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
8.1 Discontinuation of Study Treatment
Liver Function Stopping Criteria
QTc stopping criteria
Appendix 7: Liver Safety: Suggested Actions and Followup Assessments [and Study Treatment Rechallenge
Guidelines]
6.2
Liver Safety: Suggested Actions and
Follow-up Assessments and Study
Treatment Rechallenge Guidelines
Exclusion Criteria
MEDICAL CONDITIONS
1. [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
2. Abnormal blood pressure [as determined by the investigator]
3. Symptomatic herpes zoster within 3 months prior to screening
4. 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.
5. Significant allergies to humanized monoclonal antibodies
6.
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)
7.
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal
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Common Protocol Template Healthy Volunteer Library v2.0
cell or squamous epithelial carcinomas of the skin that have been resected with no
evidence of metastatic disease for 3 years
8. Breast cancer within the past 10 years
9. Abnormalities in lumbar spine previously known or determined by a screening
lumbar x-ray (if conducted)
10. 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
11. 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
12. Allergy to lidocaine (Xylocaine®) or its derivatives
13. Medical or surgical conditions for which lumbar puncture is contraindicated
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14. ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
fractionated and direct bilirubin <35%)
15. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with
the exception of Gilbert's syndrome or asymptomatic gallstones)
16. [QTc >450 msec for male participants] [or >470 msec for female participants]
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 either machine-read
or manually over-read.

The specific formula that will be 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.
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PRIOR/CONCOMITANT THERAPY
17. [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]
18. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines
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Common Protocol Template Healthy Volunteer Library v2.0
during the study
19. 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
20. Participation in the study would result in donation of blood or blood products in excess of
[X] mL within [X]
21. Exposure to more than [4] new chemical entities within 12 months prior to the first dosing
day
22. 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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23. 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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24. Positive pre-study drug/alcohol screen
25. Positive HIV antibody test
26. Regular use of known drugs of abuse
OTHER EXCLUSIONS
27. Regular alcohol consumption within [X] months prior to the study defined as:

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.
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28. Sensitivity to heparin or heparin-induced thrombocytopenia
29. 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
8.1
Discontinuation of Study Treatment
Liver Function Stopping Criteria
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Study treatment will be discontinued for a participant if liver function stopping criteria are met.
Phase I Liver Function Stopping Algorithm
Continue Study Treatment
No
ALT ≥ 3xULN
Yes
Discontinue Study Treatment
 Must refer toLiver Safety Required Actions and Follow up Assessments section in the Appendix
 Report as an SAE if possible Hy’s Law case: ALT≥3xULN and Bilirubin ≥2xULN (>35% direct)
Or INR>1.5, if measured*
*INR value not applicable to participants on anticoagulants
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].
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QTc Stopping Criteria
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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]
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Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and
Study Treatment Rechallenge Guidelines]
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Phase I liver function stopping criteria are designed to assure participant safety and to evaluate
liver event etiology.
Phase I Liver Function Stopping Criteria and Follow-Up Assessments
Liver Function Stopping Criteria
ALT-absolute
ALT ≥3xULN
If ALT ≥3xULN AND bilirubin  2xULN (>35% direct bilirubin) or INR
>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 treatment
Report the event to the [sponsor] within 24
hours
 Complete the liver event CRF, and complete
an SAE data collection tool if the event also
met the criteria for an SAE2
 Perform liver function follow-up
assessments
 Monitor the participant until liver function
test abnormalities resolve, stabilize, or
return to baseline (see MONITORING)
MONITORING:
If ALT ≥3xULN AND bilirubin 2xULN or
INR >1.5
 Repeat liver function tests (include ALT,
AST, alkaline phosphatase, bilirubin) and
perform liver function follow-up
assessments within 24 hrs
 Monitor participant twice weekly until liver
function test abnormalities resolve, stabilize
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






Viral hepatitis serology3
Blood sample for pharmacokinetic (PK)
analysis obtained [insert time interval
recommended by clinical
pharmacokinetics representative] after the
most recent dose4
Serum creatine phosphokinase (CPK) and
lactate dehydrogenase (LDH)
Fractionate bilirubin, if total bilirubin
 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
Common Protocol Template Healthy Volunteer Library v2.0

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
perform liver function follow-up
assessments within 24 to 72 hours
 Monitor participants weekly until liver
function abnormalities resolve, stabilize, or
return to baseline
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 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
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study treatment 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.
2.
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 measurement is not required and the stated threshold value will
not apply to participants receiving anticoagulants.
3.
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.
4.
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].
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 Metab Dispos 2009; 37:1779-1784.
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