Appendix 2 Clinical Laboratory Tests - TransCelerate



Common Protocol Template (CPT) Patient Library v005Section in CPTLibrary Content5.1 Inclusion Criteria: SexInstructions and content, including decision tree for contraception, barriers, and pregnancy testing requirements5.2. Exclusion CriteriaInstructions and suggested and common text7.1. Discontinuation of Study InterventionCommon text for Liver Chemistry Stopping Criteria and QTc Stopping Criteria10.2 Appendix 2 Clinical Laboratory TestsInstructions and text for pregnancy testing10.4 Appendix 4 Contraceptive and Barrier Guidance and Collection of Pregnancy InformationInstructions and text for contraceptive use Appendix 6: Liver Safety: Suggested Actions and Followup Assessments [and Study Intervention Rechallenge Guidelines]Instructions and text for liver safety 5.1 Inclusion CriteriaSex4. Contraception, barriers, and pregnancy testing requirements: Contraception/abstinence and pregnancy testing requirements for a given study should be based upon a risk assessment of the potential for genotoxicity and teratogenicity/fetotoxicity of the intervention(s) in the study. Risk should be determined for each intervention with input from the company’s pre-clinical safety assessment group. Determination of risk for a marketed compound should also consider the risks outlined in the product label.The common text language, per International Council on Harmonization [ICH] Guideline M3(R2) and Clinical Study Facilitation Group (CTFG) Guidance which supports EU536/2014, should be used for most studies. The template language provided is intended to be sufficiently flexible to accommodate variability with local recommendation/regulation when defining appropriate contraception for the study.The following Decision Tree and associated template language is based upon CHMP guidelines set forth in the CTFG Document: Recommendations related to contraception and pregnancy testing in clinical trials Tree for Contraception and BarriersReview the following schema and determine the appropriate option for contraception and barrier methods based on the genotoxicity and teratogenicity/fetotoxicity of the intervention(s) in the study; each outcome is aligned with corresponding template text options found in Sections 5.1, Inclusion Criteria, Appendix 2, Clinical Laboratory Tests and Appendix 4, Contraceptive Guidance and Collection of Pregnancy Information.Modify the duration for contraception use by males and females as appropriate for the study. Male ParticipantsSelect one of the two following options for studies with male participants. Delete these text options from studies enrolling only female participants or if there are no measures required for the study.Option M1A: For all studies in which the decision tree is Yes for clinically relevant genotoxicity, in addition to male condom use, a highly effective method of contraception should be used in women of childbearing potential (WOCBP) partners of male participants to prevent any potential for fertilization by sperm that contain damaged DNA due to the intervention. CTFG recommendations suggest to consider contraception methods for the female partner. Contraception methods outlined below are required from the beginning of study intervention through the period where WOCBP who are partners of male participants no longer need protection from seminal study intervention exposureNote: In cases where there is potential for additional toxicity associated with exposure through ejaculate beyond those risks specifically assessed for genotoxicity and teratogenicity/fetotoxicity above, condom use should also be considered when engaging in activities with any partner (different or same sex) to prevent potential passage of study intervention in the ejaculate.<Start of common text>Male Participants:Male participants are eligible to participate if they agree to the following during the intervention period and for at least [X days/weeks, corresponding to time needed to eliminate study intervention(s) (e.g., 5 terminal half-lives) plus an additional 90 days (a spermatogenesis cycle) after the last dose of study intervention]: Refrain from donating spermPLUS either:Be abstinent from heterosexual [or homosexual] intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent ORMust agree to use contraception/barrier as detailed below Agree to use a male condom Consider adding one of the following methods 1.) [with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year as described in Appendix 4 ] OR 2.) [and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak] when having sexual intercourse with a woman of childbearing potential who is not currently pregnant[Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person]<End of common text>Option M1B: For all studies in which the decision tree is Yes for ‘Should the WOCBP partner become pregnant, is there risk of teratogenicity/fetotoxicity to the fetus in the WOCBP partner exposed to study intervention via ejaculate?’, in addition to male condom use, a highly effective method of contraception may be considered in WOCBP partners of male participants to prevent passage of study intervention through the ejaculate, e.g., when a man is sexually active with a WOCBP or a woman who is pregnant; however this is not a requirement based upon CTFG recommendations. Contraception methods outlined below are required from the beginning of study intervention through the period where WOCBP who are partners of male participants no longer need protection from seminal study intervention exposure. Note: In cases where there is potential for additional toxicity associated with exposure through ejaculate beyond those risks specifically assessed for genotoxicity and teratogenicity/fetotoxicity above, condom use should also be considered when engaging in activities with any partner (different or same sex) to prevent potential passage of study intervention in the ejaculate.<Start of common text>Male Participants:Male participants are eligible to participate if they agree to the following during the intervention period and for at least [X days/weeks, corresponding to time needed to eliminate study intervention(s) (e.g., 5 terminal half-lives) after the last dose of study intervention)]: Refrain from donating spermPlus either: Be abstinent from heterosexual [or homosexual] intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent ORMust agree to use contraception/barrier as detailed belowAgree to use a male condom [and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak] when having sexual intercourse with a woman of childbearing potential who is not currently pregnant[Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person]<End of common text>Female participantsSelect one of the following text options for studies with female participants. Delete these text options if only enrolling male participants.All Options: For studies that have requirements for multiple pregnancy tests, add additional criteria as needed (e.g., if there is a requirement for test to be performed within a proximal time frame prior to first dose, specify as inclusion criteria, if at a specified visit, or at end of study intervention note in SoA and provide any necessary details in Appendix 2, Clinical Laboratory Tests. A serum pregnancy test may diagnose pregnancy ~6 to 10 days after fertilization; a urine pregnancy test, because it is less sensitive, will diagnose pregnancy a few days after a serum pregnancy test As serum pregnancy tests have a lower detection limit and will detect pregnancy closer to the date of conception, serum testing is the preferred test if there is a requirement to know pregnancy status within a few days of the first dose of study intervention.Option F1A: For all studies in which the decision tree is Yes for risk of clinically relevant genotoxicity:For intervention with genotoxic drugs (if there is effect of the study intervention on ova) specify that female participants should not donate eggs, modify timeframe if longer duration is required.Note: for this option, CTFG guidelines state that highly effective contraception with low user dependency is preferred. If the study will require methods to have low user dependency remove the word ‘preferably’. If urine test allowed, retain the text listed in the last blue bracketed bullet. <Start of common text>Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:Is not a woman of childbearing potential (WOCBP) ORIs a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), [preferably] with low user dependency, as described in Appendix [4] during the intervention period and for at least [X days/weeks, corresponding to the time needed to eliminate any study intervention(s) (e.g., 5 terminal half-lives) plus 30 days (a menstrual cycle)] after the last dose of study intervention [and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.]. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within [24 hours] before the first dose of study intervention.[If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.]Additional requirements for pregnancy testing during and after study intervention are located in Appendix [2].The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy<End of common text>Option F1B: For all studies in which the decision tree is Yes for demonstrated or suspected risk of human teratogenicity/fetotoxicity:Consider adding a timeframe after discontinuation of study intervention for not donating eggs, dependent upon the effect of the study intervention on ova.Note: for this option, CTFG guidelines state that highly effective contraception with low user dependency is preferred. If the study will require methods to have low user dependency remove the word ‘preferably’.If urine test allowed, retain the text listed in the last blue bracketed bullet. <Start of common text>A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:Is not a woman of childbearing potential (WOCBP) ORIs a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), [preferably] with low user dependency, as described in Appendix [4] during the intervention period and for at least [X days/weeks, corresponding to the time needed to eliminate any study intervention(s) (e.g., 5 terminal half-lives)] after the last dose of study intervention [and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for a period of (insert timeframe)]. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within [24 hours] before the first dose of study intervention. [If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive]. Additional requirements for pregnancy testing during and after study intervention are located in Appendix [2].The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy<End of common text>Option F2: For all studies in which the decision tree is Yes for possible risk of human teratogenicity/fetotoxicity:If urine test allowed, retain the text listed in the last blue bracketed bullet. <Start of common text>Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:Is not a woman of childbearing potential (WOCBP) ORIs a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Appendix [4] during the intervention period and for at least [X days/weeks, corresponding to the time needed to eliminate any study intervention(s) (e.g., 5 terminal half-lives)] after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.A WOCBP must have a negative highly sensitive [Appendix 2] pregnancy test (urine or serum as required by local regulations) within [specify timeframe] before the first dose of study intervention. [If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive]. Additional requirements for pregnancy testing during and after study intervention are located in Appendix [2].The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy<End of common text>Option F3: For all studies in which the decision tree is Yes for unlikely risk of human teratogenicity/fetotoxicityIf urine test allowed, retain the text listed in the last blue bracketed bullet. <Start of common text>Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:Is not a woman of childbearing potential (WOCBP) ORIs a WOCBP and using an acceptable contraceptive method as described in Appendix [4] during the intervention period (at a minimum until after the last dose of study intervention). The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.A WOCBP must have a negative highly sensitive (Appendix [2]) pregnancy test (urine or serum as required by local regulations) within [specify timeframe] before the first dose of study intervention. [If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive]. Additional requirements for pregnancy testing during and after study intervention are located in Appendix [2].The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy5.2 Exclusion CriteriaMEDICAL CONDITIONSThese criteria are specific for molecules that are immune modulators. Delete if not applicable or modify wording as required.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 antibodiesClinically 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) is 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 (e.g., 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 for Phase I1studies>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)<End of common text for Phase 1 studies><Start of common text for Phase 2 studies>Alanine transaminase (ALT) >2.0x 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)<End of common text for Phase 2 studies><Start of common text for Phase 3 studies>12. Alanine transaminase (ALT) >2x upper limit of normal (ULN) 13. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)14. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE : Stable chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C -e.g., presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention) is acceptable if the participant otherwise meets entry criteria<End of common text for Phase 3 studies><Start of common text for Phase 1--4 studies in Patients>State the corrected QT interval (QTc) exclusion criteria as shown. These criteria should serve as the general default values for all studies. Due to the different benefit/risk profiles of study interventions as well as the different participant populations, exceptions to these criteria may occur. These should be proposed and agreed upon by all relevant parties within the sponsor organization.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 electrocardiogram (ECG) machines preprogrammed with the chosen QT correction formula must have all of the QTc data appropriately calculated using the chosen formula. The notes 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 (i.e., a lower value for QTc).[QTc >450 msec for male participants] [or QTc >470 msec for female participants] or QTc >480 msec in participants with bundle branch block. 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 from the trial <End of common text>PRIOR/CONCOMITANT THERAPYSummarize the classes of treatments that participants cannot take concomitantly, and cross reference Section 6 Study Intervention 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 6.5 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 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 dosing.PRIOR/CONCURRENT CLINICAL TRIAL EXPERIENCEParticipation in the study would result in loss of blood or blood products in excess of [X] mL within [X]Exposure to more than [X] new chemical entities within 12 months prior to the first dosing dayCurrent enrollment or past participation within the last [X] days before [signing of consent] in any other clinical study involving an investigational study treatment or any other type of medical researchConsider 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 clinical study. DIAGNOSTIC ASSESSMENTS Positive pre-study drug/alcohol screenPositive human immunodeficiency virus (HIV) antibody test<Start of common text for Phase 1 or 2 studies>NOTE: For Phase 3 studies, hepatitis B and C testing at screening is not required unless potent immunosuppressive agents will be administered For studies of immunosuppressive agents, participants with chronic stable hepatitis B and/or hepatitis C (e.g., presence of HBsAg or positive hepatitis C ribonucleic acid [RNA] test result at screening or within 3 months prior to first dose of study intervention) should generally be excluded. participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.NOTE: The Hepatitis C antibody test is a standard test used at screening to determine eligibility, and hepatitis C RNA testing is optional and only performed when the antibody test is positive in order to consider participants with positive Hepatitis C antibody test for enrollment into the study. Where hepatitis C RNA testing is unavailable, a positive hepatitis C antibody test will be used for exclusion.For potent immunosuppressive agents, participants with presence of hepatitis B core antibody (HBcAb) should be excluded even if HBsAg is negative. If these participants are to be included, then additional screening, anti-viral prophylaxis, monitoring, and follow-up measures may be required. For such studies, the relevant sponsor Safety Panel should be consulted for additional guidance. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention. Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study intervention. NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention. NOTE: Test is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing<End of common text for Phase 1 or 2 studies>OTHER EXCLUSIONSModify suggested wording 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 spiritsThese criteria should be considered depending on known metabolic/safety issues of the study intervention or site-specific factors:Regular use of drugs of abuseSensitivity to heparin or heparin-induced thrombocytopeniaSensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator [or Medical Monitor], contraindicates participation in the study.7.1 Discontinuation of Study Intervention Liver Chemistry Stopping Criteria <Start of common text> Study intervention will be discontinued for a participant if liver chemistry stopping criteria are met.<Start of common text for Phase 1 studies>Phase 1 Liver Chemistry Stopping AlgorithmAbbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of normal.Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix 6 .<End of common text for Phase 1 studies> <Start of common text for Phase 2 studies>Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring AlgorithmAbbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of normal.Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [6] . <End of common text for Phase 2 studies><Start of common text for Phase 3-4 studies>Phase 3-4 Liver Chemistry Stopping Criteria and Increased Monitoring AlgorithmAbbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of normal.Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [6].Phase 3-4 Liver Chemistry Increased Monitoring Algorithm with Continued Study Intervention for Participants with ALT 3xULN but <8xULN Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of normal.Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [6.] <End of common text for Phase 3-4 studies>QTc Stopping Criteria<Start of common text for Phase 1-4 studies in patients> A participant who meets [the OR either] bulleted criterion based on the average of triplicate ECG readings will be withdrawn from study intervention. QTc >500 msec OR Uncorrected QT >600 msec[Change from baseline of QTc >60 msec]For participants with underlying bundle branch block, follow the discontinuation criteria listed below:Baseline QTc with Bundle Branch BlockDiscontinuation QTc Threshold with Bundle Branch Block< 450 msec> 500 msec450 to 480 msec≥ 530 msec<End of common text for Phase 1-4 studies in patients>Appendix 2 Clinical Laboratory Tests Select ONE of the options corresponding with the contraceptive option selected from the.decision tree in section 5.1.Option F1A: For all studies in which the decision tree is Yes for clinically relevant genotoxicity (The decision tree is located in Section 5.1) <Start of common text> Pregnancy testing (urine or serum as required by local regulations) should be conducted at monthly intervals during intervention Pregnancy testing (urine or serum as required by local regulations) should be conducted at the end of relevant systemic exposure plus an additional 30 days and correspond with the time frame for female participant contraception in Section 5.1, Inclusion Criteria<End of common text>Option F1B: For all studies in which the decision tree is Yes for demonstrated or suspected risk of human teratogenicity/fetotoxicity (The decision tree is located in Section 5.1):<Start of common text> Pregnancy testing (urine or serum as required by local regulations) should be conducted at monthly intervals during intervention Pregnancy testing (urine or serum as required by local regulations) should be conducted at the end of relevant systemic exposure and correspond with the time frame for female participant contraception in Section 5.1, Inclusion Criteria<End of common text>Option F2: For all studies in which the decision tree is Yes for possible risk of human teratogenicity/fetotoxicity (The decision tree is located in Section 5.1):Additional pregnancy testing should be considered. As a minimum, pregnancy testing should be conducted at the end of relevant systemic exposure.<Start of common text>Pregnancy testing (urine or serum as required by local regulations) should be conducted at [specify intervals based upon mechanism of action, study design etc. X] during intervention Pregnancy testing (urine or serum as required by local regulations) should be conducted at the end of relevant systemic exposure. <End of common text>Option F3: For all studies in which the decision tree is Yes for unlikely risk of human teratogenicity/fetotoxicity (The decision tree is located in Section 5.1): Additional pregnancy testing following screening is generally not necessary.<Start of common text>All Options:Additional serum or urine pregnancy tests may be performed, as determined necessary by the investigator or required by local regulation, to establish the absence of pregnancy at any time during the subject's participation in the study.<End of common text>Appendix 4 Contraceptive and Barrier Guidance and Collection of Pregnancy InformationContraception Guidance:Select relevant wording to include in protocol from options below.All Female Participant Options If a clinically relevant interaction between study intervention(s) and contraceptive steroids has been observed or is suspected that may compromise efficacy of hormonal contraception, hormonal contraception should not be used. If interaction observed however is not considered to exert a clinically relevant compromise to the efficacy of hormonal contraception, the hormonal contraception method should be supplemented with male condom.Option F1A: For all studies in which the decision tree is Yes for risk of clinically relevant genotoxicity (The decision tree is located in Section 5.1):Note: for this option, CTFG guidelines state that highly effective contraception with low user dependency is preferred. <Start of common text> CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:Highly Effective Methodsb That Have Low User Dependency Implantable progestogen-only hormone contraception associated with inhibition of ovulationcIntrauterine device (IUD)Intrauterine hormone-releasing system (IUS)cBilateral tubal occlusionVasectomized partner(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.)Highly Effective Methodsb That Are User Dependent If “[preferably]” is not selected and low user dependency is required, delete these User Dependent Methods (retain sexual abstinence).Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationcoralintravaginaltransdermalinjectableProgestogen-only hormone contraception associated with inhibition of ovulationcoralinjectableSexual abstinence(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)a)Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those participating in clinical studies.b)Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly.c.)If hormonal contraception is prohibited, delete this footnote. If hormonal contraception efficacy is potentially decreased due to interaction with study intervention(s) add the following footnote:[Male condoms must be used in addition to hormonal contraception] If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should not be used together (due to risk of failure with friction)<End of common text> Option F1B: For all studies in which the decision tree is Yes for demonstrated or suspected risk of human teratogenicity/fetotoxicity (The decision tree is located in Section 5.1):Note: for this option, CTFG guidelines state that highly effective contraception with low user dependency is preferred. If the study will require methods to have low user dependency remove the word ‘preferably’.<Start of common text> CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly.Implantable progestogen-only hormone contraception associated with inhibition of ovulationcIntrauterine device (IUD)Intrauterine hormone-releasing system (IUS)cBilateral tubal occlusionVasectomized partner(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.)Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when used consistently and correctly.If “[preferably]” is not selected and low user dependency is required, delete these User Dependent Methods (retain sexual abstinence).Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationcoralintravaginaltransdermalinjectableProgestogen-only hormone contraception associated with inhibition of ovulationcoralinjectableSexual abstinence(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)a)Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those participating in clinical studies.b)Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly.c)If hormonal contraception is prohibited, delete this footnote. If hormonal contraception efficacy is potentially decreased due to interaction with study intervention add the following footnote: [Male condoms must be used in addition to hormonal contraception]. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male condom and female condom should not be used together (due to risk of failure with friction)<End of common text> Option F2: For all studies in which the decision tree is Yes for possible risk of human teratogenicity/fetotoxicity (The decision tree is located in Section 5.1):<Start of common text> CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly.Implantable progestogen-only hormone contraception associated with inhibition of ovulationcIntrauterine device (IUD)Intrauterine hormone-releasing system (IUS)cBilateral tubal occlusionVasectomized partner(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.)Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and bined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationcoralintravaginaltransdermalinjectableProgestogen-only hormone contraception associated with inhibition of ovulationcoralinjectableSexual abstinence(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)a)Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those participating in clinical studies.b)Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly.c.)If hormonal contraception is prohibited, delete this footnote. If hormonal contraception efficacy is potentially decreased due to interaction with study intervention add the following footnote: [Male condoms must be used in addition to hormonal contraception]. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male condom and female condom should not be used together (due to risk of failure with friction)<End of common text> Option F3: For all studies in which the decision tree is Yes for unlikely risk of human teratogenicity/fetotoxicity (The decision tree is located in Section 5.1)<Start of common text> CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly.Implantable progestogen-only hormone contraception associated with inhibition of ovulationbIntrauterine device (IUD)Intrauterine hormone-releasing system (IUS) bBilateral tubal occlusionVasectomized partner(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.)Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and bined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationcoralintravaginaltransdermalinjectableProgestogen-only hormone contraception associated with inhibition of ovulationcoralinjectableSexual abstinenceSexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)ACCEPTABLE METHODSdProgestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of actionMale or female condom with or without spermicideeCervical cap, diaphragm, or sponge with spermicideA combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier methods)ca)Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those participating in clinical studies.b)Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly.c.)If hormonal contraception is prohibited, delete this footnote. If hormonal contraception efficacy is potentially decreased due to interaction with study intervention add the following footnote: [Male condoms must be used in addition to hormonal contraception]. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.d)Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. e)Male condom and female condom should not be used together (due to risk of failure with friction).<End of common text> Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Intervention Rechallenge Guidelines]<Start of common text for Phase I studies > For single-dose studies exclude text related to discontinuation of study intervention, intervention restart and rechallenge, and pharmacokinetic (PK) blood samples in the table and the corresponding footnote. If study intervention restart and rechallenge is applicable, consider including details on suggested follow-up assessments (e.g., follow up for overall survival or disease recurrence or progression).Phase 1 liver chemistry stopping criteria are designed to assure participant safety and to evaluate liver event etiology.Phase 1 Liver Chemistry Stopping Criteria and Follow-Up AssessmentsLiver Chemistry Stopping Criteria – Liver Stopping EventALT-absoluteALT≥3xULNIf ALT ≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) OR international normalized ratio (INR) >1.5, report as a serious adverse event (SAE).1,2See additional actions and follow-up assessments listed belowSuggested Actions and Follow up AssessmentsActionsFollow Up AssessmentsImmediately discontinue study intervention.Report the event to the [sponsor] within 24 hoursComplete the liver event case report form (CRF), and complete a SAE data collection tool if the event also met the criteria for an SAE.2Perform liver chemistry follow-up assessments. Monitor the participant until liver chemistry test abnormalities resolve, stabilize, or return to baseline (see MONITORING).Do not restart/rechallenge participant with study intervention unless allowed per protocol and [sponsor] approval is granted. If restart/rechallenge is either not allowed per protocol or not granted, permanently discontinue study intervention. The participant may continue in the study for any protocol-specified follow-up assessments MONITORING:If ALT 3xULN AND bilirubin 2xULN or INR >1.5:Repeat liver chemistry tests (include ALT, aspartate transaminase [AST], alkaline phosphatase, bilirubin and INR) and perform liver event follow-up assessments within 24 hours.Monitor participant twice weekly until liver chemistry 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 chemistry tests (include ALT, AST, alkaline phosphatase, bilirubin and INR) and perform liver chemistry follow-up assessments within 24 to 72 hours.Monitor participants weekly until liver chemistry abnormalities resolve, stabilize, or return to baseline.Viral 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 dose4 Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)Fractionate bilirubin, if total bilirubin ?2xULNObtain complete blood count with differential to assess eosinophiliaRecord the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the adverse event (AE) CRF Record use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications) on the concomitant medications CRF.Record alcohol use on the liver event alcohol intake CRF.If 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 globulins.Serum 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 [ REF James2009 \h \* MERGEFORMAT 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 CRFs.Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study intervention 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 stated threshold value will not apply to participants receiving anticoagulants. Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and 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 interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention 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]. References: James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. <End of common text for Phase 1 studies > <Start of common wording for Phase 2 studies>For single-dose studies exclude text related to discontinuation of study intervention, intervention restart and rechallenge, and pharmacokinetic (PK) blood samples in the table and the corresponding footnote. If study intervention restart and rechallenge is applicable, consider including details on suggested follow-up assessments (e.g., follow up for overall survival or disease recurrence or progression).For single-dose studies in the table “Phase 2 Liver Chemistry Increased Monitoring Criteria with Continued Study Intervention” exclude text on continuation of study intervention.Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate liver event etiology.Phase 2 Liver Chemistry Stopping Criteria and Follow-Up AssessmentsLiver Chemistry Stopping CriteriaALT-absoluteALT 5xULNALT IncreaseALT 3xULN persists for 4 weeksBilirubin1, 2ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)INR2ALT 3xULN and international normalized ratio (INR) >1.5, if INR measuredCannot MonitorALT 3xULN and cannot be monitored weekly for 4 weeksSymptomatic3ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver injury or hypersensitivitySuggested Actions and Follow-up Assessments ActionsFollow-Up AssessmentsImmediately discontinue study intervention. Report the event to the [sponsor] within 24 plete the liver event case report form (CRF), and complete a serious adverse event (SAE) data collection tool if the event also met the criteria for an SAE.2Perform liver chemistry follow-up assessments. Monitor the participant until liver chemistry test abnormalities resolve, stabilize, or return to baseline (see MONITORING).Do not restart/rechallenge participant with study intervention unless allowed per protocol and [sponsor] approval is grantedIf restart/rechallenge not allowed per protocol or not granted, permanently discontinue study intervention and continue participant in the study for any protocol specified follow up assessments MONITORING:If ALT 3xULN AND bilirubin 2xULN or INR >1.5: Repeat liver chemistry tests (include ALT, aspartate transaminase [AST], alkaline phosphatase, bilirubin and INR) and perform liver event follow-up assessments within 24 hours.Monitor participant twice weekly until liver chemistry 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 chemistry tests (include ALT, AST, alkaline phosphatase, bilirubin and INR) and perform liver chemistry follow-up assessments within 24 to 72 hours.Monitor participants weekly until liver chemistry abnormalities resolve, stabilize, or return to baseline.Viral hepatitis serology4Obtain 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 dose5.Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)Fractionate bilirubin, if total bilirubin 2xULNObtain complete blood count with differential to assess eosinophiliaRecord the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the adverse event (AE) report formRecord use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications) on the concomitant medications CRF.Record 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 globulins.Serum 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 [ REF James2009 \h \* MERGEFORMAT James, 2009].) NOTE: Not required in China.Liver imaging (ultrasound, magnetic resonance, or computerized tomography) and/or liver biopsy to evaluate liver disease; complete liverSerum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study intervention 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 INRstated threshold value will not apply to participants receiving anticoagulants. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and 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 interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to the 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].Phase 2 Liver Chemistry Increased Monitoring Criteria with Continued Study InterventionLiver Chemistry Increased Monitoring Criterion and Follow-UpCriterionActionsALT 3xULN and <5xULN and bilirubin <2xULN, without symptoms believed to be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 weeksNotify the [sponsor within 24 hours of learning of the abnormality to discuss participant safety. Participant can continue study intervention. Participant must return weekly for repeat liver chemistry tests (ALT, AST, alkaline phosphatase, bilirubin) until the abnormalities resolve, stabilize or return to baseline. If at any time, the participant meets liver chemistry stopping criteria, proceed as described in [location].If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor participants twice monthly until liver chemistry tests resolve, stabilize, or return to baseline.ReferencesJames LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.<End of common wording for Phase 2 studies><Start of common wording for Phase 3-4studies>For single-dose studies exclude text related to discontinuation of study intervention, intervention restart and rechallenge, and pharmacokinetic (PK) blood samples in the table and the corresponding footnote. If study intervention restart and rechallenge is applicable, consider including details on suggested follow-up assessments (e.g., follow up for overall survival or disease recurrence or progression).For single-dose studies in the table “Phase 3-4Liver Chemistry Increased Monitoring Criteria with Continued Study Intervention” exclude text on continuation of study intervention.Phase 3-4liver chemistry stopping criteria are designed to assure participant safety and to evaluate liver event etiology.Phase 3-4 liver Chemistry Stopping Criteria and Follow-Up assessments Liver Chemistry Stopping CriteriaALT-absoluteALT 8xULNALT IncreaseALT 5xULN but <8xULN persists for 2 weeksALT 3xULN but <5xULN persists for 4 weeksBilirubin1, 2ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) INR2 ALT 3xULN and international normalized ratio (INR) >1.5, if INR measuredCannot MonitorALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeksALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeksSymptomatic3ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver injury or hypersensitivitySuggested Actions and Follow up AssessmentsActionsFollow Up AssessmentsImmediately discontinue study intervention.Report the event to the [sponsor] within 24?plete the liver event case report form (CRF), and complete a serious adverse event (SAE) data collection tool if the event also met the criteria for an SAE.2Perform liver chemistry follow-up assessments. Monitor the participant until liver chemistry test abnormalities resolve, stabilize, or return to baseline (see MONITORING).Do not restart/rechallenge participant with study intervention unless allowed per protocol and [sponsor] approval is granted.If restart/rechallenge not allowed per protocol or not granted, permanently discontinue study intervention and continue participant in the study for any protocol specified follow up assessments.MONITORING:For bilirubin or INR criteria Repeat liver chemistry tests (include ALT, aspartate transaminase [AST], alkaline phosphatase, bilirubin and INR) and perform liver event follow-up assessments within 24 hours.Monitor participant twice weekly until liver chemistry test abnormalities resolve, stabilize, or return to baseline.A specialist or hepatology consultation is recommended.For all other criteria Repeat liver chemistry tests (include ALT, AST, alkaline phosphatase, bilirubin and INR) and perform liver chemistry follow-up assessments within 24 to 72 hours.Monitor participants weekly until liver chemistry abnormalities resolve, stabilize, or return to baseline.Viral hepatitis serology4:only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen), quantitative hepatitis B deoxyribonucleic acid (DNA) and hepatitis delta antibody5Obtain 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 dose5Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)Fractionate bilirubin, if total bilirubin 2xULNObtain complete blood count with differential to assess eosinophiliaRecord the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the adverse event (AE) report formRecord use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications) on the concomitant medications CRF.Record alcohol use on the liver event alcohol intake CRFFor bilirubin or INR criteria:Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulins.Serum 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 [ REF James2009 \h \* MERGEFORMAT James, 2009]). NOTE: Not required in China.Liver imaging (ultrasound, magnetic resonance, or computerizsed tomography) andor liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver Biopsy CRFs.Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study intervention 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 stated threshold value will not apply to participants receiving anticoagulants. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and 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. If hepatitis delta antibody assay cannot be performed,, it can be replaced with a polymerase chain reaction (PCR) of hepatitis D RNA virus (where needed) [Le Gal, 2005].PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention 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].Phase 3-4Liver Chemistry Increased Monitoring Criteria with Continued Study InterventionLiver Chemistry Increased Monitoring CriteriaCriteriaActionsALT 5xULN and <8xULN and bilirubin <2xULN without symptoms believed to be related to liver injury or hypersensitivity, and who can be monitored weekly for 2 weeks.ORALT 3xULN and <5xULN and bilirubin <2xULN without symptoms believed to be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 weeks.Notify the [sponsor] within 24 hours of learning of the abnormality to discuss participant safety. Participant can continue study intervention. Participant must return weekly for repeat liver chemistry tests (ALT, AST, alkaline phosphatase, bilirubin) until the abnormalities resolve, stabilize, or return to baseline. If at any time, the participant meets liver chemistry stopping criteria, proceed as described in [location].If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, continue to monitor liver chemistries weekly. If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor participants twice monthly until liver chemistry tests resolve, stabilize, or return to baseline.ReferencesJames LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, et al. Quantification of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients. J Clin Microbiol. 2005;43(5):2363–2369. <End of common text for Phase 3-4studies> Liver Safety: Study Intervention Rechallenge Guidelines This part of the appendix is optional and should ONLY be included if study intervention restart/rechallenge will be allowed for participants in the study. If this part of the appendix is not included, then change the title of the appendix accordingly. This section does not apply to single dose studies.This section should ONLY be included if:Study intervention rechallenge is allowed after intervention-related injury in participants because study intervention has a compelling benefit (i.e., a critical or life-saving medicine for which no alternative therapy is available) and a benefit/risk assessment of continuing study intervention is considered to be favorable (applies to Phase?I4studies excluding healthy volunteer studies). AND/ORStudy intervention restart is allowed after a participant(s) has a transient and resolved/resolving non-intervention-related liver injury in Phase 3-4studies (available to all studies and particularly suggested for long-term outcome studies). Study intervention restarts are generally limited to Phase 3-4studies, but can be considered in Phase 1 and 2 studies if there is compelling evidence of benefit from a critical or life-saving medicine, there is no alternative approved medicine available, and a benefit/risk assessment of continuing study intervention is considered to be favorable.If this section is included, ensure that the following are utilized:The restart and/or rechallenge informed consent form (ICF). (Note: The restart or rechallenge ICF may be created and reviewed a priori with the main consent form, but is only used after an event has occurred and intervention restart or rechallenge is being considered.) The liver CRFs.Pharmacokinetic sample processing and data capture.If approval to restart/rechallenge is not granted, consider including any applicable details on suggested follow-up assessments (e.g., follow-up for overall survival or disease recurrence or progression).NOTE: Intervention restarts are generally limited to Phase 3-4studies, but can be considered in Phase I and 2 studies if there is compelling evidence of benefit from a critical or life-saving medicine, there is no alternative approved medicine available, and a benefit/risk assessment of continuing study intervention is considered to be favorable.<Start of common text if study intervention restart/rechallenge is allowed>A participant who met liver chemistry stopping criteria cannot restart study intervention unless all of the following conditions are met:[Sponsor] approval is granted (as described below)Institutional Review Board/Independent Ethics Committee (IRB/IEC) approval is obtainedSeparate ICF for intervention restart/rechallenge is signed by the participantIf [sponsor] approval to restart/rechallenge the participant with study intervention is not granted, then the participant must permanently discontinue study intervention and may continue in the study for protocol-specified follow-up assessments. Rechallenge Following Liver Chemistry Events that are Possibly Related to Study InterventionFollowing study intervention-induced liver injury, rechallenge is associated with 13% mortality across all study interventions in prospective studies.1 Clinical outcomes vary with nearly 50% fatality with halothane readministered within one month of the initial injury. However, some interventions seldom result in recurrent liver injury or fatality. Risk factors for a fatal rechallenge outcome include:Hypersensitivity with initial liver injury (e.g., fever, rash, eosinophilia) 1 Jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of total)Ongoing severe liver injury defined by ALT 3xULN AND bilirubin 2xULN (direct bilirubin >35% of total) OR INR>1.5Serious adverse event or fatality previously observed with rechallenges2,3Evidence of intervention-related preclinical liability (e.g., reactive metabolites, mitochondrial impairment)3Rechallenge refers to resuming study intervention following drug-induced liver injury (DILI). Because of the risks associated with rechallenge after DILI, this should only be considered if there is compelling evidence of benefit from a critical or life-saving medicine, there is no alternative approved medicine available, and a benefit/risk assessment of rechallenge is considered to be favorable.Approval by the [sponsor] for rechallenge with study intervention can be considered when:The Principal Investigator (PI) requests consideration of rechallenge with study intervention for a participant who is receiving compelling benefit with study intervention that exceeds risk and for whom no effective alternative therapy is available. IRB/IEC approval for rechallenge with study intervention has been obtained.If the rechallenge is approved by the [sponsor] in writing: The participant must be provided with a clear description of the possible benefits and risks of study intervention administration including the possibility of recurrent, more severe liver injury or death. The participant must provide signed informed consent specifically for the rechallenge with study intervention. Documentation of informed consent must be recorded in the study file. Study intervention must be administered at the dose specified by the [sponsor].Participants approved by the [sponsor] for rechallenge with study intervention must return to the clinic twice a week for liver chemistry tests until stable liver chemistry tests have been demonstrated and then standard laboratory monitoring may resume as per protocol.If the participant meets protocol-defined liver chemistry stopping criteria after study intervention rechallenge, study intervention should be permanently discontinued. The [sponsor] and the IRB/IEC, must be informed of the outcome for the participant following study intervention rechallenge. The [sponsor] must be notified of any adverse events. AND/ORRestart Following Transient Resolving Liver Chemistry Events Not Related to Study InterventionRestart refers to resuming study intervention following liver chemistry events for which there are clear underlying causes (other than DILI) (e.g., biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity.Approval by the [sponsor] for study intervention restart can be considered when:The investigator requests consideration for study intervention restart if liver chemistry events have a clear underlying cause (e.g., biliary obstruction, pancreatic events, hypotension, acute viral hepatitis) and liver chemistry tests have improved to normal or are within 1.5 x baseline and ALT <3xULN.Possible DILI has been excluded by the investigator and the study team. This includes the absence of markers of hypersensitivity (otherwise unexplained fever, rash, eosinophilia). Where a study intervention has an identified genetic marker associated with liver injury (e.g., lapatinib, abacavir, amoxicillin/clavulanate), the presence of the marker should be excluded. If study intervention-related liver injury cannot be excluded, the guidance on rechallenge in the previous part of this Appendix will apply.There is no evidence of alcoholic hepatitis.IRB/IEC approval of study intervention restart has been obtained.If restart of study intervention is approved by the [sponsor] in writing: The participant must be provided with a clear description of the possible benefits and risks of study intervention administration including the possibility of recurrent, more severe liver injury or death. The participant must provide signed informed consent specifically for the restart of study intervention. Documentation of informed consent must be recorded in the study file. Study intervention must be administered at the dose specified by the [sponsor].Participants approved by the [sponsor] for restart of study intervention must return to the clinic twice a week for liver chemistry tests until stable liver chemistry tests have been demonstrated and then standard laboratory monitoring may resume as per protocol.If the participant meets protocol-defined liver chemistry stopping criteria after study intervention restart, study intervention should be permanently discontinued. The [sponsor], and the IRB/IEC, must be informed of the outcome for the participant following study intervention restart. The [sponsor] must be notified of any adverse events. References:Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90. Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review. Hepatol. 2010;52:2216-2222.<End of common text > ................
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