Common Protocol Template Healthy Volunteer Library V2.0

Common Protocol Template Healthy Volunteer Library v2.0

Section in Common Protocol Template(CPT) V1.0 / Library Content
6.2 Exclusion Criteria / Exclusion Criteria
8.1Discontinuation of Study Treatment / Liver FunctionStopping Criteria
QTc stopping criteria
Appendix 7: Liver Safety:Suggested Actions and Follow-up Assessments[andStudy TreatmentRechallenge Guidelines] / Liver Safety: Suggested Actions and Follow-up Assessments and Study Treatment Rechallenge Guidelines

6.2Exclusion Criteria

MEDICAL CONDITIONS
Study treatment-specific exclusion criteria: Include any conditions that may impact safety or the integrity of data (eg, history of epilepsy or history of asthma). Ensure these primary conditions are listed before the common hepatic disease and cardiovascular disease criteria.
EXAMPLES TO CONSIDER:

[History or presence of/significant history of or current] cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data
Abnormal blood pressure [as determined by the investigator]

Criteria below are for molecules that are immune modulators.Delete if not applicable.

Symptomatic herpes zoster within 3 months prior toscreening

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 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.
Criteria below are for large molecules that are 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, erythemamultiforme major, linearimmunoglobulin A (IgA)dermatosis, toxic epidermal necrolysis, andexfoliative dermatitis)

Depending on the molecule, some regulatory agencies require exclusion of ANY history of malignancy.Modify the text below 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 years
Breast cancer within the past 10 years

Suggested criteria if 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 (for example, degenerative disease, spinal deformity or spinal surgery) that may predispose participant to complications or technical difficulty with lumbar puncture
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
Allergy to lidocaine (Xylocaine®) or its derivatives
Medical or surgical conditions for which lumbar puncture is contraindicated

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ALT and 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)
[QTc >450 msec for male participants][or >470 msec for female participants]

NOTE: Use the ECG data from the study treatment development program thus far, including the thorough QT study if one has been performed, to determine if there is a potential QT 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.
NOTES:

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 eithermachine-read or manually over-read.
The specific formula that will be used to determine eligibility and discontinuation for an individual participantshould be determined prior to initiation of the study. In other words, several different formulascannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant.

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The specific QT correction formula(s) that will be used for data analysis should be determined prior to initiation ofthe study and recorded in the SAP.
If a protocol is prescriptive in its choice of QTc correction formula(s) for data analysis, then any study site that does not have available ECG machines pre-programmed with the chosen QT correction formula must have all of the QTc data appropriately calculated using the chosen formula.
The bullet points above exist within the standard text of the protocol 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).

PRIOR/CONCOMITANT THERAPY
Summarize the classes of treatmentsthat participants cannot take concomitantly, and cross referenceSection 7 Study Treatments for details.

[Past or] intended use of over-the-counter or prescription medication[including herbal medications] within [X] days prior to dosing[Specific medications listed in Section 7.7 may be allowed]

Criteria below are for molecules that are immune modulators. Delete if not applicable.

Live vaccine(s) within 1 month prior toscreening, or plans to receive such vaccinesduring the study

Criteria below are for large molecules. 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 STUDY EXPERIENCE

Participation in the study would result in donation 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 the first dosing day

Consider adding the following criteria if participants can only be enrolled once per study.

Current enrollment or past participation within the last [X]days before[signing of consent] in [this or]any other clinical study involving an investigational study treatment or any other type of medical research

DIAGNOSTIC ASSESSMENTS
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Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to starting study treatment.For potent immunosuppressive agents, presence of the hepatitis B core antibody (HBcAb) should also lead to exclusion from the study

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Positive pre-study drug/alcohol screen
Positive HIV antibody test

26. Regular use of known drugs of abuse
OTHER EXCLUSIONS

Regular alcohol consumption within [X] months prior tothe study defined as:

Choose from wording options below or replace with country specific text

For UK sites: An average weekly intake of >21 units for males or >14 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 measure (25 mL) of spirits.
For US sites: An average weekly intake of >14 drinks for males or >7 drinks for females.One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces (45 mL) of 80 proof distilled spirits.

The following criteria should be considered depending on known metabolic/safety issues of the study treatmentor site-specific factors:

Sensitivity to heparin or heparin-induced thrombocytopenia
Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study

8.1Discontinuation ofStudy Treatment

Liver FunctionStopping Criteria

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Study treatment will be discontinuedfor a participantif liver functionstopping criteria are met.

Phase I Liver Function Stopping Algorithm

Liver Safety:SuggestedActions and Follow-up Assessments can be found in Appendix [X].

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QTc Stopping Criteria

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A participantwhomeets [the OR either]bulletedcriterion 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]

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Appendix 7: Liver Safety:Suggested Actions and Follow-up Assessments[andStudy Treatment Rechallenge Guidelines]

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Phase I liver functionstopping criteria are designed to assure participant safety and to evaluate liver event etiology.

Phase I Liver FunctionStopping Criteria and Follow-Up Assessments

Liver Function Stopping Criteria
ALT-absolute / ALT≥3xULN
IfALT≥3xULNANDbilirubin2xULN (>35% direct bilirubin) orINR >1.5, report as an SAE1,2
See additional actions and follow-up assessments below
Required Actions and Follow-up Assessments
Actions / Follow-Up Assessments

Immediately discontinue study treatmentDo not include for single-dose studies

Report the event to the [sponsor]within 24 hours
Complete the liver event CRF, and complete anSAE data collection tool if the event also met the criteria for an SAE2

Perform liver functionfollow-up assessments
Monitor the participant until liver function test abnormalities resolve, stabilize, or return tobaseline (see MONITORING)

MONITORING:
If ALT≥3xULN AND bilirubin2xULNor INR >1.5

Repeat liver function tests(include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within24 hrs

Monitor participanttwice weekly until liver function test abnormalitiesresolve, stabilize or return to baseline
A specialist or hepatology consultation is recommended

If ALT≥3xULN AND bilirubin <2xULNand INR ≤1.5:

Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin)and perform liver function follow-up assessments within 24 to 72 hours
Monitor participants weekly until liver function abnormalitiesresolve, stabilize, or return to baseline

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) analysis obtained [insert time interval recommended by clinical pharmacokinetics representative]after themost recentdose4Do not include for single-dose studies.

Serum creatinephosphokinase (CPK) and lactate dehydrogenase (LDH)
Fractionate bilirubin, if total bilirubin2xULN
Complete blood count with differential to assess eosinophilia
Record the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the AE report form
Record use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications)on the concomitant medications report form
Record alcohol use on the liver event alcohol intake CRF

If ALT≥3xULN AND bilirubin2xULNor 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 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 CRFs

Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study treatment if ALT 3xULN andbilirubin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 andbilirubin2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5may indicate severe liver injury (possible ‘Hy’s Law’) andmust be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).The INR measurement is not required and the stated threshold value will not apply to participantsreceiving anticoagulants.
Includes: Hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B Core Antibody (HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody;Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing);and hepatitis E IgM antibody.
PK sample may not be required for participants known to be receiving placebo or non-comparator treatments.Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to the 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].Do not include for single-dose studies.

References

JamesLP, 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 MetabDispos 2009; 37:1779-1784.

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