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Common Protocol Template Patient Library v2.1
Section in Common Protocol Template (CPT)
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6.2. Exclusion Criteria
Exclusion Criteria
8.1. Discontinuation of Study Treatment
Liver Chemistry Stopping Criteria
QTc Stopping Criteria
Appendix 7: Liver Safety: Suggested Actions and
Follow-up Assessments [and Study Treatment
Rechallenge Guidelines]
Liver Safety: Suggested Actions and
Follow-up Assessments [and Study
Treatment Rechallenge Guidelines]
6.2 Exclusion Criteria
MEDICAL CONDITIONS
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 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.
3. Significant allergies to humanized monoclonal antibodies
4. 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)
5. 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
6. Breast cancer within the past 10 years
7. Abnormalities in lumbar spine previously known or determined by a screening
lumbar X-ray (if conducted)
8. History of clinically significant back pain, back pathology, and/or back injury (eg,
degenerative disease, spinal deformity, or spinal surgery) that may predispose
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participant to complications or technical difficulty with lumbar puncture
9. 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
10. Allergy to lidocaine (Xylocaine®) or its derivatives
11. Medical or surgical conditions for which lumbar puncture is contraindicated
<Start of common text for Phase I studies>
12. Alanine transaminase (ALT) >1.5x 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 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>
12. Alanine transaminase (ALT) >2.0x 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 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. Alanine transaminase (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 active liver or biliary disease (with the exception of Gilbert’s syndrome or
asymptomatic gallstones or otherwise stable chronic liver disease per investigator
assessment). NOTE A: Stable chronic liver disease should be defined by the absence of
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices,
persistent jaundice, and cirrhosis. NOTE B: 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 treatment) 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>
15. [QTc >450 msec for male participants] [or QTc >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
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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
16. [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.]
17. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during
the study
18. 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
19. Participation in the study would result in loss of blood or blood products in excess of [X] mL
within [X]
20. Exposure to more than [X] new chemical entities within 12 months prior to the first dosing
day
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>
24. Presence of hepatitis B surface antigen (HBsAg) at screening. NOTE: For potent
immunosuppressive agents, presence of the hepatitis B core antibody (HBcAb) should also
lead to exclusion from the study even if HBsAg is negative.
25. Positive hepatitis C antibody test result at screening or within 3 months prior to starting study
treatment. NOTE: Particpants with positive hepatitis C antibody due to prior resolved
disease can be enrolled 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
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study treatment. NOTE: Test is optional and particpants 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
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 (25
mL) measure of spirits
28. Regular use of drugs of abuse
29. Sensitivity to heparin or heparin-induced thrombocytopenia
30. 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.
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8.1 Discontinuation of Study Treatment
Liver Chemistry Stopping Criteria
<Start of common text>
Study treatment will be discontinued for a participant if liver chemistry stopping criteria are
met.
<Start of common text for Phase I studies>
Phase I Liver Chemistry Stopping Algorithm
Continue Study Treatment
No
ALT ≥3xULN
Yes
Discontinue Study Treatment
 Must refer to Liver 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 subjects on anticoagulants
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].
<End of common text for Phase I studies>
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<Start of common text for Phase II studies>
Phase II Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm
 If subject to be monitored weekly must refer to Liver Safety Required Actions and Follow up
Assessments section in the Appendix
Continue Study Treatment
Plus
Yes
Bilirubin≥2x
No
ULN (>35%
ALT≥3xULN
ALT≥3xULN
direct)
Plus
Yes
No
No Symptoms of No but able to Yes
or plus
monitor
ALT≥3xULN
ALT≥5xULN
INR>1.5, if
liver injury
weekly for
or
measured*
4 weeks
Possible
hypersensitivity
Hy’s Law
Yes
No
Yes
Yes
No
ALT≥3xULN
persist for
4 weeks or
stopping
criteria
met
Yes
Discontinue Study Treatment
 Must refer to Liver 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 subjects on anticoagulants
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].
<End of common text for Phase II studies>
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<Start of common text for Phase III-IV studies>
Phase III-IV Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm
Continue Study Treatment
No
Yes
ALT≥3xULN
Plus
Bilirubin≥2x
ULN (>35%
direct) or plus
INR>1.5, if
measured*
Possible
Hy’s Law
Yes
Plus
No Symptoms of No
liver injury
or
hypersensitivity
Yes
ALT
No
Yes
ALT
≥3xULN
≥8xULN
but
<8xULN
See algorithm
for continued
therapy with
increased liver
chemistry
monitoring
Yes
Discontinue Study Treatment
 Must refer to Liver 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 subjects on anticoagulants
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].
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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued Therapy
for Participants with ALT 3xULN but <8xULN
 Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Continue Study Treatment and Monitor Liver Chemistry
Yes
ALT ≥5xULN
Yes
ALT≥5xULN Yes
but <8xULN
+ bili <2xULN +
no symptoms
Able to
monitor
weekly
for ≥2
weeks
No
Persists for
≥2 weeks
or other
Yes stopping
criteria
met
ALT <5xULN
Yes
No
No
Yes
Able to
monitor
ALT ≥3xULN
Yes weekly
but <5xULN
for ≥4
weeks
+ bili <2xULN +
Persists for
≥4 weeks
or other
Yes stopping
criteria
met
no symptoms
No
No
Yes
Yes
Discontinue Study Treatment
 Must refer to Liver 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 subjects on anticoagulants
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].
<End of common text for Phase III-IV studies>
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Common Protocol Template Patient Library v2.1
QTc Stopping Criteria
<Start of common text for Phase I-IV studies iin patients>

QTc >500 msec OR Uncorrected QT >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 QTc Threshold 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>
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Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and
Study Treatment Rechallenge Guidelines]
<Start of common text for Phase I studies >
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 AND bilirubin 2xULN (>35% direct bilirubin) OR 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 discontinue study treatment.
 Report the event to the [sponsor] within 24
hours
 Complete the liver event case report form (CRF),
and complete a serious adverse event (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 to
baseline (see MONITORING).
 Do not restart/rechallenge participant with
study treatment unless allowed per protocol and
[sponsor] approval is granted.
 If restart/rechallenge is either not allowed per
protocol or not granted, permanently
discontinue study treatment. 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 alanine
transferase (ALT), aspartate transaminase
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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 the most 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)
Common Protocol Template Patient Library v2.1
[AST], alkaline phosphatase, bilirubin) and
perform liver event follow-up assessments
within 24 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.
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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.
Common Protocol Template Patient Library v2.1
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 (HBsAg) 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 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 Metab Dispos 2009; 37:1779-1784.
<End of common text for Phase I studies >
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Common Protocol Template Patient Library v2.1
<Start of common wording for Phase II studies>
details on suggested follow-up assessments (eg, follow up for overall survival or disease
recurrence or progression).
For single-dose studies in the table “Phase II Liver Chemistry Increased Monitoring Criteria with
Continued Therapy” exclude text on continuation of study treatment.Phase II liver chemistry
stopping criteria are designed to assure participant safety and to evaluate liver event etiology.
Phase II Liver Chemistry Stopping Criteria and Follow-Up Assessments
Liver Chemistry Stopping Criteria
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
INR2
Cannot
Monitor
Symptomatic3
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
ALT 3xULN and INR >1.5, if INR measured
ALT 3xULN and cannot be monitored weekly for 4 weeks
ALT 3xULN associated with symptoms (new or worsening) believed to be
related to liver injury or hypersensitivity
Suggested 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 case report form
(CRF), and complete a serious adverse event
(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 to
baseline (see MONITORING).
Do not restart/rechallenge participant with
study treatment unless allowed per protocol and
[sponsor] approval is granted
If restart/rechallenge not allowed per protocol
or not granted, permanently discontinue study
treatment and continue participant in the study
for any protocol specified follow up
assessments
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






Viral hepatitis serology4
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
the most recent dose5.
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) report form
Common Protocol Template Patient Library v2.1

MONITORING:
If ALT 3xULN AND bilirubin 2xULN or INR
>1.5:
 Repeat liver chemistry tests (include alanine
transferase (ALT), aspartate transaminase
[AST], alkaline phosphatase, bilirubin) and
perform liver event follow-up assessments
within 24 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.

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
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.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
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4.
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.
5.
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].
Phase II Liver Chemistry Increased Monitoring Criteria with Continued Therapy
Liver Chemistry Increased Monitoring Criterion and Follow-Up
Criterion
ALT 3xULN and <5xULN and
bilirubin <2xULN, without symptoms
believed to be related to liver injury or
hypersensitivity, and who can be
monitored weekly for 4 weeks
Actions





Notify the [sponsor] medical monitor within 24
hours of learning of the abnormality to discuss
participant safety.
Participant can continue study treatment
Participant must return weekly for repeat liver
chemistry tests (ALT, AST, alkaline phosphatase,
bilirubin) until the abnormalities resolve, stabilize
or return to baseline.
If at any time, the participant meets liver chemistry
stopping criteria, proceed as described in
[location].
If, after 4 weeks of monitoring, ALT <3xULN and
bilirubin <2xULN, monitor participants twice
monthly until liver chemistry tests resolve,
stabilize, or return to baseline.
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.
<End of common wording for Phase II studies>
<Start of common wording for Phase III-IV studies>
details on suggested follow-up assessments (eg, follow up for overall survival or disease
recurrence or progression).
For single-dose studies in the table “Phase III-IV Liver Chemistry Increased Monitoring Criteria
with Continued Therapy” exclude text on continuation of study treatment.Phase III-IV liver
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Common Protocol Template Patient Library v2.1
chemistry stopping criteria are designed to assure participant safety and to evaluate liver event
etiology.
Phase III-IV liver Chemistry Stopping Criteria and Follow-Up assessments
Liver Chemistry Stopping Criteria
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubin1, 2
INR2
Cannot
Monitor
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
ALT 3xULN and INR >1.5, if INR measured
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3 ALT 3xULN associated with symptoms (new or worsening) believed to be
related to liver injury or hypersensitivity
Suggested 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 case report form
(CRF), and complete a serious adverse event
(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
to baseline (see MONITORING).
 Do not restart/rechallenge participant with
study treatment unless allowed per protocol
and [sponsor] approval is granted.
 If restart/rechallenge not allowed per
protocol or not granted, permanently
discontinue study treatment and continue
participant in the study for any protocol
specified follow up assessments.
MONITORING:
For bilirubin or INR criteria
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
Viral hepatitis serology4

Obtain INR and recheck with each liver
chemistry assessment until the
transaminases values show downward
trend

Only in those with underlying chronic
hepatitis B at study entry (identified by
positive hepatitis B surface antigen),
quantitative hepatitis B deoxyribonucleic
acid (DNA) and hepatitis delta antibody5

Obtain blood sample for pharmacokinetic
(PK) analysis [insert time interval
recommended by clinical
pharmacokinetics representative] after the
most recent dose5
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




Common Protocol Template Patient Library v2.1

Repeat liver chemistry tests (include alanine
transferase (ALT), aspartate transaminase
[AST], alkaline phosphatase, bilirubin) and
perform liver event follow-up assessments
within 24 hours.
 Monitor participant twice weekly until liver
chemistry test abnormalities resolve,
stabilize, or return to baseline.
 A specialist or hepatology consultation is
recommended.
For all other criteria
 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.


clinical symptoms of liver injury, or
hypersensitivity, on the adverse event
(AE) report form
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
For bilirubin or INR criteria:
 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 computerizsed tomography)
andor 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.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
4.
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.
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a polymerase chain reaction
(PCR) of hepatitis D RNA virus (where needed) [Le Gal, 2005].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 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
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Common Protocol Template Patient Library v2.1
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].
Phase III-IV Liver Chemistry Increased Monitoring Criteria with Continued Therapy
Liver Chemistry Increased Monitoring Criteria
Criteria
Actions

ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms
believed to be related to liver injury or
hypersensitivity, and who can be
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms
believed to be related to liver injury or
hypersensitivity, and who can be
monitored weekly for 4 weeks.





Notify the [sponsor] medical monitor within 24
hours of learning of the abnormality to discuss
participant safety.
Participant can continue study treatment
Participant must return weekly for repeat liver
chemistry tests (ALT, AST, alkaline phosphatase,
bilirubin) until the abnormalities resolve, stabilize,
or return to baseline.
If at any time, the participant meets liver chemistry
stopping criteria, proceed as described in
[location].
If ALT decreases from ALT 5xULN and
<8xULN to ≥3xULN but <5xULN, continue to
monitor liver chemistries weekly.
If, after 4 weeks of monitoring, ALT <3xULN and
bilirubin <2xULN, monitor participants twice
monthly until liver chemistry tests resolve,
stabilize, or return to baseline.
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.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E. Quantification of
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different Patterns
of Virological Response to Interferon Therapy in Chronically Infected Patients. J Clin Microbiol.
2005;43(5):2363–2369.
<End of common text for Phase III-IV studies>
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Common Protocol Template Patient Library v2.1
Liver Safety: Study Treatment Rechallenge Guidelines
<Start of common text if study treatment restart/rechallenge is allowed>
A participant who met liver chemistry stopping criteria cannot restart study treatment unless all
of the following conditions are met:



[sponsor] approval is granted (as described below)
IRB/IEC approval is obtained
Separate ICF for treatment restart/rechallenge is signed by the participant
If [sponsor] approval to restart/rechallenge the participant with study treatment is not granted,
then the participant must permanently discontinue study treatment and may continue in the study
for protocol-specified follow-up assessments.
Rechallenge Following Liver Chemistry Events that are Possibly Related to
Study Treatment


Following study treatment-induced liver injury, rechallenge is associated with 13%
mortality across all study treatments in prospective studies.1 Clinical outcomes vary with
nearly 50% fatality with halothane readministered within one month of the initial injury.
However, some treatments seldom result in recurrent liver injury or fatality.
Risk factors for a fatal rechallenge outcome include:
o Hypersensitivity with initial liver injury (eg, fever, rash, eosinophilia) 1
o Jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of
total)
o Ongoing severe liver injury defined by ALT 3xULN AND bilirubin 2xULN
(direct bilirubin >35% of total) OR INR1.5
o Serious adverse event or fatality previously observed with rechallenges2,3
o Evidence of treatment-related preclinical liability (eg, reactive metabolites,
mitochondrial impairment)3


Rechallenge refers to resuming study treatment following drug-induced liver injury
(DILI). Because of the risks associated with rechallenge after DILI, this should only be
considered if there is compelling evidence of benefit from a critical or life-saving
medicine, there is no alternative approved medicine available, and a benefit/risk
assessment of rechallenge is considered to be favorable.
Approval by the [sponsor] for rechallenge with study treatment can be considered when:
o The Principal Investigator (PI) requests consideration of rechallenge with study
treatment for a participant who is receiving compelling benefit with study
treatment that exceeds risk and for whom no effective alternative therapy is
available.
o IRB/IEC approval for rechallenge with study treatment has been obtained.
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Common Protocol Template Patient Library v2.1
If the rechallenge is approved by the [sponsor] in writing:

The participant must be provided with a clear description of the possible benefits and
risks of study treatment administration including the possibility of recurrent, more severe
liver injury or death.

The participant must provide signed informed consent specifically for the rechallenge
with study treatment. Documentation of informed consent must be recorded in the study
file.

Study treatment must be administered at the dose specified by the [sponsor].

Participants approved by the [sponsor] for rechallenge with study treatment must return
to the clinic twice a week for liver chemistry tests until stable liver chemistry tests have
been demonstrated and then standard laboratory monitoring may resume as per protocol.

If the participant meets protocol-defined liver chemistry stopping criteria after study
treatment rechallenge, study treatment should be permanently discontinued.

The [sponsor] Medical Monitor, and the IRB/IEC, must be informed of the outcome for
the participant following study treatment rechallenge.

The [sponsor] must be notified of any adverse events.
AND/OR
Restart Following Transient Resolving Liver Chemistry Events Not Related to
Study Treatment


Restart refers to resuming study treatment following liver chemistry events for which
there are clear underlying causes (other than DILI) (eg, biliary obstruction, pancreatic
events, hypotension, acute viral hepatitis). Furthermore, there should be no evidence of
alcoholic hepatitis or hypersensitivity.
Approval by the [sponsor] for study treatment restart can be considered when:
o The investigator requests consideration for study treatment restart if liver
chemistry events have a clear underlying cause (eg, biliary obstruction, pancreatic
events, hypotension, acute viral hepatitis) and liver chemistry tests have improved
to normal or are within 1.5 x baseline and ALT <3xULN.
o Possible DILI has been excluded by the investigator and the study team. This
includes the absence of markers of hypersensitivity (otherwise unexplained fever,
rash, eosinophilia). Where a study treatment has an identified genetic marker
associated with liver injury (eg, lapatinib, abacavir, amoxicillin/clavulanate), the
presence of the marker should be excluded. If study treatment-related liver injury
cannot be excluded, the guidance on rechallenge in the previous part of this
Appendix will apply.
o There is no evidence of alcoholic hepatitis.
o IRB/IEC approval of study treatment restart has been obtained.
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Common Protocol Template Patient Library v2.1
If restart of study treatment is approved by the [sponsor] in writing:

The participant must be provided with a clear description of the possible benefits and
risks of study treatment administration including the possibility of recurrent, more severe
liver injury or death.

The participant must provide signed informed consent specifically for the restart of study
treatment. Documentation of informed consent must be recorded in the study file.

Study treatment must be administered at the dose specified by the [sponsor].

Participants approved by the [sponsor] for restart of study treatment must return to the
clinic twice a week for liver chemistry tests until stable liver chemistry tests have been
demonstrated and then standard laboratory monitoring may resume as per protocol.

If the participant meets protocol-defined liver chemistry stopping criteria after study
treatment restart, study treatment should be permanently discontinued.

The [sponsor] Medical Monitor, and the IRB/IEC, must be informed of the outcome for
the participant following study treatment restart.

The [sponsor] must be notified of any adverse events.
References:
1. Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.
2. Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM. Drug-induced liver
injury following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90.
3. Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug
rechallenge after drug-induced liver injury: A systematic review. Hepatol. 2010;52:22162222.
<End of common text >
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