Clinical trial NCT02653625
Conditions: Primary Sclerosing Cholangitis
Keywords: Primary Sclerosing Cholangitis
Sponsor: Tobira Therapeutics, Inc.
Start date: 2016-03-14; Completion date: 2017-08-31
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, proof of concept (PoC) study of Cenicriviroc (CVC) in adult participants with Primary Sclerosing Cholangitis (PSC). The main objective of this PoC study is to assess changes in alkaline phosphatase (ALP) both individually and as a group, over 24 weeks of treatment with CVC.

Detailed description:

Arms: arm 1: One tablet of Cenicriviroc 150 mg once daily with food in the morning for 24 weeks.
Interventions: intervention 1: Cenicriviroc 150 mg
Intervention descriptions: intervention 1: One tablet of CVC 150 mg once daily taken with food in the morning.

Protocol documents:
Prot_000.pdf: 
NCT02653625 
 
Study ID: 652‐205 
 
Title:  PERSEUS: A Phase 2 Proof of Concept Study Investigating the Preliminary Efficacy and Safety of 
Cenicriviroc in Adult Subjects with Primary Sclerosing Cholangitis (PSC) 
 
 
Protocol Amendment 3 Date: 14 June 2016 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 1 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
 
 
 
 
 
 
Title: 
PERSEUS: A Phase 2 Proof of Concept Study Investigating 
the Preliminary Efficacy and Safety of Cenicriviroc in 
Adult Subjects with Primary Sclerosing Cholangitis (PSC) 
 
 
Protocol Number: 
652-205 
 
 
Product: 
Cenicriviroc Mesylate (CVC) 
 
 
Phase of Study: 
Phase 2 
 
 
Sponsor: 
Tobira Therapeutics, Inc. 
 
701 Gateway Blvd, Suite 300 
 
South San Francisco, CA 94080 
 
United States of America  
 
 
 
 
 
 
Date of Protocol: 
 19 November 2015 
Date of Amendment 1.1: 
 29 December 2015 
Date of Amendment 2:  
 06 April 2016 
Date of Amendment 3: 
 14 June 2016 
 
 
 
 
 
The information in this document is privileged and confidential. No part of this information may be duplicated, 
referenced, or transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) 
without the prior written consent of Tobira Therapeutics. 
 
 


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Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 6 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
2.1 
List of In-Text Tables 
Table 20-1 
Schedule of Assessments .......................................................................................... 72 
 
2.2 
List of In-Text Figures 
Figure 7-1 
Study Design Schematic ........................................................................................... 25 
 
 
 


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Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 8 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
Abbreviation 
Definition  
  
 
 
 
 
 
IBD 
inflammatory bowel disease 
 
 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
 
y 
 
 
 
 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intention to treat 
 
 
 
 
 
 
 
 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MRCP 
magnetic resonance cholangiopancreatography 
 
 
 
 
 
 
 
 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK 
pharmacokinetic(s) 
PoC 
proof of concept 
PP 
per protocol 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 9 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
Abbreviation 
Definition  
 
 
PSC 
primary sclerosing cholangitis 
QD 
once daily (quaque die) 
 
 
REB 
Research Ethics Board 
 
 
SAE 
serious adverse event 
 
 
 
 
SOC 
System Organ Class 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half-life 
TE 
TEAE 
transient elastography 
treatment-emergent adverse event 
 
 
Tobira 
Tobira Therapeutics, Inc. 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
US 
United States  
UV 
Ultraviolet 
 
 


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Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 11 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
4. In subjects receiving treatment with ursodeoxycholic acid (UDCA), therapy 
must be stable for at least 3 months, and at a dose not greater than 
20 mg/kg/day 
5. Serum ALP ≥1.5 × upper limit of normal (ULN) 
6. 
 
 
 
 
 
 
 
7. Ability to understand and sign a written informed consent form (ICF) 
8. Subjects receiving allowed concomitant medications need to be on stable 
therapy for 28 days prior to the Baseline Visit (see Section 9.3 for list of 
restricted medications), with the exception of UDCA in which subjects 
need to be on stable therapy for ≥ 3 months 
Exclusion Criteria 
1. Presence of documented secondary sclerosing cholangitis (such as ischemic 
cholangitis, recurrent pancreatitis, intraductal stone disease, severe bacterial 
cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic 
cholangitis, choledocholithiasis, toxic slerosing cholangitis due to chemical 
agents, or any other cause of secondary sclerosing cholangitis) on prior 
clinical investigations 
2. Small duct PSC 
3. Presence of percutaneous drain or bile duct stent 
4. History of cholangiocarcinoma or high clinical suspicion over dominant 
stricture within 1 year by MRCP/ERCP or clinical judgement 
5. Ascending cholangitis within 60 days prior to Screening 
6. Alcohol consumption greater than 21 units/week for males or 14 units/week 
for females (one unit of alcohol is ½ pint of beer [285 mL], 1 glass of spirits 
[25 mL] or 1 glass of wine [125 mL]) 
7. Prior or planned liver transplantation 
8. Presence of alternative causes of chronic liver disease, including alcoholic 
liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, 
autoimmune hepatitis 
9. History of cirrhosis and/or hepatic impairment (Child-Pugh classes A, B 
and C) and/or hepatic decompensation including ascites, encephalopathy or 
variceal bleeding. Subjects who show evidence of significant worsening of 
hepatic function will be excluded  
10. Subjects with evidence of cirrhosis, as determined by local transient 
elastography (TE; e.g., FibroScan®) values of ≥ 13.0 kPa, taken within the 
last 6 months. If TE has not been conducted within the 6 months prior to 
screening then one will be conducted during the screening period and can 
be used as the Baseline value 
11. Moderate to Severe active IBD or flare in colitis activity within the last 
90 days requiring intensification of therapy beyond Baseline treatment. 
Subjects with stable mild to moderate IBD, who are on treatment, are 
allowed provided they are stable for 3 months with 5-amino salicylic acid 
drugs or Azathioprine (allowed dose of azathioprine is 50-200 mg/day)  
12. Use of oral prednisolone > 10 mg/day, biologics and/or hospitalization for 
colitis within 90 days are disallowed  


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13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT); 
above the allowed cut-offs, as determined by the Screening values: 
• 
AST > 200 IU/L males and females 
• 
ALT: males > 250 IU/L and females > 200 IU/L 
14. Total Bilirubin and Direct Bilirubin; above the allowed cut-offs, as 
determined by the Screening values:  
• 
Total Bilirubin  > 2.0 mg/dL  
• 
Direct Bilirubin  > 0.8 mg/dL  
15. International normalized ratio (INR) > 1.3 in the absence of anticoagulants. 
16. Immunoglobulin G4 (IgG4) > 4 × ULN at Screening or evidence of IgG4-
related sclerosing cholangitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
34. Any other clinically significant disorders or prior therapy that, in the 
opinion of the investigator, would make the subject unsuitable for the study 
or unable to comply with the dosing and protocol requirements 
Test Article(s)  
CVC 150 mg tablet 
Dosage and 
Administration 
CVC 150 mg, administered orally once daily and taken every morning with 
food  
Placebo 
There is no placebo group in this study 
Study Procedures/ 
Frequency 
Screening will occur within 6 weeks before the Baseline Visit (Day 1).  Eligible 
subjects will be seen at Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, 
and Week 24.  A safety follow-up visit will be conducted at Week 28 ± 3 days 


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(i.e., 4 weeks after last intake of study medication) or at the time of early 
termination (if applicable). On visit days, subjects will be need to come into the 
clinic fasting. Blood samples will be collected prior to dosing.  Subjects will be 
required to bring in study medication on the days of clinic visits and dosing will 
be conducted on site with a morning snack.   
Study procedures include: 
• The informed consent will be reviewed and signed at the Screening 1 visit, 
as well as all eligibility assessments, per the schedule of evaluations 
• IgG Total, IgG1 and IgG4 will be collected at Baseline, and Week 24 
(IgG4 will also be collected at Screening)  
• Clinical laboratory tests will be measured at Screening, Baseline and each 
study visit: clinical chemistries, hematology, liver parameters including 
ALP, bilirubin, serum albumin, serum bile acids, gamma-glutamyl 
transferase (GGT), ALT and AST 
• Partial Mayo Risk scoring for assessment of IBD will be conducted at 
Baseline and at each visit 
• Transient elastography will be assessed once during the Screening period 
(between Screening to Baseline) and at Week 24 
• 
 
 
 
 
  
 
  
• Serum samples will be collected and stored for future analysis for 
biomarkers of interest at Baseline, Weeks 12 and 24 
• Plasma pharmacokinetic (PK) samples will be drawn pre-dose and post-
dose at Baseline and at Weeks 12, and 24 
• Weight will be measured at Screening, Baseline and Weeks 12 and 24; 
height will be measured only at Screening 
• Complete or symptom directed physical examinations and laboratory 
analyses will be performed at each visit 
• Electrocardiograms will be performed at Baseline and at Weeks 12 and 24 
• Adverse events and concomitant medications will be assessed at each visit 
Efficacy Evaluation 
The primary endpoint for this study is the percent change from Baseline through 
Week 24 in serum alkaline phosphatase  
 
 
 
 
 
 
 
 
Safety Evaluation 
Safety endpoints: 
• Evaluate the safety and tolerability of CVC through 24 weeks of treatment 
in adult subjects with PSC 
• Evaluate the proportion of subjects with a treatment-emergent AE or a 
clinically significant laboratory abnormality (overall and of any given 
type)  


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• Evaluate the proportion of subjects who discontinue due to an AE 
Other Exploratory 
Evaluation 
 
 
 
 
 
  
 
 
 
 
 
  
Statistical Analysis 
This is a single arm open label study in adult subjects with PSC. Descriptive 
statistical methods will be used to summarize data from this study. Displays of 
treatment-related efficacy and safety profiles for each patient and overall will be 
summarized. 
Efficacy Analysis 
Percent changes in ALP from Baseline will be summarized using descriptive 
statistics for the respective pre-treatment and on-treatment visits.  A repeated 
measures mixed model will be fit to the data for all pre-treatment and on-
treatment visits, and this model will include explanatory variables for visits and 
Baseline; and it will have compound symmetry as the covariance structure. 
Through this model, 95% confidence intervals will be produced for the mean 
percent change at each visit. Also, a comparison of pre-treatment change per 
week with on-treatment change per week will be made through an estimate 
specification and the corresponding 95% confidence interval. Descriptive 
comparisons will be made with historical data where UDCA was administered 
and/or with the natural history of the disease, as appropriate. 
Safety Analysis 
Clinical laboratory and safety data will be summarized using descriptive 
analysis. 
Sample Size 
Each patient will serve as their own control when observing ALP relative to 
Baseline. 
 
 
 
 
 
 
 
 
 


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5
1 P
s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Amendment 3 
 
 
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5
2 P
s 
 
 
 
 
 
 
 


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 14 June2016 
8.3 
Exclusion Criteria 
A subject will not be eligible for participation in this study if any of the following criteria 
apply. 
1. Presence of documented secondary sclerosing cholangitis (such as ischemic cholangitis, 
recurrent pancreatitis, intraductal stone disease, severe bacterial cholangitis, surgical or 
blunt abdominal trauma, recurrent pyogenic cholangitis, choledocholithiasis, toxic 
slerosing cholangitis due to chemical agents, or any other cause of secondary sclerosing 
cholangitis) on prior clinical investigations 
2. Small duct PSC 
3. Presence of percutaneous drain or bile duct stent 
4. History of cholangiocarcinoma or high clinical suspicion over dominant stricture within 
1 year by MRCP/ERCP or clinical judgement 
5. Ascending cholangitis within 60 days prior to Screening 
6. Alcohol consumption greater than 21 units/week for males or 14 units/week for females 
(one unit of alcohol is ½ pint of beer [285 mL], 1 glass of spirits [25 mL] or 1 glass of 
wine [125 mL]) 
7. Prior or planned liver transplantation 
8. Presence of alternative causes of chronic liver disease, including alcoholic liver disease, 
nonalcoholic steatohepatitis, primary biliary cirrhosis, autoimmune hepatitis 
9. History of cirrhosis and/or hepatic impairment (Child-Pugh classes A, B and C) and/or 
hepatic decompensation including ascites, encephalopathy or variceal bleeding. Subjects 
who show evidence of significant worsening of hepatic function will be excluded  
10. Subjects with evidence of cirrhosis, as determined by local transient elastography (TE; 
e.g., FibroScan®) values of ≥ 13.0 kPa, taken within the last 6 months. If TE has not been 
conducted within the 6 months prior to screening then one will be conducted during the 
screening period and can be used as the Baseline value 
11. Moderate to Severe active IBD or flare in colitis activity within the last 90 days requiring 
intensification of therapy beyond Baseline treatment. Subjects with stable mild to 
moderate IBD, who are on treatment, are allowed provided they are stable for 3 months 
with 5-amino salicylic acid drugs or Azathioprine (allowed dose of azathioprine is 50-200 
mg/day) 
12. Use of oral prednisolone > 10 mg/day, biologics and/or hospitalization for colitis within 
90 days are disallowed  
13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT); above the 
allowed cut-offs, as determined by the Screening values: 


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Amendment 3 
 
 
CONFIDENTIAL 
 
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• AST > 200 IU/L males and females 
• ALT males > 250 IU/L and females > 200 IU/L 
14. Total Bilirubin and Direct Bilirubin; above the allowed cut-offs, as determined by the 
Screening values:  
• Total Bilirubin  > 2.0 mg/dL  
• Direct Bilirubin  > 0.8 mg/dL  
15. International normalized ratio (INR) > 1.3 in the absence of anticoagulants. 
16. Immunoglobulin G4 (IgG4) > 4 × ULN at Screening or evidence of IgG4-related 
sclerosing cholangitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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34. Any other clinically significant disorders or prior therapy that, in the opinion of the 
investigator, would make the subject unsuitable for the study or unable to comply with 
the dosing and protocol requirements 
 
 
 


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with food. Unused medication and the medication bottle will be collected from each subject 
at each visit starting Week 4 until Week 24. 
9.2.5 Investigational Product Accountability 
Responsibility for drug accountability at the study site rests with the investigator; however, 
the investigator may assign some of the drug accountability duties to an appropriate 
pharmacist or designee. Inventory and accountability records must be maintained and must 
be readily available for inspection by the study monitor and are open to inspection at any 
time by any applicable regulatory authorities. 
The investigator or designee will be expected to collect and retain all used, unused, and 
partially used containers of study medication. The investigator or designee must maintain 
records that document the following: 
• Study medication delivery to the study site 
• Inventory at the site 
• Storage conditions 
• Use by each subject, including tablet counts from each supply dispensed 
• Return of study medications to the investigator or designee 
• Destruction of returned and residual containers 
These records should include dates, quantities, batch/serial numbers (if available), and the 
unique code numbers (if available) assigned to the study medication and study subjects. 
The study medication must be used only in accordance with the protocol. The investigator 
will also maintain records adequately documenting that the subjects were provided the study 
medication specified. 
Completed accountability records will be archived by the site. Study monitors will check 
drug accountability records and verify destruction of empty containers. 
The investigator or designee will oversee destruction of any empty containers and residual 
study drug according to institutional standard operating procedures (SOPs). In the absence of 
an institutional SOP, the clinical research associate (CRA) will be responsible for ensuring 
that the drug is sent to an appropriate drug destruction facility. The CRA will verify drug 
accountability records and destruction at regular intervals throughout the study. A certificate 
of destruction will be provided to the CRA for all destroyed drug. 
9.2.6 Study Drug Administration 
Subjects will take 1 tablet of study treatment daily for 24 weeks of treatment. Subjects will 
be instructed to take the study treatment every morning with food. 
All subjects will come into the clinic fasting and hold their daily dose on the day of each 
on-treatment clinic visit. Subjects will bring their study drug bottle to the clinic and take one 
dose of the study medication under witnessed dosing with food, after blood draws.  
If a subject has missed a dose of study drug and is still within 12 hours of the time it is 
usually taken, the subject should take a dose of the missed drug as soon as possible, with 


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food. The subject may then continue the usual dosing schedule. If the subject has missed a 
dose of a study drug more than 12 hours after the time it is usually taken, subject should not 
take the missed dose and simply resume the usual dosing schedule. The subject should not 
take a double dose to make up for a missed dose or take more than 1 tablet per day and 
should not discard any unused medication. 
9.3 
Prior and Concomitant Therapy 
All medications (or treatments) other than study drug taken or received by the subject at any 
time during the study from Screening through the 4-Week Follow-up visit will be considered 
concomitant medications (or treatments). All concomitant medications and treatments must 
be recorded in the case report form (CRF). Any prior medication received within 28 days of 
the first dose of study drug will be recorded in the CRF. Concomitant treatments that are 
required to manage a subject’s medical condition during the trial will also be recorded in the 
CRF.  
Subjects will be allowed to continue their usual standard-of-care medications that are not 
specifically excluded by the protocol. Required dose modifications of medications not 
excluded by the protocol may be performed per the clinical judgement of the investigator. 
The detailed list of disallowed study medications and the list of medications that are allowed 
but with specific restrictions are provided in Appendix 20.4.  
The following classes of medications are disallowed during the study: 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In instances where a disallowed medication is initiated prior to discussion with the medical 
monitor and/or Sponsor, the investigator must notify Tobira as soon as he/she is aware of the 
use of the excluded medication to discuss the subject's continued participation in the study. 
Medications that are commonly used for IBD or for PSC symptoms are listed below. The 
detailed list of disallowed study medications and the list of medications that are allowed but 
with specific restrictions are provided in Appendix 20.4. 


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9.4 
Additional Restrictions and Precautions 
Subjects should refrain from strenuous physical activity (e.g., weight lifting, strenuous yard 
work, intensive exercise workouts) for 48 hours prior to study visits and laboratory 
evaluations. 
Although no cases of photosensitivity reactions have been reported in completed clinical 
studies, previous nonclinical studies indicated that CVC and/or its metabolites have an 


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10.2 
Baseline Visit (Day 1) 
Subjects who have signed the ICF and meet all the eligibility criteria (see Sections 8.2 and 
8.3) will be enrolled in the study. If subjects are deemed eligible once results from the 
Screening visit are received, Baseline visit can take place immediately or approximately 
within 6 weeks after the Screening visit. 


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10.4 
4-Week Follow-up (Week 28, Day 196) 
Subjects will undergo follow-up evaluations approximately 4 weeks after the last dose of 
study drug (Week 28). Subjects who discontinue study drug prior to completion of 24 weeks 
of treatment will be required to return for an Early Discontinuation Visit within 48 hours 
after the last dose of study drug and this 4-week Follow-up Visit.  
The following procedures and assessments for the 4-Week Follow-up Visit will be 
conducted: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.5 
Early Discontinuation Visit  
Subjects may discontinue study treatment at any time for any reason (see Section 10.7).  
For subjects who discontinue study drug prior to having completed 24 weeks of treatment, 
every effort should be made to ensure that they return for Early Discontinuation procedures 
within 48 hours after discontinuing study drug. The procedures and assessments for Early 
Discontinuation will include all assessments in Section 10.3 and in the Schedule of 
Assessments in Section 20.1. 
After the Early Discontinuation Visit, these subjects will be required to return to the clinic 
4 weeks after completion of the Early Discontinuation Visit for a Follow-up Visit 
(Section 10.4). 
10.6 
Missed Scheduled Visits 
Every attempt should be made to have subjects stay on schedule for study visits (Table 20-1).  


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10.7 
Criteria for Discontinuation of Study Treatment 
 
 
    
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Study medication must also be discontinued in the following instances: 
• Unacceptable toxicity, as defined in the toxicity management section of the protocol 
(see Section 11.4.6), or which, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures, or is considered to not be in the 
subject’s best interest 
• Acute viral hepatitis Types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
hypoxic/ischemic hepatopathy 
• Subject requests to discontinue treatment for any reason 
• Pregnancy during the course of the study 
• Discontinuation of the study at the request of Tobira, Regulatory Agency or 
Institutional Review Board (IRB) / Research Ethics Board (REB) 
If subjects discontinue from the study for reasons other than safety, replacement subjects will 
be considered.  


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(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
11.4.1.1.2 Adverse Drug Reaction 
An adverse drug reaction (ADR) is defined as any AE caused by the use of a pharmaceutical 
product. Adverse reactions are a subset of all suspected adverse reactions for which there is 
reason to conclude that the pharmaceutical product caused the event. 
11.4.1.1.3 Suspected Adverse Reaction  
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
study treatment caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study treatment and AE. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means an AE 
caused by a study treatment. 
11.4.1.1.4 Unexpected Adverse Event or Reaction 
An AE or suspected adverse drug reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan.  
11.4.1.1.5 Events Related to Disease Under Study  
Worsening of a pre-existing illness other than the disease under study will be assessed as an 
AE. If such an AE meets the definition of an SAE (see Section 11.4.1.1.9), it must be 
reported as such (see Section 11.4.1.5). 
11.4.1.1.6 Clinically Significant Laboratory Abnormalities 
Any laboratory abnormalities deemed clinically significant by the investigator must be 
reported as an AE. A clinically significant abnormality is a confirmed abnormality (by repeat 
test) that is changed sufficiently from Baseline so that in the judgment of the investigator a 
change in management is warranted. This alteration may include: monitoring the laboratory 
test further, initiating other diagnostic tests or procedures, changing ongoing treatment, or 
administering new treatment. See Section 11.4.2.2 for details regarding the management and 
monitoring of laboratory abnormalities of interest. 
11.4.1.1.7 Surgical Procedures 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions 
that require surgery. The condition for which the surgery is required may be an AE, if it 
occurs or is detected during the study period. Planned surgical measures permitted by the 
clinical study protocol and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the start of the study treatment. In the latter case, the 
condition should be reported as medical history. 


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11.4.1.1.8 Overdose 
Tobira also considers the occurrence of overdose (regardless of adverse outcome) as an event 
that must be reported as an AE. An overdose is defined as a subject’s report of taking more 
than 1 tablet of study medication (i.e., more than 1 tablet per day of CVC). Overdose of any 
concomitant medication without any signs and symptoms will not be considered an AE. For 
reporting purposes, overdose will be considered an SAE only if any of the seriousness 
criteria are met (see definition in Section 11.4.1.1.9). 
11.4.1.1.9 Serious Adverse Event or Serious Adverse Reaction 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening AE 
• An AE or suspected AE is considered life-threatening if, in the view of either the 
investigator or Sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an AE or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
• Inpatient hospitalization (i.e., admission, overnight stay) or prolongation of existing 
hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/birth defect 
• Important medical events 
• An important medical event is one that, when based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above in the definition of an SAE. 
(Examples of such events include allergic bronchospasm requiring intensive 
treatment at an emergency room or at home, blood dyscrasias, convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.) 
11.4.1.2 
Adverse Event Recording 
AEs fall into the categories of “nonserious” and “serious.” From the time of informed 
consent and throughout the study, all AEs must be recorded in the CRF, regardless of 
apparent causality from use of the study treatment. The AE should be reported in standard 
medical terminology. If known, the diagnosis of the underlying illness or disorder should be 
recorded, rather than its individual symptoms. If a definitive diagnosis is not possible, the 
individual symptoms and signs should be recorded. 
The following information should be captured for all AEs: date of onset and end date or 
outcome (e.g., ongoing), severity of the event, seriousness of the event, investigator’s opinion 
of the relationship to investigational product (CVC), action taken with regard to any of the 


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study medication and treatment required for the AE, cause of the event (if known), and 
information regarding the resolution/outcome. 
AEs classified as serious must be recorded on the appropriate SAE reporting tool and 
reported to Tobira using expeditious handling to comply with regulatory requirements (see 
Section 11.4.1.5). 
11.4.1.3 
Adverse Event Classification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.4.1.4 
Adverse Event Coding 
AE verbatim terms provided by the investigator will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), Version 16.0 or later. 
11.4.1.5 
Reporting of Serious Adverse Events 
Tobira is required to expedite to regulatory authorities reports of SAEs, serious ADRs, or 
SUSARs in line with relevant legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the European Commission Clinical Trials Directive 
(2001/20/EC), and other country specific legislation or regulations. Expectedness of SAEs 
will be determined by Tobira using reference safety information specified in the Investigator 
Brochure.  
Any SAE, serious ADR or SUSAR that occurs during the study from the time of signing the 
ICF to within 28 days following discontinuation of study treatment, regardless of relationship 
to the study treatment, must be reported within 24 hours to the contact below:  
SAE Contact 
 
Primary Contact: 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 


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Secondary Contact:  
 
  
 
 
 
   
 
 
 
 
   
  
 
 
 
 
  
 
The required SAE information must be completed on the SAE Form (MedWatch or CIOMS). 
Tobira may request additional information from the investigator to ensure the timely 
completion of accurate safety reports. 
A copy of the submitted SAE form must be retained on file by the investigator. The 
investigator must submit the SAE to the IRB/IEC according to local requirements and retain 
documentation of these submissions in the site study file. 
The investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF and the event description section of the SAE Form. 
If the investigator detects an SAE in a study subject after the end of the period of 
observation, and considers the event possibly related to prior study treatment, he/she should 
contact Tobira to determine how the event should be documented and reported. 
In case of emergency, contact the Tobira medical monitor (see Section 11.4.1.5 for contact 
information). 
The Investigator will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB/IEC as soon as is practical, of serious events in writing 
where this is required by local regulatory authorities, and in accordance with the local 
institutional policy. 
In accordance with the European Union Clinical Trials Directive (2001/20/EC), Tobira or 
specified designee will notify worldwide regulatory authorities and the relevant Ethics 
Committees in concerned Member States of applicable SUSARs as individual notifications 
or through a periodic line listing. 
11.4.1.6 
Follow-up of AEs and SAEs 
AEs (including SAEs) will be collected from the time of informed consent, throughout the 
treatment period, until 28 days after the last dose of study medication is administered. 


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All subjects who have AEs, whether considered associated with the use of the investigational 
product or not, must be monitored to determine the outcome. The clinical course of the AE 
will be followed up according to accepted standards of medical practice, even after the end of 
the period of observation, until a satisfactory explanation is found or the investigator 
considers it medically justifiable to terminate follow-up. Should the AE result in death, a full 
pathologist’s report should be supplied if and when available.  
11.4.1.7 
Pregnancy 
If a subject becomes pregnant during the study, the subject must be instructed to discontinue 
study drug and inform the investigator immediately. The investigator should report all 
pregnancies occurring in a subject or partner of a subject participating in the study that occur 
up to 3 months following the last dose of study drug to Tobira Drug Safety within 24 hours 
of becoming aware of the pregnancy. The investigator should counsel the subject regarding 
the possible effects of prior study drug exposure on the fetus and the need to inform the study 
site of the outcome of the pregnancy. 
Any pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE or a SAE. Elective abortion procedures, without complications, should 
not be considered as AEs. 
All reports of congenital abnormalities/birth defects and spontaneous abortions/miscarriages 
should be reported as an SAE for this study. Furthermore, any SAE occurring as an adverse 
pregnancy outcome post study must be reported to Tobira Drug Safety. 
All pregnancies that occur during the study should be reported using the Pregnancy Report 
Form, which should be faxed to Tobira Drug Safety within 24 hours of first knowledge by 
the investigator. Monitoring of the subject should continue until the conclusion of the 
pregnancy. The outcome should be reported to Tobira Drug Safety using the Pregnancy 
Outcome Report Form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Tobira Drug Safety. Pregnancies that 
occur more than 28 days after the subject has discontinued study drug do not require 
monitoring.  
11.4.2 Laboratory Assessments 
11.4.2.1 
Measurement of Laboratory Assessments 
A central laboratory will perform all clinical safety laboratory tests. Urine drug screens will 
also be analyzed at the central laboratory. Urine pregnancy tests will be performed at the site 
using a dipstick method, except at Screening where a serum pregnancy test will be 
performed. If there is a positive urine pregnancy test while on-study, a serum pregnancy test 
will be conducted by the central lab.  
Samples for hematology, serum chemistry, liver function tests and urinalysis will be prepared 
using standard procedures. Refer to the laboratory manual provided by Tobira for further 
details and specifications for sample handling, processing, and shipment.  


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 48 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
 
 
A complete list of all laboratory tests is provided in Appendix 20.5. 
11.4.2.2 
Clinically Significant Laboratory Abnormalities 
Any laboratory test showing abnormal results (including those recorded as AEs) that are 
believed to be possibly/probably related to study drug treatment will be repeated weekly (or 
as often as deemed prudent by the investigator) until the abnormality is resolved, returns to 
Baseline, or is otherwise explained. Whenever possible, the etiology of the abnormal findings 
will be documented on the CRF. See Section 11.4.1.1.6 for a definition of clinically 
significant laboratory abnormality. For management of subjects with elevated liver tests, 
please refer to Section 11.4.6.4.  
11.4.3 Vital Signs  
Vital sign measurements (systolic and diastolic blood pressure, temperature, heart rate, and 
respiration rate) will be taken at each visit. For subjects who discontinue study medication 
early, vital signs will be measured at the Early Discontinuation Visit within 48 hours of 
stopping study medication. Vital signs will be performed with the subject in the sitting 
position after 5 minutes of rest. 
11.4.4 Electrocardiogram 
A 12-lead ECG will be taken at the Baseline/Day 1 Visit, and at Week 24. ECGs will be 
performed with the subject in the supine position after 5 minutes of rest. 
11.4.5 Physical Examination 
A complete physical examination will be performed at the Screening 1 Visit and the 
Baseline/Day 1 Visit. A symptom-directed physical examination will be performed, as 
needed, at the Screening 2 Visit, at all On-treatment Visits, at the Early Discontinuation Visit 
within 48 hours of stopping study medication, and at the 4-Week Follow-up Visit. The 
complete physical examination will include (but not limited to) the following organ or body 
system assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular; 
abdomen (liver and spleen); extremities; lymph nodes; and a brief neurological exam. 
Abbreviated symptom-directed physical examinations will target signs and symptoms; any 
abnormal findings that are reported as AEs will be recorded in the CRF. 
11.4.6 Toxicity Management 
Clinical events and clinically significant laboratory abnormalities will be graded according 
NCI CTCAE version 4.03 (Appendix 20.2). 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 49 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 50 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
11.4.6.4 
Management of Subjects with Elevated ALP, ALT, AST or Bilirubin 
If a subject is asymptomatic but experiences clinically significant elevations of liver 
transaminases or Bilirubin, subjects must repeat physical examination and laboratory 
evaluation within 48-72 hours for repeat testing and close monitoring, preferably at the 
clinical research site or alternately at a local laboratory.  
 
 
 
 
 
 
 
 
  
 
 
For confirmed elevations of above parameters, the subject must interrupt study drug. Close 
monitoring of study subjects includes: 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
 
  
 
    
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 51 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
11.5 
Biomarker Analysis 
Serum samples will be stored at the central lab for potential evaluation of biomarkers of 
interest at Baseline and at Weeks 12 and 24. 
11.6 
Assessments of Medication Adherence 
Drug accountability through the assessment of pill counts will be performed by clinic staff at 
each on-treatment evaluation visit.   
 
 
 
 
 
 
 
 
 
 
 


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Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 53 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
12.4 
Efficacy 
12.4.1 Efficacy Endpoint 
The primary efficacy endpoint for this study is the percent change from Baseline through 
Week 24 in serum alkaline phosphatase. 
 
 
 
12.4.2 Methods of Analysis for Primary and Secondary Efficacy Endpoints 
Percent changes in ALP from Baseline will be summarized using descriptive statistics for the 
respective pre-treatment and on-treatment visits.  
 
 
 
 
 
 
  
 
 
 
 
12.5 
Safety 
12.5.1 Safety Endpoints 
Safety endpoints include: 
• Evaluation of the safety and tolerability through 24 weeks of treatment in adult PSC 
subjects 
• Evaluation of AEs, clinical laboratory tests, physical exam and 12-lead ECG. 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 54 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
12.5.2 Methods of Analysis for Safety Endpoints 
12.5.2.1 
Adverse Events 
AEs will be tabulated by the MedDRA preferred term and system-organ classification. The 
occurrence of TEAEs will be summarized by treatment group using MedDRA preferred 
terms, system organ classifications, and severity (see Sections 11.4.1.3 and 11.4.1.4).  
All AEs will be listed for individual subjects showing both verbatim and preferred terms. 
Separate summaries of treatment-emergent SAEs and TEAEs related to study drug will be 
generated. 
Any event reported on the CRF that occurs on or after the initiation of study drug is defined 
as treatment-emergent. Additionally, it is assumed that an AE that was reported to have 
started on Day 1 without an associated onset time may have occurred after the initiation of 
study drug. Hence, AEs occurring on Day 1 with no associated onset time are assumed to be 
treatment-emergent. 
12.5.2.2 
Clinical Laboratory Tests  
Descriptive summaries of clinical laboratory results will be presented by study visit. 
Laboratory abnormalities will be graded according to NCI CTCAE version 4.03 (see 
Appendix 20.2). The number and percentage of subjects experiencing treatment-emergent 
graded toxicities will be summarized by treatment group and severity grade. Laboratory 
toxicity shifts from Baseline to post-Baseline assessments will be summarized by treatment 
group. Changes from Baseline in laboratory tests will be summarized for each treatment 
group. 
12.5.2.3 
Physical Examination and Vital Signs 
Any abnormal findings that are considered clinically significant in the opinion of the 
investigator will be recorded as AEs or be captured as medical history, if already present at 
Screening. 
Descriptive summaries of vital signs will be presented by study visit. Descriptive summaries 
of quantitative changes in vital signs will be presented by treatment group and study visit. 
Vital sign results will be reviewed for clinically notable abnormalities, according to 
predefined criteria, and adverse changes will be summarized.  
12.5.2.3.1 Electrocardiograms 
ECG results will be reviewed locally for clinically notable abnormalities according to 
predefined criteria. Patients exhibiting Grade 3 or 4 PR or QTc interval will be summarized. 
12.5.2.3.2 Prior and Concomitant Medications 
Prior and concomitant medications will be mapped to a World Health Organization preferred 
term and drug classification. The number and percent of subjects taking concomitant 
medications will be summarized using preferred terms and drug classifications. 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 55 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
 
 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
  
 
 
 
 


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Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 58 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
14.3 
Informed Consent 
Preparation of the consent form is the responsibility of the investigator and Tobira or 
designee and must include all elements required by the ICH, GCP, and applicable regulatory 
requirements, and must adhere to GCP and to the ethical principles that have their origin in 
the Declaration of Helsinki. 
A template will be provided by Tobira or designee. Tobira or designee must review and 
approve all changes to site-specific ICFs. 
The consent form must include a statement that Tobira or designee and regulatory authorities 
have direct access to subject records. Prior to the beginning of the study, the investigator 
must have the IRB/IEC’s written approval/favorable opinion of the written ICF and any other 
information to be provided to the subjects. 
Before being enrolled in the clinical study, subjects must consent to participate after the 
nature, scope, and possible consequences of the study have been explained in a form 
understandable to them. 
An informed consent document that includes both information about the study and the 
consent form will be prepared and given to the subject. This document will contain all the 
elements required by the ICH E6 Guideline for Good Clinical Practice and any additional 
elements required by local regulations. The document must be in a language understandable 
to the subject and must specify who informed the subject. Where required by local law, the 
person who informs the subject must be a physician. 
A copy of the signed consent document must be given to the subject. The original signed 
consent document will be retained by the investigator. 
The investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained. 
The investigator must inform the subject’s primary physician about the subject’s 
participation in the trial if the subject has a primary physician and if the subject agrees to the 
primary physician being informed. 
14.4 
Subject Confidentiality 
Applicable data privacy laws and regulations must be adhered to. The investigator and Tobira 
are responsible for ensuring that sensitive information is handled in accordance with local 
requirements (e.g., Health Insurance Portability and Accountability Act). Appropriate 
consent and authorizations for use and disclosure and/or transfer (if applicable) of protected 
information must be obtained. 
Subject names will not be supplied to Tobira. Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to 
Tobira. Study findings stored on a computer will be stored in accordance with local data 
protection laws. The subjects will be informed that representatives of Tobira, IRB/IEC, or 
regulatory authorities may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws. 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 59 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
14.5 
Study Conduct 
The study will be conducted in compliance with the Declaration of Helsinki (October 2008) 
and the ICH E6 Guideline for GCP. All national, state, and local laws of the pertinent 
regulatory authorities will be followed. 
If it is necessary to amend either the protocol or the ICF, the investigator will be responsible 
for ensuring that the IRB/IEC reviews and approves the amended documents. Amended ICFs 
must be obtained and used for obtaining consent from new subjects. 
14.6 
Study Discontinuation 
Both Tobira and the investigator reserve the right to terminate the study, according to the 
terms specified in the study contract. The investigator is to notify the IRB/IEC in writing of 
the study’s completion or early termination, and send a copy of the notification to Tobira and 
retain one copy for the site study regulatory file. 
 
 


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Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 61 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
All CRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in 
compliance with applicable record retention regulations. Tobira will retain the original paper 
CRF data and audit trail. 
15.2.3 Study Monitoring and Access to Source Documents 
Qualified representatives of Tobira or its designees (“study monitors”) will monitor the study 
according to a predetermined monitoring plan. Monitoring visits provide Tobira with the 
opportunities to do the following: 
• Evaluate the progress of the study 
• Verify the accuracy and completeness of CRFs 
• Assure that all protocol requirements, applicable laws and/or regulations, and 
investigator’s obligations are being fulfilled 
• Resolve any inconsistencies in the study records 
The investigator must allow the study monitors to periodically review, at mutually 
convenient times during the study and after the study has been completed, all CRFs and 
office, hospital, and laboratory records supporting the participation of each subject in the 
study. The CRFs and other documentation supporting the study must be kept up-to-date by 
the investigator and the research staff at the investigative site. These study materials must be 
available for review by the study monitor, and/or other qualified representatives of Tobira, at 
each monitoring visit. 
The study monitor will review the various records of the study (CRFs, subject medical and 
laboratory records, and other pertinent data). The study monitor will verify the CRF data 
against original source documentation for accuracy and completeness. The study monitor will 
identify data discrepancies and collaborate with the investigator and research staff to resolve 
the discrepancies in a timely manner. Protocol deviations will also be identified and recorded 
on a “Protocol Deviation Log.” The study monitor will follow an “Issue Escalation” plan in 
order to ensure that each issue identified during a monitoring visit is appropriately 
documented, reported, and resolved in a timely manner in accordance with the plan’s 
requirements. 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 62 of 82 
Amendment 3 
 
CONFIDENTIAL 
 
 14 June2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 63 of 82 
Amendment 3 
 
 
CONFIDENTIAL 
 
 14 June2016 
 
 
 
 
 
 
 
 
 


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Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 72 of 82 
Amendment 3 
CONFIDENTIAL  
 
14 June 2016 
20.1 
Schedule of Assessments 


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Page 73 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 


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Clinical Study Protocol 652-205 
 
Page 74 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
 
20.2 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE)  
Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
Quick Reference 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) is a 
descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided 
for each AE term. 
Components and Organization 
System Organ Class 
System Organ Class (SOC), the highest level of the MedDRA hierarchy, is identified by anatomical 
or physiological system, etiology, or purpose (e.g., SOC investigations for laboratory test results). 
CTCAE terms are grouped by MedDRA Primary SOCs. Within each SOC, AEs are listed and 
accompanied by descriptions of severity (grade).  
CTCAE Terms 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medical treatment or procedure that may or may 
not be considered related to the medical treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical documentation and scientific analyses. Each 
CTCAE v4.0 term is a MedDRA lowest level term (LLT). 
Definitions 
A brief definition is provided to clarify the meaning of each AE term. 


Tobira Therapeutics, Inc. 
 
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Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
Grades 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE. 
 
A semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available. 
Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than 5 options 
for grade selection. 
Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 76 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
20.3 
Information on Contraception Effectiveness 
For Female Study Subjects of Child-Bearing Potential and For Male Study Subjects with Female 
Partners 
The following methods have been determined to be more than 99% effective (failure rate < 1% per 
year, when used consistently and correctly) (Trussell 2004) and are permitted under this protocol: 
• Complete abstinence from sexual intercourse if this is the subject’s usual and preferred lifestyle 
• Dual method of contraception: 
o Condom with spermicide in conjunction with use of an intrauterine device 
o Condom with spermicide in conjunction with use of a diaphragm 
o Condom with birth control patch or vaginal ring* 
o Condom with oral, injectable, or implanted contraceptives* 
• Tubal ligation or vasectomy (surgical sterilization**) 
* Note: Subjects who are using hormonal contraceptives should be instructed to use an additional 
contraceptive measure during the study (see above for other methods). 
** Note: For the purpose for this study protocol, “surgical sterilization” also includes hysterectomy 
and/or bilateral oophorectomy. 
 
Trussell J. Contraceptive failure in the United States. Contraception 2004;70:89-96. 
 
 


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Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 77 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
20.4 
Disallowed Medications 
Caution should always be exercised when administering concomitant medications based on the 
individual medication profile and clinical risk-benefit assessment.  
The subject must not take the following disallowed medications at any time during the study, from 
Screening through the 4-Week Follow-up visit.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 78 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
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Clinical Study Protocol 652-205 
 
Page 79 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
 


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Clinical Study Protocol 652-205 
 
Page 80 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
20.5 
Clinical Laboratory Tests  
 
 
 


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Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
  
 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 82 of 82 
Amendment 3 
 
CONFIDENTIAL  
 
14 June 2016 
 
Adiponectin  


Clinical Protocol 652-205 
Amendment 3: 14 June 2016 
 
Tobira Therapeutics 
 
 
 
Confidential 
Page 1 of 2 
PROTOCOL AMENDMENT 3 SUMMARY OF CHANGES  
1. 
Major changes 
• Removal of pre-Baseline visit.  Subjects diagnosed with PSC often have elevated but 
fluctuating liver enzymes (AST, ALT, Total Bilirubin and Direct Bilirubin).  
Repeating liver enzymes at the pre-Baseline visit, and taking the average value of the 
Screening and pre-Baseline values for inclusion, has proven prohibitive in subject 
enrollment due to these normal fluctuations.  Subjects with evidence of cirrhosis or 
hepatic impairment will be excluded by exclusion criterion 9. With the removal of 
the pre-Baseline visit, the mean values of the AST, ALT, Total Bilirubin and Direct 
Bilirubin parameters no longer apply, and are revised in exclusion criteria 13 and 14. 
• The upper cut-off values of Total Bilirubin and Direct Bilirubin have been changed 
to: 
o Total Bilirubin > 2.0 mg/dL 
o Direct Bilirubin > 0.8 mg/dL 
• Removal of Week 2 visit. Frequent site visits negatively impacts on subjects’ 
willingness to participate in this 6-month study. Therefore, it is decided that monthly 
visits are sufficient for the first 4 months, then 2 months later at Month 6 (end of 
treatment period). Based on safety data from other CVC studies, where subjects have 
been treated for one year, there is no safety impact with the removal of the Week 2 
visit.  
• Revision of inclusion criterion 3 to allow subjects without inflammatory bowel 
disease (IBD) to be eligible for the study. There is no impact on safety by allowing 
patients with or without IBD to participate. 
• Revision of inclusion criterion 5 to allow serum ALP ≥ 1.5 x ULN, rather than only 
greater than, for study entry.  
2. 
Administrative changes 
• Updated version date throughout protocol amendment 3. 
• 
 
 
• Plasma PK samples will not be drawn at Week 2. 
• Updated Section 9.3 Prior and Concomitant Therapy medication to allow the use of 
   
• Updated Section 9.4 Additional Restrictions and Precautions stating results from 
additional studies indicating that CVC did not demonstrate phototoxic potential in 
neutral red uptake phototoxicity.  
 
 


Clinical Protocol 652-205 
Amendment 3: 14 June 2016 
 
Tobira Therapeutics 
 
 
 
Confidential 
Page 2 of 2 
•
 
 
•
 
• Updated S
 
 
 
 
 
  
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 1 of 2 
CONFIDENTIAL  
 
06 April 2016 
 
 
 
 
SUMMARY OF CHANGES 
 
 
 
Title: 
A Phase 2 Proof of Concept Study Investigating the 
Preliminary Efficacy and Safety of Cenicriviroc in Adult 
Subjects with Primary Sclerosing Cholangitis (PSC) 
 
 
Protocol Number: 
652-205 
 
 
Product: 
Cenicriviroc Mesylate (CVC) 
 
 
Phase of Study: 
Phase 2 
 
 
Sponsor: 
Tobira Therapeutics, Inc. 
 
701 Gateway Blvd, Suite 300 
 
South San Francisco, CA 94080 
 
United States of America 
 
 
Date of Original Protocol: 19 November 2015 
Date of Amendment 1.1: 
29 December 2015 
Date of Amendment 2: 
06 April, 2016 
 
 
 
 
 
 
 
The information in this document is privileged and confidential. No part of this information may be duplicated, 
referenced, or transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) 
without the prior written consent of Tobira Therapeutics. 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 2 of 2 
CONFIDENTIAL  
 
06 April 2016 
Summary of Changes for Protocol 652-205: PERSEUS 
The most noteworthy changes for Study 652-205, Amendment 2 are detailed below.  All relevant sections have been 
updated with the appropriate changes including the Schedule of Assessments. In addition, various administrative 
corrections and edits have been made for clarity. A redline version of the protocol has been provided for comparison from 
Amendment 1.1 to Amendment 2.0.   
 
 
  
 
Added clarification that if subjects are deemed eligible (based on their Pre-Baseline results), the Baseline visit can 
take place immediately or approximately within 2 weeks prior to the Baseline visit 
 
 
 
 
 
INR was added for every visit 
 
Clarified if the subjects do not fast, subjects will need to return to the center in the afternoon (approximately 6 hours 
later) for his/her fasting blood draw or the visit may be rescheduled within 72 hours 
 
Added clarification on replacing subjects. If subjects discontinue from the study for reasons other than safety, 
replacement subjects will be considered. 
 
The “Special Situations Report” Section has been deleted (Previously in Section 11.4.1.8). This section was 
inadvertently included in the original protocol. However, for the purpose of this study, reports of medication error, 
abuse, misuse, or overdose, and reports of adverse reactions associated with product complaints will be reported to 
Tobira and 
 for investigation and reporting. Any corrective action items will be followed through with the 
investigators, as appropriate. Clarified the language referring to guidance if any Grade 4 laboratory abnormalities or 
clinical events occur.    
 
Fibrates have been excluded as they may decrease ALP and confound efficacy results 
 
Clarified IgG total and IgG1 should be performed at Baseline and Week 24 
. 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 1 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
 
 
 
SUMMARY OF CHANGES 
 
 
 
Title: 
A Phase 2 Proof of Concept Study Investigating the 
Preliminary Efficacy and Safety of Cenicriviroc in Adult 
Subjects with Primary Sclerosing Cholangitis (PSC) 
 
 
Protocol Number: 
652-205 
 
 
Product: 
Cenicriviroc Mesylate (CVC) 
 
 
Phase of Study: 
Phase 2 
 
 
Sponsor: 
Tobira Therapeutics, Inc. 
 
701 Gateway Blvd, Suite 300 
 
South San Francisco, CA 94080 
 
United States of America 
 
 
Date of Original Protocol: 19 November 2015 
Date of Amendment 1.0: 
29 December 2015 
 
 
 
 
 
 
 
The information in this document is privileged and confidential. No part of this information may be duplicated, 
referenced, or transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) 
without the prior written consent of Tobira Therapeutics. 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 2 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Major Changes 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
Section 4 
Synopsis (Inclusion 
Criteria) 
and  
Section 8.2 Inclusion 
Criteria 
2. Clinical diagnosis of PSC as evident by 
chronic cholestasis of more than six months 
duration with either a consistent magnetic 
resonance cholangiopancreatography 
(MRCP)/endoscopic retrograde 
cholangiopancreatography (ERCP) 
showing sclerosing cholangitis, or a liver 
biopsy taken at any time consistent with 
PSC in the absence of a documented 
alternative etiology for sclerosing 
cholangitis. 
2. Clinical diagnosis of PSC as evident by 
chronic cholestasis of more than six months 
duration with either a consistent magnetic 
resonance cholangiopancreatography 
(MRCP)/endoscopic retrograde 
cholangiopancreatography (ERCP) showing 
sclerosing cholangitis, or a liver biopsy taken 
at any time consistent with PSC in the 
absence of a documented alternative etiology 
for sclerosing cholangitis. If diagnosis of PSC 
was made by histology alone, it must require 
the presence of fibro-obliterative lesions (i.e., 
onion skin lesions). 
Additional sentence “If diagnosis of PSC 
was made by histology alone, it must 
require the presence of fibro-obliterative 
lesions (onion skin lesions)” was added to 
ensure histological diagnosis included this 
morphological observation. 
Section 4 
Synopsis (Inclusion 
Criteria)  
and 
Section 8.2 Inclusion 
Criteria 
3. Confirmed Inflammatory Bowel Disease 
(IBD)  
 
3. Documented evidence of Inflammatory 
Bowel Disease (IBD) either by prior 
endoscopy or in previous medical records, for 
≥6 months. In addition, subjects will be 
required to enter the study with a Partial 
Mayo Risk score of 0-3, inclusively 
Added language to confirm IBD 
diagnosis, as well as severity of IBD.  
Section 4  
Synopsis (Exclusion 
Criteria)  
and  
Section 8.3  
Exclusion Criteria 
13. Aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) > 5 × ULN 
 
13. Aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT); above the 
allowed cut-offs, as determined by the mean 
Screening and pre-Baseline values (subjects 
who show evidence of significant worsening 
of liver transaminases on repeat measure will 
be excluded): 
 
AST > 200 IU/L males and females  
 
ALT: males > 250 IU/L and females 
> 200 IU/L  
Added detail to ensure that patients do not 
have deteriorating liver function prior to 
enrolment 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 3 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
Section 4  
Synopsis (Exclusion 
Criteria) 
and  
Section 8.3  
Exclusion Criteria 
14. Bilirubin > 3 × ULN  
14. Total Bilirubin and Direct Bilirubin; 
above the allowed cut-offs, as determined by 
the mean Screening and pre-Baseline values 
(subjects who show evidence of significant 
worsening of bilirubin will be excluded):  
 
Total Bilirubin ≥ 1.5 mg/dL  
 
Direct Bilirubin ≥ 0.5 mg/dL 
Added detail to ensure that patients do not 
have deteriorating liver function prior to 
enrolment 
Figure 7-1  
Study Design 
Schematic 
<added a pre-baseline visit in the 
schematic> 
-14d (-2wk) 
Added pre baseline visit day in order to 
ensure that there is no deteriorating liver 
function on repeat testing prior to 
enrollment 


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Clinical Study Protocol 652-205 
 
Page 4 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
Section 10.0  
Study Procedures 
<New paragraphs added> 
Eligible subjects will be required to complete 
a diary daily to assess stool frequency and 
blood in the stool (Partial Mayo Risk score), 
daily. In addition, the diary will include a 
question regarding abdominal pain in order to 
assess if the subject develops any significant 
increase in abdominal pain.  If a subject 
exceeds a Partial Mayo Risk score of 4 at any 
time, by investigator assessment of patient 
diary as well as subject evaluation, then the 
subject will be reevaluated for his or her IBD 
at the clinical research site. Should subjects 
experience an increase in abdominal pain, 
stool frequency or blood in their stool 
between visits, they will be instructed to 
contact the site immediately for clinical 
assessment for their IBD.   
The principal investigator or delegate will be 
instructed to inquire about abdominal pain at 
each study visit. As with all adverse events, 
any abdominal pain will be assessed for 
severity and causality by the investigator in 
the eCRF, per Section 11.4. 
Added detail on patient diary which will 
also now include abdominal pain question 
to assess abdominal pain. The principal 
investigator will be required to ask about 
abdominal pain at each visit. 
In addition, as patients are entering the 
study with a Partial Mayo Risk score of 0-
3, any patient who exceeds a score of 4, 
will be required to be reevaluated for their 
IBD. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 


Tobira Therapeutics, Inc. 
 
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Clinical Study Protocol 652-205 
 
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CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 6 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 s
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 7 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 8 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
  
 
 
 
    
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 9 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
 
 
 
 
 
 
 


Tobira Therapeutics, Inc. 
 
Cenicriviroc 
Clinical Study Protocol 652-205 
 
Page 10 of 18 
CONFIDENTIAL  
 
29 December 2015 
 
Minor Changes 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
Section 4.0 
Synopsis (Study 
Design) 
Screening will occur within 4 weeks before 
the Baseline Visit (Day 1).  At Day -28 
(approximately), subjects will undergo all 
eligibility evaluations per the schedule of 
assessments. 
Screening will occur within 6 weeks before 
the Baseline Visit (Day 1).  At Day -42 
(approximately), subjects will undergo all 
eligibility evaluations per the schedule of 
assessments. A pre-Baseline visit will occur 
2 weeks (Day -14) prior to the Baseline visit 
for liver parameter testing. 
Screening within 4 weeks of Baseline 
Visit (Day 1) was updated from 4 weeks 
to 6 weeks and Day -28 was updated to -
42 because of inclusion of the pre-
Baseline visit, which occurs at week -2 
(day -14)  in order to get a repeat of liver 
function parameters prior to enrollment.  
Additional sentence regarding a pre-
Baseline Visit was added as per above.  
Section 4  
Synopsis (Exclusion 
Criteria) 
and 
Section 8.3  
Exclusion Criteria 
1. Presence of documented secondary 
sclerosing cholangitis on prior clinical 
investigations  
 
1. Presence of documented secondary 
sclerosing cholangitis (such as ischemic 
cholangitis, recurrent pancreatitis, intraductal 
stone disease, severe bacterial cholangitis, 
surgical or blunt abdominal trauma, recurrent 
pyogenic cholangitis, choledocholithiasis, 
toxic slerosing cholangitis due to chemical 
agents, or any other cause of secondary 
sclerosing cholangitis) on prior clinical 
investigations 
 
Examples of secondary sclerosing 
cholangitis have been included. 
Section 4  
Synopsis (Exclusion 
Criteria)  
and  
Section 8.3  
Exclusion Criteria 
9. History of cirrhosis and/or hepatic 
decompensation including ascites, 
encephalopathy or variceal bleeding 
9. History of cirrhosis and/or hepatic 
impairment (Child-Pugh classes A, B and C) 
and/or hepatic decompensation including 
ascites, encephalopathy or variceal bleeding. 
Subjects who show evidence of significant 
worsening of hepatic function will be 
excluded 
Added the verbiage “impairment (Child-
Pugh classes A, B, and C) to clarify no 
hepatic decompensation or cirrhosis 
allowed.  


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Clinical Study Protocol 652-205 
 
Page 11 of 18 
CONFIDENTIAL  
 
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Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
Section 4  
Synopsis (Exclusion 
Criteria) 
and  
Section 8.3  
Exclusion Criteria 
10. Subjects with fibrosis evidence of 
cirrhosis, as determined by local transient 
elastography (TE; e.g., FibroScan®) values 
of ≥ 13.0 kPa, taken within the last 6 
months. If TE has not been conducted 
within the 6 months prior to screening then 
one will be conducted during the screening 
period and can be used as the Baseline 
value 
10. Subjects with evidence of cirrhosis, as 
determined by local transient elastography 
(TE; e.g., FibroScan®) values of ≥ 13.0 kPa, 
taken within the last 6 months. If TE has not 
been conducted within the 6 months prior to 
screening then one will be conducted during 
the screening period and can be used as the 
Baseline value 
Removed the word ‘fibrosis’ due to typo 
in original version (sentence was 
incorrect and nonsensical). 
Section 4  
Synopsis (Exclusion 
Criteria) 
and  
Section 8.3  
Exclusion Criteria 
11. Moderate to Severe active IBD or flare 
in colitis activity within the last 90 days 
requiring intensification of therapy beyond 
Baseline treatment. Subjects with stable 
mild to moderate IBD, who are on 
treatment, are allowed provided they are 
stable for 3 months with 5-amino salicylic 
acid drugs or Azathioprine  
11. Moderate to Severe active IBD or flare in 
colitis activity within the last 90 days 
requiring intensification of therapy beyond 
Baseline treatment. Subjects with stable mild 
to moderate IBD, who are on treatment, are 
allowed provided they are stable for 3 
months with 5-amino salicylic acid drugs or 
Azathioprine (allowed dose of azathioprine is 
50-200 mg/day). 
Added  the allowable dose range for 
azathioprine of 50-200mg/day 
Section 4  
Synopsis (Exclusion 
Criteria) 
and  
Section 8.3  
Exclusion Criteria 
15. International normalized ratio > 1.3 in 
the absence of anticoagulants.  
 
15. International normalized ratio (INR) 
> 1.3 in the absence of anticoagulants. 
 
Abbreviation “(INR)” added as it is used 
elsewhere in the protocol 
Section 4 Synopsis 
(Study 
Procedures/Frequency) 
Screening will occur within 4 weeks before 
the Baseline Visit.  
Screening will occur within 6 weeks before 
the Baseline Visit.  A pre-Baseline visit will 
occur 2 weeks before Baseline. 
Screening within 4 weeks of Baseline 
Visit (Day 1) was updated to 6 weeks. 
Additional sentence regarding a pre-
Baseline Visit was added to include a -2 
week (Day -14) visit in order to get a 
repeat of liver function parameters prior 
to enrollment 
Section 4 Synopsis 
(Study 
Procedures/Frequency) 
IgG Total, IgG1 and IgG4 will be collected 
at Baseline, and Week 24 
IgG Total, IgG1 and IgG4 will be collected 
at Baseline, and Week 24 (IgG4 will also be 
collected at Screening) 
Clarification that IgG4 will also be 
collected at Screening 


Tobira Therapeutics, Inc. 
 
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Clinical Study Protocol 652-205 
 
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CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
Section 4 Synopsis 
(Study 
Procedures/Frequency) 
Transient elastography will be assessed 
once during the Screening period (between 
Day -28 to Baseline) and again at Week 24 
Transient elastography will be assessed once 
during the Screening period (between Day 
- 42 to Baseline) and again at Week 24 
Changed Day -28 to Day -42 according 
to new schedule 
Section 4 Synopsis 
(Study 
Procedures/Frequency) 
Plasma pharmacokinetic (PK) samples will 
be drawn pre-dose at Baseline and at 
Weeks 2, 12, and 24 
Plasma pharmacokinetic (PK) samples will 
be drawn pre-dose and post-dose at Baseline 
and at Weeks 2, 12, and 24 
Added new post dose sampling  
Section 5.4  
Clinical Studies with 
CVC 
Overall, 599 subjects have been exposed to 
CVC, including 440 healthy subjects (of 
which 8 had mild and 8 had moderate 
hepatic impairment] and 159 HIV 1 
infected subjects) have received at least 1 
dose of CVC. 
Overall, 599 unique subjects have been 
exposed to CVC in completed studies, 
including 440  subjects participating in Phase 
1 studies (of which 8 had mild and 8 had 
moderate hepatic impairment) and 159 HIV-
1-infected subjects participating in Phase 2 
studies who have received at least 1 dose of 
CVC. 
Updated this section administratively 
Section 7.1  
Overall Study Design 
and Plan 
Screening will occur within 4 weeks before 
the Baseline Visit.  
Screening will occur within 6 weeks before 
the Baseline Visit. A pre-Baseline visit for 
repeat measure of liver parameter tests will 
occur within 2 weeks before the Baseline 
visit. 
Screening within 4 weeks of Baseline 
Visit (Day 1) was updated to 6 weeks. 
Additional sentence regarding a pre-
Baseline Visit was added to include a -2 
week (Day -14) visit in order to get a 
repeat of liver function parameters prior 
to enrollment 
Figure 7-1  
Study Design 
Schematic 
-28d (-4wk) in the schematic 
-42d (-6wk) in the schematic 
Screening within 4 weeks of Baseline 
Visit (Day 1) was updated from 4 weeks 
to 6 weeks and Day -28 was updated to -
42 because to include a -2 week (Day -
14) visit in order to get a repeat of liver 
function parameters prior to enrollment 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Study Protocol 652-205 
 
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CONFIDENTIAL  
 
29 December 2015 
 
Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
  
 
 
 
 
 
Section 10.1 Screening 
<Screening (Days -28; Visit 1> 
Prior to any clinical procedures and 
evaluations, written signed informed 
consent must be obtained. Screening 1 is to 
occur approximately 4 weeks (28 days) 
before the Baseline Visit (see Section 
10.2). 
 
<Screening (Days -42; Visit 1> 
Prior to any clinical procedures and 
evaluations, written signed informed consent 
must be obtained. Screening  is to occur 
approximately 4 weeks (28 days) before the 
pre-Baseline visit (see Section 10.2), and 6 
weeks (42 days) before the Baseline Visit 
(see Section 10.3). 
Screening within 4 weeks of Baseline 
Visit (Day 1) was updated to 6 weeks. 
Additional sentence regarding a pre-
Baseline Visit was added to include a -2 
week (Day -14) visit in order to get a 
repeat of liver function parameters prior 
to enrollment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
   
Section 10.5  
4-Week Follow-up 
<section title> 
4-Week Follow-up (Week 28, Day 196; 
Visit 9) 
<section title> 
4-Week Follow-up (Week 28, Day 196; Visit 
10) 
Additional Pre-Baseline Visit included so 
Visit number assigned to 4-Week 
Follow-up is now Visit 10 instead of 
Visit 9
Section 11.4.2.2 
Clinically Significant 
Laboratory 
Abnormalities 
Any laboratory test showing abnormal 
results (including those recorded as AEs) 
that are believed to be possibly/probably 
related to study drug treatment will be 
repeated weekly (or as often as deemed 
prudent by the investigator) until the 
abnormality is resolved, returns to 
Baseline, or is otherwise explained. 
Whenever possible, the etiology of the 
abnormal findings will be documented on 
the CRF. See Section 11.4.1.1.6 for a 
definition of clinically significant 
laboratory abnormality. 
Any laboratory test showing abnormal results 
(including those recorded as AEs) that are 
believed to be possibly/probably related to 
study drug treatment will be repeated weekly 
(or as often as deemed prudent by the 
investigator) until the abnormality is 
resolved, returns to Baseline, or is otherwise 
explained. Whenever possible, the etiology 
of the abnormal findings will be documented 
on the CRF. See Section 11.4.1.1.6 for a 
definition of clinically significant laboratory 
abnormality. For management of subjects 
with elevated liver tests, please refer to 
Section 11.4.6.4.
Added the last sentence to refer to section 
11.4.6.4 


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Revised Text (Amendment 1.0) 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 
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Revised Text (Amendment 1.0) 
Rationale 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 


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Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Study Protocol 652-205 
 
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Section 
Previous Text (Original Protocol) 
Revised Text (Amendment 1.0) 
Rationale 
Section 20.5 Clinical 
Laboratory Tests 
Pre-dose PK Samples (for storage): 
Baseline and Weeks 12 and 24 
PK samples will be stored for analysis and 
assessment of study drug compliance, if 
applicable 
PK Samples: Baseline and Weeks 2, 12 and 
24 
PK samples will be collected and stored for 
analysis. A PK sample must be drawn upon 
repeat testing for abnormalities of ALP, 
ALT, AST or total bilirubin 
Correction and additional detail for PK 
samples. Also added that PK samples 
must be drawn if liver function testing is 
repeated for abnormalities.  
 
Additional minor editorial changes, clarifications, and corrections are not listed. 

SAP_001.pdf: 
NCT02653625 
 
Study ID: 652‐205 
 
Title:  
PERSEUS: A Phase 2 Proof of Concept Study Investigating the Preliminary Efficacy and Safety of 
Cenicriviroc in Adult Subjects with Primary Sclerosing Cholangitis (PSC) 
 
 
Statistical Analysis Plan Date: 12 June 2017 


CONFIDENTIAL 
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FINAL 
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STATISTICAL ANALYSIS PLAN 
 
Tobira Therapeutics, Inc., a subsidiary of Allergan plc 
 
A Phase 2 Proof of Concept Study Investigating the Preliminary Efficacy 
and Safety of Cenicriviroc in Adult Subjects with Primary Sclerosing 
Cholangitis (PSC)  
 
 
 
 
 
12 June 2017 
 
 
Version 1.0 
  
 
 
 
 
 
 
Confidentiality Statement 
 
This statistical analysis plan is the confidential information of Tobira Therapeutics, Inc., a subsidiary of Allergan plc, and is 
intended solely for the guidance of the clinical investigation.  This statistical analysis plan may not be disclosed to parties not 
associated with the clinical investigation or used for any purpose without the prior written consent Tobira Therapeutics, Inc., a 
subsidiary of Allergan plc. 
 
 








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LIST OF TABLES 
 
Page 
 
Table 1 
Schedule of Time and Events 
.......................................................................................................... 
13 
Table 2 
Conventions for Presentation in the analysis displays .................................................................... 
35 
Table 3. 
Conventions for Calculations and Tabulations ............................................................................... 
36 
 
 
 


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LIST OF FIGURES 
 
Page 
 
Figure 1 
Study design schematic. 
.................................................................................................................. 
10 
 
 
 
 
 




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1.0  
STUDY INTRODUCTION   
1.1  
STUDY OBJECTIVES 
The  primary  objective  is  to  evaluate  effects  of  cenicriviroc  (CVC)  on  serum 
alkaline  phosphatase  (ALP)  over  24  weeks  of  treatment  in  adult  subjects  with 
primary sclerosing cholangitis (PSC). 
The  secondary  objective is  
to evaluate  
the safety  and  
tolerability  of  CVC  over 
24 weeks in adult subjects with PSC. 
1.2  
BACKGROUND 
CVC is a novel, once-daily, orally active, and potent inhibitor of ligand binding to 
chemokine receptor type 2 (CCR2) and chemokine receptor type 5 (CCR5). It is 
currently being developed for the treatment of nonalcoholic steatohepatitis in adult 
subjects with liver fibrosis, and in obese subjects with prediabetes or type 2 diabetes 
mellitus  with  suspected  nonalcoholic  fatty  liver  disease.  Given  the  evidence 
supporting the role of CCR2 and CCR5 in inflammatory- and fibrotic-related liver 
diseases, this study will evaluate CVC in adult subjects with PSC by assessing the 
effects on ALP over 24 weeks. 
PSC is  a  life-threatening  idiopathic chronic  cholestatic  disease that affects  the 
intrahepatic or extrahepatic bile ducts of the liver and that cannot be ascribed to 
another  cause,  thus  differentiating  it  from  secondary  sclerosing  cholangitis.  
Inflammation and fibrosis of the bile ducts leading to formation of a beaded pattern 
and  multifocal  bile  duct  strictures  are  
the  hallmark  of  
this  progressive  disease, 
thereby  resulting  in destruction  of  the  bile  ducts,  fibrosis,  cirrhosis,  portal 
hypertension, and ultimately hepatic decompensation resulting in liver failure. 
There  are  currently  no  approved  effective  
therapies  
for  PSC,  with  drug  
therapy 
being used to manage complications and treat symptoms.  Several drugs have been 
used in an attempt to control the disease process but have not shown significant 
benefit.  The  stage  and  degree  of  progression  of  
the  disease  dictate  
the  extent  of 
care, with liver transplantation being the only option  
that can  alter outcome and 
survival.  
 Ursodeoxycholic  acid  (UDCA) has  been  shown  
to  
improve  
the  
liver 
function profile in some patients; however, improvement in long-term survival has 
not been proven.  


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The  established  safety  profile  of  CVC  combined  with  the  well-defined 
anti-inflammatory  and  antifibrotic  properties  associated  with  CCR2/CCR5 
blockade, along with the results from the nonclinical studies, provide a medically 
plausible rationale for development of CVC for PSC. 
The open-label, single-arm, proof of concept (PoC) study aims to evaluate for the 
first time the effects of CVC in adults with PSC by assessing changes in ALP for 
up to 24 weeks.  Furthermore, this study will evaluate the safety and tolerability of 
CVC  in  this  population.  Findings  from  this  study  are  expected  to  expand  the 
understanding of CVC activity in PSC, for which there are no effective treatments 
available, and also will determine if further controlled studies are warranted in this 
orphan disease. 
1.3  
STUDY DESIGN 
This  
is  a  Phase  2,  single-arm,  open-label,  PoC  study  of  CVC  
in  approximately 
25 adult subjects with PSC.  The main objective of this PoC study is exploratory in 
nature and will assess changes in ALP both individually and as a group.  A dose of 
150 mg of CVC (DP7 formulation) will be evaluated. 
Screening will occur within 6 weeks before the baseline visit.  At the baseline visit, 
subjects  who  have  signed  the  informed  consent  form  (ICF) and  meet  all  the 
eligibility  criteria  will  be  enrolled  
in  
the  study  and  begin  
treatment  with  CVC. 
Subjects will return to the study site for on-treatment evaluations at Weeks 2, 4, 8, 
12, 16, and 24.  Approximately 4 weeks after the last dose of study drug (Week 28), 
subjects will undergo follow-up evaluations.  Subjects who discontinue study drug 
before completion of 24 weeks of treatment will be required to return to the clinic 
for an early discontinuation visit. 
The dosing regimen and schedule for this study are shown in Figure 1. 


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Figure 1  
Study design schematic. 
 
ALP = alkaline phosphatase; CVC = cenicriviroc; IBD = inflammatory bowel disese; PSC = 
primary sclerosing cholangitis; ULN = upper limit of normal. 
1.4  
SAMPLE SIZE 
Approximately 25 subjects in total are planned for enrollment, all of whom will be 
treated with open-label CVC. 
Each patient will serve as his or her own control when observing ALP relative to 
baseline.  
 
 
 
 
 
 
 
 
 
 
  
1.5  
RANDOMIZATION 
Since this is a single-arm study, no randomization will be used. 


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1.6  
STUDY PROCEDURES 
Screening will occur within 6 weeks before the baseline visit.  Subjects enrolled 
under Amendments 1 and 2 were also required to have a pre-baseline visit, which 
was removed in Amendment 3.  Eligible subjects will be seen at baseline (Day 1), 
(Week 2), Week 4, Week 8, Week 12, Week 16, and Week 24.  A safety follow-up 
visit will be conducted at Week 28 (±3) days (i.e., 4 weeks after last intake of study 
medication) or at the time of early termination (if a subject discontinues the study 
early).  On visit days, subjects will be asked to come in to the clinic while fasting.  
Blood samples will be collected before dosing.  Subjects will be required to bring 
in study medication on the days of clinic visits, 
and dosing will be conducted on-site 
with a morning snack. 
Data will be collected as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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– 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 


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1.7  
SCOPE OF PLAN 
This  statistical  analysis  plan  (SAP)  provides  a  more  technical  and  detailed 
elaboration of the statistical analyses of the efficacy and safety data as outlined or 
specified  in  the  final  protocol  of  Study Protocol  652-205  (version 
dated 19 November 2015)  and  the  most  recent  amendment  (Version 3  dated 
[14 June 2016]).  Specifications of tables, figures, and data listings are contained in 
a separate document. 
 
This SAP will indicate the methods to be used to analyze the safety and efficacy 
data collected during the study and will supersede any statistical analyses specified 
in the protocol.  The planned analyses identified in this SAP will be included in 
regulatory submissions and future manuscripts.  Additional exploratory analyses, 
which are not defined in this SAP, will be labeled as such in any study report or 
regulatory submission.  


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2.0  
STUDY POPULATIONS 
2.1  
DEFINITIONS OF POPULATIONS FOR ANALYSIS 
The  analysis sets  will  be defined  as specified  in  Sections 2.1.1  through 
Section 2.1.3. 
2.1.1  
Intent-to-Treat Analysis Set  
The intent-to-treat (ITT) analysis set will include all enrolled subjects who received 
at least one dose of study treatment.  This analysis set will be used for all baseline 
characteristics and efficacy analyses. 
2.1.2  
Per Protocol Analysis Set 
Although planned in the protocol, the per protocol analysis will not be conducted 
as determined by the sponsor. 
2.1.3  
Safety Analysis Set   
The safety analysis set will include all subjects who received at least one dose of 
study drug.  This analysis set will be used for all safety analyses.   
As defined in the protocol, the ITT analysis set and safety analysis set are identical.  
Subjects who only receive one dose of study drug and do not return for any post-
baseline visits will be included in the ITT analysis set, although they only provide 
data for safety assessments and no efficacy measurements.  
 




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4.0  
SUBJECT ENROLLMENT AND DISPOSITION 
The following will be summarized with frequencies and percentages of subjects in 
safety  analysis  set:  subject  enrollment  (subjects  enrolled  who  signed  ICF); 
inclusion  in  analysis sets (ITT  and  safety analysis  sets); number  of  subjects 
completing  the  study; number  of  subjects  discontinuing  the  study  before  study 
completion; reasons  for  premature  discontinuation; and  the  number  of  days  on 
study.  The number of subjects discontinued by visit will also be presented.  
Date and time of last dose will also be provided in a listing. 


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5.0  
EVALUATION OF BASELINE MEASUREMENTS 
This  section  describes  
the  analysis of all  demographics,  baseline  characteristics, 
medical  history, and  
tests performed  as  part  of  
inclusion  and  exclusion criteria, 
evaluated at screening exclusively.  
5.1  
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic  parameters  (e.g.,  age [based  on  date  of  birth  and  date  of signed 
informed  consent  form],  sex,  race,  ethnicity,  height,  weight, body mass index 
[BMI]) and baseline characteristics (e.g., type of IBD, and Partial Mayo Risk score 
at baseline)  will be summarized descriptively for  
the  ITT  analysis  set.  
 BMI  
is 
calculated as a person
's weight in kilograms divided by height in meters squared 
(kg/m
2).  
  Demographic  and  baseline  characteristic  data  will  be  summarized  and 
listed for the safety analysis set.  
5.2  
MEDICAL HISTORY   
Medical history, including  pre-treatment AEs, will  be  collected  at the screening 
visit.  Medical history will include all information on a subject until the first dose 
of  study  medication.  
 Medical  history  data (medical  history  verbatim term, start 
date, end date or ongoing status at baseline) will be provided in an appendix listing 
for the safety analysis set.   
5.3  
SCREENING BLOOD TESTS  
At screening, blood will be drawn for infectious disease assessments (hepatitis B 
surface antigen, hepatitis C virus antibody, human immunodeficiency virus 1 and 
human  
immunodeficiency  virus 2  antibodies, and  anti–smooth  muscle  antibody.  
Infectious  diseases  assessments and  anti–smooth  muscle  antibody data  will  be 
provided in a listing for the safety analysis set. 
5.4  
URINE DRUG SCREEN AND PREGNANCY TESTS 
A urine drug result will be collected at screening for amphetamines, barbiturates, 
cocaine, methadone, and opiates.  
  For  
females  of  childbearing  potential  only,  a 
urine pregnancy test (dipstick) and serum pregnancy test will be performed also at 


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screening.  Urine drug screen data and pregnancy test data for enrolled subjects will 
be provided in an appendix listing for the safety analysis set. 


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6.0  
EVALUATION OF TREATMENT EXPOSURE AND COMPLIANCE 
All eligible subjects will receive 150 mg CVC daily for 24 weeks.  CVC should be 
taken every morning with food.  Study medication (i.e., CVC) will be supplied in a 
bottle  containing  37  
tablets  for  each  subject,  which  
is  sufficient  for 28  days of 
dosing.  
 Study  drug  bottles are  dispensed, and  any  unused  medication  and  the 
medication bottles are returned at baseline (dispensed only) and at Week 4, Week 
8, Week 12, Week 16, and Week 24 (returned only). 
6.1  
EXPOSURE TO TREATMENT  
The treatment duration is calculated as the number of days from the date of the first 
dose  of  study  medication  taken  to  the  date  of  last  dose  taken,  inclusively.  
Descriptive statistics will be presented for the safety analysis set. 
6.2  
COMPLIANCE TO STUDY TREATMENT 
Study medication dosing compliance for a specified period is defined as the total 
number of tablets taken by a subject during that period divided by the number of 
tablets expected to be taken during the same period multiplied by 100.  
The number of tablets actually taken will be calculated by subtracting the tablets 
returned  from the  total  number  of  tablets  dispensed.  The  number  of  tablets 
expected to be taken for a specified period is the number of days in that period.  
Descriptive  statistics  for  
the  study  medication  compliance  will  be  presented  
for 
each period between two consecutive visits, and over the 24 weeks (overall) for the 
safety analysis set. 


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7.0  
EVALUATION OF EFFICACY PARAMETERS 
This study will evaluate the effects of CVC in adult subjects with PSC.   
 
 
 
   
 
 
 
7.1  
PRIMARY EFFICACY ENDPOINT  
The primary endpoint for this study is the percent change from baseline through 
Week 24 in ALP. 
The percent change from baseline will be calculated as follows:  
ALP (%) = (value at each visit – baseline value)   ×   100 
   baseline value    
 
 
 
 
 
  
 
 
 
 
 
 
 
.  
If  the  normality  and  homogeneity  of  variance  assumptions  are  significantly 
violated, then the baseline and percentage change from baseline parameters are first 
ranked separately, using the combined data from all visits.  Tied values will receive 
the  mean  value  
(midranks)  of  
the  corresponding  
ranks.  
  Then, the  same mixed-


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effect  repeated  measure model  with  ranked  data  will  be  used  for  the  primary 
efficacy analyses. 
7.1.1  
Pre-treatment Change per Week with On-treatment Change per Week 
Also a comparison of pre-treatment change per week with on-treatment change per 
week will be made through an estimate specification and the corresponding 95% 
confidence  
interval will  be  reported.  
  To  
this  end,  a  similar  
linear  mixed-effect 
repeated measure model will be fit with change from baseline at the visit as the 
dependent variable, visits (baseline, Weeks 4, 8, 12, 16, and 24) as fixed factors, 
baseline score and baseline score-by-visit interaction as covariates, the visit nested 
within  subject and  subject  as  a  random  effect  
to  model  correlations  among  
the 
within-subject repeated measures.  A compound symmetry structure will be used 
initially in the model for the correlation pattern among the repeated measures.  If 
this  does  not  converge,  
then  other  covariance  structure,  
for  example,  
the  spatial 
power  covariance  structure  for  unequally  spaced  
time  
intervals  will  be  used  
to 
model the repeated assessment over time.  Denominator degrees of freedom will be 
estimated using the Kenward-Roger method.  
Pre-treatment change from baseline is defined as follows: 
screening value – baseline value 
For multiple t-test, pairwise comparisons based on the Bonferroni adjusted t-test 
would  produce  comparisons  of  
the  group  means  for on-treatment  change from 
baseline at the visit back to pre-treatment change.  Through this model, two-sided 
95% confidence intervals will be produced for comparisons of the group means at 
the visit (on-treatment change) back to the first time point (pre-treatment change).  
Percent  changes  in  ALP  from baseline  will  be  summarized  using  descriptive 
statistics for the respective pre-treatment and on-treatment visits. 
The ALP raw values and the percent change from baseline in ALP at each visit will 
be  summarized  descriptively  by  visit: before treatment  
(screening,  baseline) and 
during treatment (Weeks 2, 4, 8, 12, 16, and 24).  
Descriptive comparisons will be made for the following:  
• Subjects with a history of IBD vs. no history of no IBD at screening 
• Subjects who received UDCA for at least 3 months before screening vs. who 
have not received UDCA for at least 3 months before screening   
Figures for the percent changes in ALP from baseline by visit will also be presented.  


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7.2  
SECONDARY EFFICACY ENDPOINTS 
Secondary efficacy endpoints include the following: 
•  
The proportion  of  patients  who  achieve  ALP  normalization  
(ALP  values 
outside of the central laboratory reference range at baseline, but within the 
central  laboratory  reference  range  at  each  visit according  to  the  central 
laboratory reference ranges) at each visit, with secondary endpoint defined 
at Week 24  
•  
The proportion of patients who achieve a decrease in ALP of <1.5 × ULN 
at each visit with secondary endpoint defined at Week 24  
•  
The  proportion  of  patients  who  achieve  a  50%  decrease  in  ALP  from 
baseline at each visit, with secondary endpoint defined at Week 24  
 
 
 
  
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 


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. 


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7.4  
PATIENT PROFILE 
Subject profiles will be used to further explore the biological activity of CVC.  The 
subject profiles will contain stick plots of ALP over time, plotted simultaneously 
with  ALT  over  
time.  
  Demographic and  baseline  
factors  
that  will  appear in  
the 
figure will include the following: age, sex, race, type of IBD, Partial Mayo Risk 
score at the screening visit, and treatment-emergent serious adverse events (SAEs).   
8.0  
EVALUATION OF SAFETY PARAMETERS 
The  safety analysis  will  be  performed  using  
the safety  analysis  set.  
 The  safety 
parameters will include AEs, clinical laboratory parameters, vital signs, and ECG 
parameters. 


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The safety endpoints to be summarized are as follows: 
•  
Evaluation  of the  safety  and  tolerability  of  CVC  through  24  weeks  of 
treatment in adult subjects with PSC 
•  
Evaluation of the proportion of subjects with a treatment-emergent adverse 
event (TEAE) or a clinically significant laboratory abnormality (overall and 
of any given type) 
•  
Evaluation of the proportion of subjects who discontinue due to an AE 
•  
Evaluation  of  AEs,  clinical  laboratory  tests,  physical  examination,  and 
12-lead ECG 
Unless otherwise specified, safety will be evaluated using the safety analysis set 
and will be presented in appropriate listings and frequency tables. 
8.1  
ADVERSE EVENTS 
An adverse event is defined as any untoward medical occurrence in a subject or 
clinical  investigation  subject  administered  a  pharmaceutical  product  and  which 
does  not  necessarily  have a  causal  
relationship  with  
this  
treatment.  
 An  AE  can 
therefore  be  any  unfavorable  and  unintended  sign  (including  an  abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, regardless of whether related to the medicinal 
(investigational) product. 
Verbatim  descriptions  of AEs  will  be  coded  by  using  Medical  Dictionary  for 
Regulatory  Activities (MedDRA), Version  18.1 or  later.  
 The  investigator  will 
assess the grade for each AE and SAE reported during the study. 
The  AE severity will  be  graded  according  
to  
the  scale  below, in  addition  
to  
the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.03, Table for Grading the Severity of Adult Adverse Events.  
The clinical significance of the AE is determined by the investigator.   
•  
Grade  1  (mild): asymptomatic  or  mild  symptoms;  clinical  or  diagnostic 
observations only; intervention not indicated 


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•  
Grade 2 (moderate): minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL) 
•  
Grade  3  (severe): medically  significant  but  not  immediately  life-
threatening;  hospitalization  or  prolongation  of  hospitalization  indicated; 
disabling; limiting self-care ADL 
•  
Grade  4  (life-threatening):  life-threatening  consequences;  urgent 
intervention indicated 
•  
Grade 5 (death): death related to AE 
8.1.1  
Serious Adverse Events 
An AE or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 
•  
Death 
•  
Life-threatening AE  (An AE or suspected AE is considered life-threatening 
if, in the view of either the investigator or sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an AE or 
suspected  adverse  reaction  that,  had  it  occurred  in  a  more  severe  form, 
might have caused death.) 
•  
Inpatient hospitalization (i.e., admission, overnight stay) or prolongation of 
existing hospitalization 
•  
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
•  
Congenital anomaly/birth defect 
•  
Important  medical  events (An important medical event is one that,  when 
based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed above in the definition of an SAE. Examples of such events include 
allergic bronchospasm requiring intensive treatment at an emergency room 
or  at  home,  blood  dyscrasias,  convulsions  
that  do  not  result  
in  
inpatient 
hospitalization, or the development of drug dependency or drug abuse.) 


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A treatment-emergent adverse event is defined as any AE (classified by preferred 
term [PT]) not present before the first dose of the study medication or any adverse 
event already present that worsens in severity grade after the first dose of the study 
drug.  If more than one AE is reported before the first dose of the study medication 
and coded to the same PT, then the AE with the greatest severity will be used as the 
benchmark for comparison to the AEs occurring during the study that were  also 
coded to that PT.  Dates and times for AEs will not be imputed.  AEs with a missing 
start  date  or  time  that  leads  to  ambiguity about whether  the  AE  is 
treatment emergent will be considered treatment emergent.  
The incidence of TEAEs will be summarized overall by system organ class (SOC) 
and PT.  For each level of SOC and PT, a subject will be counted only once for the 
purpose of summarization. 
The incidence  of  treatment-emergent SAEs, TEAEs  leading  to study  drug 
discontinuation, and TEAEs related to study drug will summarized by SOC and PT. 
A summary of TEAEs occurring in 5% or more of subjects will be reported by SOC 
and PT, and information can be extracted from the main TEAE incidence table. 
Separate summaries will be presented for Grade 3 toxicities resulting in study drug 
interruption  by  SOC and  PT  and for Grade  4 toxicities resulting  
in study drug 
discontinuation by SOC and PT. 
In the summary tables (except the summaries of the TEAEs reported by maximum 
severity) the number and percentage of subjects reporting at least one TEAE will 
be presented, followed by the number of events.  For each SOC, the number and 
percentage  of  subjects  reporting  one  or  more  TEAEs  within  that  SOC  will  be 
reported.  Then, each PT within that SOC will be reported, showing number and 
percentage of subjects reporting at least one TEAE classified as that particular PT.  
The  summary  will  be  produced  at  the  SOC  level  according  to  the  MedDRA 
internationally  agreed  sorting  order, and  then  within  the  SOC  by  descending 
frequency at the PT level. 
For the summary of TEAE by maximum severity grade, if a subject has more than 
one event with different severities within a given PT, then the most severe event 
will be included in the table.  Within each SOC, each TEAE listed by PT will have 
up to five associated rows, one for each observed severity grade.  The number and 


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percentage of subjects who have at least one TEAE with that PT at that greatest 
severity will be shown.  If a subject had more than one TEAE mapped to the same 
PT, then that TEAE will be represented according to the corresponding maximal 
level of severity.  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
. 
8.2  
PRIOR AND CONCOMITANT MEDICATIONS 
Any prior medication received within 28 days of the first dose of study drug will 
be recorded in the case report form (CRF).  All medications (or treatments) other 
than study drug taken or received by the subject at any time during the study from 


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screening  through  the  4-week follow-up  visit  will  be  considered  concomitant 
medications (or treatments). 
If a medication has an end date that occurs before first dose date, that medication 
will be considered a prior medication.  If a medication has a start date that occurs 
before  first  dose  date  and  an  end  date  that  occurs after  first  dose  date,  that 
medication will be considered both prior and concomitant.  If a medication has a 
start  date  that  occurs  after  first  dose  date,  that  medication  will  be  considered 
concomitant.  
 If a  missing  start  date,  start  
time,  end  date,  or  end  
time  
leads to 
ambiguity in whether a medication is prior or concomitant, the medication will be 
considered concomitant. 
Prior and concomitant medications will be mapped to a World Health Organization 
Drug  Dictionary  Enhanced  (WHO  DDE), September  2015.   The  number  and 
percent  of  subjects  taking  concomitant  medications  will  be  summarized  by 
Anatomical Therapeutic Classification Level 1 code, by descending frequency at 
the PT level.  Prior and concomitant medication will be listed. 
8.3  
CLINICAL LABORATORY PARAMETERS 
Hematology, clinical chemistry, and urinalysis data will be collected at screening, 
the baseline/Day 1 visit, and at the Week 2, Week 4, Week 8, Week 12, Week 16, 
and Week 24 visits. 
Coagulation profile will be performed only at screening, baseline, and Week 24 and 
will include INR. 
Hematologic profile will report the following parameters: hematocrit, hemoglobin, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean 
corpuscular volume, platelet count, red blood cell distribution width, red blood cell 
count,  white  blood  cell  count, and  white  blood  cell  differential  
(absolute  counts 
only): basophils, eosinophils, lymphocytes, monocytes, and neutrophils. 
Clinical chemistry profile will include: cholesterol (total), high-density lipoprotein, 
low-density  lipoprotein,  triglyceride, amylase  (reflex  lipase  if  amylase  ≥1.5  × 
ULN), bicarbonate, blood urea nitrogen, calcium, chloride, creatine phosphokinase, 
creatinine, glucose,  lactate  dehydrogenase,  magnesium,  phosphorus,  potassium, 
sodium, total protein, and uric acid. 


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Urinalysis  profile  will  report color  and  appearance,  pH  and  specific  gravity, 
bilirubin,  glucose, ketones, leukocytes,  nitrite, occult  blood, protein,  and 
urobilinogen. 
All hematology, coagulation, clinical chemistry, and nominal urinalysis data will 
be  summarized  at  each  time  point  for  the  actual  values  and  for  changes  from 
baseline.   Descriptive  summaries of  quantitative  changes  in urinalysis will  be 
presented by study visit in a separate table. 
Laboratory abnormalities will be graded according to NCI CTCAE, Version 4.03, 
and recorded as AEs. 
The number and percentage of subjects experiencing with Grade 3 or 4 Treatment-
emergent abnormal clinical chemistry values will be presented. 
8.4  
ELECTROCARDIOGRAMS 
A 12-lead ECG will be taken at the baseline/Day 1 visit, and at Week 24.  ECGs 
will be performed with the subject in the supine position after 5 minutes of rest and 
before any blood draws. 
 
ECG parameters include ventricular heart rate 
(beats/min), 
RR interval (msec), PR interval (msec), QRS interval (msec), QT interval (msec), 
QTcF interval (msec).  Results will be classified as follows: normal; abnormal, not 
clinically significant; and abnormal, clinically significant. 
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS 
duration, QT interval, and QTc) at each visit (Baseline and Week 24) and changes 
from baseline values at Week 24 will be presented.  The QTc will be calculated 
using the Fridericia correction. 
A  shift  table  from  baseline  to Week  24 in  the clinical  significance  as per 
investigator’s overall interpretation of the ECG will be presented for the following 
categories: normal;  abnormal, not  clinically  significant;  and  abnormal, clinically 
significant.  The tabular display will also show total number of subjects with post 
baseline, clinically significant ECG abnormalities according to the investigator’s 
overall interpretation. 
ECG data will be listed. 


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8.5  
VITAL SIGNS 
Vital sign measurements (sitting systolic and diastolic blood pressure, temperature, 
heart rate, and respiration rate) will be taken at screening, the baseline/Day 1 visit, 
and at the Week 2, Week 4, Week 8, Week 12, Week 16, and Week 24 visits.   
Descriptive  summaries  of raw  values  of vital  signs  (systolic  blood  pressure, 
diastolic blood pressure, heart rate) will be presented at study visit.  Descriptive 
summaries of changes from baseline in vital signs will also be presented by study 
visit.    
Vital signs will be listed. 
8.6  
PHYSICAL EXAMINATION  
A complete physical examination will be performed at the Screening 1 visit and the 
baseline/Day 1 visit.  A symptom-directed physical examination will be performed, 
as  needed,  at  the  Screening  2 visit,  at  all on-treatment visits,  at  the early 
discontinuation visit within 48 hours of stopping study medication, and at the 4-
week follow-up visit.  The complete physical examination will include (but will not 
be limited to) the following organ or body system assessments: skin; head, eyes, 
ears, nose, and throat; thyroid; lungs; cardiovascular; abdomen (liver and spleen); 
extremities;  lymph  nodes;  and  a  brief  neurological  examination.    Abbreviated 
symptom-directed physical examinations will target signs and symptoms. 
Any abnormal findings that are considered clinically significant in the opinion of 
the investigator will be recorded as AEs or be captured as medical history, if already 
present at screening. 
Physical examination data will be listed. 
8.7  
PROCEDURES AND THERAPIES 
Any  procedures  and  non-drug  therapies  administered  during  the  study that  are 
recorded in the (CRF) will be listed. 


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9.0  
SPECIFICATIONS FOR ANALYSIS DISPLAYS 
9.1  
ANALYSIS DISPLAY FORMAT 
All  analysis  displays  will  be  created  by  using  statistical  and  summarization 
procedures in 
  Displays will be produced by using the Courier 
New 8-point font.  Headers will also be in Courier New 8-point font. 
All displays are intended to be printed as landscape on 8.5- × 11-in paper.  The top 
and bottom margins will be 0.50 in, and the left and right margins will be 0.75  in.   
9.2  
CONVENTIONS FOR PRESENTATION 
The  conventions  for presentation  in  the  analysis  displays  are  shown  in  
Table 2.   
Table 2   
Conventions for Presentation in the analysis displays 
Convention 
Description 
Decimals for summary 
statistics 
General rule: Relative to number of decimals in original data, use 
1 more decimal for mean, median, and percentiles, 2 more decimals 
for standard deviation/error, and same number for minimum, 
maximum, and range. Do not exceed 4 decimals. Some laboratory 
parameters or other data may require judicious deviation from this 
rule. 
Format for percentages  
Display percentages with 1 decimal. 
Sort order in listings  
Subject identification is sorted sequentially. 
 
 
 


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9.3  
CONVENTIONS FOR CALCULATIONS AND TABULATIONS 
The conventions for calculations and tabulations are shown in Table 3. 
Table 3.   
Conventions for Calculations and Tabulations 
Convention 
Description 
Age calculation 
Age is calculated as an integer in years as the difference 
between the subject’s date of informed consent and the date of 
birth.  
AE counting: general 
summary 
In summary displays, AEs are counted only once per subject 
within MedDRA category (e.g., overall, system organ class, 
and preferred term). 
AE counting: summary by 
assessment 
When AEs are summarized within levels of another AE 
assessment (e.g., causality or severity), AEs are counted once 
per subject at the worst level of the assessment (e.g., strongest 
relationship to study drug or greatest severity).  A missing or 
unknown value for the assessment will be considered 
Unknown. 
“Other” category counting 
For purposes of summarization, conditions recorded in the case 
report form as an “Other” category condition will be counted 
only once per subject.  Hence, the count becomes the number 
of subjects reporting at least one “Other” condition vs. subjects 
reporting none.  All conditions will be listed in the appendix. 
AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities. 
 


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10.0  
REFERENCES 
1  
Vickers AJ. The use of percentage change from baseline as an outcome in 
a controlled trial is statistically inefficient: a simulation study.  2001:1-6. 
2  
Keene  ON.  The  
log  
transformation  
is  special.  Stat  Med  1995;14(8):811-
819. 
3  
Törnqvist  L,  Vartia  P,  Vartia  Y.  How  Should  Relative  Changes  be 
Measured? The American Statistician 1985;39(1):43-46.