Common Protocol Template Healthy Volunteer Library v004

Common Protocol Template Healthy Volunteer Library v004

Section in CommonProtocol Template (CPT) / Library Content
5.1 Inclusion Criteria: Sex / Inclusion Criteria: Sex
5.2 Exclusion Criteria / Exclusion Criteria
7.1 Discontinuation of Study Intervention / Liver Chemistry Stopping Criteria
QTc Stopping Criteria
10.2 Appendix 2 Clinical Laboratory Tests / Clinical Laboratory Tests
10.4 Appendix 4 Contraceptive and Barrier Guidance and Collection of Pregnancy Information / Contraceptive and Barrier Guidance and Collection of Pregnancy Information
Appendix 6: Liver Safety:Suggested Actions and Follow-up Assessments[and Study InterventionRechallenge Guidelines] / Liver Safety: Suggested Actions and Follow-up Assessments and Study Intervention Rechallenge Guidelines

5.1 Inclusion Criteria

Sex

4.

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

© 2017 TransCelerate BioPharma1

Common Protocol Template Healthy Volunteer Library v004

Decision Tree for Contraception and Barriers

Review 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.

© 2017 TransCelerate BioPharma1

Common Protocol Template Healthy Volunteer Library v004

Modify the duration for contraception use by males and females as appropriate for the study.

Male Participants

Select 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 forclinically relevant genotoxicity, in addition to male condom use, a highly effective method of contraception should be used in WOCBP partners of male participantsto 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 requiredfrom 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.

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  1. 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 sperm

PLUS 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

OR

  • Must 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 Appendix4 ]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 participantsto 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 requiredfrom 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.

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  1. 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 sperm

Plus 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

OR

  • Must agree to use contraception/barrier as detailed below
  • Agree 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 usemale condom when engaging in any activity that allows for passage of ejaculate to another person]

<End of common text>

Female participants

Select 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 forrisk 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.

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  1. 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)

OR

  • Is 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 havea 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 fordemonstrated or suspected riskof 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)

OR

  • Is 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 havea 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 forpossibleriskof human teratogenicity/fetotoxicity:

If urine test allowed, retain the text listed in the last blue bracketed bullet.

<Start of common text>

  1. 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)

OR

  • Is 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 havea negativehighly 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 forunlikely riskofhuman teratogenicity/fetotoxicity

If urine test allowed, retain the text listed in the last blue bracketed bullet.

<Start of common text>

  1. 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)

OR

  • Is a WOCBP and using an acceptable contraceptive method as described in Appendix [4]during the intervention period (at a minimum untilafter 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 havea 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

5.2Exclusion Criteria

MEDICAL CONDITIONS
Study 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.
  1. [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 data
  2. Abnormal blood pressure [as determined by the investigator]
These criteria are specific for immune modulators. Delete if not applicable.
  1. Symptomatic herpes zoster within 3 months prior to screening
  2. Evidence 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 72hours, 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.
  1. Significant allergies to humanized monoclonal antibodies
  2. 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.
  1. 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 years
  2. Breast cancer within the past 10 years
Suggested criteria, if cerebrospinal fluid (CSF)will be collected. Delete if not applicable.
  1. Abnormalities in lumbar spine previously known or determined by a screening lumbar X-ray (if conducted)
  2. 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 puncture
  3. Evidence 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 insertion
  4. Allergy to lidocaine (Xylocaine®) or its derivatives
  5. Medical or surgical conditions for which lumbar puncture is contraindicated
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  1. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN)
  2. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
  3. 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 textof 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).
  1. [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 THERAPY
Summarize the classes of treatments that participants cannot take concomitantly, and cross reference Section 6Study Interventionfor details.
  1. [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.
  1. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study
This criterion isspecific for antibodies. Delete if not applicable.
  1. 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 STUDY EXPERIENCE
  1. Participation in the study would result in loss of blood or blood products in excess of [X] mL within [X]
  2. Exposure to more than [4] new chemical entities within 12 months prior to dosing
Consider adding this criterion if participants can only be enrolled once per study.
  1. 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 research

DIAGNOSTIC ASSESSMENTS
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  1. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to dosing
  2. 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 if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained
  3. Positive 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 testing
  4. For potent immunosuppressive agents, presence of the hepatitis B core antibody (HBcAb) even if HBsAg is negative
<End of common text
  1. Positive pre-study drug/alcohol screen
  2. Positive human immunodeficiency virus (HIV) antibody test

OTHER EXCLUSIONS
Adapt the wording option or replace with country specific text
  1. Regular 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:
  1. Regular use of known drugs of abuse
  2. Sensitivity to heparin or heparin-induced thrombocytopenia
  3. Sensitivity 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

7.1Discontinuation of Study Intervention