CPT HEALTHY VOLUNTEER LIBRARY - TransCelerate

?Common Protocol Template Healthy Volunteer Library v2.1Section in Common Protocol Template (CPT)Library Content6.2 Exclusion CriteriaExclusion Criteria8.1 Discontinuation of Study TreatmentLiver Chemistry Stopping CriteriaQTc Stopping CriteriaAppendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Treatment Rechallenge Guidelines]Liver Safety: Suggested Actions and Follow-up Assessments and Study Treatment Rechallenge Guidelines6.2Exclusion CriteriaMEDICAL CONDITIONSStudy treatment-specific exclusion criteria: Include any conditions that may impact safety or the integrity of data (eg, history of epilepsy or history of asthma). Ensure these primary conditions are listed before the common hepatic disease and cardiovascular disease criteria.[History or presence of/significant history of or current] cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of dataAbnormal blood pressure [as determined by the investigator]These criteria are specific for immune modulators. Delete if not applicable.Symptomatic herpes zoster within 3 months prior to screeningEvidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest X-rays (posterior anterior and lateral), and TB testing: either a positive tuberculin skin test (TST; defined as a skin induration <5 mm at 48 to 72?hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not indeterminate) QuantiFERON TB Gold test. NOTE: The choice to perform a TST or a QuantiFERON-TB Gold test will be made by the investigator according to local licensing and standard of care. The QuantiFERON-TB Gold test can only be used in countries where it is licensed, and the use of this test is dependent on previous treatment(s). This test may not be suitable if previous treatment(s) produced significant immunosuppression.These criteria are specific for antibodies. Delete if not applicable.Significant allergies to humanized monoclonal antibodies Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis)Depending on the molecule, some regulatory agencies require exclusion of ANY history of malignancy. Modify the text as needed.Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 yearsBreast cancer within the past 10 yearsSuggested criteria, if cerebrospinal fluid (CSF) will be collected. Delete if not applicable.Abnormalities in lumbar spine previously known or determined by a screening lumbar X-ray (if conducted)History of clinically significant back pain, back pathology, and/or back injury (for example, degenerative disease, spinal deformity, or spinal surgery) that may predispose participant to complications or technical difficulty with lumbar punctureEvidence or history of significant active bleeding or coagulation disorder or use of non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet function within 14 days prior to lumbar catheter insertionAllergy to lidocaine (Xylocaine?) or its derivativesMedical or surgical conditions for which lumbar puncture is contraindicated<Start of common text>Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)NOTE: Use the electrocardiogram (ECG) data from the study treatment development program thus far, including the thorough QTc study if one has been performed, to determine if there is a potential QTc effect. Based on these data, determine appropriate QTc exclusion and discontinuation criteria as well as the extent of ECG/other monitoring if the criteria above are no longer considered appropriate. The specific QT correction formula(s) used for data analysis should be determined prior to initiation of the study and recorded in the SAP. If a protocol is prescriptive in its choice of QTc correction formula(s) for data analysis, then any study site that does not have available ECG machines pre-programmed with the chosen QT correction formula must have all of the QTc data appropriately calculated using the chosen formula. The bullet points within the common text of the protocol exist so that QTc results are not chosen based upon the QT correction formula that presents a more favorable result (ie, a lower value for QTc).[QTc >450 msec for male participants] [or >470 msec for female participants] NOTE A: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-read or manually over-read. NOTE B: The specific formula used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulas cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant.<End of common text>PRIOR/CONCOMITANT THERAPYSummarize the classes of treatments that participants cannot take concomitantly, and cross reference Section 7 Study Treatments for details.[Past or] intended use of over-the-counter or prescription medication [including herbal medications] within [X] days prior to dosing [Specific medications listed in Section 7.7 may be allowed]This criterion is specific for immune modulators. Delete if not applicable.Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the studyThis criterion is specific for antibodies. Delete if not applicable.Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosingPRIOR/CONCURRENT CLINICAL STUDY EXPERIENCEParticipation in the study would result in loss of blood or blood products in excess of [X] mL within [X]Exposure to more than [4] new chemical entities within 12 months prior to dosingConsider adding this criterion if participants can only be enrolled once per study.Current enrollment or past participation within the last [X] days before [signing of consent] in [this or] any other clinical study involving an investigational study treatment or any other type of medical researchDIAGNOSTIC ASSESSMENTS <Start of common text> Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to dosingPositive hepatitis C antibody test result at screening or within 3 months prior to starting study treatment. NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtainedPositive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. NOTE: Test is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testingFor potent immunosuppressive agents, presence of the hepatitis B core antibody (HBcAb) even if HBsAg is negative<End of common text> Positive pre-study drug/alcohol screenPositive human immunodeficiency virus (HIV) antibody testOTHER EXCLUSIONSAdapt the wording option or replace with country specific textRegular alcohol consumption within [X] months prior to the study defined as: For [X sites]: an average weekly intake of >[X] units for males or >[X] units for females. One unit is equivalent to 8 g of alcohol: a half pint (240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.These criteria should be considered depending on known metabolic/safety issues of the study treatment or site-specific factors:Regular use of known drugs of abuseSensitivity to heparin or heparin-induced thrombocytopeniaSensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study8.1Discontinuation of Study Treatment Liver Chemistry Stopping Criteria<Start of common text>Study treatment will be discontinued for a participant if liver chemistry stopping criteria are met.Phase I Liver Chemistry Stopping Algorithm Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].<End of common text> QTc Stopping Criteria<Start of common text> A participant who meets [the OR either] bulleted criterion based on the average of triplicate ECG readings will be withdrawn from the study. [QTc, QTcB, QTcF] >500 msec[Change from baseline: QTc >60 msec]<End of common text>Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Treatment Rechallenge Guidelines]<Start of common text> For single-dose studies exclude text related to discontuation of study treatment, blood sample PK in the table and the corresponding footnote.Phase I liver chemistry stopping criteria are designed to assure participant safety and to evaluate liver event etiology.Phase I Liver Chemistry Stopping Criteria and Follow-Up AssessmentsLiver Chemistry Stopping CriteriaALT-absoluteALT ≥3xULNIf ALT ≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) or INR >1.5, report as a serious adverse event (SAE)1,2See additional actions and follow-up assessments belowRequired Actions and Follow-up Assessments ActionsFollow-Up AssessmentsImmediately discontinue study treatmentReport the event to the [sponsor] within 24?hoursComplete the liver event case report form (CRF), and complete an SAE data collection tool if the event also met the criteria for an SAE2Perform liver function follow-up assessmentsMonitor the participant until liver function test abnormalities resolve, stabilize, or return to baseline (see MONITORING)MONITORING:If ALT ≥3xULN AND bilirubin 2xULN or INR >1.5Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 hours.Monitor participant twice weekly until liver function test abnormalities resolve, stabilize, or return to baseline.A specialist or hepatology consultation is recommended.If ALT ≥3xULN AND bilirubin <2xULN and INR ≤1.5:Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 to 72 hoursMonitor participants weekly until liver function abnormalities resolve, stabilize, or return to baselineViral hepatitis serology3Obtain INR and recheck with each liver chemistry assessment until the transaminases values show downward trendObtain blood sample for pharmacokinetic (PK) analysis [insert time interval recommended by clinical pharmacokinetics representative] after the most recent dose4Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)Fractionate bilirubin, if total bilirubin ?2xULNComplete blood count with differential to assess eosinophiliaRecord the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the adverse event (AE) CRFRecord use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications) on the concomitant medications CRFRecord alcohol use on the liver event alcohol intake CRFIf ALT ≥3xULN AND bilirubin 2xULN or INR >1.5:Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulinsSerum acetaminophen adduct high performance liquid chromatography (HPLC) assay (quantifies potential acetaminophen contribution to liver injury in participants with definite or likely acetaminophen use in the preceding week [James, 2009]) NOTE: Not required in China.Liver imaging (ultrasound, magnetic resonance, or computerized tomography) and/or liver biopsy to evaluate liver disease; complete liver imaging and/or liver biopsy CRFsSerum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study treatment if ALT 3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to participants receiving anticoagulants. Includes: Hepatitis A IgM antibody; hepatitis B surface antigen (HBsAg) and hepatitis B Core Antibody (HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and hepatitis E IgM antibody. PK sample may not be required for participants known to be receiving placebo or non-comparator treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the [Study Reference Manual].ReferencesJames LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.<End of common text> ................
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