterectomy;Posthysterectomy.For the purposes of the study, effective contraception is defined as follows:Females: Using 1 or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation), intrauterine contraception/device, hormonal contraception, or any 2 barrier methods (a combination of male or female condom with diaphragm, sponge or cervical cap).Males: Effective male contraception includes a vasectomy with negative semen analysis at follow up, or the use of condoms.Abstinence can be considered an acceptable method of contraception at the discretion of the investigator. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not considered acceptable methods of contraception.Study drug discontinuation and withdrawalTopic should be included per ICHE6(R1). Study drug interruption or discontinuationBefore trial medication is administered, changes in the subject health status including laboratory results if applicable, since the previous visit or previous dose in case of a multiple dose regimen, have to be checked. The investigator must temporally interrupt or permanently discontinue the study drug if continued administration of the study drug is believed to be contrary to the best interests of the subject. The interruption or premature discontinuation of study drug might be triggered by an Adverse Event (AE), a diagnostic or therapeutic procedure, an abnormal assessment (e.g., ECG or laboratory abnormalities), or for administrative reasons in particular withdrawal of the subject’s consent. The reason for study drug interruption or premature discontinuation must be documented.Subject withdrawalSubjects have the right to withdraw from the study at any time for any reason. Should a subject decide to withdraw from the study, all efforts should be made to complete and report the observations, particularly the follow-up examinations, as thoroughly as possible.Replacement policyUse or modify the following text:Subjects withdrawing for reasons other than adverse events or any other tolerability issues with the treatment will be replaced.INVESTIGATIONAL MEDICINAL PRODUCTDelete/avoid ‘medicinal’ and or ‘drug’ throughout the entire document in case no drug treatment is studied e.g., investigational product/treatment Study drugs include the investigational drug and the active comparative drug or matching placebo, if any, administered during the course of the study. More information here.NON-INVESTIGATIONAL MEDICINAL PRODUCTSIf study uses a NIMP, copy this chapter on IMP and amend accordingly.The chapter is applicable for any other product that is used in the study, like challenge agents or products used to asses end-points in the trial. This can be a medicinal product or a food product or a chemical compound or stable isotope or other product.This chapter does not include co-medication or escape medication; these are mentioned in other sections.For drugs to be used as in usual clinical practice refer to the SmPC and provide dosage and route information. Investigational drug and matching placeboTopic should be included per ICHE6(R1), including:Name of drugRoute of administration, e.g., p.o., i.v., etcDose(s).Dose regimen, e.g., o.d., b.i.d., t.i.d.Titration and maintenance phases, as applicableGive instructions related to the timing of study drug administration, e.g., time, interval, relation to meal, etc.Give instructions regarding potential missing doses.Give instructions for the case that the subject should not or cannot take the study drugs him/herself, and somebody else should administer the study drugs to the subject, e.g., parents in a paediatric study, study nurses to coma patients, etc.Storage conditions.Mention minimal shelf life, as appropriate.Any special procedure, e.g., re-supply of study drug with a limited shelf life or prolongation of retest / expiry date.Example:Study drug or placebo will be administered to the subjects as detailed in REF _Ref371581918 \h \* MERGEFORMAT Table 1. x strengths of active, xx?mg and xx?mg <IMP name>, and matching placebo formulations will be manufactured. Doses in the study can be adapted with ongoing assessment of safety, tolerability and systemic exposure prior to initiation of the next dose. At each dose level x subjects will be randomized to receive <IMP name> and x to receive placebo. <IMP name>/placebo will be administered following a 4hour period of fasting with xxx mL of still water. The following dose groups are planned:Cohort 1: 50?mg <IMP name> / matching placeboCohort 2: 200?mg <IMP name> / matching placeboCohort 3: 400?mg <IMP name> / matching placeboCohort 4: 800?mg <IMP name> / matching placeboCohort 5: 1600?mg <IMP name> / matching placeboCohort 6: 3200?mg <IMP name> / matching placebo Comparative drug Delete if not applicable.Provide the same information as for investigational drug, as applicable.Mention source of comparative drug in general terms.Study drug dosing schemeIf of added value compared to Figure 1. Delete if not.Use and modify the sample table to describe the dosing scheme of each treatment group during each treatment period, as applicable.Study drug up- and down-titrationEither: State:Not applicable.Or: Use or modify the title above, e.g., up-titration not applicable.Differentiate between forced and optional up-titration.Specify triggers for optional down-titration in case of known safety or tolerability drug-related issue, e.g., hypotension or increase in liver enzymes, etc.Describe minimum and maximum dose adjustments allowed.Indicate any special requirement needed to up- or down-titrate the study drug, e.g., blood pressure level.Study drug packaging and labelling Topic should be included per ICHE6(R1)State the content of the study drug packaging.Use or modify the standard text:Bulk study drug will be supplied in bottles of XX tablets each, packaged and labelled by <manufacturer> in accordance with local regulations. Upon arrival at the pharmacy, the investigational products should check them for damage and verify proper identity, quantity, integrity of seals and temperature conditions, and report any deviations or product complaints upon discovery. The dispensing of the study drug will be performed by the pharmacy. Study drug will be dispensed for each subject according to the randomization list. Study drug packaging will be overseen by the <Leiden University Medical Centre Pharmacy> and bearing a label with the identification required by local law, the protocol number, drug identification, and dosage. <IMP name> tablet storage should not exceed 25 ?C in the containers provided. All drug supplies must be stored in a secure, temperature-controlled area with limited access. For batchspecific storage instructions, see the packaging. The pharmacy should provide labels according to GMP annex 13: §26-30 and table 1.<For internal studies insert the label(s) provided by the pharmacy. For sponsored studies provide as separate document D3 in the trial dossier >Study drug preparationDelete if not applicable.Drug accountabilityTopic should be included per ICHE6(R1). Use or modify the following text:Drug accountability will be maintained by the Leiden University Medical Centre Pharmacy and assessed by maintaining adequate study drug dispensing records. The investigator is responsible for ensuring that dosing is administered in compliance with the protocol. Delegation of this task must be clearly documented and approved by the investigator. All study drug administration will occur under medical supervision. Treatment assignment and blindingTopic should be included per ICHE6(R1). Randomization and treatment assignmentSubjects must be randomized in a consecutive order starting with the lowest number. Either: State for studies without cohorts:Subject numbers consist of 1 to 3 digits, as depicted in the table belowDigit 1Status: 0 for planned subjects, 1 for first set replacement subjects, 2 for second set replacement numbers and 9 for reserve subjectsDigit 2-3Consecutive subject numberE.g for a study with 24 subjects and 2 replacement sets and 2 reserve subjects: planned set 001-024, replacement set 1 101-124, replacement set 2 201-224 and reserves 925, 926Or: State for studies with cohortsSubject numbers consist of 4 or 5 digits, as depicted in the table belowDigit 1-2Cohort numberDigit 3Status: 0 for planned subjects, 1 for first set replacement subjects, 2 for second set replacement numbers and 9 for reserve subjectsDigit 4-5Consecutive subject number within the cohortE.g. for a study with 3 cohorts, 8 subjects per cohort, 1 replacement set and 2 reserves per cohort: planned set 01001-01008, 02001-02008, 03001-03008, replacement set 01101-01108, 02101-02108, 03101-03108, and reserves 01909, 01910, 02909, 02910, 03909, 03910Stratification for gender takes place in Promasys, by adding key value “F” to subject numbers for females and “M” to subject numbers for males.The randomization code will be generated using specify the name of the software and its version by a study-independent, CHDR statistician. The randomization code will be unblinded/broken and made available for data analysis only after study closure, i.e., when the study has been completed, the protocol deviations determined, and the clinical database declared complete, accurate and locked. The randomization code will be kept strictly confidential. Sealed individual randomization codes, per subject and per treatment, will be placed in a sealed envelope containing the and labelled 'emergency decoding envelopes' will be kept in a safe cabinet at CHDR. BlindingTopic should be included per ICHE6(R1). Either: State:Not applicable.Or: Use or modify the following text (blind until end):This study will be performed in a double-blind fashion. The investigator, study staff, subjects, sponsor, and monitor will remain blinded to the treatment until study closure. The investigational drug and its matching placebo and/or active comparative drug are indistinguishable and will be packaged in the same way.Or: Use or modify the following text (blind until end with blinded interim reports):This study will be performed in a double-blind fashion. With the exceptions described in this section, the randomization list will not be available to the investigator, study staff, subjects, sponsor, or monitors. The investigational drug and its matching placebo and/or active comparative drug are indistinguishable and will be packaged in the same way.The randomization list will be made available to the pharmacist preparing the study drug, to the individual responsible for PK sample bioanalysis and to statisticians or programmers involved in preparing blinded summaries, graphs and listings to support the dose decisions. The summaries, graphs and listings provided by the statisticians or programmers will be produced in an area to which other team members do not have access. The reports will be made available to project leader and the DSMB for the dose decision. The DSMB may share the reports with other individuals, experts or decision bodies if it is necessary that they participate in the dose decision process. Or: Use or modify the following text (blind until end with unblinded interim reports):This study will performed in a double-blind fashion. With the exceptions described in this section, the randomization list will not be available to the investigator, study staff, subjects, sponsor, or monitor. The investigational drug and its matching placebo and/or active comparative drug are indistinguishable and will be packaged in the same way.In order for the sponsor to make recommendations or decisions regarding further development of the drug, the study management team may unblind the individual cohort after the data for all subjects on these cohorts have been entered into the database, cleaned and locked (except possibly for data to be received directly from third parties e.g. laboratories in electronic form). And: Use or modify the following text:The investigator will receive a set of sealed emergency codes to be broken in case of emergency situations and duplicates will be kept by the <sponsor>. If the identity of the study drug administered needs to be known in order to manage the subject’s condition i.e., in case of a medical emergency or in the case a SUSAR occurs, the treatment emergency code for that subject may be broken and the study drug identified. All such occurrences should be documented in the study file. Treatment emergency codes should not be broken except in emergency situations and, if possible, the investigator/sponsor should be contacted before the emergency code is opened. <At the final monitoring visit/Just prior to database lock> the unused emergency code labels will be checked and a statement to the effect that all are intact (or not as the case may be) will be made on the database lock form. STUDY ENDPOINTSTopic should be included per ICHE6(R1)Study endpoints (e.g., efficacy, safety or tolerability) are the parameters/variables that are analyzed.The assessments are the data, which are collected on the data collection form/case report form. Although some endpoints are directly collected, in most situations they are derived from several assessments.Define for each endpoint how it is derived from specific assessments, as applicable.Endpoints must always be related to specific time points or periods.Endpoints should refer to baseline as appropriate. Efficacy endpointsDelete if not applicable, e.g., phase I studySafety and tolerability endpointsModify the following text:Treatment-emergent (serious) adverse events ((S)AEs).Concomitant medicationClinical laboratory testsHaematologyChemistryUrinalysisVital signsPulse Rate (bpm)Systolic blood presuure (mmHg)Diastolic blood pressure (mmHg)ECGHeart Rate (HR) (bpm), PR, QRS, QT, QTcB, QTcFPharmacokinetic endpointsDelete if not applicable.Or: Indicate the pharmacokinetic variables to be evaluated for the investigational drug and/or its metabolite(s), e.g., Cmax,, AUC0-∞, CL, Vss, t?.Use or modify the following text:The following endpoints will be determined for <compound> for each treatment <and day/period>. They will be derived by non-compartmental analysis of the <plasma/serum> concentration-time data <and urine data>:Single ascending dose<Plasma/Serum> PK parameters of <compound>: AUCinf, AUClast, CL/F, Cmax, t1/2, tlag, tmax, Vz/FDose-normalized <plasma/serum> PK parameters of <compound>: AUCinf, AUClast, Cmax<Urine PK parameters of compound: Aelast, Aelast%, CLR> Multiple ascending dose<Plasma/Serum> PK parameters of <compound>: AUCtau, CL/F, Cmax, Ctrough, t1/2, tmax, Vz/FDose-normalized <plasma/serum> PK parameters of <compound>: AUCtau, Cmax, Ctrough<Urine PK parameters of compound: Aetau, Aetau%, CLR> Pharmacodynamic endpointsIndicate the pharmacodynamic variables to be evaluated, e.g., blood pressure, neurohormones, etc.Use or modify the following text:Saccadic eye movements:saccadic reaction time (second), saccadic peak velocity (degrees/second), and saccadic inaccuracy (%); Smooth pursuit eye movements:percentage of time the eyes of the subjects are in smooth pursuit of the target (%);Body sway:antero-posterior sway (mm);Adaptive tracking: average performance (%);Visual Analog Scales (VAS) according to Bond and Lader to assess: mood (mm), alertness (mm), and calmness (mm).During each treatment period:Visual Verbal Learning Test (VVLT) memory testing Immediate recall trial 3 (number correct), Delayed recall (number correct), andDelayed recognition (number correct)Delayed recognition (reaction time correct) (msec)Baseline is defined as the < last/average> value prior to dosing.Total and free cholesterol, triglycerides, phospholipids and levels of apoproteins, LCAT activity and ex vivo cholesterol efflux capacity.Cytokines induced by ex vivo LPS challenge,Circulating cytokines induced by in vivo LPS challenge,C-reactive protein (CRP) levels and vital signs (temperature, heart rate, blood pressure) after in vivo LPS challenge can be regarded as PD parameters.?Thrombin generation assay output (at variable assay conditions), including lag time, time topeak, peak, and endogenous thrombin potential (ETP); activated partial thromboplastin time(aPTT); prothrombin time (PT). Besides its use in the PK analyses, FVIIa activity is alsoregarded a PD parameter.STUDY ASSESSMENTSTopic should be included per ICHE6(R1). The assessments are the data that are collected on the case report form/data collection form/electronically. This section should indicate when and how the data are to be measured and reported. Do NOT repeat information included in the schedule of assessments. See REF _Ref371581918 \h \* MERGEFORMAT Table 1 for the time points of the assessments.Efficacy assessmentsDelete if not applicable, e.g., phase I study.Safety and tolerability assessmentsThe definitions, reporting and follow-up of AEs, SAEs and potential pregnancies are described in section REF _Ref328636211 \r \h \* MERGEFORMAT 8. Specific safety and tolerability assessmentsDelete if not applicable.Add level 4 headings as needed for each study or project safety or tolerability assessment, if any.Vital signsDelete if not applicable.Or: Use or modify the following text: Evaluations of systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature will be performed throughout the study. Pulse and blood pressure will be taken after <5> minutes in the supine position. Automated oscillometric blood pressures and pulse rate will be measured using a Dash 3000, Dash 4000, Dynamap 400 or Dynamap ProCare 400.Weight and heightDelete if not applicable.Or: Use or modify the following text: Weight (kg) will be recorded at screening and the follow-up visit or upon early termination. Height (cm) will be recorded and body mass index (BMI) calculated at screening.Physical examinationDelete if not applicable.Describe the physical examination and the body systems to be examined.Use or modify the following text:Physical examination (i.e., inspection, percussion, palpation and auscultation) is performed during the course of the study. Clinically relevant findings that are present prior to study drug initiation must be recorded with the subject’s Medical History. Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new AE or worsening of previously existing condition) must be recorded.ElectrocardiographyUse or modify the following text:ECGs will be obtained during the course of the study using Marquette 800/2000/5500 or Dash 3000 and stored using the MUSE Cardiology Information System. ECGs will be taken after <5> minutes in the supine position. The investigator will assess the ECG recording as 'normal', 'abnormal - not clinically significant', or 'abnormal - clinically significant' and include a description of the abnormality as required. The ECG parameters assessed will include heart rate, PR, QRS, QT, and QTc<B/F> (calculated using <Bazett’s/Fredericia's> method). Laboratory assessmentsLaboratory parametersBlood and other biological samples will be collected for the following clinical laboratory tests:LabTestsCollection & AnalysisHaematologyHaemoglobin [including Mean Corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC)], haematocrit, red cell count (RBC), total white cell count (WBC)and Platelet count. Differential blood count, including: basophils, eosinophils, neutrophils, lymphocytes, and monocytes.2 mL of venous blood in a BD Vacutainer? K2EDTA tube. Samples will be analysed by the Clinical Chemistry Laboratory (AKCL) of Leiden University Medical Center (LUMC).Chemistry and electrolytesSodium, potassium, calcium, inorganic phosphate, total protein, albumin, triglycerides, blood urea nitrogen (BUN), creatinine, uric acid, total bilirubin2, alkaline phosphatase, AST, ALT gamma-GT and LDH.3.5 mL of venous blood in a BD Vacutainer? SST Gel and Clot Activator tube. Samples will be analysed by the AKCL of LUMCGlucoseGlucose1 2 mL of venous blood in a BD Vacutainer? Sodium Fluoride tube. Samples will be analysed by the AKCL of LUMCCoagulationInternational Normalised Ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), Fibrinogen2,7 mL of venous blood in a BD Vacutainer? Sodium Citrate (99NC BD) tube. Samples will be analysed by the AKCL of LUMCSerologyHIV1 and HIV2 antigen and antibodies, Hepatitis B surface antigen, Hepatitis B antibodies and Hepatitis C antibodies5 mL of venous blood in a BD Vacutainer? SST Gel and Clot Activator tube. Samples will be analysed by the Microbiology Laboratory (CKML) of the LUMCUrinalysisLeucocytes, blood, nitrite, protein, urobilinogen, bilirubin, pH, specific gravity, ketones, glucose. If there is a clinically significant positive result, urine will be sent to the AKCL for microscopy and/or culture.A midstream, clean-catch urine specimen will be analysed by dipstick (Multistix? 10 SG, Siemens Healthcare Diagnostics, Frimley, UK).Pregnancy3hCG. If there is a clinically significant, positive result, urine will be sent to the AKCL for confirmation.A urine specimen will be analysed at CHDR by test kit (InstAlert, Innovacon, San Diego, USA).AlcoholAlcohol Breath TestThe hand-held Alco-Sensor IV meter (Honac, Apeldoorn, the Netherlands) will be used to measure the breath ethanol concentrations.Urine drug screenCocaine, amphetamines, opiates (morphine), benzodiazepines and cannabinoids.A urine specimen will be analysed at CHDR by test kit (InstAlert, Innovacon, San Diego, USA).1After 4-hours fasting. 2Conjugated bilirubin will be reported only when total bilirubin is outside the reference range. 3Pregnancy test for women of childbearing potential will be performed at <screening and/or baseline> and if pregnancy is suspected during the study.Pharmacokinetic and pharmacodynamic assessmentsFor PK and “wet” PD Delete if not applicable.Or: Add level 4 headings to describe:Drug(s) and/or metabolites and/or neurohormones, etc., to be measured.Type of biological fluid (serum, plasma, urine, CSF, other) to be sampled.Collection period and conditions of sampling (e.g., relationship to drug administration, time of day, meals, etc).Specify if pharmacokinetic samples are to be collected from all subjects or from a subset only.Analytical and quality control procedures to be utilized.Storage condition or analysis of laboratory samples.If blood has to be collected, use or modify the following statement: Approximately XX mL blood will be collected via an i.v. catheter placed in an antecubital vein in the arm in <appropriate/K2EDTA/K3EDTA/Lithium Heparin/Plain/etc> tubes. The indwelling catheter will be kept patent by saline flush after each blood sampling. Immediately following collection of the required blood volume, the tubes will be slowly tilted backwards and forwards (no shaking) to bring the anticoagulant into solution <delete for plain tubes>, <protected from light> and <immediately cooled on ice>. Within 30?minutes of collection, the tubes will be centrifuged at approximately 2000 g for 10?minutes at 2 to 8 °C. The <plasma/serum> will be [transferred into one]/[split into two] labelled polypropylene tube, avoiding carryover of erythrocytes. All samples will be stored in an upright position at - 40 °C or lower. The exact actual clock time of withdrawal of the blood sample will be recorded.LabellingUse or modify the following text: Pre-printed, waterproof labels will be used to identify the tubes used during sample collection and for storage of separated plasma. Each label will contain the following information:CHDR Protocol numberSubject Number & InitialsOccasion number (date) Protocol (delta) time Activity: Sample type (blood) & purpose (PK)Last line optional: Sponsor ID or free text [~16 characters]Shipping ProceduresUse or modify the following text: CHDR will arrange shipment of the samples. The samples must be packed securely together with completed shipment forms in polystyrene insulated shipping containers together with enough dry ice to last for 48?hours. Samples must be shipped to <sponsor or central laboratory name> at time intervals agreed with the sponsor.BioanalysisSpecify the method(s) of analysis.Specify limits of quantification for each method.Use or modify the following text: <Plasma/Serum> <drug> concentrations will be measured by a validated <LC/MS/MS> method. <Plasma/Serum> samples may also be used for exploratory assessment of the <pro-drug> and/or metabolites, if applicable.Pharmacodynamic assessments and questionnairesDelete if not applicable.Or: Add level 4 headings to describe the pharmacodynamic test(s):The descriptions can be copied from the relevant SOP (maintaining future tense)Or, describe:What the test measures or is related to e.g., Saccadic peak velocity is one of the most sensitive parameters for sedationReference the literature the test is based on.Describe the methodology to be used including the appropriate details of equipment i.e. equipment name (company and country).Avoid further mentioning when the test is performed, refer to table 1.Burden for the subject including the duration of the test.Concomitant medicationsUse or modify the following text:Concomitant medications initiated, stopped, up-titrated or down-titrated for an AE will be recorded.Sequence of assessments and time windowsWhen the following assessments are scheduled to be performed at the same time-point, the order (of priority) will be as follows: ECG, vital signs, physical examination, blood sampling for safety, activity 1, activity 2, etc. When a PK assessment is scheduled for the same nominal time as another scheduled assessment, the PK sample will take precedence.The deviations of actual time points from the expected time points will be within ten percent, calculated from the zero point (time of drug administration) or the last relevant activity. The expected timepoints are defined as the timepoints in Promasys. Deviations of more than 10% will be explained in a note. These time deviations only apply for ECG, vital signs, blood sampling for PK and PD, activity 1, activity 2, etc.Pre-dose assessments are given in indicative expected times.In case of multiple dosing: Use or modify the following text:In case of multiple dosing the time window for the second dosing at CHDR is plus or minus ten minutes. In case of further dosing this will take place at the initial dosing time with a window of plus or minus 10 minutes. If dosing takes place twice or thrice per 24 hours, subsequent time of dosing must be related to the first dosing time of the day. When subjects are dosed on return visits a time window of plus or minus one hour is acceptable. This must always be related to the initial dosing time. Total blood volumeRight click > Worksheet object >edit. Do not use the open function.Total blood volumes over 500 mL (in adults, 600 ml is study takes over a month), are generally not allowed by the EC. If unavoidable, justification must be provided why more than 500 mL is needed and why it is safe to do so e.g. samples taken over a period of 3 months. SAFETY REPORTINGDefinitions of adverse eventsAn Adverse Event (AE) is any untoward medical occurrence in a subject who is participating in a clinical study performed. The AE does not necessarily have to follow the administration of a study drug, or to have a causal relationship with the study drug. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory or vital sign finding), symptom, or disease temporally associated with the study participation, whether or not it is related to the study drug.Intensity of adverse events The intensity of clinical AEs is graded three-point scale as defined below: Mild: discomfort noticed but no disruption of normal daily activity;Moderate: discomfort sufficient to reduce or affect normal daily activity;Severe: inability to work or perform daily activity.Relationship to study drug “Definite” is not standard by CHDR SOP. Addition of “definite” could be considered for MAD studies or after sponsors request. For each AE the relationship to drug as judged by the investigator: Probable; Possible; Unlikely; Unrelated.Chronicity of adverse eventsThe chronicity of the AE will be classified by the investigator on a three-item scale as defined below:Single occasion: single event with limited duration;Intermittent: several episodes of an event, each of limited duration;Persistent: event which remained indefinitely.ActionEventual actions taken will be recorded.Serious adverse eventsA Serious Adverse Event (SAE) is defined by the International Conference on Harmonization (ICH) guidelines as any AE fulfilling at least one of the following criteria:-results in death;-is life threatening (at the time of the event);-requires hospitalisation or prolongation of existing inpatients’ hospitalisation;-results in persistent or significant disability or incapacity;-is a congenital anomaly or birth defect; or-any other important medical event that did not result in any of the outcomes listed above due to medical or surgical intervention but could have been based upon appropriate judgement by the investigator.An elective hospital admission will not be considered as a SAE.Suspected unexpected serious adverse reactionsApplicable for studies with medicinal products (both NIMP and IMP), otherwise delete.A SUSAR (Suspected Unexpected Serious Adverse Reaction) is a SAE that is unexpected, (nature or severity of which is not consistent with the applicable product information (e.g., investigator's brochure for an unauthorised investigational product or summary of product characteristics for an authorised product)) and suspected (a reasonable possibility of causal relationship with investigational drug, regardless of the administered dose).Reporting of serious adverse eventsSAEs and SUSAR's will be reported according to the following procedure.In case other timelines are mentioned in a sponsor protocol, these protocol timelines prevail over the timelines of CHDR’s SOP.Sponsors are encouraged to enforce the waiver for submitting SUSAR reports to the MEB Agency and to send SUSAR reports directly to the EMA. Sponsors who are not yet ready to send SUSAR reports to the EMA can report SUSAR reports in E2B(M) format to the MEB Agency directly. If sponsors are not yet ready to report in E2B(M) format, submission of CIOMs forms is acceptable until further notice. In this event sponsor also do not need Eudra Vigilance registration or MedDRA coding system.If certain SAEs do not require( expedited) reporting to the accredited EC, please specify these SAEs as well as the frequency of reporting of these SAEs in line listings, or in a annual safety report or otherwise.For details, refer to the CBG-MEB website. As of 1 October 2015, expedited (individual) SAE reports has to be reported through the webportal ToetsingOnline. This is not mandatory for SUSAR reports. See also chapter 9.2.3. Instructions for this can be found in the user manual, see : for phase 1 and phase 2 studies, use:The sponsor/investigator will report the SAEs through the web portal ToetsingOnline (see ) to the accredited EC that approved the protocol, within 24 hours of first knowledge of the SAE. SUSARS must be reported to the EC that approved the study, the CA and the Dutch Medicines Evaluation Board (College ter Beoordeling van Geneesmiddelen).SUSARS must be reported to the EC that approved the study, the CA and the Dutch Medicines Evaluation Board (College ter Beoordeling van Geneesmiddelen).OR: for all other studies, use:The sponsor/investigator will report the SAEs through the web portal ToetsingOnline (see ) to the accredited EC that approved the protocol, within 7 days of first knowledge for SAEs that result in death or are life threatening followed by a period of maximum of 8 days to complete the initial preliminary report. All other SAEs will be reported within a period of maximum 15 days after the sponsor has first knowledge of the SAE.SUSARS must be reported to the EC that approved the study, the CA and the Dutch Medicines Evaluation Board (College ter Beoordeling van Geneesmiddelen).Either: State for sponsor studies:The sponsor will report expedited the following SUSARs to the EC:SUSARs that have arisen in the clinical trial that was assessed by the EC;SUSARs that have arisen in other clinical trials of the same sponsor and with the same medicinal product, and that could have consequences for the safety of the subjects involved in the clinical trial that was assessed by the EC.The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every half year to the EC. This line-listing provides an overview of all SUSARs from the study medicine, accompanied by a brief report highlighting the main points of concern. The expedited reporting of SUSARs through the web portal EMA Eudravigilance is sufficient as notification to the CA and the Dutch Medicines Evaluation Board, a separate notification is not necessary.The sponsor can delegate reporting SUSARS to the EC to CHDR, but CHDR cannot take over the sponsor responsibility of reporting a SUSAR to the EMA EudraVigilance database. The sponsor will report expedited all SUSARs to the competent authorities in other Member States, according to the requirements of the Member States. The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report.The sponsor can prepare additional reports for other authorities (e.g. FDA).OR: State for investigator initiated studies:The investigator will report expedited the following SUSARs through the web portal ToetsingOnline to the EC:SUSARs that have arisen in the clinical trial that was assessed by the EC;SUSARs that have arisen in other clinical trials of the same sponsor and with the same medicinal product, and that could have consequences for the safety of the subjects involved in the clinical trial that was assessed by the EC.The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as notification to the EC, CA and the Dutch Medicines Evaluation Board, a separate notification is not necessary. To prevent a double notification, it must be indicated in ToetsingOnline if the SUSAR is reported in the EMA EudraVigilance database, this will prevent the notification of the CA and the Dutch Medicines Evaluation Board through the web portal ToetsingOnline.For international investigator initiated studies: The investigator will report expedited all SUSARs to the competent authorities in other Member States, according to the requirements of the Member States. The expedited reporting will occur not later than 15 days after the first knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report.Follow-up of adverse eventsAll AEs will be followed until they have abated, returned to baseline status or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist.Temporary halt for reasons of subject safetyIn accordance to section 10, subsection 4, of the WMO, the investigator will inform the subjects and the EC if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the EC, except insofar as suspension would jeopardise the subjects’ health. The investigator will ensure that all subjects are kept informed. Annual safety report or development safety update reportOnly applicable for studies with IMPs, otherwise delete.For more information on DSURs consult guideline E2F.In addition to the expedited reporting of SUSARs, the sponsor/investigator will submit, once a year throughout the clinical trial, a safety report to the EC, CA and CAs of the concerned Member States.This safety report consists of:a list of all suspected (unexpected or expected) serious adverse reactions, along with an aggregated summary table of all reported serious adverse reactions, ordered by organ system, per study;a report concerning the safety of the subjects, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the medicine under investigation.PregnancyTeratogenicityIndicate whether the investigational drug is teratogenic or potentially teratogenic (i.e., known class effect in absence of specific knowledge about the investigational drug) or if the teratogenic risk is still unknown.Indicate the precautions to be taken to avoid pregnancy during the study.Or: Use, delete or modify the following text:If a woman becomes pregnant when on study drug, permanent discontinuation of study drug should be considered as appropriate. The investigator must counsel the subject and discuss the risks of continuing with the pregnancy and the possible effects on the foetus. Monitoring of the subject should continue until the outcome of the pregnancy is known.Reporting of pregnancyUse, delete or modify the following text:Irrespective of the treatment received by the subject, any pregnancy occurring during study drug administration or <during the x?months following study drug discontinuation/until follow-up>, must be reported within 24?hours of the investigator's knowledge of the event to the sponsor.Data safety monitoring boardMention if a Data and Safety Monitoring Board (DSMB) is necessary and will be used otherwise delete if not applicable.In case a DSMB is established to perform ongoing safety surveillance and to perform interim analyses on the safety data, this committee should be an independent committee. The composition of the DSMB should be described and it should be clear that each member has no conflict of interest with the sponsor of the study.See also the EMA guideline on Data Monitoring Committees for assessing the need for a DSMB and for information on the establishment of a DSMB and their working procedures (EMA/CHMP/EWP/5872/03 dd 27 July 2005). The DAMOCLES Study Group published a template for a charter for a data monitoring committee which might help for the structure and organisation of a DSMB. See Lancet 2005;365:711-722 & ccmo-website, this should also be submitted as part of the trial dossier under K5.The task and responsibility of the DSMB should be described (see chapter 10.4 for interim analyses either for safety or for futility or positive efficacy)Criteria on which the DSMB may decide to terminate the trial prematurely should be clearly defined before the trial has started.The advice of the DSMB will only be sent to the sponsor of the study. Should the sponsor decide not to fully implement the advice of the DSMB, the sponsor will send the advice to the reviewing METC, including a note to substantiate why (part of) the advice of the DSMB will not be followed.In case a DSMB is not needed, but some safety review is deemed appropriate, information on this safety committee should be given here. Information should be provided on the composition of the committee and (in)dependence of the members, the reason to establish this committee, type of data that will be reviewed and moment of review, possible measures to be takenUse or modify the following text:Screening (enrolment) for the next cohort (the next planned dose level) will not begin until the DSMB has approved dosing for that cohort. The DSMB will comprise the principal investigator, a clinical pharmacologist from CHDR (non-voting member), a medical director from the sponsor, a statistician (non-voting member), and ad hoc members (non-voting), as required. The DSMB is empowered to recommend modifications of the protocol (to enhance subject safety) or to recommend early termination of the study if major concerns arise about the subject's safety at any time during the course of this study or during any other study with the same investigational drug. There is no limit to the number and timing of interim analyses aimed at guaranteeing the safety of the subjects.The data to be reviewed by the DSMB is listed in Section REF _Ref326918429 \r \h \* MERGEFORMAT 9.11.STATISTICAL METHODOLOGY AND ANALYSESStatistical analysis planSection is not required if protocol thoroughly describes the statistical methodology and analyses.Either use, modify or delete the following text:All safety and statistical programming is conducted with SAS 9.4 for Windows or newer (SAS Institute Inc., Cary, NC, USA). PK variable programming is conducted with R 3.5.3 for Windows or newer (R Foundation for Statistical Computing/R Development Core Team, Vienna, Austria, 2010.If a SAP is requested by the sponsor use or modify the following text,Otherwise delete:A Statistical Analysis Plan (SAP) will be written and finalized before the study closure, i.e., database closure and unblinding of the randomization code (delete if not applicable). The SAP will provide full details of the analyses, the data displays and the algorithms to be used for data derivations. The SAP will include the definition of major and minor protocol deviations and the link of major protocol deviations to the analysis sets. Protocol violations/deviationsDefine the specific protocol deviations that could impact the analysis (e.g. major deviations and a definition of a major deviation) and specify the methods used to describe and analyse them.As a minimum, all exclusion/inclusion criteria, as well as all major protocol deviations leading to the exclusion of a subject from one of the analysis sets, need to be captured in the protocol deviation listing.ICH E3 recommends that the following protocol deviations should be appropriately summarized in the clinical study report:Subjects who entered the study, although they did not satisfy the entry criteriaSubjects who developed withdrawal criteria during the study drug but were not withdrawnSubjects who received the wrong treatment or incorrect doseSubjects who received an excluded concomitant medicationEither use, modify or delete the following text:Protocol deviations will be identified based on conditions related to the categories below:Protocol entry criteriaForbidden concomitant medicationsMissing evaluations for relevant endpointsOther protocol deviations occurring during study conduct.Major protocol deviations will be identified before the study closure, and listed where appropriate.Power calculationTopic should be included per ICHE6(R1)Either Use, modify or delete the following text:Not applicable.Or Use, modify or delete the following text:Power calculations were performed for the parameter <parameter> using the data available at CHDR/based on literature. For <parameter>, a sample size of xx will have 80% power to detect a difference in means of xx.xxx, assuming a standard deviation of differences of xx.xxx, using a paired t-test with a 0.050 two-sided significance level. The estimated average score under placebo is xxx.xx, so a true improvement of circa x% will be significant in x out of x studies with xx subjects.Missing, unused and spurious dataTopic should be included per ICHE6(R1)Describe how missing or incomplete other data will be handled. Either use, modify or delete the following text:All missing or incomplete safety and PD data, including dates and times, are treated as such. Missing test results or assessments will not be imputed. Missing PD data, indicated as ‘M’ in the data listing, will be estimated within the statistical mixed model using SAS PROC MIXED.Describe how data below the LOD/LOQ is handled and the % of data points necessary for the calculation of the mean/CV etc.For graphical and summary purposes PD and safety values below the limit of quantification will be set to half (?) of the limit of quantification. For analysis no undetermined values will be replaced.If single data points for <plasma/serum> <drug> concentrations are missing, the AUC parameters will be derived by interpolating with regard to the two neighboring non-missing concentrations. For calculation of PK parameters, all <plasma/serum> <drug>concentration values below the quantification limit (BLQ) occurring prior to Cmax will be replaced by 0, except for embedded BLQ values (between two measurable time points) which will be treated as “missing”. All BLQ values after Cmax will be treated as “missing”.The handling of missing, unused and spurious data will be documented in the study report.Analysis setsTopic should be included per ICHE6(R1)Either Use, modify or delete the following text:Data of all subjects participating in the study will be included in the analyses if the data can meaningfully contribute to the objectives of the study.Safety setThe safety population will be defined as all subjects who were validated (randomised) and received at least 1 dose of study treatment.Pharmacokinetic analysis setThe PK analysis population is defined as all subjects who were validated (randomised), received at least one dose of study treatment, and have at least one measurable drug concentration in samples collected.Pharmacodynamic analysis setThe analysis population for <pharmacodynamics/efficacy> is defined as all subjects who were validated (randomised), received at least one dose of study treatment, and have at least one post-baseline assessment of the parameter being analyzed.Subject dispositionThis section should determine how the population membership and population size for each treatment (to be used in most table headers) will be determined.Either use, modify or delete the following text:Subject disposition will be listed by subject.The following subject data will be summarized:number and percentage of subjects screened,number and percentage of subjects enrolled,number and percentage of subjects completed,number and percentage of subjects included in safety population andnumber and percentage of subjects included in the PD analysis population.A subject who completed the study is defined as a subject where the last (72 hour) PK blood sample was assessed.Baseline parameters and concomitant medicationsDemographics and baseline variablesIdentify all variables that will be considered as demographic or baseline variables, recorded at, or shortly, before randomisation or first treatment administration. If transformation of data will occur (e.g. age coarsening into 18-40, 41-65, over 65) then define this exactly in this section. It may be appropriate to summarise these data by centre.Either use, modify or delete the following text:Continuous demographic variables (e.g., age, height, weight, BMI) will be summarized by descriptive statistics (n, mean, SD, median, Min, Max).Qualitative demographic characteristics (sex, race/ethnicity) will be summarized by counts and percentages. The results of the <name> questionnaire at screening will only be listed.Medical history Either use, modify or delete the following text:Medical history will only be listed.Concomitant MedicationsNOT standard practice, include ONLY if required.The definitions used to distinguish prior and concurrent should be provided. Include a description of which, if any, coding system was used (e.g. WHO drug dictionary).Either use, modify or delete the following text:Previous and concomitant medications will be listed by International Nonproprietary Names, dose, regimen, route and for which indication it was prescribed. The following text could be added if requested:Previous and concomitant medications will be coded according to the World Health Organization (WHO) drug code and the anatomical therapeutic chemical (ATC) class code.Treatment compliance/exposureExamples of the assessment of treatment compliance include: remaining pill count, diary records of medication. Any method for calculating a measure of treatment compliance should be defined clearly here. The variables used to assess treatment compliance should be identified. Either use, modify or delete the following text:Exposure to study treatment is described in terms of duration of treatment and average infusion rate. The average infusion rate (mL/hr) is summarized by mean, SD, median, Q1, Q3, Min, Max.Safety and tolerability endpoints Use or modify the following text:The safety set is used to perform all safety analyses. Baseline is defined as the <last/average> value prior to dosing. Change from baseline will be calculated for all continuous safety parameters. Adverse eventsDescribe how AEs are analyzed and how any differences between treatment groups are explored.Either use, modify or delete the following text:The AE coding dictionary for this study will be Medical Dictionary for Regulatory Activities (MedDRA). It will be used to summarize AEs by primary system organ class (SOC) and preferred term (PT).All adverse events will be displayed in listings.A treatment-emergent adverse event (TEAE) is defined as an adverse event observed after starting administration of the specific treatment, and <prior to the start of another treatment, if any OR up to 5 days (120 hours) after study drug administration>. If a subject experiences an event both prior to and after starting administration of a treatment, the event will be considered a TEAE (of the treatment) only if it has worsened in severity (i.e., it is reported with a new start date) after starting administration of the specific treatment, and prior to the start of another treatment, if any. All TEAEs collected during the investigational period will be summarized.<The number of and/or the number of subjects with> treatment emergent AEs will be summarized by: treatment, MedDRA SOC and PT;treatment, MedDRA SOC, PT and severity;treatment, MedDRA SOC, PT and drug relatedness.Vital signsEither use, modify or delete the following text:At each time point, absolute values and change from baseline of supine blood pressure and pulse rate will be summarized with n, mean, SD, SEM, median, Min, and Max values. The number of available observations and out-of-range values (absolute and in percentage) will be presented. Values outside the reference range will be flagged in the listing. ‘H’ and ‘L’, denoting values above or below the investigator reference range (when present), will flag out-of-range results. ECGEither use, modify or delete the following text:At each time point, absolute values and change from baseline of ECG numeric variables will be summarized with n, mean, SD, SEM, median, Min, and Max values. The number of available observations and out-of-range values (absolute and in percentage) will be presented. Values outside the investigator’s normal range will be flagged in the listing. ‘H’ and ‘L’, denoting values above or below the investigator reference range (when present), will flag out-of-range results. Clinical laboratory testsDescribe how laboratory data are analyzed and how any differences between treatment groups are explored.Either use, modify or delete the following text:At each time point, absolute values and change from baseline of clinical laboratory variables will be summarized with n, mean, SD, SEM, median, Min, and Max values. The number of available observations and out-of-range values (absolute and in percentage) will be presented. All laboratory data (including re-check values if present) will be listed chronologically. ‘H’ and ‘L’, denoting values above or below the investigator reference range (when present), will flag out-of-range results. Pharmacokinetic and pharmacodynamic endpointsIn consultation with the statistician and/or pharmacometrician, use or modify the following text:PharmacokineticsIn consultation with the statistician and/or pharmacometrician, use or modify the following text:The individual <plasma/serum> <drug> concentrations will be listed by treatment, subject, visit and time. Individual <plasma/serum> <drug> concentrations versus time will be plotted in panel plots for each treatment using both a linear and log y-axis. <The amount excreted of <compound> at each collection interval will be listed by treatment, subject, and visit.>The individual <plasma/serum> <drug> concentrations will be summarised (n, mean, SD, %CV, median, Min and Max values) by treatment and time, and will also be presented graphically as mean over time, with standard deviation as error bars. If more than one third of the concentrations are BLQ then Mean and SD will not be provided. If one concentration is BLQ then %CV will not be provided. <The amount of <compound> in urine will be summarized (n, mean, SD, %CV, median, Min and Max values) by treatment, visit and collection interval.>When an actual sampling time of a drug concentration sample differs from the protocol time by more than <10% and at least 5 minutes>, the concentration will be excluded from calculation of descriptive statistics and a note will be added to the sample in the listing.The individual PK parameters (except tmax and tlag) will be summarized (n, mean, SD, %CV, geometric mean, geometric %CV, median, Min and Max) per treatment group and will be presented graphically as boxplots. For tmax and tlag,the n, median, Min and Max statistics will be reported. .PharmacodynamicsIn consultation with the statistician and/or pharmacometrician, use or modify the following text:The final analysis will be preceded by a <blind > data review which consists of individual graphs per visit by time of all pharmacodynamic measurements by time. The graphs will be used to detect outliers and measurements unsuitable for analysis.The PD parameters will be listed by treatment, subject, visit and time. Individual graphs by time will be generated.All <repeatedly measured> PD endpoints will be summarised (n, mean, SD, SEM, median, Min and Max values) by treatment and time, and will also be presented graphically as mean over time, with standard deviation as error bars. All <single measured> PD endpoints will be summarised (mean, SD, SEM, median, Min and Max values) by treatment, and will also be presented graphically as mean in a bargraph, with standard deviation as error bars.Parameters will initially be analyzed without transformation, but if the data suggest otherwise, log-transformation may be applied. Log-transformed parameters will be back-transformed after analysis where the results may be interpreted as percentage change.To establish whether significant treatment effects can be detected on the <repeatedly measured> PD parameters, each parameter will be analyzed with a mixed model analysis of covariance (ANCOVA) with treatment, time, <period> and treatment by time as fixed factors and subject, subject by treatment and subject by time as random factors and the (average) baseline measurement as covariate. Single measured PD parameters will be analyzed with a mixed model analysis of variance (ANOVA) with treatment <and period> as fixed factor<s> and subject as random factor.The Kenward-Roger approximation will be used to estimate denominator degrees of freedom and model parameters will be estimated using the restricted maximum likelihood method.The general treatment effect and specific contrasts will be reported with the estimated difference and the 95% confidence interval, the least square mean estimates and the p-value. Graphs of the Least Squares Means(LSM) estimates over time by treatment will be presented with 95% confidence intervals as error bars, as well as change from baseline LSM estimates. The following contrasts will be calculated within the model:Treatment 1 - PlaceboTreatment 2 - PlaceboInferential methodsTopic should be included per ICHE6(R1)The study is exploratory and no formal null hypothesis is set. No adjustments for multiple comparisons will be applied.PK/PD modellingIn consultation with the statistician and/or pharmacometrician, use or modify the following text:Population PK and PK/PD models may be developed to address objectives that require an integrative interpretation of the study results. These include assessment of the dose proportionality, investigation of the nature of the PK/PD relationship, and the use of study results as part of a larger model-based data analysis. If population PK/PD models are developed, a separate Pharmacometric Analysis Plan will be written.Exploratory analyses and deviationsUse or modify the following text:Exploratory data-driven analyses can be performed with the caveat that any statistical inference will not have any confirmatory value. Deviations from the original statistical plan will be documented in the clinical study report.Interim analysesTopic should be included per ICHE6(R1)Either: State:No interim analysis is planned.Or: Describe: Number, purpose, type and timing of each interim analysis.Endpoints to be analyzed.Data sets to be used for the interim analysis-(es).Details of the statistical approach implemented to preserve the type-1 and-2 errors.How blinding will be preserved, e.g., how access to interim results and dissemination of the information will be controlled and documented.Why the interim analysis will not bias the further conduct of the study.And/or: Use or modify the following text as appropriate, if safety interim analyses are planned: The following blinded safety data will be reviewed by the DSRC for the ongoing cohorts and used to determine if dose escalation can occur:AEs and SAEs through <xx> days after the last dose of study treatment;Post-dosing physical examination results up to <xx> days after the last dose of study treatment; andPharmacodynamic results at up to <xx> days after the last dose of study treatment.GOOD CLINICAL PRACTICE, ETHICS AND ADMINISTRATIVE PROCEDURES Good clinical practiceEthics and good clinical practiceTopic should be included per ICHE6(R1)The investigator will ensure that this study is conducted in full compliance with the protocol, the principles of the Declaration of Helsinki (), ICH GCP guidelines (), and with the laws and regulations of the country in which the clinical research is conducted. Ethics committee / institutional review board[CA only for studies with a medicinal product]The investigator will submit this protocol and any related documents to an Ethics Committee (EC) and the Competent Authority (CA). Approval from the EC and the statement of no objection from the CA must be obtained before starting the study, and should be documented in a dated letter/email to the investigator, clearly identifying the trial, the documents reviewed and the date of approval. A list of EC members must be provided, including the functions of these members. If study staff were present, it must be clear that none of these persons voted.Modifications made to the protocol after receipt of the EC approval must also be submitted as amendments by the investigator to the EC in accordance with local procedures and rmed consentIt is the responsibility of the investigator to obtain written informed consent from each individual participating in this study after adequate explanation of the aims, methods, objectives and potential hazards of the study. The investigator must also explain to the subjects that they are completely free to refuse to enter the study or to withdraw from it at any time for any reason. The Informed Consent and Subject Information will be provided in the local language/Dutch.InsuranceTopic should be included per ICHE6(R1)The sponsor/investigator has a liability insurance which is in accordance with article 7, subsection 6 of the WMO.The sponsor/investigator (also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research in Humans of 23rd June 2003). This insurance provides cover for damage to research subjects through injury or death caused by the study.€ 650,000.- (i.e., six hundred and fifty thousand Euro) for death or injury for each subject who participates in the Research;€ 5,000,000.- (i.e., five million Euro) for death or injury for all subjects who participate in the Research; € 7,500,000.- (i.e., seven million and five hundred thousand Euro) for the total damage incurred by the organisation for all damage disclosed by scientific research for the Sponsor as ‘verrichter’ in the meaning of said Act in each year of insurance coverage.The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study.Study fundingTopic should be included per ICHE6(R1)For external studies:xxx is the sponsor of the study and is funding the study. All financial details are provided in the separate contract(s) between the CHDR, and the sponsor. For internal studies:CHDR is the sponsor of the study and is funding the study. Data handling and record keepingTopic should be included per ICHE6(R1): Data collectionUse or modify the following text: For electronic data collection:Data will be recorded on electronic data collection forms in Promasys and will be entered after quality control in a sponsor eCRF for subsequent tabulation and statistical analysis. The data will be handled confidentially.A Subject Screening and Enrolment Log will be completed for all eligible or non-eligible subjects with the reasons for exclusion.Use or modify the following text: For paper data collection:Data will be recorded on paper data collection forms and will be entered after quality control in a Promasys database and subsequently in a sponsor eCRF for tabulation and statistical analysis. The data will be handled confidentially.A Subject Screening and Enrolment Log will be completed for all eligible or non-eligible subjects with the reasons for exclusion.Database management and quality controlUse or modify the following text (Promasys studies): All data from paper source will be entered into the Promasys database twice, by two different individuals. A quality control check will be done by CHDR staff on all data entered in the Promasys database, using data entry progress checks and database listings (blind data review). Errors with obvious corrections will be corrected before database lock. If laboratory samples are analyzed centrally, complete and use the following sentence:Results of computer (NeuroCart/PainCart/ECG) tests and electronically captured questionnaires, clinical laboratory and pharmacokinetic analyses will be sent electronically to CHDR and loaded into the plete the paragraph with the following text:After the database has been declared complete and accurate, the database will be locked. Any changes to the database after that time can only be made by joint written agreement between the investigator, sponsor and the statistician.Access to source data and documentsTopic should be included per ICHE6(R1)Data should be handled confidentially and if possible anonymously. Where it is necessary to be able to trace data to an individual subject, a subject identification code list can be used to link the data to the subject. The code should not be based on the subject initials and birth-date. The key to the code should be safeguarded by the investigator in case the data or human material is kept for a longer period of time(see also the code of proper use: fmwv.nl). The handling of personal data should comply with the Dutch Personal Data Protection Act (in Dutch: De Wet Bescherming Persoonsgegevens, WBP).All study data will be handled confidential. The investigator will retain the originals of all source documents generated at CHDR for a period of 2 years after the report of the study has been finalised, after which all study-related documents will be archived (at a minimum) on micro-film which will be kept according to GCP regulations. After 2 years the sponsor will be notified that the source documents can be retained with the sponsor or destroyed.The investigator will permit trial-related monitoring, audits, EC review and regulatory inspections, providing direct access to source data and documents.Quality control and quality assuranceTopic should be included per ICHE6(R1)This study will be conducted according to applicable Standard Operating Procedures (SOPs). Quality assurance will be performed under the responsibility of CHDR’s Quality Assurance manager.MonitoringUse or modify the following text as appropriate:An initiation visit will be performed before the first subject is included. Monitoring visits and contacts will occur at regular intervals thereafter, according to a frequency defined in the study-specific monitoring plan. A close-out visit will be performed after study closure.Protocol amendmentsSee also the Communication from the Commission — Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01). Any change to a protocol has to be considered as an amendment.Substantial amendmentSignificant changes that affect subject safety and/or the scientific value of a trial require a substantial amendment. Examples of significant changes are given in EU guidelines on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1, 2010/C 82/01). The need for submitting a substantial amendment is the responsibility of the sponsor. Substantial amendments are to be approved by the appropriate EC and the CA will need to provide a ‘no grounds for non-acceptance’ notification prior to the implementation of the substantial amendment.Non-substantial amendmentNon substantial amendments do not affect subject safety or the scientific integrity of the trial. Non-substantial amendments will be approved (signed) by the investigator(s) and will be recorded and filed by the investigator/sponsor. Non-substantial amendments will be submitted to the EC for information only. The CA will only be notified by changes in Eudract form and ABR form (if applicable) at toetsingonline. The implementation of a?non-substantial amendment can be done immediately. The EU guideline CT-1 2010/C 82/01 stipulates the importance of preventing over-reporting. Therefore the following changes are by definition non-substantial in this study:change in amount and timing of the samples (maximum of 2 samples without a > 50 ml increase in the amount of blood taken and not exceed 500 ml of blood in total)changes in assay-type and / or institution where an assay will be performed, provided that validated assays will be used;editorial changes to documents in the submission dossier including the volunteer information sheets and the protocol. An editorial change is defined as a modification in the documents of typographical errors and other modifications that in no way alter the meaning or content of the documentdetermination of additional parameters in already collected materials, which are in agreement with the study objectives and do not provide prognostic or genetic information;other statistical analyses than described in the protocol.A change in clinical staff, including the principal investigator, when this concerns regular staff members of CHDR who comply with internal regulations for training and authorisation.A change in dosing schedule in an ascending dose trial, provided the expected exposure of the subjects does not exceed the preset values indicated in this protocol.Urgent amendmentAn urgent amendment might become necessary to preserve the safety of the subjects included in the study. The requirements for approval should in no way prevent any immediate action being taken by the investigators or the sponsor in the best interests of the subjects. Therefore, if deemed necessary, an investigator can implement an immediate change to the protocol for safety reasons. This means that, exceptionally, the implementation of urgent amendments will occur before submission to and approval by the EC(s) and CA.End of study reportEither: The following text is applicable for studies with an investigational medicinal product.In case the final study report will not be available within one year, another term should be defined including the reasons Use or modify the following text as appropriate:The sponsor will notify the EC and the CA of the end of the study within a period of 90 days. The end of the study is defined as the last subject’s last visit. In case the study is ended prematurely, the investigator/sponsor will notify the EC and the CA within 15 days, including the reasons for the premature termination.The sponsor will notify the EC immediately of a temporary halt of the study, including the reason of such an action.Within one year after the end of the study, the investigator and/or sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the EC and the CA. The principal investigator and the sponsor’s representative will be the signatories for the study report. Or: The following text is applicable for studies without an investigational medicinal product.Use or modify the following text as appropriate:For studies with an investigational medicinal product, end of study report should also be submitted to the competent authority within a period of 90 days and 15 days for premature ending.The investigator will notify the EC of the end of the study within a period of 8 weeks. The end of the study is defined as the last subject’s last visit. In case the study is ended prematurely, the investigator/sponsor will notify the EC within 15 days, including the reasons for the premature termination.The sponsor will notify the EC immediately of a temporary halt of the study, including the reason of such an action.Within one year after the end of the study, the investigator and/or sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the EC. The principal investigator and the sponsor’s representative will be the signatories for the study report. Public disclosure and publication policyTopic should be included per ICHE6(R1)The CCMO statement on publication policy can be found here. This statement contains the basic principles of the CCMO’s position on the disclosure/ publication of research results obtained form studies involving human subjects. It is the opinion of the CCMO that the results of scientific research involving human subjects must be disclosed unreservedly.Prospective Trial Registration: The International Committee of Medical Journal Editors will require, as a condition for consideration for publication, registration of the clinical trial in a public trial registry before the first subject is recruited (N Engl J Med 2004; 351(12): 1250-1).Either: Use or modify the following text as appropriate:In accordance with standard editorial and ethical practice, the results of the study will be published, if applicable. The authorship guidelines of the Vancouver Protocol will be followed regarding co-authorship.The principal investigator will have the opportunity to review the analysis of the data and to discuss with the sponsor the interpretation of the study results prior to publication.Any study-related article or abstract written independently by investigators should be submitted to the sponsor for review at least 60?days prior to submission for publication or presentation.The list of authors of any formal publication or presentation of study results may include, as appropriate, representatives of the sponsor and will be determined by mutual agreement.Or: Use or modify the following text as appropriate:In accordance with standard editorial and ethical practice, the results of the study will be published, if applicable. Conditions are subject to a separate contract between CHDR and the sponsor. The authorship guidelines of the Vancouver Protocol will be followed regarding co-authorship.STRUCTURED RISK ANALYSISThis chapter is applicable for research with any product: medicinal product, food product, medical device or other (as described in previous chapters).In case more than one product is concerned, make separate sections per product.This section can be deleted if the sub-section in chapter 1 is sufficient and covers the same material.Potential issues of concern In this final paragraph of the research protocol a structured risk analysis which consists of a number of steps is required. The analysis should result in a comprehensive overall synthesis of the direct risks for the research subjects in this study in section.2. The risk considerations on the various issues listed below should be supported by up to date information and should be clearly described to allow a thorough review by the EC.(Kenter MJH and AF Cohen, Lancet 2006;368:1387-91) For details one may refer to the previous chapters, the investigator’s Brochure (IB) or a similar document (if applicable), peer reviewed papers in (biomedical/scientific) journals. The issues below are provided to structure your considerations and allows an efficient communication with the EC when questions arise as a result of the review of your research protocol. The remarks per item are provided as guidance for describing your considerations. Should issues not be applicable, please indicate so.For registered products to be used within the indication and not in combination with other products section 1 can be skipped; explain in section 2 why 13.1 is skipped.Level of knowledge about mechanism of actionIs there a plausible mechanism? Is there adequate clinical and patho-physiological knowledge about the mechanism? Particularly consider potential activation of self-amplifying mechanisms (immunologic, psychiatric, coagulatory)Previous exposure of human beings with the test product(s) and/or products with a similar biological mechanismInvestigate direct mechanism, assess related mechanisms and analogue disease states, investigate primary and secondary pharmacologyCan the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell material?Receptor homology? post-receptor mechanism similar? measurement system applicable? human ex-vivo tests available?Selectivity of the mechanism to target tissue in animals and/or human beingsReceptor distribution in tissues; General pharmacological studies; Toxicology studiesAnalysis of potential effectPredictions of safety window (anticipated drug levels for beneficial vs potentially harmful effects); Dose- or concentration –effect relation; Nature and seriousness of potential adverse effects (vital organ systems affected)Pharmacokinetic considerationsHalf-life in relevant effect compartment; Pharmacokinetic dynamic relations; Active or toxic metabolitesStudy populationFor instance are research subjects healthy volunteers or patients suffering from a life threatening disease? Are the research subjects patients at an Intensive Care? Is the condition of the patients that participate in this study stable? Are women with child bearing potential included in the study? Interaction with other productsFor studies where a combination of products is given, or participants are allowed to use certain products/medicines: Systematically consider potential pharmacokinetic interactions (CYP450, P-gp) and pharmacodynamic interactions (pharmacological/physiological)Predictability of effectBiomarkers for effect in animal and man; Precision and accuracy of measurement; Relation of marker to clinical effectCan effects be managed?Antidotes or antagonists; Other countermeasures; for instance assurance of access to adequate medical support in case of emergencies (also considering the number of concomitant participants and the risk of the intervention)SynthesisThis should include uncertainties and the unknown and the overall risk:Make clear what measures have been taken to reduce what risksExamples can be: type of study population, certain in- or exclusion criteria, additional safety measurements, prolonged supervision of participants, establishing a DSMB or safety committeeMake clear why in your opinion the remaining risks are acceptable for the subjects participating in the study.REFERENCESTopic should be included per ICHE6(R1)References to literature and data that are relevant, and that provide background for the trial.Whenever possible, quote external rather than internal documents, i.e., publications rather than study reports.Keep the number of references to a minimum, as they are not generally required in a protocol.When possible use Reference ManagerUse the British Journal of Clinical Pharmacology style of citation/referencing (below). Reference manager will automatically place reference list at end of document. Simply cut and past whole list to this section. On last ‘update of citation and bibliography’ remove the word ‘reference’ by placing cursor at end of word and hitting backspace.Sometimes it is necessary to remove RefMan field codes: choose the "Reference Manager > Convert to Plain Text" command. NB this will save a new unsaved version of the document!!Example:In the seminal research investigating the CNS effects of lamotrigine … [1].1. Cohen AF, Ashby L, Crowley D, Land G, Peck AW, Miller AA. Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmacol 1985; 20: 619-629.APPENDIX SEQ Appendix \* ARABIC \* MERGEFORMAT 1 TITLE Questionnaires (or can be included at F1 of the trial dossier), etc ................
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