Common Protocol Template (CPT) Patient Library V003

Common Protocol TemplatePatient Library v003

Common Protocol Template (CPT) Patient Library v003

Section in CPT / Library Content
5.2. Exclusion Criteria / Exclusion Criteria
7.1. Discontinuation of Study Intervention / Liver Chemistry Stopping Criteria
QTc Stopping Criteria
Appendix 6: Liver Safety: Suggested Actions and Followup Assessments [and Study Intervention Rechallenge Guidelines] / Liver Safety: Suggested Actions and Follow-up Assessments [and Study Intervention Rechallenge Guidelines]

5.2Exclusion Criteria

MEDICAL CONDITIONS
These criteria are specific for molecules that are immune modulators. Delete if not applicable.

Symptomatic herpes zoster within 3 months prior to screening
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.

Significantallergies 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, 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 years

Breast cancer within the past 10 years

Suggested 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 (eg, 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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Alaninetransaminase (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 I studies>
Start of common text for Phase II studies

Alaninetransaminase (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 II studies
<Start of common text for Phase III studies
12. Alaninetransaminase (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, oesophageal 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 -eg, 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 III studies>
<Start of common text for Phase I-IV 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 (ie, a lower value for QTc).

[QTc >450 msec for male participants][orQTc >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 THERAPY
Summarize the classes of treatments that participants cannot take concomitantly, and cross reference Section 6Study Interventionfor 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 study

This 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 EXPERIENCE

Participation 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 day

Consider adding this criterion if participants can only be enrolled once per study.
21.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
22.Positive pre-study drug/alcohol screen
23.Positive human immunodeficiency virus (HIV) antibody test
<Start of common text for Phase I or II studies>
NOTE: For Phase III 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 (eg, 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. participantswith 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.
24.Presence of Hepatitis B surface antigen (HBsAg) at screening screening
25.Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment.NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
26.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
<End of common text for Phase I or II studies>
OTHER EXCLUSIONS
Modify suggested wording or replace with country specific text
27.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 (25mL) measure of spirits
These criteria should be considered depending on known metabolic/safety issues of the study intervention or site-specific factors:
28.Regular use of drugs of abuse
29.Sensitivity to heparin or heparin-induced thrombocytopenia
30.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.

7.1 Discontinuation of Study Intervention

Liver Chemistry Stopping Criteria

Study intervention will be discontinuedfor a participant if liver chemistry stopping criteria are met.

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Phase I Liver Chemistry Stopping Algorithm

Abbreviations: ALT = alaninetransaminase; 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 Appendix6.

<End of common text for Phase I studies

<Start of common text for Phase II studies>

Phase II Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm

Abbreviations: ALT = alaninetransaminase; 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 Appendix6.

<End of common text for Phase II studies>

<Start of common text for Phase III-IV studies>

Phase III-IV Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm

Abbreviations: ALT = alaninetransaminase; 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.

Common Protocol TemplatePatient Library v003

Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued Study Intervention for Participants with ALT 3xULN but <8xULN

Abbreviations: ALT = alaninetransaminase; 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 III-IV studies>

QTc Stopping Criteria

<Start of common text for Phase I-IV studies iin patients>

A participant who meets [the OR either] bulleted criterion based on the average of triplicate ECG readings will be withdrawn from studyintervention.

QTc >500 msec OR UncorrectedQT >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 Block / Discontinuation QTcThreshold with Bundle Branch Block
< 450 msec / > 500 msec
450 to 480 msec / ≥ 530 msec

<End of common text for Phase I-IV studies in patients>

Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments[and Study InterventionRechallenge 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 (eg, follow up for overall survival or disease recurrence or progression).

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 Assessments

Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute / ALT≥3xULN
If ALT≥3xULN ANDbilirubin2xULN (>35% direct bilirubin) ORinternational normalized ratio (INR) >1.5, report as a serious adverse event (SAE).1,2
See additional actions and follow-up assessments listed below
Suggested Actions and Follow up Assessments
Actions / Follow Up Assessments

Immediately discontinuestudy intervention.
Report the event to the[sponsor]within 24 hours

Complete the liver event case report form (CRF), and complete a SAE data collection tool if the event also met the criteria for an SAE.2

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

Do not restart/rechallengeparticipant with study intervention unless allowed per protocoland [sponsor] approvalis granted.
If restart/rechallengeis 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, aspartatetransaminase [AST], alkaline phosphatase, bilirubin) and perform liver eventfollow-up assessments within24 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 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 serology3
Obtain INR and recheck with each liver chemistry assessment until the transaminases values show downward trend
Obtain blood sample for pharmacokinetic (PK) analysis [insert time interval recommended by clinical pharmacokinetics representative] after themost recent dose4

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)
Fractionate bilirubin, if total bilirubin2xULN
Obtain complete blood count with differential to assess eosinophilia
Record 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 [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 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 >1.5 may 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 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, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure.Drug MetabDispos 2009; 37:1779-1784.

<End of common text for Phase I studies >

Common Protocol TemplatePatient Library v003

<Start of common wording for Phase II studies>