CPT HEALTHY VOLUNTEER LIBRARY - TransCelerate



Common Protocol Template Healthy Volunteer Library v004Section in Common Protocol Template (CPT)Library Content5.1 Inclusion Criteria: SexInclusion Criteria: Sex5.2 Exclusion CriteriaExclusion Criteria7.1 Discontinuation of Study InterventionLiver Chemistry Stopping CriteriaQTc Stopping Criteria10.2 Appendix 2 Clinical Laboratory TestsClinical Laboratory Tests10.4 Appendix 4 Contraceptive and Barrier Guidance and Collection of Pregnancy InformationContraceptive and Barrier Guidance and Collection of Pregnancy InformationAppendix 6: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Intervention Rechallenge Guidelines]Liver Safety: Suggested Actions and Follow-up Assessments and Study Intervention Rechallenge Guidelines5.1 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, Appendix 2, Clinical Laboratory Tests and Appendix 4, Contraceptive and Barrier 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 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, teams may however select more conservative language 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) (eg, 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.) [ 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, eg, 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) (eg, 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 (eg, 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) (eg, 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 (eg, 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) (eg, 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 (eg, 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) (eg, 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 (eg, 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 (eg, 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 pregnancy5.2Exclusion CriteriaMEDICAL CONDITIONSStudy intervention-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 intervention; 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 intervention 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 statistical analysis plan (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 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 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 intervention 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 intervention. 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 intervention or site-specific factors:Regular use of known 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 study7.1Discontinuation of Study InterventionLiver Chemistry Stopping Criteria<Start of common text>Study intervention will be discontinued for a participant if liver chemistry stopping criteria are met.Phase I Liver Chemistry Stopping Algorithm Abbreviations: 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> 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 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.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 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.)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 single-dose studies exclude text related to discontinuation of study intervention, blood sample pharmacokinetics (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 interventionReport 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, aspartate transaminase [AST], alkaline phosphatase, bilirubin and INR) 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 INR) 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 international normalized ratio (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 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].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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