Conditions: Hepatitis C Chronic Hepatitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate daclatasvir in combination with sofosbuvir given to children with chronic hepatitis C infection

Detailed description:

Arms:
arm 1: Specified dose on specified days for specified duration

Interventions: intervention 1: Daclatasvir intervention 2: Sofosbuvir
Intervention descriptions: intervention 1: Specified dose on specified days for specified duration intervention 2: Specified dose on specified days for specified duration

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
AI444423
IND Number:
N/A
EX-US
Non-IND
EUDRACT Number:
2017-003338-94
Date:
30-Nov-2017 
Revised Date:
18-Dec-2019
Clinical Protocol AI444423
Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Safety and Efficacy of 
Daclatasvir (DCV) in Combination with Sofosbuvir (SOF) in Children from 3 to less than 18 
Years of Age with GT-1 to -6 Chronic Hepatitis C (CHC) Infection
Revised Protocol 01
Study Director
Medical Monitor
Michelle Treitel, PhD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
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promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Revised 
Protocol 01
18-Dec-2019

Early termination of the study

Participants will not be enrolled in Cohorts 2 and 3

Long-term follow-up period will be reduced from the initially planned 96 
week follow-up period after Post-Treatment Week 12.

Limitation of enrollment in Cohort 1 to participants weighing 45 kg

Removal of the analyses related to the secondary objectives of evaluation 
of genotypic substitution(s) associated with virologic failure and the 
assessment of palatability and acceptability of the daclatasvir 
formulations

 

Removal of Interim Analysis

Update of Appendix 5 with July 2017 version 2.1 of DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events
Original 
Protocol
30-Nov-2017 
Not applicable
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section 
Number & 
Title
Description of Change
Brief Rationale
Title Page
Update with name of new Medical Monitor
Document 
History
Added Revised Protocol 01 to the table
 
 
Synopsis
Updated to align with changes made in the protocol body as 
described below
 
 
Table 2-2: On 
Treatment 
Procedural 
Outline
Addition of footnote to clarify drug dispensing and dosing 
at the Treatment Week 12 visit
 
 
 
 
 
Table 2-3:Post-
Treatment 
Procedural 
Outline
Addition of note to indicate that upon approval of Revised 
Protocol 01, participants should perform an End of Study 
visit and do not need to complete any other post-treatment 
visit if not yet conducted
 
 
 
 
Addition of note: With early termination of this study, only 
participants 12 to <18 years of age will be enrolled in the 
study (Cohort 1). Upon approval of the revised protocol, all 
enrolled participants will be asked to return to the clinic to 
perform an End of Study (EOS) visit and will not complete 
the initially planned 96 week LTFU period. No participants 
3 to <12 years of age will be enrolled (Cohorts 2 and 3).
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section 
Number & 
Title
Description of Change
Brief Rationale
Added note: On 18 October 2019, the PDCO adopted a 
positive opinion on BMS’ PIP request for a full product-
specific waiver (EMEA-001191-PIP01-11-M03) on the 
grounds that clinical studies with DAKLINZA cannot be 
expected to be of significant therapeutic benefit to or fulfil a 
therapeutic need of the specified paediatric subsets.  As a 
result, BMS will terminate Study AI444423 early.
 
 
 
 
 
 
 
Added note: With regard to paediatric HCV treatment 
regimens, all-oral, pangenotypic, non-DCV containing 
regimens, are being developed with the intention to 
commercialize them in the context of their existing adult 
MA; these regimens are more advanced in their 
development than the DCV+SOF regimen, the regimen 
being investigated in this study. In this context, on 18 
October 2019, the PDCO of the EMA adopted a positive 
opinion on BMS’ PIP request for a full product-specific 
waiver (EMEA-001191-PIP01-11-M03) on the grounds that 
clinical studies with DAKLINZA cannot be expected to be 
of significant therapeutic benefit to or fulfil a therapeutic 
need of the specified paediatric subsets. As a result, BMS 
will terminate Study AI444423 early.
 
 
 
 
 
.
Section 4 
Objectives and 
Endpoints
Added note: With the early termination of this study, 
previously collected data to address PK, SVR, and select 
safety assessments (e.g. AEs, laboratory tests, end of 
treatment subject status) will be reported only within 
adolescent participants 12 to <18 years of age. The 
secondary objectives related to assessment of genotypic 
substitutions associated with virologic failure and the 
acceptability and palatability of the daclatasvir formulations 
and the exploratory objective regarding durability of 
response will not be reported.
 
 
Section 5.1 
Overall Design
Addition of note: Due to the early termination of the study, 
only participants 12 to <18 years of age were enrolled in the 
study into Cohort 1; no participants will be enrolled in 
Cohorts 2 and 3. The duration of the Long-Term Follow-Up 
period for these participants will be less than the initially 
planned 96 weeks. Upon approval of this revised protocol, 
participants will return to the study center to conduct an 
EOS visit.
 
 
Section 5.2 
Number of 
Participants
Addition of note: Although the original protocol provided 
for a total of 30 participants, only 5 participants, limited to 
Cohort 1, will have been enrolled in the study, as the result 
of the early termination of this study.
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section 
Number & 
Title
Description of Change
Brief Rationale
 
 
Added note: Due to the early termination of the study, only 
5 participants 12 to <18 years of age were enrolled in the 
study into Cohort 1; the duration of the Long-Term Follow-
Up period for these participants will be less than the 
initially planned 96 weeks. No participants will be enrolled 
in Cohorts 2 and 3.
 
 
 
Section 6.1 
Inclusion 
Criteria
Added limitation of enrollment to Cohort 1 participants ≥ 
45 kg on Day 1
 
 
 
Section 7.1 
Treatments 
Administered
Updated text with the  limitation of participants in Cohort 1 
to participants ≥ 45 kg on Day 1
Added note: Due to the early termination of the study, 
participants will only have been enrolled in Cohort 1 and 
administered the adult formulations of DCV and SOF (60 
mg dose of DCV and 400 mg dose of SOF). No paediatric 
formulations will be administered in the study.
Added footnote to Table 7.1-1 to clarify that adult 
formulation would only be administered to participants in 
Cohort 1 who were required to be ≥ 45kg
 
 
 
Section 8.1.1 
Post Study 
Treatment 
Follow Up
Clarified duration of follow up period for participants who 
discontinue as ‘completion of the designated follow up 
period’ versus ‘conclusion of study’
 
Section 8.2 
Discontinuation 
from the Study
Added that follow-up procedures should be completed prior 
to initiation of alternate HCV therapy
 
 
Section 9.2.1 
Time Period 
and Frequency 
for Collecting 
AE and SAE 
Information
Added SOF SmPC as reference safety information
 
 
Section 9.4.4 
Clinical Safety 
Laboratory 
Assessments
Added note: All laboratory assessments scheduled for the 
Post-Treatment Week 108 visit should be performed at the 
EOS visit.
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 9.8.2.1
HCV Virologic 
Resistance 
Testing
Added note that resistance testing will not be performed on 
Baseline samples
 
Section 9.8.2.3 
Brief 
Questionnaire/I
nterim Phone 
Contact
Added note: Due to the early termination of the study, 
participants will perform an EOS visit and interim 
telephone contact will not be necessary after the EOS visit.
 
 
Section 10.1 
Sample Size 
Determination
Added note: Not Applicable due to the early termination of 
the study; a total of 5 participants will have been enrolled in 
the study into Cohort 1.
 
Section 10.3 
Statistical 
Analyses
Added note: With the early termination of this study, 
previously collected data to address PK, SVR, and select 
safety assessments (e.g. AEs, laboratory tests, end of 
treatment subject status) will be reported only within 
adolescent participants 12 to <18 years of age. Given the 
small number of subjects enrolled in the study, no statistical 
analyses will be performed. Genotypic substitution(s) 
associated with virologic failure and the acceptability and 
palatability of the DCV formulations will not be reported. 
Likewise, an interim analysis will not be performed.
 
Section 10.3.2 
Resistance 
Analyses
Added note: These data will not be reported because the 
prevalence of the relevant RAV varies from 4-10% and as 
such might not be detected at Baseline in a sample size of 
5 participants. As of 18 October 2019, all participants had 
completed at least 41 weeks of post-treatment follow-up 
and none had experienced viroloogic failure.
 
Section 10.3.5.1 
Acceptability 
and Palatability 
Assessments of 
Daclatasvir 
Formulations
Added note: These data will not be reported as only the 
adult formulation was administered in the study and there is 
no value to perform an analysis of the adult formulation
 
Section 10.3.6 
Interim 
Analysis
Added note: An interim analysis will not be performed. As 
only 5 subjects will be enrolled in this study, analyses are 
not needed to guide dosing for additional participants.
 
Appendix 5
Updated version of DIADS table from December 2004 to 
July 2017 version 2.1 of DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events
 
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01 ......................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
 
 
 
 
 
 
 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
 
 
 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
 
 
 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.2 Adverse Events ................................................................................................. 
 
1
3
5
10
13
19
31
31
31
32
33
33
34
34
36
38
38
38
38
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9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital signs................................................................................................. 
 
9.4.3 Electrocardiograms ................................................................................. 
 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.5 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetics .............................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Resistance Analyses ............................................................................... 
 
10.3.3 Safety Analyses....................................................................................... 
 
10.3.4 Pharmacokinetic Analyses ..................................................................... 
 
10.3.5 Other Analyses ....................................................................................... 
 
10.3.5.1 Acceptability and Palatability Assessments of Daclatasvir 
Formulations ......................................................................................... 
 
10.3.6 Interim Analyses ..................................................................................... 
 
 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
49
50
50
50
50
51
51
52
52
52
52
52
52
53
55
55
58
58
58
59
59
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APPENDIX 4 FEMALE OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 DIVISION OF AIDS (DAIDS) TABLE FOR GRADING THE 
SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH 
DATE: JULY, 2017 ................................................................................................ 
 
 
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1
SYNOPSIS
Protocol Title: Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Safety and 
Efficacy of Daclatasvir (DCV) in Combination with Sofosbuvir (SOF) in Children from 3 to 
less than 18 Years of Age with GT-1 to -6 Chronic Hepatitis C (CHC) Infection
Study Phase: 2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Population:
Paediatric patients (3 years to < 18 years of age) monoinfected with Hepatitis C virus (genotypes 
(GT)-1 to -6) who are non-cirrhotic and either treatment-naive or treatment-experienced. 
Note: With the early termination of the study, only adolescent participants 12 to <18 years 
of age will have been enrolled in the study.
Objectives and Endpoints:
Note: With the early termination of this study, previously collected data to address PK, 
SVR, and select safety assessments (e.g. Adverse Events (AEs), laboratory tests, end of 
treatment subject status) will be reported only within adolescent participants 12 to <18 years 
of age. The secondary objectives related to assessment of genotypic substitutions 
associated with virologic failure and the acceptability and palatability of the daclatasvir 
formulations 
 will not be
reported.
Objectives
Endpoints
Primary

To evaluate the PK profile of DCV in 
combination with SOF in children and 
adolescents aged 3 to <18 years of age

Pharmacokinetic parameters (Cmin, Cmax, Tmax, AUC 
(TAU), CLT/F) for DCV derived from plasma concentration
versus time data on Day 10 (+/-3 days) within a dosing 
interval.

In Cohort 3 (ages 3 to <6 years of age); PK parameters will 
be assessed using model-based analyses with 5 samples from 
each participant.
Secondary

To assess the safety and tolerability of the 
DCV+SOF 
regimen 
in 
paediatric 
participants

To 
determine 
the 
proportion 
of 
participants with SVR12

Frequencies of serious adverse events (SAEs), adverse 
events (AEs) leading to discontinuation of study therapy, 
AEs by intensity, and laboratory abnormalities by toxicity 
grade on treatment and during follow-up

Proportion of participants with HCV RNA <LLOQ (TD or 
TND) at post-treatment follow-up Week 12
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Objectives
Endpoints

To evaluate
genotypic substitution(s) 
associated with virologic failure

To assess the acceptability and palatability 
for the age-appropriate chewable tablet 
formulation, and acceptability for adult 
film-coated tablet

Frequencies of NS5A and NS5B resistance-associated 
variants (RAVs) emergent at the time of virologic failure on 
treatment and during follow-up in non-responders

Summary of responses from questionnaire assessing
acceptability and palatability at Day 1, Week 4, and Week 12
 
 
 
 
 
Overall Design:
The study will be an open-label, single-arm, descending-age cohort trial evaluating the PK profile, 
safety, tolerability, and efficacy of DCV+SOF administered for 12 weeks to paediatric participants
(3 < 18 years of age) with CHC virus infection.  
Enrolment will begin with Cohort 1, followed by Cohorts 2 and 3.  

Cohort 1: 12 to < 18 years of age

Cohort 2: 6 to < 12 years of age

Cohort 3: 3 to < 6 years of age
Note: Due to the early termination of the study, only participants 12 to <18 years of age were 
enrolled in the study into Cohort 1; no participants will be enrolled in Cohorts 2 and 3.
Samples for assessment of DCV PK will be collected on Day 10 of the study.  In each cohort, DCV 
PK will be evaluated after the initial 5 participants complete their Day 10 visit in order to determine 
if the target DCV exposure is achieved. 
Enrolment in Cohorts 2 and 3 will be dependent on the availability of the European Commission 
(EC) approved SOF age appropriate dose and formulation for the corresponding age cohort.
Post treatment, participants will be followed for 12 weeks to assess sustained virologic response 
at Post-treatment Week 12 (SVR12) and then for an additional 2 years (96 weeks) as long-term 
follow-up to assess 
, durability of response, long-term safety, and the persistence of 
resistance variants in non-responders. 
Note: With the early termination of this study, participants will not complete the initially 
planned 96 weeks of LTFU. As of 18 October 2019, all participants will have completed their 
Post Treatment Week 24 visit and approximately 41 to 53 weeks of post-treatment follow-up; 
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participants will be asked to return to the study site to perform an EOS visit upon approval of 
the revised protocol.
Number of Participants: 
A minimum of 30 participants will be evaluated for the primary endpoint (PK), and assigned to 
3 age-descending cohorts (12 to <18 years of age, 6 to < 12 years of age and 3 to < 6 years of age); 
at least 8 participants will be treated in each age cohort.
Note: Although the original protocol provided for a total of 30 participants, only 5 participants,
limited to Cohort 1, will have been enrolled in the study as the result of the early termination 
of this study.
For further information regarding sample size determination, please refer to Section 10.1.
Treatment Arms and Duration:
This will be a single-arm study in which participants will be administered DCV+SOF QD for 
12 weeks.  
Study treatment:
Product Description / 
Class and Dosage 
Form
Potency
IP/
Non-
IMP
Blinded 
or Open 
Label
Packaging / Appearance
Storage 
Conditions
(per label)
Daclatasvira
(BMS-790052-
05/DCV) Film Coated 
Tablet
60 mg 
(as the 
free base)
IP
Open
Bottle
Each tablet is plain, green, 
biconvex, pentagonal and 
film-coated.
Store per IP 
Label.
Daclatasvir 
Dihydrochloride 
Chewable Tablet
20 mg
IP
Open
Blister
A white to off white, flat, plain 
oval tablet
Store per IP 
Label.
Daclatasvir 
Dihydrochloride 
Chewable Tablet
10 mg
IP
Open
Blister
A white to off white, flat, plain 
round tablet
Store per IP 
Label.
Daclatasvir 
Dihydrochloride 
Chewable Tablet
5 mg
IP
Open
Blister
A white to off white, flat, plain 
round tablet
Store per IP 
Label.
Sofosbuvirb, (SOF)
Film Coated Tablet
400 mg
IP
Open
Bottle
Yellow, capsule-shaped, film-
coated tablets debossed with “GSI” 
on one side and “7977” on the 
other side
Store per IP 
Label
Sofosbuvir (SOF)
(paediatric formulation, 
TBD)
50 mg
IP
Open
TBD
Store per IP 
Label
a Daclatasvir clinical presentation, adult formulation
b Sofosbuvir adult formulation
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Note: Due to the early termination of the study, participants will only have been enrolled 
in Cohort 1 and administered the adult formulations of DCV and SOF. The paediatric 
formulations will not be administered in the study.
Study Schematic:
The total duration of the study for each participant is approximately 2.5 years:

Screening: 42 days

Treatment Duration: 12 weeks

Post-Treatment Follow-up Duration: Upon completion of the Post-treatment Week 12 visit, 
participants will be followed for an additional 2 years (96 weeks) as long-term follow-up to 
assess SVR24, durability of response, long term safety, and the persistence of resistance 
variants in non-responders.
Note: With the early termination of this study, the duration of the study for participants will be 
less than 2.5 years; participants will not complete the initially planned 96 weeks of long-term
follow-up. As of 18 October 2019, all participants will have already completed their Post 
Treatment Week 24 visit and approximately 43 to 51 weeks of post-treatment follow-up. Upon 
approval of the revised protocol, participants will be asked to return to the study site to perform 
an EOS visit.
The dose of DCV will be determined according to the weight of the participant prior to dosing on 
Day 1; the dose will not be adjusted to weight over the course of the study. 
DCV should be administered as the adult film-coated 60-mg tablet formulation to adolescent 
participants 12 to < 18 years of age (Cohort 1 who are 45 kg) and as a paediatric chewable-tablet 
formulation (5, 10, 20 mg) to all participants < 12 years of age (Cohorts 2 and 3) according to 
Table 7.1-1.
The SOF dose administered will be the dose and formulation approved by the European 
Commission for the corresponding age cohort.  Cohort 1 will receive the 400-mg adult 
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formulation. Enrollment in Cohorts 2 and 3 will begin following EC approval of the age 
appropriate dose and formulation for SOF for those respective age groups.
Doses of DCV and SOF assigned on Day 1 cannot be modified but can be interrupted or 
discontinued to manage adverse events. In the event of interruption or discontinuation, both DCV 
and SOF must be stopped simultaneously. DCV+SOF treatment can be interrupted for a maximum 
of 7 days, and if not restored after 7 days, the treatment should be permanently discontinued.
Note: DCV dose modification will only be permissible if PK data from the initial 5 participants in 
the cohort suggest that the dose administered does not achieve the desired exposure criteria. The 
sponsor will advise how to modify the dose of DCV being administered, if needed.
Note: With the early termination of this study, only the adult formulations of DCV and SOF 
will be administered in this study.
Revised Protocol No.: 01
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (AI444423)
Procedure
Screening Visita
Notes
Eligibility Assessments
Informed Consent and Assent (where applicable)
X
Inclusion/Exclusion Criteria
X
Medical History
X
To include route of HCV transmission and prior response to anti-HCV 
medications, if applicable
HCV Serology
X
HCV RNA and backup HCV RNA sample
X
HCV Genotype
X
HIV, HBV Serology
X
Alpha fetoprotein (AFP)
X
Assessment of liver fibrosis status by liver biopsy, 
Fibroscan or Serologic test (APRI [AST to platelet ratio 
index])
X
Refer to Section 6.2 for fibrosis determination criteria and timing of 
assessments
Safety Assessments
Physical Examination
X
Physical Measurements
X
Height and weight
Vital Signs
X
Includes body temperature, respiratory rate, and seated blood pressure and 
heart rate. Blood pressure and heart rate should be measured after the 
participant has been at rest
Serious Adverse Events Assessment
X
Report SAEs that occur after consent is obtained
Concomitant and Previous Medication Use
X
Refer to Section 7.7.1 for details 
Laboratory Tests
X
Fasting not required, see Section 9.4.4
ECG, Single 12-Lead
X
ECG should be recorded after the participant has been at rest
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Table 2-1:
Screening Procedural Outline (AI444423)
Procedure
Screening Visita
Notes
Pregnancy Test FOCBP only
X
Urine pregnancy test (minimum sensitivity equivalent units 25 IU/L or
equivalent units of HCG); Collect serum sample if urine is positive.
Pregnancy test should be repeated within 24 hours prior to first dose of study 
treatment
Obtain participant number via IRT
X
a All screening procedures, except where noted, must be completed within 42 days of the screening visit
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Table 2-2:
On Treatment Procedural Outline (AI444423)
Procedure
Day 1 
Visit
During 
Treatment
Day 10 
(3 days)
During 
Treatment 
Weeks 4 and 8
(3 days)
End of 
Treatment/
Week 12
(3 days)/Early 
Discontinuation
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Review eligibility criteria prior to treatment to 
ensure requirements are met
Safety Assessments
Targeted Physical Examination
X
X
X
Should include assessment of heart, lung, and 
abdomen
Physical Measurements
X
X
X
X
Height and weight
Vital Signs
X
X
X
X
Includes body temperature, respiratory rate, and 
seated blood pressure and heart rate; blood 
pressure and heart rate should be measured after 
the participant has been at rest
Serious Adverse Event Assessment
X
X
X
X
Adverse Events Assessment
X
X
X
X
AE assessment begins after Day 1 study 
treatment administration
Concomitant Medication Use
X
X
X
X
See Section 7.7.1
Laboratory Tests
X
X
X
X
Fasting not required.  See Section 9.4.4
Pregnancy Test FOCBP only
X
X
X
Urine pregnancy test (minimum sensitivity 
equivalent units 25 IU/L or equivalent units of 
HCG); results of urine test, performed within 
24 hours of first dose, should be negative prior 
to dosing
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Table 2-2:
On Treatment Procedural Outline (AI444423)
Procedure
Day 1 
Visit
During 
Treatment
Day 10 
(3 days)
During 
Treatment 
Weeks 4 and 8
(3 days)
End of 
Treatment/
Week 12
(3 days)/Early 
Discontinuation
Notes
Efficacy Assessments
HCV RNA and backup HCV RNA
X
X (primary 
tube 
required; 
backup 
sample 
optional)
X
X
Participants with indeterminate HCV RNA 
testing or with suspected on treatment failure 
(HCV virologic breakthrough) will be retested 
for HCV RNA, HCV genotype, and HCV 
resistance along with PK trough levels at an 
unscheduled visit as soon as possible before their 
next regular visit
HCV Resistance and back up HCV 
Resistance 
X
X (primary 
tube 
required; 
backup 
sample 
optional)
X
X
HCV Genotype
HCV Genotype sample to be collected at time of HCV RNA sample collection to confirm suspected virologic 
breakthrough/other on-treatment failure
Other Assessments
 
X
Serial Blood PK of DCV and trough 
levels of SOF and its metabolites (all 
participants)
X
See Section 9.5
Trough Blood PK: DCV, SOF and its 
metabolites (all participants) 
X
X
See Section 9.5
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Table 2-2:
On Treatment Procedural Outline (AI444423)
Procedure
Day 1 
Visit
During 
Treatment
Day 10 
(3 days)
During 
Treatment 
Weeks 4 and 8
(3 days)
End of 
Treatment/
Week 12
(3 days)/Early 
Discontinuation
Notes
Acceptability and Palatability 
Questionnaire 
X
X
X
Day 1, Week 4, and Week 12/
End of treatment/Early Discontinuation, See 
Section 9.8.2.2
Brief Questionnaire
X
X
A brief questionnaire will be completed by the 
participant/guardian to include contact details 
such as email address, primary care physician, 
and 2 non-residing contacts in case the 
participant/guardian cannot be reached for their 
study assessments unless prohibited by local 
laws or regulations
Study Treatment
Register eligible participants for 
treatment via IRT 
X
Day 1 age and weight to be used for determining 
formulation and dose 
Dispense Study Treatment and on-site 
dosing
X
X
Xa
Study treatment should be administered in office
at all study visits and after trough PK sample 
collection on all visits after Day 1
Assessment of Study Medication 
Use/Treatment Compliance 
X
X
X
See Section 7.6
a If the participant cannot attend the Treatment Week 12 visit as scheduled, the participant should complete treatment on Day 84. Treatment Week 12 assessments 
should be conducted once the participant returns to the site and no additional dispensing or dosing will occur on this visit. Similarly drug dispensing and dosing 
will not occur for those participants that discontinue early from the study
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Table 2-3:
Post-Treatment Long-term Procedural Outline (AI444423)
Procedure
Post-
Treatment
Week 4
(7 days)
Post-
Treatment
Weeks 12 
and 24
(7 days)
Post-
Treatment
Weeks 48, 72, 
96
(6 weeks)
Post-Treatment
Week 108/
End of Study
(6 weeks) 
Notes
Safety Assessments
Targeted Physical Examination
X
X
Should include assessment of heart, lung, 
and abdomen
Physical Measurements
X
X
X
X
Height and weight
Vital Signs
X
X
X
X
Includes body temperature, respiratory 
rate, and seated blood pressure and heart 
rate. Blood pressure and heart rate should 
be measured after the participant has 
been at rest.
Serious Adverse Events Assessment
X
X
X
X
Only SAEs related to study drug or
protocol-specified procedure(s) should be 
reported after Post-Treatment Week 4. 
Adverse Events Assessment
X
Hepatic disease progression
X
X
X
X
Development of cirrhosis and/or its 
complications
Laboratory Tests
X
X
X
X
Fasting not required
Pregnancy Test FOCBP only
X
Post-Treatment Week 4 only.  Urine
pregnancy test; collect serum if urine is 
positive
Efficacy Assessments
HCV RNA and backup HCV RNA 
sample
X
X
X
X
Participants with suspected relapse will 
have samples collected to retest HCV 
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Table 2-3:
Post-Treatment Long-term Procedural Outline (AI444423)
Procedure
Post-
Treatment
Week 4
(7 days)
Post-
Treatment
Weeks 12 
and 24
(7 days)
Post-
Treatment
Weeks 48, 72, 
96
(6 weeks)
Post-Treatment
Week 108/
End of Study
(6 weeks) 
Notes
HCV Resistance and backup HCV 
Resistance
X
X
X
X
RNA, HCV genotype, and HCV 
resistance at an unscheduled visit as soon 
as possible before their next regular visit
HCV Genotype
HCV Genotype sample to be collected at time of HCV RNA sample collection for suspected relapse to evaluate for 
possible re-infection/relapse
Other Assessments
Confirm Brief Questionnaire 
Responsesa
X
X
X
X
Interim Phone Contacts 
Required on a quarterly basis in between office visits (ie, post-treatment Week 36, 60, and 84 (2 weeks)). The 
purpose of the phone contact is to verify the participant’s continuation in the study and to confirm the next study 
visit.  
a Applicable where local regulations permit
Note: Upon approval of Revised Protocol 01, participants should perform an End of Study visit and do not need to complete any other post-treatment visits if 
not yet conducted.
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Note: With the early termination of this study, previously collected data to address PK, 
SVR, and select safety assessments (e.g. AEs, laboratory tests, end of treatment subject 
status) will be reported only within adolescent participants 12 to <18 years of age. The 
secondary objectives related to assessment of genotypic substitutions associated with 
virologic failure and the acceptability and palatability of the daclatasvir formulations and 
the exploratory objective regarding durability of response will not be reported.
Objectives
Endpoints
Primary

To evaluate the PK profile of DCV in 
combination with SOF in children and 
adolescents aged 3 to <18 years of age

Pharmacokinetic parameters (Cmin, Cmax, Tmax, AUC 
(TAU), CLT/F) for DCV derived from plasma concentration
versus time data on Day 10 (3 days) within a dosing interval.

In Cohort 3 (ages 3 to < 6 years of age); PK parameters will be 
assessed using model-based analyses with 5 samples from each 
participant.
Secondary

To assess the safety and tolerability of the 
DCV+SOF 
regimen 
in 
paediatric 
participants

Frequencies of serious adverse events (SAEs), adverse events 
(AEs) leading to discontinuation of study therapy, AEs by 
intensity, and laboratory abnormalities by toxicity grade on 
treatment and during follow-up

To determine the proportion of participants 
with SVR12

Proportion of participants with HCV RNA <LLOQ (TD or 
TND) at post-treatment follow-up Week 12

To 
evaluate
genotypic 
substitution(s) 
associated with virologic failure

Frequencies of NS5A and NS5B resistance-associated variants 
(RAVs) emergent at the time of virologic failure on treatment 
and during follow-up in non-responders

To assess the acceptability and palatability 
for the age-appropriate chewable tablet 
formulation, and acceptability for adult 
film-coated tablet

Summary of responses from questionnaire assessing
acceptability and palatability at Day 1, Week 4, and Week 12
 
 
 
5
STUDY DESIGN
5.1
Overall Design
The study will be an open-label, single-arm, descending age cohort trial evaluating the PK profile, 
safety, tolerability, and efficacy of DCV+SOF, administered for 12 weeks, to paediatric 
participants (3 years to < 18 years of age), monoinfected with the hepatitis C virus (genotypes 
(GT) -1 to -6), who are non-cirrhotic and either treatment naive or treatment experienced.
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The total duration of the study for each participant is approximately 2.5 years:

Screening Duration: 42 days

Treatment Duration: 12 weeks

Post-Treatment Follow-up Duration: 108 weeks. Upon completion of the Post-treatment Week 
12 visit, participants will be followed for an additional 2 years (96 weeks) as long-term follow-
up to assess SVR24, durability of response, long term safety, and the persistence of resistance 
variants in non-responders.
A minimum of 30 participants will be evaluated for the primary endpoint (PK), with at least 8 
treated per age cohort:

Cohort 1: 12 to < 18 years of age

Cohort 2: 6 to < 12 years of age

Cohort 3: 3 to < 6 years of age
Enrolment will begin with Cohort 1, followed by Cohorts 2 and 3.  Enrolment in Cohorts 2 and 3 
will be dependent on the availability of the European Commission approved age-appropriate SOF
formulation and dose for the corresponding age cohort.
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
Note: Due to the early termination of the study, only participants 12 to <18 years of age 
were enrolled in the study into Cohort 1; no participants will be enrolled in Cohorts 2 and 
3. The duration of the Long-Term Follow-Up period for these participants will be less than 
the initially planned 96 weeks. Upon approval of this revised protocol, participants will 
return to the study center to conduct an EOS visit.
5.1.1
Data Monitoring Committee and Other External Committees
Not applicable.
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5.2
Number of Participants
It is expected that approximately 45 participants will be screened.  A minimum of 30 participants,
evaluable for the primary end point, will be assigned to 3 age descending cohorts (12 to < 18 years 
of age, 6 to < 12 years of age, and 3 to < 6 years of age); at least 8 participants evaluable for the 
primary end point will be treated in each age cohort.
For further information regarding sample size determination, please refer to Section 10.1.
Note: Although the original protocol provided for a total of 30 participants, only 5 
participants, limited to Cohort 1, will have been enrolled in the study, as the result of the 
early termination of this study.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is
defined as the last visit shown in the Schedule of Activities for the last participant. Study
completion is defined as the final date on which data for the primary endpoint is expected to be
collected, if this is not the same.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The investigator, or a person designated by the investigator, will obtain written informed 
consent from each study participant or the participant's legally acceptable representative, 
parent(s), or legal guardian [and the participant’s assent, when applicable,] before any 
study-specific activity is performed that is not part of normal patient care [unless a waiver 
of informed consent has been granted by an Institutional Review Board (IRB)/Ethics 
Committee (EC)]. The investigator will retain the original copy of each participant's signed 
consent [assent] document;
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b) Participants must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, and other requirements of the study;
c) Should a participant become capable or reach the age of majority, his or her consent should 
be obtained as soon as possible. The explicit wish of a participant who is a minor or unable 
to give his or her written consent, but who is capable of forming an opinion and assessing 
information to refuse participation in, or to be withdrawn from, the clinical study at any 
time should be considered by the investigator.
2) Type of Participant and Target Disease Characteristics
a) Participants with chronic HCV infection GT-1 to -6, as documented by positive HCV RNA 
at screening and either:
i)
Positive anti-HCV antibody, HCV RNA , or a positive HCV genotype test at least 6 
months prior to screening; 
OR
ii) Documented liver biopsy results consistent with chronic HCV infection
b) HCV RNA 1,000 IU/mL at Screening
c) Participants who are HCV-treatment naive defined as no previous exposure to any 
interferon formulation (i.e. IFN, peg-IFN) or RBV, or HCV DAAs
OR
d) Participants who are HCV-treatment experienced:
i)
All anti-HCV therapies (for example IFNwith or without RBV, cyclophilin inhibitors 
and inhibitors of microRNA) are permitted with the exception of previous exposure to 
SOF and/or any NS5A inhibitors
ii) All permitted prior anti-HCV therapies must be discontinued or completed 12 weeks 
prior to dosing
Documentation of prior virologic response to treatment is desirable but not strictly required.
e) Participants must be non-cirrhotic. Absence of cirrhosis will be defined as any one of the 
following:
i)
Documented liver biopsy results within 3 years before Screening suggestive of absence 
of cirrhosis (F0-F3 stage of fibrosis by METAVIR or equivalent) 
OR
ii) Documented Fibroscan (transient elastography) measurement within 1 year before Day 
1 consistent with absence of cirrhosis (< 12.5 kPa) 
OR
iii) APRI score at Screening (aspartate aminotransferase to platelet ratio index) consistent 
with absence of liver cirrhosis (0.5).
If fibrosis stage data are available by several modalities, then the biopsy takes 
precedence over Fibroscan results, and Fibroscan measurements supersede APRI test. 
f)
Participants with body weight 10 kg at Day 1; participants in Cohort 1 must have a body 
weight 45kg at Day 1.
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3) Age and Reproductive Status
a) Males and Females, ages, 3 to < 18 years of age on Day 1 of study treatment.
b) Females of childbearing potential (FOCBP) must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the 
start of study treatment.
c) Females must not be breastfeeding.
d) FOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for 
the duration of treatment with DCV+SOF plus 5 half-lives of study treatment plus 30 days 
(duration of ovulatory cycle) for a total of 5 weeks post-treatment completion.
e) Males who are sexually active with FOCBP must agree to follow instructions for method(s) 
of contraception (Appendix 4) for the duration of treatment with DCV+SOF plus 5 half-
lives of the study treatment plus 90 days (duration of sperm turnover) for a total of 14 
weeks post-treatment completion. In addition, male participants must be willing to refrain 
from sperm donation during this time. 
f)
Azoospermic males are exempt from contraceptive requirements. FOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel FOCBP, and male participants who are sexually active with FOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, which have a 
failure rate of < 1% when used consistently and correctly (Appendix 4).
6.2
Exclusion Criteria
1) Medical Conditions
a) Mixed genotype HCV infections
b) Evidence of an ongoing medical condition contributing to chronic liver disease other than 
HCV (such as, but not limited to: autoimmune hepatitis, Wilson disease, inherited 
metabolic and cholestatic liver diseases, alpha-1 anti-trypsin deficiency, cystic fibrosis, 
toxin exposures)
c) Evidence of cirrhosis, either compensated or decompensated
d) Positive serological test for chronic HBV-infection (HBsAg+) and/or HIV-infection. 
Participants with isolated anti-HBcore or in combination with anti-HBs (anti-HBcore
positive ± anti-HBs) may participate.
e) Documented or suspected HCC, as evidenced by previously obtained imaging studies or 
liver biopsy (or on a screening imaging study/liver biopsy if this was performed)
f)
Evidence of current or history of pre-malignant lesions and malignancies, including 
hematological, within 5 years prior to Screening
g) Liver or any other organ transplant (including hematopoietic stem cell transplants)
h) Use of chemotherapy within 2 months prior to Day 1
i)
Uncontrolled diabetes (any participant with a confirmed screening HbA1c ≥ 8.5 must be 
excluded)
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j)
Participant with any gastrointestinal disease or surgical procedure that may impact the 
absorption of study drug including malabsorption syndrome 
k) Other serious medical conditions that might preclude completion of this study
l)
Clinically relevant alcohol or drug abuse within 12 months of screening; or psychiatric 
hospitalization, suicide attempt, or disability resulting from psychiatric illness, severe 
psychiatric disorders (eg. schizophrenia, psychosis, bipolar disorder, post-traumatic stress 
disorder, mania, etc.) within 5 years prior to Screening
m) Known history of genetic coagulopathy including, but not limited to, hemophilia
n) Inability to tolerate oral medication
o) Poor venous access that would impair the participant’s ability to comply with the study
protocol
2) Prior/Concomitant Therapy
a) Medications prohibited and restricted prior to Day 1 visit are described in Section 7.7.1
3) Physical and Laboratory Test Findings
a) Any clinically significant findings on ECG, such as but not limited to QT prolongation.
b) ALT or AST 10 x the upper limit of normal (ULN)
c) Albumin < 35 g/L
d) Total bilirubin > 1.1 mg/dL unless participant has confirmed Gilbert syndrome 
e) Alpha-fetoprotein > 50 ng/mL (> 41.3 IU/mL)
f)
Absolute neutrophil count < 1500 x 106/L 
g) Hb level < 100 g/L
h) Platelets < 100 x 109/L
i)
Creatinine clearance < 60 ml/min as calculated by the Schwartz formula:
i)
CrCl (ml/min/1.73m2)=  [length (cm) x k] / Serum Cr
k =0.55 for children 3 to < 13 years; k=0.55 for adolescent females 13 to < 18 years of 
age; k = 0.7 for adolescent males 13 to < 18 years of age
4) Allergies and Adverse Drug Reaction
a) History of hypersensitivity to drugs with a similar biochemical structure to DCV or SOF
b) Any other criteria or known contraindication that would exclude the participant from 
receiving DCV or SOF (see section 4.3 of DCV and SOF SmPCs)
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific 
circumstances a person who has been imprisoned may be included as a participant. Strict 
conditions apply and Bristol-Myers Squibb approval is required).
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Concurrent enrolment in another interventional clinical study
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Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently treated in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
This study permits the re-enrollment of a participant that has discontinued the study as a pre-
treatment failure (ie, participant has not been treated). If re-enrolled, the participant must be re-
consented.
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to dosing is the value by which study inclusion will be assessed, as 
it represents the participant’s most current clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline, may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

Daclatasvir dihydrochloride chewable tablet (paediatric formulation)-IP

Daclatasvir film-coated tablet (adult formulation)-IP

Sofosbuvir (paediatric formulation)-IP

Sofosbuvir film-coated tablet (adult formulation)-IP
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An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. Not applicable for this study.
Study treatments are summarized in Table 7-1.
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Table 7-1:
Study treatments for AI444423
Product Description / Class and 
Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
Daclatasvira
(BMS-790052-05/DCV) Film Coated 
Tablet
60 mg 
(as the free base)
IP
Open
Bottle
Each tablet is plain, green, biconvex, 
pentagonal and film-coated.
Store per IP Label.
Daclatasvir Dihydrochloride 
Chewable Tablet
20 mg
IP
Open
Blister
A white to off white, flat, plain oval tablet
Store per IP Label.
Daclatasvir Dihydrochloride 
Chewable Tablet
10 mg
IP
Open
Blister
A white to off white, flat, plain round tablet
Store per IP Label.
Daclatasvir Dihydrochloride 
Chewable Tablet
5 mg
IP
Open
Blister
A white to off white, flat, plain round tablet
Store per IP Label.
Sofosbuvirb, (SOF)
Film Coated Tablet
400 mg
IP
Open
Bottle
Yellow, capsule-shaped, film-coated tablets 
debossed with “GSI” on one side and 
“7977” on the other side
Store per IP Label
Sofosbuvir (SOF)
(paediatric formulation, TBD)
50 mg
IP
Open
TBD
Store per IP Label
a Daclatasvir clinical presentation, adult formulation
b Sofosbuvir adult formulation
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7.1
Treatments Administered
DCV+SOF will be administered QD for 12 weeks as outlined in Table 7.1-1 and Table 7.1-2.
The dose of DCV will be determined according to the weight of the participant prior to dosing on 
Day 1; the dose will not be adjusted to weight over the course of the study. 
DCV should be administered as the adult film-coated 60 mg tablet formulation to adolescent 
participants 12 to < 18 years of age (Cohort 1 who are 45 kg) or as a paediatric chewable tablet 
formulation to all participants < 12 years of age (Cohorts 2 and 3) according to Table 7.1-1 below.
The SOF dose administered (refer to Table 7.1-2) will be the dose and formulation approved by 
the European Commission for the corresponding age cohort8. Cohort 1 (12 to < 18) will receive 
the 400 mg SOF tablet.  Enrollment in Cohorts 2 and 3 will begin following European Commission
approval of the age appropriate dose and formulation for SOF for those respective age groups.
On study visit days, DCV+SOF should be administered at the site after the trough PK sample is 
collected.
Table 7.1-1:
Selection and Timing of DCV Dose
Weight on Day 1
(kg)
Study Treatment
DCV (mg)a
Dosage formulation
Frequency of Administration
Route of 
Administration
-10 --< 30
20 mg
QD
PO
30 - < 45
40 mg
QD
PO
45
60 mgb
QD
PO
a DCV strength and formulation (approved or under investigation): 5, 10, 20 mg chewable tablet; 60 mg film coated 
adult tablet;  the DCV dose may be adjusted if PK data suggest that the dose did not meet the targeted exposure 
criteria.
b  Adult formulation (60 mg) only used for Cohort 1
Table 7.1-2:
Selection and Timing of SOF Dose
Cohort
(Age range)
Study Treatment
SOF (mg)a
Dosage formulation
Frequency of Administration
Route of 
Administration
Cohort 1 (12 to <18)
400 mg
QD
PO
Cohort 2 (6 to <12)
TBDb
TBDb
PO
Cohort 3 (3 to <6)
TBDb
TBDb
PO
a SOF strength and formulation (approved or under investigation): European Commission approved paediatric
formulation; 400 mg film coated tablet
b SOF dose will be the European Commission approved dose and formulation for the age range in the cohort. Refer 
to most current SOF SmPC for dosing guidance.
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Note: Due to the early termination of the study, participants will only have been enrolled in 
Cohort 1 and administered the adult formulations of DCV and SOF (60 mg dose of DCV and 
400 mg dose of SOF). No paediatric formulations will be administered in the study.
7.2
Method of Treatment Assignment
All participants will be assigned to treatment using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT.
During the screening visit, the investigative site will call into the enrollment option of the 
Interactive Response Technology (IRT) designated by BMS for assignment of a 5-digit participant 
number that will be unique across all sites. Enrolled participants, including those not dosed, will 
be assigned sequential participant numbers starting with 00001, (eg, 00001, 00002, 00003.... 
00010). The participant identification number (PID) will ultimately be comprised of the site 
number and participant number. For example, the first participant screened (ie, enrolled) at site 
number 1, will have a PID of 0001 00001. Once it is determined that the participant meets the 
eligibility criteria following the screening visit, the investigative site will call the IRT, prior to the 
start of study treatment administration, to assign the participant into a cohort and to receive DCV 
and SOF treatment assignment. The site will record the treatment assignment on the applicable 
case report form.
Participants without evaluable Day 10 PK data may be replaced. 
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2).
7.3
Blinding
This is an open-label study, blinding procedures are not applicable.
7.4
Dosage Modification
Doses of DCV and SOF assigned on Day 1 cannot be modified but can be interrupted or 
discontinued to manage adverse events (See Section 8.1). In the event of interruption or 
discontinuation, both DCV and SOF must be stopped simultaneously. DCV+SOF treatment can 
be interrupted for a maximum of 7 days, and if not restored after 7 days, the treatment should be 
permanently discontinued.
Note: DCV dose modification will only be permissible if PK data from the initial 5 participants in 
a cohort suggest that the dose administered does not achieve the desired exposure criteria. The 
sponsor will advise how to modify the dose of DCV being administered, if needed.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
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concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and the site should contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).

Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2.
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not Applicable 
7.6
Treatment Compliance
Study treatment compliance will be assessed at all on-treatment study visits through review of the 
participant’s dosing diary and drug accountability (review of used/unused study medication).
Participants [or the participant’s legally acceptable representative, parent(s), or legal guardian] will 
be instructed to record dosing in a dosing diary and to bring unused study medication containers 
to each visit as well as any empty containers.  The diaries will be reviewed at each visit in 
combination with drug accountability, and the sites should discuss any discrepancies noted.
Study drugs will be collected at all visits and new study drug may be dispensed; unused SOF will
be redispensed. The dates and number of DCV tablets and SOF tablets/European Commission
approved paediatric formulation dispensed and returned must be recorded on the drug 
accountability form maintained on-site. 
On Day 10, when the serial PK sampling will be performed, treatment should be administered at 
the clinic and not taken at home. Likewise, on visits when trough PK samples are collected, Week 
4, Week 8 and Week 12, treatment should be administered at the clinic after collection of the PK 
sample.  The timing of the dose prior to PK sample collection should be recorded in the diary.
 
 
 
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7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of DCV or SOF is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government sponsored or private 
health program. In all cases BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Participant’s [or the participant's legally acceptable representative, parent(s), or legal guardian]
request to stop study treatment. Participants who request to discontinue study treatment will 
remain in the study and must continue to be followed for protocol specified follow-up 
procedures. The only exception to this is when a participant [or the participant's legally 
acceptable representative, parent(s), or legal guardian] specifically withdraws consent for any 
further contact with him/her or persons previously authorized by participant to provide this 
information

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant.  Strict conditions apply and BMS approval is required.)

Laboratory or Clinical Criteria: If any of the following laboratory or clinical criteria is obtained 
for any participant, the test must be repeated/confirmed within 72 hours and the BMS medical 
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monitor should be informed. If the results are confirmed, the participant must discontinue 
treatment. Clinical criteria must have Principal Investigator or Sub-investigator assessment 
prior to proceeding to permanent discontinuation.

Evidence of confirmed hepatic decompensation (Child-Pugh Class B or C, Score >6)

ALT > 2 x baseline and 5 x ULN and either total bilirubin > 2 x ULN or INR > 2

Any Grade 4 AE or clinically significant laboratory abnormality considered study drug 
related

Virologic Breakthrough (confirmatory results must be obtained 2 weeks from original 
result) defined as:
Confirmed increase in HCV RNA 1 log10 IU/mL on-treatment from nadir 
Confirmed increase in HCV RNA LLOQ after HCV RNA declined to < LLOQ 
TD/TND while on treatment 
In the event of interruption or discontinuation, both DCV and SOF must be stopped 
simultaneously. DCV+SOF treatment can be interrupted for a maximum of 7 days, and if not 
restored by 7 days, the treatment should be permanently discontinued.
If discontinuation of therapy is required, this must occur no later than the next study visit.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
during a clinical trial, the study treatment must be discontinued immediately. In most cases, the 
study treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy. If the investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.1
Post Study Treatment Study Follow-up
In this study, PK is the primary endpoint while safety and tolerability, efficacy, long term safety 
and evolution of resistance variants in virologic failures are key endpoints of the study. Post study 
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follow-up is of critical importance and is essential to preserving participant safety and the integrity
of the study. Participants who discontinue study treatment must continue to be followed for 
collection of follow-up data as required and in line with Section 5 until death or completion of the 
designated follow up period.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant [or the participant's legally acceptable representative, parent(s), or legal guardian]
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by participant to provide this information. 

Participants [or the participant's legally acceptable representative, parent(s), or legal guardian]
should notify the investigator of the decision to withdraw consent from future follow-up in 
writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant [or the participant's legally acceptable representative, parent(s), or legal 
guardian] withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.

If a participant initiates alternate anti-HCV therapy, the participant should complete the 
procedures specified for Post-treatment Week 4 (Table 2-3) prior to study discontinuation and 
prior to the initiation of any alternate therapy.
8.3
Lost to Follow-Up

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant [or the participant's 
legally acceptable representative, parent(s), or legal guardian].

Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
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
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities (Section 2).

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria prior to dosing. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities (Section 2).
9.1
Efficacy Assessments
HCV RNA collected on treatment, at Post-treatment Week 12, and at other post-treatment visits 
will be used for antiviral efficacy assessments. 

The Roche COBASAmpliPrep/COBASTaqManHCV Test (LLOQ = 15 IU/mL) will 
be used to measure HCV RNA levels. 
Samples will be collected to perform phylogenetic analyses at baseline and in the event of virologic
failure.

The Versant HCV genotype 2.0 assay (LIPA) will be used for all genotype/subtype 
assessments. For samples where HCV genotype or subtype results are unavailable or 
inconclusive, the Abbott RealTime HCV Genotype II assay or viral sequence analysis may be 
used for genotype/subtype assessments. 

HCV RNA and HCV genotype will be analyzed by the central laboratory.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
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AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting are specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment and at
the time-points specified in the Schedule of Activities (Section 2). Nonserious AE information 
should also be collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the participants.
Section 4.8 of the DCV SmPC13 and/or SOF SmPC8 represent the reference safety information
for the DCV+SOF regimen to determine expectedness of serious adverse events for expedited
reporting. Following the participant’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be associated 
with protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 30 days of 
discontinuation of dosing.
The investigator must report any SAE that occurs after these time periods that is believed to be 
related to study drug, protocol-specified procedure or hepatic disease progression (i.e. 
development of liver cirrhosis and/or its complications).

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
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9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant [or the participant's legally acceptable representative, 
parent(s), or legal guardian]. Care should be taken not to introduce bias when collecting AE and/or 
SAEs.  Inquiry about specific AEs should be guided by clinical judgement in the context of known 
adverse events, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/European 
Commission and FDA Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR 
(Suspected, Unexpected Serious Adverse Reaction) is a subset of SAEs and will be reported to the 
appropriate regulatory authorities and investigators following local and global guidelines and 
requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
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to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or electronic SAE Report Form, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) ALT 5x baseline or nadir value, whichever is lower, AND 10 times upper limit of normal 
(ULN)
AND
2) Total bilirubin 2 times ULN
AND
3) No other immediately apparent possible causes of ALT elevation and hyperbilirubinemia, 
including but not limited to, acute viral hepatitis, cholestasis, pre-existing hepatic disease 
excluding HCV or the administration of other drug(s), herbal medications, or substances 
known to be hepatotoxic.
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After the initial event, subsequent monitoring should be discussed with the BMS Medical Monitor.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
An overdose of DCV is defined as follows:

for participants assigned to a 60mg dose of DCV, any total daily dose of DCV 200 mg; 

for participants assigned to a 40 mg dose, any daily dose 120 mg

for participants assigned to a 20 mg dose, any daily dose 60 mg 
An overdose of SOF for participants assigned a 400 mg dose is any daily dose greater than 800 
mg. For paediatric formulations, refer to the SmPC8 for guidance on overdose.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
9.4.1
Physical Examinations
A full physical examination will be performed at the screening visit. A targeted physical exam 
should be performed during the on-treatment visits (except Day 10). A targeted physical 
examination may be performed by a qualified professional guided by the examiner’s observations 
and/or participant complaints on new or changed conditions, symptoms or concerns.  Targeted 
physical exam should include assessment of heart, lung and abdomen. 
Refer to Schedule of Activities.
9.4.2
Vital signs
Refer to Schedule of Activities.
9.4.3
Electrocardiograms
Refer to Schedule of Activities.
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9.4.4
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report.

The following assessments, listed in Table 9.4.4-1, will be analyzed by a central laboratory or 
other BMS specified laboratory. 

Participants are not required to be fasting prior to any laboratory assessments.
Table 9.4.4-1:
Laboratory Assessments
Screening
(Table 2-1)
Study Visits
On Treatment
(Table 2-2)
Study Visit
Post-Treatment
Week 4
(Table 2-3)
Study Visits
Post-Treatment
Weeks 12 to 108
(Table 2-3)
Hematology
Hemoglobin
X
X
X
-
Hematocrit
X
X
X
-
White Blood Cell (WBC)
Count with Differential
X
X
X
-
ANC (neutrophils plus
band)
X
X
X
-
Platelets
X
X
X
X
Coagulation
INR
X
X
Not required Day 10
X
X
Chemistry
Albumin
X
X
X
X
Total Protein
X
X
X
-
Aspartate aminotransferase
(AST)
X
X
X
X
Alanineaminotransferase
(ALT)
X
X
X
X
Total bilirubin
X
X
X
X
Direct Bilirubin
X
X
X
X
Alkaline Phosphatase
X
X
X
X
Lactate dehydrogenase
(LDH)
X
X
X
X
Creatinine
X
X
X
X
CreatinineClearance
X
X
X
X
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Table 9.4.4-1:
Laboratory Assessments
Screening
(Table 2-1)
Study Visits
On Treatment
(Table 2-2)
Study Visit
Post-Treatment
Week 4
(Table 2-3)
Study Visits
Post-Treatment
Weeks 12 to 108
(Table 2-3)
Creatininephosphokinase
(CPK)
-
For AST elevation
Grade 1 without ALT elevation
Creatine Kinase MB
Isoenzyme (CK-MB)
-
Reflex if CPK is elevated
> 5xULN
Lipase
X
X
X
-
Gamma-Glutamyl
Transferase (GGT)
X
X
X
X
Electrolytes (sodium,
bicarbonate,
potassium,choloride
X
-
X
-
Blood Urea Nitrogen
(BUN)
X
-
X
-
Glucose
X
-
X
-
HbA1c
X
Only in participant 
with elevated plasma
glucose level 200 
mg/dL (11.1 
mmol/L)
-
X
-
Calcium
X
-
X
-
Phosphate
X
-
X
-
Uric Acid
X
-
X
-
Alfa fetoprotein (AFP)
X
-
X
-
APRI
X
-
X
X
Week 108 only
Other
Urine pregnancy test
(reflex to serum if positive)
X
24 hours prior to
dosing in FOCBP
X
Every 4 weeks
X
-
HCV RNA (and back up
HCV RNA sample)
X
X
X
X
HCV resistance specimen
for storage
-
X
X
X
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Table 9.4.4-1:
Laboratory Assessments
Screening
(Table 2-1)
Study Visits
On Treatment
(Table 2-2)
Study Visit
Post-Treatment
Week 4
(Table 2-3)
Study Visits
Post-Treatment
Weeks 12 to 108
(Table 2-3)
HCV genotype
X
Participants with suspected virologic breakthrough or relapse will
have samples collected to retest HCV RNA, HCV resistance and
HCV Genotype at an unscheduled visit as soon as possible before
their next regular visit.
Anti-HCV
X
-
-
-
HIV-1 and -2 antibody
X
-
-
-
HBsAg, anti-HBcore
X
-
-
-
-
X (Day 1 only)
-
-
PK Samples DCV, SOF
and its metabolites
-
Day 10; Weeks 4, 8 and 
12; and virologic 
breakthrough
See Section 9.5
-
-
Total approx. blood 
volume per visit, mL
18
17 (Day 1);
19-20 (Day 10);
16 (Week 4, 8 and 12)
14
14
For all participants, local standards for volumes of blood based on body weight that may be drawn 
within a specific time period should be followed. Blood volumes will be minimized as best as 
possible. If, despite the use of these measures, the blood volumes required in the Schedule of 
Activities (Section 2) for a time point will exceed those recommended for the participant, then the 
Sponsor should be contacted for instructions on which blood tests can be omitted or modified to 
meet volume requirements. These will likely be back up samples, since all required laboratory 
assessments should be performed. The volume of blood required will be detailed in the Informed 
Consent as well as in the Procedure Manual.
Note: All laboratory assessments scheduled for the Post-Treatment Week 108 visit should 
be performed at the EOS visit.
9.4.5
Imaging Safety Assessment
Not applicable.
9.5
Pharmacokinetics
Pharmacokinetic parameters (Cmin, Cmax, Tmax, AUC (TAU), CLT/F) for DCV will be derived 
from plasma concentration versus time data on Day 10 (3 days). The observed trough plasma 
concentrations of DCV and SOF/metabolites (Ctrough) will be assessed.
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Table 9.5-1 lists the pharmacokinetic sampling schedule to be followed for the assessment of DCV 
and SOF/metabolites pharmacokinetics. On Day 10, when the serial PK sampling will be 
performed, treatment should be administered at the clinic and not taken at home. Likewise, on 
visits when trough PK samples are collected, treatment should be administered at the clinic after 
collection of the PK sample. The timing of the dose prior to the PK sample collection should be 
recorded. There is no restriction on food consumption with regard to dosing and PK sample 
collection. Detailed instructions for the pharmacokinetic blood collection, labeling, processing, 
storage, and shipping will be provided to the site in the procedure manual.
Table 9.5-1:
Pharmacokinetic Sampling Schedule for DCV and SOF
Study Day of 
Sample Collection
Cohort
Time
(Relative To 
Dosing)
Hour
PK
Blood Sample for 
DCV
PK
Blood Sample for 
SOF/metabolites
Day 10 +/- 3 days
All Cohorts
0 (Predose)
X
X
All Cohorts
00:30
X
-
Cohorts 1, 2 only
01:00
X
-
All Cohorts
02:00
X
-
All Cohorts
04:00
X
-
All Cohorts
08:00
X
-
Week 4
All Cohorts
0 (Predose)
X
X
Week 8
All Cohorts
0 (Predose)
X
X
Week 12 (EOT)
All Cohorts
0 (Predose)
X
X
Virologic 
Breakthrougha
All Cohorts
0 (Predose)
X
X
a When confirming on-treatment virologic breakthrough, PK samples should be collected along with the HCV RNA 
samples 
In addition, plasma samples will be archived for potential metabolite analysis, if the need arises 
and to the extent possible.
 
 
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9.8.1
Additional Research Collection
This protocol will not include sample collection and/or residual sample storage for additional 
research (AR).
9.8.2
Other Assessments
9.8.2.1
HCV Virologic Resistance Testing
Plasma specimens for possible resistance testing will be collected at study visits indicated in Table 
2-1, Table 2-2, and Table 2-3.
Phylogenetic analyses will be performed on all available baseline NS5A sequences to 
confirm/determine the HCV genotype and subtype of each treated participant.  NS5A resistance 
testing will be performed on all baseline samples.  Resistance testing will be performed using 
population-based sequencing and may be performed by next-generation sequencing on samples 
from participants with HCV RNA 1,000 IU/mL. This includes samples from all participants 
experiencing on-treatment failure or relapse, defined as:

Virologic breakthrough, defined as confirmed 1 log10 IU/mL HCV RNA on-treatment 
increase from nadir, or confirmed on-treatment increase in HCV RNA LLOQ if HCV RNA 
previously declined to < LLOQ (TD/TND); 

Relapse, defined as HCV RNA < LLOQ (TND) at EOT followed by HCV RNA LLOQ in 
any follow-up visit window;

HCV RNA LLOQ at any time point not meeting the definition of virologic breakthrough or 
relapse followed by a confirmed increase in HCV.
For participants who experience virologic failure, NS5A and NS5B resistance testing will be 
performed on samples that best approximate the time of failure, when HCV RNA levels are 1,000 
IU/mL.  The respective baseline samples from these participants will also be tested. Genotype 
testing will also be performed on virologic failure samples collected close to the time of failure. 
Further testing will occur at selected time points, if needed, using either storage specimens for 
resistance testing or other available stored specimens. Exploratory resistance testing to evaluate 
low frequency variants may be performed on subsets of samples depending on patterns of viral 
load response.
Note: With this revised protocol, resistance testing will not be performed on Baseline 
samples
9.8.2.2
Acceptability and Palatability Assessments of Daclatasvir Formulations 
Participants/caregivers will be asked to complete a questionnaire regarding the acceptability and 
palatability (including a hedonic scale) of the DCV formulations in conjunction with the dose of 
DCV administered on Day 1, Treatment Week 4, and Treatment Week 12 (10 seconds, 1 minute, 
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and 5 minutes after taking the tablet(s)); DCV will be administered at the site on the visits.  Specific 
instructions for the assessment tool and documentation of results will be provided to the sites.
After the participant has been dosed with DCV, any issue associated with the palatability of the 
investigational product should be reported as an adverse event (ie, spitting up).
9.8.2.3
Brief Questionnaire/Interim Phone Contacts
A brief questionnaire will be completed by the participant [or the participant's legally acceptable 
representative, parent(s), or legal guardian] on Day 1 to include the participant’s e-mail address, 
name of the participant’s primary care physician and 2 non-residing contacts in case the participant
cannot be reached for their study assessments. This questionnaire, unless prohibited by local laws 
or regulations, will be reviewed for the confirmation or modification (as applicable) by the 
participant [or the participant's legally acceptable representative, parent(s), or legal guardian] at 
the end of treatment visit and all post-treatment follow-up visits.
During the post-treatment follow-up phase, sites will be required to perform an interim telephone 
contact with the participant [or the participant's legally acceptable representative, parent(s), or 
legal guardian] on a quarterly basis when the participant is not required to come for an in-office 
visit (ie, post-treatment Week 36, 60, and 84). The purpose of phone contacts is to verify the 
participant’s continuation in the study and to confirm the date of the next study visit.
Note: Due to the early termination of the study, participants will perform an EOS visit and 
interim telephone contact will not be necessary after the EOS visit.
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
Note: Not Applicable due to the early termination of the study; a total of 5 participants will 
have been enrolled in the study into Cohort 1.
A minimum of 30 participants, assigned to 3 age descending cohorts, will be evaluated for the 
primary endpoint (PK) with at least 8 participants assessed in each age cohort.
The primary objective of this study is to evaluate the PK of DCV.  The PK profile of DCV has
been well characterized in the clinical development program and it has been noted that DCV is 
associated with predictable pharmacokinetics. The intra-participant variability for DCV Cmax and 
AUC (INF) was assessed from clinical studies where single oral doses of DCV were administered 
with or without food and were estimated to be low with a % CV of 18% for Cmax and 10% for 
AUC (INF). Similarly, the inter-participant variability in DCV Cmax and AUC were assessed from 
clinical studies where single and multiple oral doses of DCV administered alone, and with or 
without food in some cases, was identified to be modest with % CV values of 37.5% for Cmax 
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and 35% for AUC. PK will be assessed in all participants, however, due to the low observed 
variability in DCV exposure, assessment of the PK in the initial 5 participants per age cohort will 
provide the necessary information to match DCV exposures between adults and paediatric 
participants and either allow enrolment to be initiated in the next descending age cohort(s) or 
indicate that additional participants need to be enrolled in the cohort with a modified dose.  
Enrolment will continue in each cohort, after the initial 5 participants have completed their Day 
10 assessments, to have a minimum of 8 evaluable participants in each cohort.
Descriptive summary statistics will be provided for the secondary endpoints in this study.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled  Participants
All participants who sign informed consent and are assigned a 
Participant Identification Number
Treated Participants
All enrolled participants who take at least 1 dose of study 
treatment. 
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
A description of the participant population will be included in the statistical output reported, 
including subgroups of age, gender and race.
Note: With the early termination of this study, previously collected data to address PK, 
SVR, and select safety assessments (e.g. AEs, laboratory tests, end of treatment subject 
status) will be reported only within adolescent participants 12 to <18 years of age. Given 
the small number of subjects enrolled in the study, no statistical analyses will be performed. 
Genotypic
substitution(s) associated with virologic failure and the acceptability and 
palatability of the DCV formulations will not be reported. Likewise, an interim analysis 
will not be performed.
10.3.1
Efficacy Analyses
Efficacy endpoints will be assessed for treated participants by age cohort and total. 
The proportion of participants achieving SVR12 (HCV RNA <LLOQ, TND or TD at Post-
treatment Week 12) will be presented along with the corresponding 95% exact binomial 
confidence interval (CI). The principal analysis method will compute SVR12 on all treated 
participants, and missing HCV RNA data at post-treatment Week 12 will be imputed using the 
Next Value Carried Backwards (NVCB) approach, i.e., missing HCV RNA data in the post-
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treatment Week 12 window will be imputed using the next and closest available HCV RNA 
measurement after the follow-up Week 12 HCV RNA visit window. A sensitivity analysis will 
compute SVR12 on treated participants with observed HCV RNA at follow-up Week 12.
10.3.2
Resistance Analyses
The frequencies of NS5A RAVs at baseline will be presented by genotype, and if applicable, by 
subtype, for responders (SVR12) and virologic failures with genotypable isolates. 
The frequencies of newly emergent NS5A RAVs detected at virologic failure on treatment or 
during follow-up will be presented for virologic failures with genotypable isolates. Newly 
emergent substitutions are substitutions that were not detected at baseline.
Note: These data will not be reported because the prevalence of the relevant RAV varies 
from 4-10% and as such might not be detected at Baseline in a sample size of 5 participants. 
As of 18 October 2019, all participants had completed at least 41 weeks of post-treatment 
follow-up and none had experienced viroloogic failure. 
10.3.3
Safety Analyses
The frequencies of the following safety endpoints will be presented separately for each study 
period (on treatment and follow-up) for treated participants by age cohort and total: SAEs; AEs 
leading to discontinuation of study therapy; AEs by intensity; laboratory abnormalities by toxicity 
grade.
The Investigators will determine the intensity of AEs. The Investigators’ terms will be coded and 
grouped by system organ class using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) in production. AEs will be presented by system organ class and preferred 
term. Presentations will include both non-serious and SAEs, unless specified otherwise. If a 
participant had an AE with different intensities over time, then only the greatest intensity will be 
reported for a study period.
Laboratory toxicities will be graded according to the Division of AIDS (DAIDS) of the US 
National Institutes of Health table for grading the severity of adverse experiences ([December 
2004; clarification August 2009] ) (Appendix 5). The laboratory value during the study period with 
the highest toxicity grade will be reported for each test.
10.3.4
Pharmacokinetic Analyses
Individual pharmacokinetic parameter values for DCV will be derived from plasma concentration 
versus time using non-compartmental methods or model based approaches as needed on Day 10 
(3 days). Values will be summarized with descriptive statistics (n, arithmetic mean, standard 
deviation, geometric mean, coefficient of variation, median, minimum, maximum) by age cohort. 
Parameters will include: Cmin, Cmax, Tmax, AUC (TAU), and CLT/F. 
10.3.5
Other Analyses
10.3.5.1
Acceptability and Palatability Assessments of Daclatasvir Formulations
The acceptability and palatability questionnaire results from Day 1, Week 4, and Week 12 will be 
summarized and assessed by age cohort and total for participants treated with DCV chewable and 
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adult tablets. The age-appropriate chewable tablet formulation and adult film-coated tablet will be 
assessed separately.
Note: These data will not be reported as only the adult formulation was administered in the 
study and there is no value to performing an analysis of the adult formulation.
10.3.6
Interim Analyses 
The timing of interim analyses will depend on the availability of Day 10 PK results. An interim 
analysis will be performed when the first 5 participants in each age cohort complete the Day 10 
PK sample collection.
If the median plasma exposure in a cohort is outside the predefined therapeutic range, then dose 
modification will be performed using paediatric formulations of DCV, and an additional 5 
participants will be enrolled. Another interim analysis will be performed when these additional 
participants complete the Day 10 PK sample collection in order to confirm the exposure at the 
modified dose.  All Day 10 PK interim analyses will focus on PK and select safety listings (eg, 
AEs, laboratory abnormalities, participant disposition).  In each cohort, enrollment will continue 
in order to achieve at least 8 evaluable participants per cohort.  
Additional interim analyses will be performed when all participants in an age cohort complete the 
Post-Treatment Week 12 visit and when all participants complete the follow-up Week 12 visit in 
order to assess the primary and secondary endpoints.
The final analysis will be conducted when all participants complete long-term follow-up to assess 
long-term efficacy 
), safety, and evolution of resistance variants in virologic 
failures.
The Statistical Analysis Plan will further describe the planned interim analyses.
Note: An interim analysis will not be performed. As only 5 subjects will be enrolled in this 
study, analyses are not needed to guide dosing for additional participants.
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o  
 
 
 
 
 
 
 
 
 
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
Adverse event
AFP 
Alpha fetoprotein
ALT 
Alanine aminotransferase
ANC 
Absolute neutrophil count
APRI 
Aspartate aminotransferase platelet ratio index
AST 
Aspartate aminotransferase
AUC 
Area under the concentration-time curve
AUC(TAU)
area under the concentration-time curve in one dosing interval
BMS 
Bristol-Myers Squibb
BUN 
Blood urea nitrogen
CFR 
Code of Federal Regulations
CHC 
Chronic hepatitis C
CHMP 
Committee for Medicinal Products for Human Use
CI
Confidence interval
CK-MB 
Creatine Kinase MB Isoenzyme
CLTF
Apparent total body clearance
CPK 
Creatinine phosphokinase
Cmax, CMAX
Maximum observed concentration
Cmin, CMIN 
Trough observed concentration
CrCl 
Creatinine clearance
CRF 
Case Report Form, paper or electronic
CSR
Clinical study report
CYP 
Cytochrome p-450
DAA 
Direct acting antiviral
DAIDS 
Division of AIDS
DCV 
Daclatasvir
DCV+SOF 
Daclatasvir and sofosbuvir combination therapy
DC 
Discontinue
DILI 
Drug-induced liver injury
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Term
Definition
dL 
Deciliter
DMC 
Data Monitoring Committee
EC
Ethics Committee
ECG 
Electrocardiogram
eCRF 
Electronic Case Report Form
EDC 
Electronic Data Capture
EMA
European Medicines Agency
EOT 
End of treatment 
EPA 
Early Patient Access 
FDA 
Food and Drug Administration
FDC
Fixed dose combination
FOCBP 
Female of childbearing potential
G 
Gram
GGT 
Gamma-Glutamyl Transferase
GT 
Genotype
H 
Hour
Hb 
Hemoglobin
HbA1C
Glycated hemoglobin
HBsAg 
Hepatitis B virus surface antigen
HBV 
Hepatitis B virus
HCC 
Hepatocellular carcinoma
HCG 
Human chorionic gonadotrophin
HCV 
Hepatitis C virus
HIV 
Human Immunodeficiency Virus
IB 
Investigator Brochure
Ie 
id est (that is)
IEC 
Independent Ethics Committee
IFN
Interferon
IMP 
Investigational medicinal products
INR 
International normalized ratio
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Term
Definition
IP
Investigational products
IRB 
Institutional Review Board
IRT 
Interactive Response Technology
IST/ISR
Investigator-sponsored -trials/research
IU 
International Unit
Kg 
Kilogram
L 
Liter
LC/MS/MS
Liquid Chromotography - tandem mass spectrometry
LDH 
Lactate dehydrogenase
LDV 
Ledipasvir
LLOQ 
Lower limit of quantification
LTFU
Long term follow up
Medra
Medical Dictionary for Regulatory Activities
mg 
Milligram
Min 
Minute
mL 
Milliliter
g 
microgram
N 
number of participants or observations
NS5A
Nonstructural protein 5A
NS5B
Nonstructural protein 5B
NVCB 
Next Value Carried Backwards
PIP
Pediatric Investigational Plan
PDCO
Paediatric Committee
pegIFN 
Pegylated interferon
PID 
Patient/Participant Identification Number
PK 
Pharmacokinetics
PO
Per os
PT
Post treatment
QD, 
Quaque die, once daily
RAV 
Resistance-associated variants
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Term
Definition
RBV 
ribavirin
RNA
Ribonucleic acid
SAE 
serious adverse event
SmPC 
Summary of Product Characteristics
SNP 
single nucleotide polymorphism
SOF 
Sofosbuvir
SUSAR 
Suspected, Unexpected Serious Adverse Reaction
SVR 
Sustained virologic response
TBD 
To be determined
TD 
Target detected
Tmax
Time taken to reach maximum concentration
TND 
Target not detected
ULN 
Upper limit of normal
VBT 
Virologic breakthrough
WBC 
White blood cell
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:

IRB/IEC

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
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
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
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applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments DCV and SOF (whether supplied by BMS, its vendors, or the site) 
must substantiate study treatment
integrity and traceability from receipt, preparation, 
administration, and through destruction or return. Records must be made available for review at 
the request of BMS/designee or a Health Authority.
If
Then
Supplied 
by 
BMS 
(or 
its 
vendors):
Records or logs must comply with applicable regulations 
and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each participant, 
including unique participant identifiers

amount transferred to another area/site for dispensing 
or storage

nonstudy disposition (e.g., lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if 
applicable 

dates and initials of person responsible for 
Investigational Product dispensing/accountability, as 
per the Delegation of Authority Form.
Sourced by site, and not supplied 
by BMS or its vendors (examples 
include IP sourced from the sites 
stock or commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts responsibility for 
documenting traceability and study treatment integrity in 
accordance with requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does
not have an established system that meets these requirements.
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CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable .Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
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The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS 
(including its vendors
Any unused study treatments supplied by BMS can 
only be destroyed after being inspected and 
reconciled by the responsible Study Monitor unless 
study treatments containers must be immediately 
destroyed as required for safety, or to meet local 
regulations (eg, cytotoxics or biologics).
If study treatments will be returned, the return will 
be arranged by the responsible Study Monitor.
Study treatments sourced by site, not 
supplied by BMS (or its vendors) 
(examples 
include 
study 
treatments 
sourced 
from 
the 
sites 
stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It is the investigator’s or designee’s responsibility 
to dispose of all containers according to the 
institutional guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
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institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

Participant recruitment (eg, among the top quartile of enrollers)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
Results in persistent or significant disability/incapacity
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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Is a congenital anomaly/birth defect
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 
for reporting pregnancies).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study treatment is determined by a physician and should be used 
to assess all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study treatment
administration and the AE.
Not related: There is not a reasonable causal relationship between study treatment
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.
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Follow-up of AEs and SAEs
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be 
reported to BMS (or designee) within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms).

The preferred method for SAE data reporting collection is through the eCRF.

The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning.

In this case, the paper forms are to be transmitted via email or confirmed facsimile 
(fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
FEMALE OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Female of Childbearing Potential (FOCBP)
A female is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Female in the following categories are not considered FOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 Days after the end of study treatment, 
plus 30 days.
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion
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
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the FOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

FOCBP participants who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the FOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. Refer to DCV SmPC.
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
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CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 5 Days (5 half lives of the study drug) after the end of treatment 
plus an additional 90 days.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 5 Days after the end of 
treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 5 Days after the end of treatment.

Refrain from donating sperm for the duration of the study treatment and until 5 Days after the 
end of treatment plus an additional 90 days.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
DIVISION OF AIDS (DAIDS) TABLE FOR GRADING THE 
SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS 
PUBLISH DATE: JULY, 2017
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Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric Adverse Events 
 
Corrected Version 2.1 
July 2017 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services 
 
 
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Table of Contents 
Glossary and Acronyms ....................................................................................................................... 1 
Introduction ........................................................................................................................................... 3 
Instructions for Use .............................................................................................................................. 4 
Major Clinical Conditions .................................................................................................................... 7 
Cardiovascular ................................................................................................................................ 7 
Dermatologic .................................................................................................................................. 9 
Endocrine and Metabolic ............................................................................................................. 10 
Gastrointestinal ............................................................................................................................. 12 
Musculoskeletal ............................................................................................................................ 14 
Neurologic..................................................................................................................................... 15 
Pregnancy, Puerperium, and Perinatal ........................................................................................ 17 
Psychiatric ..................................................................................................................................... 18 
Respiratory .................................................................................................................................... 19 
Sensory .......................................................................................................................................... 20 
Systemic ........................................................................................................................................ 21 
Urinary .......................................................................................................................................... 23 
Site Reactions to Injections and Infusions ........................................................................................ 24 
Laboratory Values .............................................................................................................................. 25 
Chemistries ................................................................................................................................... 25 
Hematology ................................................................................................................................... 29 
Urinalysis ...................................................................................................................................... 31 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates ............................................. 32 
 
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 1 
Glossary and Acronyms 
AE 
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV 
Atrioventricular 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding. 
 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score 
Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity. 
BMD t-score 
Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult 
of the same sex and ethnicity as the participant. 
BMD z-score 
Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity. 
BPAP 
Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation. 
Chemical Pregnancy 
A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy loss. 
CNS 
Central nervous system 
CPAP 
Continuous positive airway pressure 
DAERS 
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited 
Adverse Events (EAEs) to DAIDS.  It facilitates timely EAE report 
submission and serves as a centralized location for accessing and 
processing EAE information for reporting purposes. 
Disability 
A substantial disruption of a person’s ability to conduct normal life 
functions. 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours, 
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency.  
INR 
International normalized ratio  
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Intervention 
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event.  
IV 
Intravenous 
IVIG 
Intravenous immune globulin 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening AE 
Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused 
death if it had occurred in a more severe form). 
NA 
Not applicable 
Participant ID 
The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs. 
PR Interval 
The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc Interval 
The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate. 
RBC 
Red blood cell 
SI 
Standard international unit 
ULN 
Upper limit of normal 
Usual Social & Functional Activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example: 
 
Adults 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby. 
 
Young Children 
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC 
White blood cell 
WHO 
World Health Organization  
WNL 
Within normal limits 
 
 
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Introduction 
The Division of AIDS (DAIDS) oversees more than 300 clinical trials domestically and 
internationally, which evaluate the safety and efficacy of therapeutic products, vaccines, and 
other preventive modalities.  Adverse event (AE) data collected during these clinical trials form 
the basis for subsequent safety and efficacy analyses of pharmaceutical products and medical 
devices.  Incorrect and inconsistent AE severity grading can lead to inaccurate data analyses and 
interpretation, which in turn can impact the safety and well-being of clinical trial participants and 
future patients using pharmaceutical products.  
 
Over the years, DAIDS scientific knowledge and experience have expanded, necessitating 
revisions of the DAIDS grading table which serves as a guide for assessing the severity of AEs 
(including clinical and laboratory abnormalities) in participants enrolled in DAIDS-sponsored 
and -supported clinical trials.  The Division of AIDS (DAIDS) Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) updates and replaces 
version 2.1 (March 2017).  
 
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and 
non-government affiliated medical subject matter experts and reviewers who were instrumental 
in the revision of the DAIDS grading table. 
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Instructions for Use 
General Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying 
AEs.  The severity of a specific event describes its intensity, and it is the intensity which is 
graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
 
Clinical sites are encouraged to report parameters in the DAIDS grading table as they are written 
to maintain data consistency across clinical trials.  However, since some parameters can be 
reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
 
The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with 
descriptions for each AE based on the following general guidelines:  
• Grade 1 indicates a mild event 
• Grade 2 indicates a moderate event 
• Grade 3 indicates a severe event 
• Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death (Note: This grade is not specifically listed on each page of the 
grading table). 
 
Other points to consider include: 
• Use age and sex values as applicable. 
• Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed 
using local laboratory normal ranges. 
• Where applicable, Standard International (SI) units are included in italics. 
 
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, 
flushing, angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be 
an acute allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term. 
 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency.  
 
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When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term 
should be entered in the “Other Events” section.  However, the severity grade for these events 
must be lower than or equal to the severity grade of the primary AE term.  In the example above, 
dyspnea and angioedema of the face may be entered in the “Other Events” section, because they 
are more descriptive and provide additional information on the severity of the acute allergic 
reaction.  However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of “Acute Allergic Reaction”. 
 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their 
protocols and CRF requirements for further instructions.  
 
Grading Adult and Pediatric AEs 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction  
between adult and pediatric populations has been made, the listed parameter should be used for 
grading an AE in both populations. 
 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID.  If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be reported using the mother's participant 
ID.  However, if an infant is enrolled in the same study as the mother or in another study, any 
identified birth defects should be reported using the infant's participant ID.  Sites should refer to 
the applicable network standards for reporting abnormal pregnancy outcomes on the CRFs. 
 
Determining Severity Grade for Parameters between Grades  
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades. 
 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the clinical case report forms.  
 
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE.  
Sites should consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an assessment of the need to report an AE. 
 
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory 
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value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1. 
 
Appendix Usage 
Appendix A takes priority over the main grading table in all assessments of total bilirubin for 
term and preterm neonates. 
 
Using Addenda 1-3: Grading Tables Used in Microbicide Studies 
In protocols involving topical application of products to the female and male genital tracts or 
rectum, strong consideration should be given to using Addenda 1-3 (see below) as the primary 
grading tables for these areas.  Although these grading tables are used specifically in microbicide 
studies, they may be used in other protocols as adjuncts to the main grading table (i.e., the 
Division of AIDS (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0).  It should be clearly stated in a protocol which addendum is being used as the 
primary grading table (and thus takes precedence over the main grading table) and which 
addendum is being used in a complementary fashion.  
• Addendum 1 – Female Genital Grading Table for Use in Microbicide Studies- 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 2 – Male Genital Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 3 – Rectal Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as 
grade 5.  
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Clinical adverse 
event NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities 
with intervention or 
hospitalization 
indicated 
Potentially life-threatening 
symptoms causing inability 
to perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 
 
 
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Major Clinical Conditions 
Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arrhythmia   
(by ECG or physical 
examination) 
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention 
indicated 
Non-life-threatening 
symptoms AND 
Non-urgent 
intervention indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile  
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia  
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
                                                          
 
 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion indicated 
Symptoms AND 
Transfusion of  ≤ 2 
units packed RBCs 
indicated  
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs  
> 10 cc/kg) indicated 
Prolonged PR Interval  
or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 to 
< 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block  
≤ 16 years of age 
1st degree AV block 
(PR interval  
> normal for age 
and rate) 
Type I 2nd degree 
AV block  
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular 
dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated  
Symptoms AND 
Intervention 
indicated  
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus)  
 
 
                                                          
2 As per Bazett’s formula. 
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Dermatologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Alopecia (scalp only)  
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 
(without skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities  
NA 
Rash 
Specify type, if 
applicable 
Localized rash  
Diffuse rash OR 
Target lesions  
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial 
ulcerations of 
mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving 
two or more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis  
 
                                                          
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 
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Endocrine and Metabolic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure)  
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
                                                          
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 
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Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation)  
Constipation 
NA 
Persistent 
constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas  
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent 
episodes of 
unformed stools OR 
Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to  6 
stools over baseline 
per 24-hour period 
Increase of  ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema  
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding  
Nausea  
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral intake 
for 24 to 48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention 
indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or  
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
98
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 14 
Musculoskeletal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform 
basic self-care functions  
Myalgia (generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care functions 
Osteopenia6 
≥ 30 years of age 
BMD t-score  
-2.5 to -1 
NA 
NA 
NA 
   < 30 years of age 
BMD z-score  
-2 to -1 
NA 
NA 
NA 
Osteoporosis6 
≥ 30 years of age 
NA  
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
 
                                                          
 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
99
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 15 
Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below)  
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or  somnolence 
causing inability to 
perform usual social 
& functional 
activities 
Delirium OR  
Obtundation OR  
Coma 
Ataxia  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
 
Specify type, if applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function  
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
100
2.0
Approved
930120844
2.0
v


Neurologic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 16 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional 
activities  
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy) 
Specify type, if applicable 
Minimal paresthesia 
causing no or 
minimal  
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or  paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure 
≥ 18 years of age 
NA 
NA  
1 to  3 seizures  
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with  
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality  
(e.g., severity or  
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Syncope  
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
101
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 17 
Pregnancy, Puerperium, and Perinatal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Stillbirth (report using 
mother’s participant ID) 
Report only one 
NA 
NA 
Fetal death occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Birth (report 
using mother’s 
participant ID) 
Live birth at 34 to  
< 37 weeks  
gestational age 
Live birth at 28 to  
< 34 weeks 
gestational age 
Live birth at 24 to  
< 28 weeks 
gestational age 
Live birth at < 24 weeks 
gestational age 
Spontaneous Abortion 
or Miscarriage7 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy  
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
 
                                                          
7 Definition:  A pregnancy loss occurring at < 20 weeks gestational age. 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
102
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 18 
Psychiatric 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Insomnia  
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal 
interference with 
usual social & 
functional activities  
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal interference 
with usual social & 
functional activities 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early causing 
inability to perform 
usual social & 
functional activities 
requiring intervention 
or hospitalization 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial 
or complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
103
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 19 
Respiratory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to  
≥ 70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to  
< 70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to  
< 50% OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation  
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal  
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 
90 to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
104
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 20 
Sensory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hearing Loss 
≥ 12 years of age 
 
NA 
 
Hearing aid or 
intervention not 
indicated 
 
Hearing aid or 
intervention indicated 
 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 4, 
6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at  ≤ 4 kHz 
> 20 dB hearing loss 
at > 4 kHz 
> 20 dB hearing loss 
at  ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, 
including hearing 
aids 
Audiologic indication 
for cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medical intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s)  
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional 
activities 
Disabling visual loss in 
affected eye(s) 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
105
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 21 
Systemic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Allergic 
Reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome8 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion)  
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to  
< 102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain9 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Pain causing inability 
to perform usual 
social & functional 
activities  
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
                                                          
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).   
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
106
2.0
Approved
930120844
2.0
v


Systemic 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 22 
Serum Sickness10 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight11 
> 5 to 19 years of 
age 
WHO BMI z-score 
< -1 to -2 
WHO BMI z-score 
< -2 to -3 
WHO BMI z-score  
< -3 
WHO BMI z-score  
< -3 with life-threatening 
consequences 
2 to 5 years of age 
WHO Weight-for-
height z-score  
< -1 to -2 
WHO Weight-for-
height z-score  
< -2 to -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening consequences 
< 2 years of age 
WHO Weight-for-
length z-score  
< -1 to -2 
WHO Weight-for-
length z-score  
< -2 to -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening consequences 
Unintentional 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR  
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
 
                                                          
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or 
dyspnea. 
  
  
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
107
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 23 
Urinary 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Urinary Tract 
Obstruction  
NA 
Signs or symptoms 
of urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
108
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 24 
Site Reactions to Injections and Infusions 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Injection Site Pain or  
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb  
Pain or tenderness 
causing inability to 
perform usual social 
& functional 
activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization 
indicated 
Injection Site Erythema 
or Redness12 
Report only one 
> 15 years of age 
 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25  to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age 
≤ 2.5 cm in 
diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus  
 
Itching localized to 
the injection site 
that is relieved 
spontaneously or in 
< 48 hours of 
treatment  
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment  
Generalized itching 
causing inability to 
perform usual social 
& functional 
activities  
NA 
                                                          
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area. 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
109
2.0
Approved
930120844
2.0
v


 
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Laboratory Values*  
Chemistries 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0  
≥ 20  to < 30  
< 2.0  
< 20  
NA 
Alkaline Phosphatase,  
High 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT or SGPT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low  
(mEq/L; mmol/L) 
16.0 to <  LLN 
16.0 to <  LLN 
11.0  to < 16.0  
11.0  to < 16.0  
8.0  to < 11.0  
8.0  to < 11.0  
< 8.0  
< 8.0  
Bilirubin 
Direct Bilirubin13, 
High 
> 28 days of age 
 
 
NA 
 
NA 
 
> ULN with other 
signs and symptoms 
of hepatotoxicity. 
 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
 
1.1 to < 1.6 x ULN 
 
1.6 to < 2.6 x ULN 
 
2.6 to < 5.0 x ULN  
 
≥ 5.0 x ULN  
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
                                                          
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be reported to DAIDS in an 
expedited time frame unless it meets protocol-specific reporting requirements. 
 
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin. 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
110
2.0
Approved
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Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 26 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5  
2.88  to < 3.13 
12.5   to < 13.5  
3.13  to < 3.38 
≥  13.5  
≥  3.38 
< 7 days of age 
11.5  to < 12.4  
2.88  to < 3.10 
12.4  to < 12.9  
3.10  to < 3.23 
12.9  to < 13.5  
3.23  to < 3.38 
≥  13.5 
≥  3.38 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8  
≥ 7.2 
≥ 1.8  
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4  
1.95  to < 2.10 
7.0   to < 7.8  
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1  
< 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
< LLN  to 4.0  
< LLN  to 1.0 
3.6 to < 4.0  
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9  
< 3.2 
< 0.8  
Cardiac Troponin I, 
High  
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
*Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 to 
< 1.5 x participant’s 
baseline 
> 1.8  to < 3.5  
x ULN OR Increase 
to 1.5 to < 2.0 x 
participant’s baseline 
≥ 3.5 x ULN OR 
Increase of  ≥ 2.0 x 
participant’s baseline 
Creatinine Clearance 14 
or eGFR, Low 
*Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2  
OR 
10 to < 30% decrease  
from participant’s 
baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 
OR 
 30 to < 50% 
decrease from 
participant’s baseline 
< 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 50% decrease from 
participant’s baseline or 
dialysis needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
 
 
110 to 125 
6.11 to < 6.95 
 
 
> 125 to 250 
6.95 to < 13.89 
 
 
 > 250 to 500  
13.89 to < 27.75 
 
 
≥  500  
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89  
> 160 to 250 
8.89 to < 13.89 
> 250  to 500 
13.89  to < 27.75  
≥  500 
≥ 27.75  
                                                          
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should 
choose the method defined in their study and when not specified, use the method most relevant to the study population. 
  
*Reminder: Choose the method that selects for the higher grade. 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
111
2.0
Approved
930120844
2.0
v


Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 27 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glucose, Low  
(mg/dL; mmol/L) 
≥ 1 month of age 
55  to 64  
3.05  to <3.55  
40  to < 55 
2.22  to < 3.05  
30  to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
< 1 month of age 
50 to 54 
2.78  to < 3.00  
40 to < 50 
2.22 to < 2.78  
30 to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
Lactate, High 
ULN to  < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences  
Lipase, High 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders  
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
 
200  to < 240 
5.18  to < 6.19  
 
240  to < 300  
6.19  to < 7.77  
 
≥  300 
≥  7.77  
 
NA 
< 18 years of age 
170  to < 200 
4.40  to < 5.15  
200 to < 300 
5.15  to < 7.77  
≥  300  
≥  7.77  
NA 
LDL, Fasting, High 
≥ 18 years of age 
 
130  to < 160  
3.37  to < 4.12  
 
160 to < 190  
4.12  to < 4.90  
 
≥ 190  
≥ 4.90  
 
NA 
> 2 to < 18 years of 
age 
110  to < 130  
2.85  to < 3.34  
130 to < 190  
3.34  to < 4.90  
≥ 190 
≥ 4.90  
NA 
Triglycerides, Fasting, 
High 
150 to 300  
1.71 to 3.42  
>300  to 500  
>3.42 to 5.7  
>500 to < 1,000  
>5.7 to 11.4  
> 1,000  
> 11.4 
Magnesium15, Low 
(mEq/L; mmol/L) 
1.2   to < 1.4  
0.60  to < 0.70  
0.9  to < 1.2  
0.45  to < 0.60  
0.6  to < 0.9  
0.30  to < 0.45  
< 0.6  
< 0.30  
Phosphate, Low  
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.65 to < LLN 
1.4 to < 2.0 
0.45 to < 0.65  
1.0 to < 1.4 
0.32 to < 0.45  
< 1.0 
< 0.32  
1 to 14 years of age 
3.0  to < 3.5 
0.97  to < 1.13  
2.5  to < 3.0 
0.81  to < 0.97  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
< 1 year of age 
3.5  to < 4.5 
1.13  to < 1.45  
2.5  to < 3.5 
0.81  to < 1.13  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0  
6.0  to < 6.5 
6.0  to < 6.5  
6.5  to < 7.0 
6.5  to < 7.0  
≥ 7.0 
≥ 7.0  
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4  
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5  
< 2.0 
< 2.0  
                                                          
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
112
2.0
Approved
930120844
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Chemistries 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 28 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150  
150  to < 154 
150  to < 154  
154  to < 160 
154  to < 160  
≥ 160 
≥ 160  
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135  
125  to < 130 
125  to < 130 
121  to < 125 
121  to < 125  
≤ 120 
≤ 120  
Uric Acid, High 
(mg/dL; mmol/L) 
7.5  to < 10.0 
0.45  to < 0.59  
10.0  to < 12.0 
0.59  to < 0.71  
12.0  to < 15.0 
0.71  to < 0.89  
≥ 15.0 
≥ 0.89  
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
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930120844
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DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 29 
Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Absolute CD4+ Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
300 to < 400 
300 to < 400 
 
 
 
200 to < 300 
200 to < 300 
 
 
 
100 to < 200 
100 to < 200 
 
 
 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low  
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
600 to < 650 
0.600 x 109 to 
< 0.650 x 109 
 
 
 
500 to < 600 
0.500 x 109 to 
< 0.600 x 109 
 
 
 
350 to < 500 
0.350 x 109 to 
< 0.500 x 109 
 
 
 
< 350 
< 0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
 
 
 
600 to 799 
0.600 x 109 to 0.799 
x 109 
 
 
 
400 to 599 
0.400 x 109 to 0.599 
x 109 
 
 
 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109 
750 to 999 
0.750 x 109 to 0.999 
x 109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109 
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100 to < 200 
1.00 to < 2.00  
OR 
0.75 to < 1.00 
x LLN 
75 to < 100 
0.75  to < 1.00  
OR 
≥ 0.50 to < 0.75 
x LLN  
50 to < 75 
0.50  to < 0.75  
OR 
0.25 to < 0.50 
x LLN 
< 50 
< 0.50  
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin16, Low 
(g/dL; mmol/L) 17 
≥ 13 years of age  
(male only) 
 
 
10.0 to 10.9 
6.19 to 6.76 
 
 
 
9.0 to < 10.0 
5.57 to < 6.19 
 
 
7.0 to < 9.0 
4.34 to < 5.57 
 
 
< 7.0 
< 4.34 
≥ 13 years of age  
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
                                                          
16 Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on hormone 
therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which they identify (i.e., a transgender 
female should be graded using the female sex at birth hemoglobin laboratory values). 
 
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results obtained by 
an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using appropriate conversion 
factor for the particular laboratory.  
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
114
2.0
Approved
930120844
2.0
v


Hematology 
DAIDS AE Grading Table Corrected Version 2.1- July 2017 
Page 30 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
57 days of age to < 13 
years of age  
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.5 x ULN 
1.5  to < 2.0 x ULN 
2.0  to < 3.0 x ULN 
≥  3.0 x ULN 
Methemoglobin  
(% hemoglobin) 
5.0  to < 10.0% 
10.0  to < 15.0% 
15.0  to < 20.0% 
≥  20.0% 
PTT, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.66  
x ULN 
1.66 to < 2.33  
x ULN 
2.33 to < 3.00  
x ULN 
≥  3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 125,000  
100.000 x 109  to 
< 125.000 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000  
25.000 x 109  to  
< 50.000 x 109 
< 25,000  
< 25.000 x 109 
PT, High  
(not on anticoagulation 
therapy 
1.1  to < 1.25  
x ULN 
1.25  to < 1.50  
x ULN 
1.50  to < 3.00  
x ULN 
≥  3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
 
 
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109 
 
 
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109 
 
 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109 
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109 
< 2,500 
< 2.500 x 109 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
115
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 31 
Urinalysis 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to   
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin) 
6  to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+  or higher 
NA 
 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
116
2.0
Approved
930120844
2.0
v


 
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Page 32 
Appendix A.  
Total Bilirubin Table for Term and Preterm Neonates 
   PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Total Bilirubin18, High 
(mg/dL; µmol/L) 19 
 
Term Neonate20 
 < 24 hours of age 
 
4 to < 7  
68.4 to < 119.7  
7 to < 10  
119.7 to < 171  
10 to < 17  
171 to < 290.7  
≥ 17 
≥ 290.7  
24 to < 48 hours of 
age 
5 to < 8  
85.5 to < 136.8  
8 to < 12  
136.8 to < 205.2  
12 to < 19  
205.2 to < 324.9  
≥ 19  
≥ 324.9  
48 to < 72 hours of 
age 
8.5 to < 13  
145.35 to < 222.3  
13 to < 15  
222.3 to < 256.5  
15 to < 22  
256.5 to < 376.2  
≥ 22  
≥ 376.2  
72 hours to < 7 days 
of age 
11 to < 16  
188.1 to < 273.6  
16 to < 18  
273.6 to < 307.8  
18 to < 24  
307.8 to < 410.4 
≥ 24  
≥ 410.4  
7 to 28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
Preterm Neonate20  
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
32 to < 35 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
10 to < 14  
171 to < 239.4 
≥ 14  
≥ 239.4 
28 to < 32 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
6 to < 10  
102.6 to < 171  
≥ 10  
≥ 171  
< 28 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
 5 to < 8  
85.5 to < 136.8  
≥ 8  
≥ 136.8  
7 to  28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
 
 
                                                          
18 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first 
week of life followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this 
appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 
4. 
19 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
20 Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks gestational age; preterm, as < 35 weeks 
gestational age; and neonate, as 0 to 28 days of age. 
Clinical Protocol
BMS-790052
AI444423
daclatasvir
Revised Protocol No.: 01
Date: 18-Dec-2019
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SAP_001.pdf: 
Official Title of Study: 
Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Safety and Efficacy of 
Daclatasvir (DCV) in Combination with Sofosbuvir (SOF) in Children from 3 to less than 18 
Years of Age with GT-1 to -6 Chronic Hepatitis C (CHC) Infection 
 
NCT Number: NCT03487848 
 
Document Date (Date in which document was last revised): December 24, 2019 
 


STATISTICAL ANALYSIS PLAN
FOR CSR
OPEN-LABEL, SINGLE-ARM TRIAL TO EVALUATE THE PHARMACOKINETICS, 
SAFETY AND EFFICACY OF DACLATASVIR (DCV) IN COMBINATION WITH 
SOFOSBUVIR (SOF) IN CHILDREN FROM 3 TO LESS THAN 18 YEARS OF AGE 
WITH GT-1 TO -6 CHRONIC HEPATITIS C (CHC) INFECTION
PROTOCOL AI444423
VERSION # 1.1
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REVISION HISTORY
Revision
Date
Revised by
Changes Made -- Reasons for the Change
1.0
28APR2018
Initial version
1.1
18JUL2018
 
•
Cover page: Removed header.
•
Section 2.1: New section added. Moved all text from Section 2 
here, and renumbered Figure 2-1 as 2.1-1.
•
Section 2.2: New section added. Moved all text from Section 5.2 
here.
•
Section 2.3: New section added to describe blinding and 
unblinding procedures.
•
Section 5.2: Moved all text to Section 2.2, and added text to 
cross-reference Section 2.2.
•
Few typos corrected.
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TABLE OF CONTENTS
REVISION HISTORY................................................................................................................2
TABLE OF CONTENTS............................................................................................................3
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................7
2.3
Blinding and Unblinding...........................................................................................7
3
OBJECTIVES AND ENDPOINTS...........................................................................7
4
SAMPLE SIZE AND POWER.................................................................................9
5
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ....................................................................................................9
5.1
Study Periods............................................................................................................9
5.2
Treatment Regimens...............................................................................................10
5.3
Populations for Analyses ........................................................................................10
6
STATISTICAL ANALYSES..................................................................................10
6.1
General Methods ....................................................................................................10
6.2
Study Conduct........................................................................................................11
6.3
Study Population ....................................................................................................11
6.3.1
Disposition of Participants .....................................................................................11
6.3.1.1
Pre-Treatment Subject Status, Enrollment, and Accrual..........................................11
6.3.1.2
End of Treatment Subject Status .............................................................................12
6.3.1.3
End of Study Subject Status.....................................................................................12
6.3.2
Demographics and Other Baseline Characteristics.................................................12
6.3.2.1
Demographics ........................................................................................................12
6.3.2.2
HCV Disease Characteristics and Virologic Resistance at Baseline........................13
6.3.2.3
ECGs, Vital Signs, and Physical Measurements at Baseline....................................14
6.3.2.4
Laboratory Tests at Baseline ..................................................................................14
6.3.2.5
Prior Non-Study Medications .................................................................................15
6.4
Extent of Exposure .................................................................................................15
6.4.1
Study Therapy and Follow-up.................................................................................15
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6.4.2
Interruption of Study Therapy.................................................................................15
6.4.3
Concomitant and Post-Treatment Non-Study Medications ......................................15
6.5
Efficacy..................................................................................................................16
6.5.1
Primary and Secondary Efficacy Endpoints............................................................16
6.5.1.1
SVR12.....................................................................................................................16
6.5.1.2
Virologic Resistance ...............................................................................................17
6.6
Safety.....................................................................................................................18
6.6.1
Deaths ....................................................................................................................18
6.6.2
Adverse Events .......................................................................................................19
6.6.2.1
AEs by Intensity or Relationship to Study Therapy..................................................20
6.6.2.2
Exposure-Adjusted Multiple AEs.............................................................................20
6.6.3
Hepatic Disease Progression..................................................................................20
6.6.4
Clinical Laboratory Evaluations.............................................................................21
6.6.4.1
Laboratory Abnormalities by Toxicity Grade..........................................................21
6.6.4.2
Laboratory Tests Changes Over Time.....................................................................22
6.6.4.3
Select Laboratory Test Results................................................................................22
6.6.5
Vital Signs ..............................................................................................................22
6.6.6
Physical Measurements ..........................................................................................22
6.6.7
Pregnancy ..............................................................................................................23
6.7
PK Analyses...........................................................................................................23
6.7.1
Intensive PK at Day 10...........................................................................................23
6.7.1.1
PK Concentration...................................................................................................23
6.7.2
PK Parameters .......................................................................................................23
6.7.3
Trough Concentrations...........................................................................................24
6.8
Questionnaires........................................................................................................24
6.8.1
Palatability Assessment of DCV..............................................................................24
6.8.2
Acceptability Assessment of DCV............................................................................24
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7
CONVENTIONS....................................................................................................25
7.1
Analysis Periods.....................................................................................................25
7.2
Analysis Windows and Multiple Records................................................................25
7.3
Derived Dates.........................................................................................................27
7.4
Domain-Specific Conventions ................................................................................27
7.4.1
AEs.........................................................................................................................27
7.4.2
Exposure ................................................................................................................27
7.4.3
Human Genotyping.................................................................................................28
7.4.4
Laboratory Test Results..........................................................................................28
7.4.5
Non-Study Medications...........................................................................................28
7.4.6
Viral Genotyping and Phenotyping.........................................................................29
7.4.7
Virology..................................................................................................................29
8
CONTENT OF REPORTS .....................................................................................29
APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS.............................................31
APPENDIX 2
NS5A AND NS5B KEY GENOTYPIC SUBSTITUTIONS ...................34
LIST OF TABLES
Table 3-1:
Objectives and Endpoints .........................................................................7
Table 5.3-1:
Populations for Analyses ........................................................................10
Table 6.3.2.1-1:
Demographic Characteristics ..................................................................12
Table 6.3.2.2-1:
HCV Disease Characteristics at Baseline ................................................13
Table 6.3.2.3-1:
ECGs, Vital Signs, and Physical Measurements at Baseline....................14
Table 6.6.2-1:
AE Summaries by Analysis Period .........................................................19
Table 6.6.3-1:
Hepatic Disease Progression Diagnoses..................................................20
Table 6.7.2-1:
PK Parameters........................................................................................23
Table 7.2-1:
Analysis Windows..................................................................................25
APP 2-1:
NS5A Reference Sequence at Key Amino Acid Positions.......................34
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic...........................................................................7
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2
STUDY DESCRIPTION
2.1
Study Design
The study is an open-label, single-arm, sequential descending age cohort trial evaluating the PK 
profile, safety, tolerability, and efficacy of DCV+SOF, administered for 12 weeks, to paediatric 
participants (3 years to < 18 years), monoinfected with the hepatitis C virus (genotypes (GT) -1 to 
-6), who are non-cirrhotic and either treatment naive or treatment experienced.
The total duration of the study for each participant is approximately 2.5 years:
•
Screening Duration: 42 days
•
Treatment Duration: 12 weeks
•
Post-Treatment Follow-up Duration: 108 weeks. Upon completion of the post-treatment 
follow-up Week 12 visit, participants are followed for an additional 2 years (96 weeks) as long-
term follow-up to assess SVR24, durability of response, long term safety, and the persistence 
of resistance variants in non-responders.
A minimum of 30 participants are evaluated for the primary endpoint, with at least 8 treated per 
age cohort:
•
Cohort 1: 12 to < 18 years old
•
Cohort 2: 6 to < 12 years old
•
Cohort 3: 3 to < 6 years old
Enrollment begins with Cohort 1, followed by Cohorts 2 and 3. Enrollment in Cohorts 2 and 3 is 
dependent on the availability of the European Commission approved SOF formulation for the 
corresponding age cohort.
The study design is presented in Figure 2.1-1.
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Figure 2.1-1:
Study Design Schematic
2.2
Treatment Assignment
All participants receive DCV+SOF in Cohort 1 (12 to < 18 years), Cohort 2 (6 to < 12 years), and 
3 (3 to < 6 years). Cohorts are determined by age at Day 1 assigned by Interactive Response 
Technology (IRT), not age at enrollment collected on the Case Report Form (CRF).
2.3
Blinding and Unblinding 
This is an open-label study; unblinding procedures are not applicable.
3
OBJECTIVES AND ENDPOINTS
Objectives and endpoints are presented in Table 3-1.
Table 3-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the PK profile of DCV in 
combination with SOF in children and 
adolescents aged 3 to <18 years of age
•
PK parameters (Cmin, Cmax, Tmax, AUC (TAU), CLT/F) 
for DCV derived from plasma concentration versus time data 
on Day 10 (± 3 days) within a dosing interval.
•
In Cohort 3, PK parameters from model-based analyses with 
5 samples from each participant.
Secondary
To assess the safety and tolerability of the 
DCV+SOF regimen in pediatric participants
Frequencies of serious adverse events (SAEs), adverse events 
(AEs) leading to discontinuation of study therapy, AEs by 
intensity, and laboratory abnormalities by toxicity grade on 
treatment and during follow-up
To determine the proportion of participants 
with SVR12
Proportion of participants with HCV RNA < LLOQ (TD or 
TND) at post-treatment follow-up Week 12
To evaluate genotypic substitution(s) 
associated with virologic failure
Frequencies of NS5A and NS5B resistance-associated variants 
(RAVs) emergent at the time of virologic failure on treatment 
and during follow-up in non-responders
To assess the acceptability and palatability for 
the age-appropriate chewable tablet 
formulation, and acceptability for adult 
filmcoated tablet
Summary of responses from questionnaire assessing acceptability 
and palatability at Day 1, Week 4, and Week 12
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Table 3-1:
Objectives and Endpoints
Objectives
Endpoints
 
 
 
 
LLOQ = lower limit of quantification; TD = target detected; TND = target not detected
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SAMPLE SIZE AND POWER
A minimum of 30 participants, assigned to 3 age descending cohorts, are evaluated for the primary 
endpoint (PK) with at least 8 participants assessed in each age cohort.
The primary objective of this study is to evaluate the PK of DCV. The PK profile of DCV has been 
well characterized in the clinical development program and it has been noted that DCV is 
associated with predictable pharmacokinetics. The intra-participant variability for DCV Cmax and 
AUC(INF) was assessed from clinical studies where single oral doses of DCV were administered 
with or without food and were estimated to be low with a % CV of 18% for Cmax and 10% for 
AUC(INF). Similarly, the inter-participant variability in DCV Cmax and AUC were assessed from 
clinical studies where single and multiple oral doses of DCV administered alone, and with or 
without food in some cases, was identified to be modest with % CV values of 37.5% for Cmax 
and 35% for AUC. PK is assessed in all participants; however, due to the low observed variability 
in DCV exposure, assessment of the PK in the initial 5 participants per age cohort provides the 
necessary information to match DCV exposures between adults and paediatric participants and 
either allow enrollment to be initiated in the next descending age cohort(s) or indicate that 
additional participants need to be enrolled in the cohort with a modified dose.
Enrollment will continue in each cohort, after the initial 5 participants have completed their Day 
10 assessments, to have a minimum of 8 evaluable participants in each cohort.
5
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
5.1
Study Periods
Study periods are defined as follows:
•
Pre-treatment period: Begins at the first screening visit and ends on the start date of study 
therapy (DCV or SOF).
•
On-treatment period: Begins after the start date of study therapy and ends on the last date of 
study therapy.  
•
Follow-up period: Begins after the last date of study therapy.
Measurements taken before Day 1 (i.e., the start date of study therapy) are considered pre-
treatment for all data domains. In addition, measurements taken on Day 1 are considered pre-
treatment for the following data domains: demography, diagnostic procedures, disease history, 
ECG, human genotyping, laboratory test results (including serology and virology), medical 
history, physical examination, physical measurements, questionnaires, subject status, viral 
genotyping, viral phenotyping, and vital signs.
Measurements taken after Day 1 through the last date of study therapy are considered on-treatment
for all data domains. In addition, measurements taken on Day 1 are considered on-treatment for 
the following data domains: AEs, drug dispensation, exposure, inclusion/exclusion, non-study 
medications, PK concentration, PK parameters, sample collection, sample inform consent and 
sample reference.
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Measurements taken after the last date of study therapy are considered follow-up for all data 
domains unless otherwise specified.
Refer to Section 7.1 for analysis periods used for analyses and reporting.
5.2
Treatment Regimens
See Section 2.2.
5.3
Populations for Analyses
Populations for analyses are presented in Table 5.3-1.
Table 5.3-1:
Populations for Analyses
Population
Description
Enrolled participants
All participants who sign informed consent and are assigned 
Participant Identification Number. This population is used for all 
non-PK listings and to summarize study conduct.
Treated participants
Enrolled participants who receive at least 1 dose of study therapy
(DCV or SOF). This population is used to summarize pre-
treatment characteristics, efficacy and on-treatment safety.
Follow-up participants
Treated participants who continue into the LTFU period, as 
indicated on the end of treatment subject status CRF. This 
population is used to summarize follow-up safety and duration of 
virologic response.
6
STATISTICAL ANALYSES
Statistical analyses are performed using the version of UNIX SAS or S-Plus in production, unless 
otherwise specified.
6.1
General Methods
All summarizes are presented by cohort and total, unless specified otherwise.
Continuous parameters are summarized using univariate statistics, i.e., number of participants (n), 
mean, standard deviation (SD), median, quartiles, minimum and maximum. Categorical 
parameters are summarized using counts and percentages, or counts and proportions depending on 
the endpoint.
In general, all confidence intervals (CIs) are 2-sided with 95% coverage, unless otherwise 
specified. CIs for binary endpoints are based on exact binomial distribution. CIs for continuous 
endpoints are based on the normal distribution.
Longitudinal summaries of efficacy, safety, and questionnaire endpoints use pre-defined analysis 
visit windows.
Laboratory test endpoints are determined from measurements analyzed at both local and central 
laboratories, and are summarized using both Système International (SI) and US standard units.
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Frequencies and percentages of participants with events are presented for the following: relevant 
protocol deviations; interruptions of study therapy; non-study medications; AEs; laboratory test 
and ECG abnormalities. Multiple occurrences of the same event are counted once per participant
selecting the worst event to summarize, unless specified otherwise.
By-participant listings are provided for select endpoints, and are sorted by cohort, site identifier, 
and subject identifier. Listings display all events regardless of study period unless otherwise
specified. Select listings (e.g., AEs, laboratory tests) display temporal dosing status according to 
the GBS standard temporal dosing model.1
Participants who move to another investigative site during the study are classified according to 
their original investigative site, country and geographic region.
Formats of tables, listings, and graphs are described in the Data Presentation Plan.
6.2
Study Conduct
Relevant protocol deviations are summarized for treated participants. Relevant protocol deviations 
are those that are programmable and could potentially affect the interpretability of the study results, 
such as:2
•
Certain inclusion or exclusion criteria;
•
Incorrect dosing or study treatment assignment;
•
Use of prohibited concomitant medications;
•
Participants remaining on treatment despite having met specified criteria for withdrawal.
APPENDIX 1 describes the relevant protocol deviations that can be programmed from the 
database. 
6.3
Study Population
6.3.1
Disposition of Participants
6.3.1.1
Pre-Treatment Subject Status, Enrollment, and Accrual
Populations for analyses (see Section 5.3) are summarized with counts only (no percentages) for 
enrolled participants.
Pre-treatment subject status is summarized for enrolled participants (total only, not by cohort) for 
the following categories: enrolled, treated, not treated, and the reasons for not being treated (e.g., 
AE, lost to follow-up, death).
Enrollment at each site by country is summarized for enrolled participants by the following 
populations (not by cohort): enrolled and treated. Enrollment by age group is summarized 
analogously. Age group categories are: in utero; preterm newborn (gestational age < 37 weeks); 
newborns (0 to 27 days); infants and toddlers (28 days to 23 months); children (2 to 11 years); 
adolescents (12 to 17 years); adults (18 to 64 years); adults (65 to 84 years); adults (≥ 85 years).
Accrual by month and year of initial study therapy is also summarized for treated participants.
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6.3.1.2
End of Treatment Subject Status
End of treatment subject status is summarized for treated participants for the following categories: 
completing the period, not completing the period (including reasons for not completing), 
continuing to the follow-up period, not continuing to the follow-up period, and not reported (i.e., 
no subject status data).
A by-participant listing of end of treatment subject status is provided for treated participants.
6.3.1.3
End of Study Subject Status
End of study subject status is summarized for follow-up participants for the following categories: 
completing the study, not completing the study (including reasons for not completing), and not 
reported (i.e., no subject status data).
A by-participant listing of end of study subject status is provided for treated participants.
6.3.2
Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics are summarized for treated participants.
Summaries of categorical parameters identify the number and percentage of participants with not 
reported (i.e., missing) measurements, unless specified otherwise.
For treated participants, the baseline value of a parameter (e.g., laboratory test, HCV RNA, ECG, 
vital sign, physical measurement, questionnaire) is defined as the last, non-missing, valid value 
collected or measured on or before the start date of study therapy.
6.3.2.1
Demographics
Demographics are presented in Table 6.3.2.1-1.
Table 6.3.2.1-1:
Demographic Characteristics
Parameter (Units)
Type
Categories
Age at Day 1 from IRT 
(years)
Continuous and categorical
3 to < 6, 6 to < 12, 12 to < 18 years
Age at enrollment 
(years)
Continuous and categorical
3 to < 6, 6 to < 12, 12 to < 18 years
Gender
Categorical
Male, Female
Race
Categorical
White
Black or African American
Asian, with the following subcategories:
•
Asian Indian
•
Asian Other
•
Chinese
•
Japanese
•
Taiwanese
American Indian or Alaska Native
Native Hawaiian or Other Pacific Islander
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Table 6.3.2.1-1:
Demographic Characteristics
Other
Ethnicity
Categorical
Hispanic or Latino
Not Hispanic or Latino
Country by Geographic 
Region
Categorical
Countries within the following regions, as applicable:
Asia (Taiwan)
Europe (Germany, Poland, Romania, Spain)
Pacific Rim/Oceania (Australia)
If sites from other countries are included or excluded in this study, then the associated geographic 
regions are redefined accordingly.
A by-participant listing of demographics is provided for enrolled participants.
6.3.2.2
HCV Disease Characteristics and Virologic Resistance at Baseline
HCV Disease Characteristics
HCV disease characteristics at baseline are presented in Table 6.3.2.2-1.
Table 6.3.2.2-1:
HCV Disease Characteristics at Baseline
Parameter (Units)
Type
Categories
HCV RNA (log10
IU/mL)
Continuous and categorical
< 800,000, ≥800,000, < 2,000,000, ≥2,000,000
IU/mL
HCV genotype
Categorical
1, 1a, 1b, 2, 3, 4, 5, 6 (example; include subtypes)
Cirrhosis status
Categorical
Present, Absent
IL28B rs12979860 host 
genotype
Categorical
CC, CT, TT
HCV treatment history
status
Categorical
Naive, Experienced
Cirrhosis status is derived as per APPENDIX 1.
HCV treatment experienced participants are defined as those who received any prior non-study 
anti-HCV treatment, while HCV treatment naive participants are defined as those who did not 
receive any prior non-study anti-HCV treatment (see APPENDIX 1).
A by-participant listings of baseline disease characteristics is provided for treated participants.
Virologic Resistance at Baseline
NS5A resistance testing at baseline is performed on all participants. NS5A key genotypic 
substitutions at baseline are summarized as categorical parameters for participants with 
genotypable baseline isolates in the following populations: (1) treated participants; (2) SVR non-
responders, which include virologic failures (see Section 6.5.1.2). 
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NS5B resistance testing at baseline is performed only for virologic failures. Thus, NS5B key 
genotypic substitutions at baseline are summarized analogously for SVR non-responders with 
genotypable baseline isolates.
See APPENDIX 2 for key NS5A and NS5B genotypic substitutions.
6.3.2.3
ECGs, Vital Signs, and Physical Measurements at Baseline
ECGs, vital signs, and physical measurements at baseline are summarized as continuous 
parameters (see Table 6.3.2.3-1).
Table 6.3.2.3-1:
ECGs, Vital Signs, and Physical Measurements at Baseline
Parameter (Units)
ECGs (msec): PR interval, QRS width, QT interval, QTC Bazett’s (QTcB), QTc Fridericia’s (QTcF)
Vital signs: heart rate (bpm), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), respiration 
(breaths/min), temperature (°C)
Physical measurements: height (cm), height for age Z score (HAZ), height for age percentile (HAP), weight at 
Day 1 from IRT (kg), weight (kg), weight for age Z score (WAZ), weight for age percentile (WAP), body mass 
index (BMI; kg/m2), BMI for age Z score (BMIAZ), BMI for age percentile (BMIAP)
Physical measurement Z scores and percentiles are calculated using the SAS program for the 2000 
Center for Disease Control (CDC) Growth Charts (ages 0 to < 20 years).3
6.3.2.4
Laboratory Tests at Baseline
Laboratory test abnormalities at baseline are summarized as categorical parameters using toxicity 
grades separately for SI and US units. Percentages are based on participants with measurements.
Commonly collected laboratory tests that are graded using the Division of AIDS (DAIDS) Table 
for Grading the Severity of Adult and Pediatric Adverse Events (2004)4 toxicity grades (Grades 0, 
1, 2, 3, 4; Grade 1 to 4; Grade 3 to 4) include the following, as applicable:
•
Hematology: hemoglobin, platelets, international normalized ratio (INR), white blood cell 
count (WBC), lymphocytes (absolute; only for Cohort 1 participants > 13 years old), and
neutrophils + bands (absolute; ANC);
•
Hepatobiliary enzymes and measures of hepatic synthetic function: alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and albumin;
•
Pancreatic enzymes and renal function tests: lipase (colorimetric or turbidimetric) and 
creatinine;
•
Electrolytes: bicarbonate (low), calcium (high and low), phosphate (low), potassium (high and 
low), and sodium (high and low).
See Protocol Appendix 5 for DAIDS toxicity grades.
In the absence of DAIDS toxicity grades, the following toxicity grade categories are provided for 
creatinine clearance using the Schwartz formula:
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•
SI units (mL/s/ m2): < 0.25 (Grade 4); 0.25 to < 0.50 (Grade 3); 0.50 to < 1.0 (Grade 2); 1.0 to
< 1.5 (Grade 1); ≥1.5 (Grade 0);
•
US units (mL/min/1.73 m2): < 15 (Grade 4); 15 to < 30 (Grade 3); 30 to < 60 (Grade 2); 60 to 
< 90 (Grade 1); ≥ 90 (Grade 0).
General Medical History
A by-participant listing of general medical history is provided for enrolled participants.
6.3.2.5
Prior Non-Study Medications
Prior non-study medications are summarized as categorical parameters alphabetically by anatomic 
class, therapeutic class, and generic name. Prior non-study medications are defined as those taken 
before the start of study therapy. These are previous non-study medications (i.e., those taken before 
informed consent) or current non-study medications (i.e., those taken on or after informed consent 
to before the start of study therapy).
6.4
Extent of Exposure
Extent of exposure is summarized for treated participants, unless specified otherwise. See Section
7.3 for derived dates and Section 7.4.2 for additional conventions.
6.4.1
Study Therapy and Follow-up
The following time-to-exposure-events (weeks) are summarized as continuous parameters:
•
Time on study therapy. Defined as (study therapy end date - study therapy start date + 1)/7. 
•
Time on each study drug and formulation: DCV (any formulation); DCV tablet; DCV 
chewable tablet; SOF (any formulation); SOF tablet; SOF pediatric formulation to be 
determined (TBD). Defined analogously to time on study therapy based on individual start/end 
dates derived for each drug and formulation.
•
Time in follow-up for follow-up participants. Defined as (last contact date - study therapy end 
date + 1)/7.
•
Time on study. Defined as (last contact date - study therapy start date + 1)/7.
6.4.2
Interruption of Study Therapy
Participants with dose interruptions of > 3 consecutive days (including reasons for dose 
modification) are summarized as categorical parameters for each drug (DCV and SOF).
6.4.3
Concomitant and Post-Treatment Non-Study Medications
Concomitant medications are summarized as categorical parameters alphabetically by anatomic 
class, therapeutic class and generic name for treated participants. These are non-study medications 
taken on or after the start date of study therapy and through the last date of study therapy.
Post-treatment medications are summarized analogously for follow-up participants. These are non-
study medications taken any time after the last date of study therapy.
A by-participant listing of all non-study medications (i.e., previous, current, concomitant, post-
treatment) is provided for enrolled participants.
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6.5
Efficacy
All efficacy endpoints in this study are either secondary 
, and are assessed for treated 
participants unless specified otherwise.
Analyses use HCV RNA results from the central laboratory only.  Visit windows are constructed 
around planned visit times for slotting purposes.
For all efficacy analyses, HCV RNA measurements are excluded after the start date of non-study 
anti-HCV medication on treatment or during follow-up (see Section 7.3).
A by-participant listing of HCV RNA values (in both IU/mL and log10 IU/mL) is provided for 
enrolled participants. Values meeting the criteria for virologic breakthrough and relapse at any 
visit are flagged (see Section 6.5.1.2).
The end of treatment (EOT) HCV RNA value is determined from the last HCV RNA value 
collected during the on-treatment analysis period.
See also Section 7.4.7 for virology conventions.
6.5.1
Primary and Secondary Efficacy Endpoints
6.5.1.1
SVR12
The proportion of treated participants with SVR12, defined as HCV RNA < LLOQ TD or TND at 
follow-up Week 12, are presented with 2-sided 95% CIs using the following 3 methods:
•
Next Value Carried Backwards (NVCB): The numerator is based on participants meeting the 
response criteria, and the denominator is based on all treated participants. Participants with 
missing HCV RNA data at follow-up Week 12 have data imputed using the next and closest 
available HCV RNA measurement after the follow-up Week 12 HCV RNA visit window.
•
Modified (mITT): The numerator is based on participants meeting the response criteria, and 
the denominator is based on all treated participants. Participants with missing follow-up Week 
12 HCV RNA are counted as non-responders (i.e., missing data are not imputed).
•
Observed values:  The numerator is based on participants meeting the response criteria, and 
the denominator is based on treated participants with an evaluable HCV RNA measurement at 
follow-up Week 12 (i.e., participants with missing data are excluded).
NVCB is the principal analysis method, whereas mITT and observed values are sensitivity analysis 
methods.
SVR12 treatment outcomes are summarized using NVCB in the following categories:
•
Responder
•
Non-responder
o
Non-responder with HCV RNA < LLOQ TND at EOT

Relapser. Defined as HCV RNA < LLOQ TND at EOT and HCV RNA ≥ LLOQ at 
follow-up Week 12                          

Other non-responder. Defined as HCV RNA < LLOQ TND at EOT and missing HCV 
RNA at follow-up Week 12 and thereafter.
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Percentages for relapse and other non-responders are calculated based on treated 
participants with HCV RNA < LLOQ TND at EOT.
o
On-treatment failure

Virologic breakthrough. Defined as either (1) confirmed ≥ 1 log10 IU/mL HCV RNA 
increase from nadir on treatment, or (2) confirmed HCV RNA ≥LLOQ on treatment 
after HCV RNA < LLOQ TD or TND on treatment. Confirmed is defined as ≥ 2 
consecutive measurements.             

Other on-treatment failure                                  
o
No post-baseline HCV RNA value
6.5.1.2
Virologic Resistance
Resistance testing is performed post-baseline for participants with HCV RNA ≥ 1,000 IU/mL who 
have experienced virologic failure, defined as any of the following:
•
Virologic breakthrough at any on-treatment visit (see Section 6.5.1.1);
•
Relapse at any follow-up visit (see Section 6.5.1.1);
•
Other: HCV RNA ≥ LLOQ at any visit not meeting the definition of virologic breakthrough or 
relapse.
Virologic resistance is assessed for SVR non-responders with paired genotypable isolates, i.e., 
genotypable at baseline and at least one post-baseline visit. SVR non-responders are those who did 
not achieve SVR using observed values at a follow-up visit through follow-up Week 108 (see 
Section 6.5.1.1). The following are summarized as categorical parameters at key amino acid 
positions defined in APPENDIX 2:
•
Emergent NS5A and NS5B genotypic substitutions. An emergent substitution is a post-
baseline substitution that was not detected at baseline;
•
Replacements of NS5A and NS5B emergent genotypic substitutions. A replacement of an 
emergent substitution occurs when only the reference or baseline sequence is detected at the 
last post-baseline genotypable isolate.
A by-participant listing of all NS5A and NS5B genotypic substitutions is provided for enrolled 
participants. This listing identifies key NS5A and NS5B key substitutions, as well as emergence 
and replacement of these key substitutions.                                     
   
 
 
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6.6
Safety
Safety endpoints include the frequencies of AEs, SAEs, AEs leading to discontinuation of study 
therapy, deaths and other significant AEs as reported on CRFs. Other safety endpoints include the 
frequencies of laboratory abnormalities, and changes from baseline in safety parameters (i.e., 
laboratory tests, ECGs, vital signs, and physical measurements) over time.
Safety endpoints are summarized separately for (1) treated participants during the on-treatment 
analysis period, and (2) follow-up participants during the follow-up analysis period, unless 
specified otherwise.
Analyses of safety data are cumulative through the time of database lock.
6.6.1
Deaths
Deaths are identified from two sources of information:
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•
Subject status CRF: Study discontinuation reason of death;
•
AE/SAE CRF: Any of the following parameters: SAE outcome of death; SAE category of 
death; non-missing character death date.
A by-participant listing of death is provided for enrolled participants, which includes the death 
date, time to death (weeks), source of information, and cause of death.
Time to death (weeks) is defined as (death date - start date of study therapy + 1)/7. 
6.6.2
Adverse Events
An AE is defined per protocol as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a patient or clinical investigation participant administered an 
investigational (medicinal) product and that 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, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. 
Verbatim terms are coded and grouped by system organ class using the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA) in production at BMS. Investigators 
determine the intensity of AEs (mild [Grade 1], moderate [Grade 2], severe [Grade 3], very severe 
[Grade 4]), and determine the relationship of AEs to study therapy (related, not related).
In order to account for AEs with multiple occurrences in the same participant, AE records are 
collapsed for each participant and preferred term when records have the same onset date, or when 
records are contiguous or overlapping10. All AE presentations are based on collapsed records.
AEs are summarized as categorical parameters by system organ class (SOC) and preferred term, 
both in descending order of total frequency. Summaries include both non-SAEs and SAEs, unless 
otherwise specified. 
AE summaries separately by analysis period are presented in Table 6.6.2-1.
Table 6.6.2-1:
AE Summaries by Analysis Period
Endpoint
On-Treatment 
Follow-up 
SAEs
X
X
AEs leading to discontinuation of study therapy
X
AEs by intensity or relationship: All Grades; Grade 3 to 4; All Grades 
related to study therapy (on-treatment only)
X
X
Non-SAEs ≥ 5% a,b
X
Exposure-adjusted multiple SAEsa
X
Exposure-adjusted multiple SAEs related to study therapya
X
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Table 6.6.2-1:
AE Summaries by Analysis Period
Endpoint
On-Treatment 
Follow-up 
Exposure-adjusted multiple non-SAEs ≥ 5%a,b
X
a ClinicalTrials.gov or EudraCT reporting requirement
b Cut-off applies to frequency of participants with preferred terms in any cohort.
A by-participant listing of all AEs is provided for enrolled participants.
6.6.2.1
AEs by Intensity or Relationship to Study Therapy
For graded summaries of AEs (e.g., AEs by intensity, AEs by relationship), AEs with missing 
intensity are included only in summaries of All Grades events.  The greatest intensity during a 
safety analysis period is presented for each AE.
AEs related to study therapy are those with a “related” or missing relationship to the study therapy. 
If relatedness to study therapy is unknown, the AE is included in summaries of AEs judged by the 
investigator to be related to study therapy.
6.6.2.2
Exposure-Adjusted Multiple AEs
Analyses take into account the number of occurrences of an AE reported by individual participants 
and their cumulative exposure on treatment.  These data are presented as the rate per 100 years of 
patient exposure. For example, if 5 participants report 7 unique episodes of headache and had a 
combined cumulative exposure of 20 years to study medication, the incidence rate is reported as 
7/20 *(100) or 35 cases per 100 patient years of exposure. 
Cumulative exposure is defined as (1) time on study therapy for participants who have not 
discontinued study therapy, and (2) time on study therapy + 7 days for participants who 
discontinued study therapy to account for on-treatment safety reporting.
6.6.3
Hepatic Disease Progression
Hepatic disease progression is summarized by the categories specified in Table 6.6.3-1 during the 
on-treatment and follow-up analysis periods combined for treated participants. Hepatic disease 
progression is identified from the Hepatic Related Diagnoses CRF.
Table 6.6.3-1:
Hepatic Disease Progression Diagnoses
Diagnoses
Cirrhosis, non-bleeding esophageal varices, bleeding esophageal varices, hepatic encephalopathy, 
hepatocellular carcinoma, spontaneous bacterial peritonitis, non-bleeding gastric varices, bleeding gastric 
varices, hepatorenal syndrome, liver transplant
A by-participant listing of hepatic disease progression is provided for enrolled participants.
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6.6.4
Clinical Laboratory Evaluations
Summaries are based on treated participants with at least one laboratory measurement during the 
analysis period. All output is presented separately for SI and US units.
EOT toxicity grades and values are determined form the last laboratory test value collected during 
the on-treatment analysis period.
End of study (EOS) toxicity grades and values are determined form the last laboratory test value 
collected during the follow-up analysis period.
By-participant listings are provided for enrolled participants for the following laboratory tests:
•
Hematology: hematocrit, hemoglobin, platelets, INR, WBC, lymphocytes (absolute), and
ANC;
•
Hepatobiliary enzymes and measures of hepatic synthetic function: ALT, AST, AST to platelet 
ratio index (APRI), alkaline phosphatase, total bilirubin, albumin, and alpha fetoprotein;
•
Pancreatic enzymes and renal function tests: lipase (colorimetric or turbidimetric), creatinine, 
and creatinine clearance using the Schwartz formula;
•
Electrolytes: bicarbonate, calcium, phosphate, potassium, and sodium.
These listings identify laboratory abnormalities using toxicity grades as specified in Section 
6.3.2.4.
6.6.4.1
Laboratory Abnormalities by Toxicity Grade
Laboratory abnormalities are summarized by analysis period (on-treatment and follow-up) in the 
following toxicity grade categories: 
•
Worst toxicity grade: 0, 1, 2, 3, 4, 3 to 4, 1 to 4;
•
Worst emergent toxicity grade: not emergent, 1, 2, 3, 4, 3 to 4, 1 to 4.
See Section 6.3.2.4 for laboratory tests with toxicity grades. Electrolytes are excluded from 
summaries due to infrequent post-baseline testing.
Emergent abnormalities on treatment are laboratory tests on treatment that have a higher toxicity 
grade than the baseline toxicity grade (including missing baseline). The category “not emergent” 
represents laboratory tests on treatment that have the same or lower toxicity grade than the baseline 
toxicity grade.
Emergent abnormalities during follow-up are laboratory tests during follow-up that have a higher 
toxicity grade than the EOT toxicity grade (including missing EOT). The category “not emergent” 
represents laboratory tests during follow-up that have the same or lower toxicity grade than the 
EOT toxicity grade.
The laboratory value during the analysis period with the worst (highest) toxicity grade is reported 
for each laboratory test. 
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6.6.4.2
Laboratory Tests Changes Over Time
Laboratory test observed values and changes from baseline are summarized as continuous 
parameters over time at baseline and each scheduled analysis visit on treatment. Laboratory tests 
may include the following:
•
Hematology: hemoglobin, platelets, INR, WBC, lymphocytes (absolute), and ANC;
•
Hepatobiliary enzymes and measures of hepatic synthetic function: ALT, AST, and total 
bilirubin; 
•
Pancreatic enzymes and renal function tests: lipase colorimetric and creatinine.
Laboratory test observed values and changes from EOT are summarized analogously over time at 
EOT and each scheduled analysis visit during follow-up.
6.6.4.3
Select Laboratory Test Results
Select laboratory test endpoints are summarized as categorical parameters as follows for treated 
participants, unless specified otherwise:
•
Confirmed creatinine clearance < 1.0 mL/s/m2 (< 60 mL/min/1.73m2) using the Schwartz 
formula on treatment. Confirmed is defined as ≥ 2 consecutive values meeting the criteria on 
treatment.
•
ALT normalization (i.e., ALT ≤1 x upper limit of normal [ULN]) at EOT by baseline ALT 
category (all; ALT ≤1 x ULN; ALT > 1 x ULN; not reported) on treatment. 
•
ALT normalization at EOS by EOT ALT category (all; ALT ≤1 x ULN; ALT > 1 x ULN; not 
reported) during follow-up for follow-up participants. 
•
AST normalization (i.e., AST ≤1 x ULN) at EOT by baseline AST category (all; AST ≤1 x 
ULN; AST > 1 x ULN; not reported) on treatment.
•
AST normalization at EOS by EOT AST category (all; AST ≤1 x ULN; AST > 1 x ULN; not 
reported) during follow-up for follow-up participants.
•
Potential Drug Induced Liver Injury (PDILI) on treatment or during follow-up, defined as 
concurrent (1) ALT ≥ 5 x minimum(baseline, nadir),  and  ALT ≥ 10 x ULN, and (2) total 
bilirubin ≥ 2 x ULN. Concurrent is defined as the total bilirubin elevation occurring within 30 
days after the ALT elevation.
6.6.5
Vital Signs
Vital signs observed values and changes from baseline are summarized as continuous parameters 
over time at baseline and each scheduled analysis visit on treatment for treated participants. See 
Section 6.3.2.3 for parameters.
A by-participant listing of vital signs is provided for enrolled participants.
6.6.6
Physical Measurements
Age-adjusted physical measurements (i.e., HAZ, HAP, WAZ, WAP, BMIAZ, BMIAP) observed 
values and changes from baseline are summarized as continuous parameters over time at baseline 
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and each scheduled analysis visit on treatment and during follow-up for treated participants. See 
also Section 6.3.2.3.
A by-participant listing of physical measurements is provided for enrolled participants.
6.6.7
Pregnancy
A by-participant listing of pregnancy test results is provided for enrolled female participants.
6.7
PK Analyses
PK analyses are performed for each cohort separately, and not combined across cohorts.
PK analysis, reporting, and exclusion criteria follow the BMS PK Harmonization Document.5
Specific guidelines for exclusionary criteria for half-life and how other PK parameters are affected 
for exclusion are in Section 9 of this document, while conventions for handling concentrations < 
LLOQ are in Section 11 (i.e., for DCV, LLOQ = 2 ng/mL; for SOF, LLOQ = 5 ng/mL; for SOF 
metabolite (GS331007), LLOQ = 10 ng/mL).
6.7.1
Intensive PK at Day 10
Intensive PK is assessed for treated PK participants with intensive PK at Day 10.
6.7.1.1
PK Concentration
DCV plasma concentration at Day 10 is summarized over time using univariate statistics (i.e., n, 
mean, SD) at each nominal collection hour: 0 (pre-dose), 30 min, 1 (Cohorts 1 and 2 only), 2, 4, 
and 8.
Two graphs are also provided:
•
Parallel line plots of individual DCV plasma concentration (linear and semi-log scales) versus 
actual collection time;
•
Longitudinal plot of mean DCV plasma concentration (linear and semi-log scales) versus 
nominal collection time, with error bars representing ± one SD.
A by-participant listing of DCV plasma concentration is provided. Values excluded from the 
summary are flagged.
6.7.2
PK Parameters
Individual PK parameter values for DCV (see Table 6.7.2-1) are derived from plasma 
concentration versus time at Day 10 using non-compartmental methods or model-based 
approaches as needed. DCV PK parameter values are summarized using univariate statistics (i.e., 
n, mean, SD, geometric mean, coefficient of variation [%CV], median, quartiles, minimum, and 
maximum).
Table 6.7.2-1:
PK Parameters
Parameter (Units)
Definition
Cmax (mg/mL)
Maximum observed plasma concentration
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Table 6.7.2-1:
PK Parameters
Parameter (Units)
Definition
Tmax (h)
Time of maximum observed plasma concentration
AUC(TAU) (h*ng/mL)
Area under the concentration-time curve in one dosing interval
Cmin (ng/mL)
Minimum (trough) observed plasma concentration
CLT/F (mL/min)
Apparent total body clearance
Concentration at pre-dose on Day 10 is used for C24 (Cmin) solely for the purpose of calculating 
AUC(TAU).
A by-participant listing of DCV PK parameter values at Day 10 is provided. Values excluded from 
the summary are flagged.
6.7.3
Trough Concentrations
Trough concentrations of DCV and SOF/metabolites are summarized over time at each scheduled 
analysis visit (Day 10, Weeks 4, 8, and 12) for treated participants using univariate statistics (i.e., 
n, mean, SD, geometric mean, %CV, median, quartiles, minimum, and maximum).
Trough concentrations must meet each of the following criteria to be included in the statistical 
summary:
•
Complete sampling and dosing times;
•
Collected within 20-28 hours (inclusive) of the previous day’s dose;
•
Collected before the next dose;
Values that do not meet all the above criteria are excluded from the analysis.
Longitudinal plots display geometric mean of trough concentrations versus visit.
By-participant listings of DCV and SOF/metabolite trough concentrations are provided. Values 
excluded from summaries are flagged.
6.8
Questionnaires
Questionnaires of DCV palatability and acceptability are assessed for treated participants.
A by-participant listing of DCV palatability and acceptability assessments is provided.
6.8.1
Palatability Assessment of DCV
Palatability of DCV is summarized over time at baseline and each scheduled analysis visit on 
treatment (Weeks 4 and 12) and by relative time (10 sec, 5 min, 10 min) in the following categories: 
super bad; bad; maybe good or maybe bad; good; super good; not reported (includes missing and 
not assessed).
6.8.2
Acceptability Assessment of DCV
Acceptability of DCV is summarized over time at baseline and each scheduled analysis visit on 
treatment (Weeks 4 and 12) in the following categories:
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•
Tablet easy to take: yes, no, and not reported. Reasons for “no” include the following
subcategories: it was too big; it got stuck on tongue; other.
•
Chewable tablet easy to take: yes, no, and not reported. Reasons for “no” include the following 
subcategories: it was too hard; it took a long time to chew; child had to drink something to help 
swallow the pieces; at times, the child experiences problems in chewing and swallowing; other.
•
Any problems with chewable tablet packaging: yes, no, and not reported. Reasons for “no” 
include the following subcategories: it was difficult to push out the tablet through the 
packaging; the tablet broke when pushed out; the package had to be cut open; other.
7
CONVENTIONS
Conventions are followed as per the following BMS documents, unless specified otherwise: Global 
Biometric Sciences General Requirements for Statistical Outputs6; Global Standard Table 
Reporting Requirements Specification;7 Global Standard Listing Reporting Requirements
Specification.8
7.1
Analysis Periods
Analysis periods are defined as follows:
•
Pre-treatment period: Begins at the first screening visit and ends on the start date of study 
therapy (DCV or SOF).
•
On-treatment period: Begins after the start date of study therapy and ends on the last date of 
study therapy plus 7 days. The 7-day cut-off reflects the point at which minimal antiviral 
activity related to study therapy is present. It is also expected that minimal drug exposure and 
undetectable drug levels will be present beyond 7 days post-dose.
•
Follow-up period: Begins after the last date of study therapy plus 7 days.
Refer to Section 5.1 for slotting Day 1 measurements according to domain.
7.2
Analysis Windows and Multiple Records
Analysis visit windows are defined within analysis periods as follows:
•
Select values in the appropriate analysis period.
•
Slot observations into analysis visit windows (e.g., “WK 4”, “F/U WK 12”) defined in Table 
7.2-1. Analysis visit windows are generally defined according to mid-points between visits.
Table 7.2-1:
Analysis Windows
Abbreviated Analysis 
Visit Label in Output
Target Visit Day in Analysis 
Period
Study Days in Analysis Period
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Table 7.2-1:
Analysis Windows
Abbreviated Analysis 
Visit Label in Output
Target Visit Day in Analysis 
Period
Study Days in Analysis Period
B/La
1
≤ 1
ON-TRT
UNS
4
[2, 6]
DAY 10
10
[7, 13]
WK 4
28
[14, 42]
WK 8
56
[43, 70]
WK 12
84
[71, 98]
WK 16
42
> 98
F/Ub
F/U WK 4
21
[7, 49]
F/U WK 12
77
[50, 119]
F/U WK 24
161
[120, 245]
F/U WK 48
329
[246, 413]
F/U WK 72
497
[414, 581]
F/U WK 96
665
[582, 707]
F/U WK 108
749
[708, 791]
F/U WK 120
833
> 791
a Baseline in longitudinal summaries
b Target visit day and study days reflect 7-day offset that defines follow-up analysis period (see Section 7.1)
For longitudinal analyses 
), if there are multiple values 
within an analysis window, then select one value for analyses as follows:
•
HCV RNA on treatment: Closest value collected relative to the target visit day (as determined 
by the absolute difference in days between the target visit day and the collection day, and the 
absolute difference in days between the target visit day and the assay day); if there are ties, 
then select first value assayed.
•
HCV RNA during follow-up: Last value collected; if there are ties, then select first value 
assayed.
•
Other: Last value measured or collected; if there are ties, then select last entered. For 
questionnaires with multiple items, all items are considered collectively, not individually, for 
each assessment and entry dates. For other parameters (e.g., laboratory tests, ECGs, vital signs, 
physical measurements), each parameter is considered individually.
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If there are multiple records collected or measured on the same day, then the last value entered is 
selected, unless specified otherwise in Section 7.4.
7.3
Derived Dates
Derived dates are obtained from full, valid numeric dates. Full dates are those that have non-
missing day, month and year. Valid dates are those that are consistent with the calendar (e.g., 
“31FEB2017” is invalid). No imputation is performed, unless specified otherwise.
•
Start date of study therapy is the earliest start date of any drug in the regimen (DCV or SOF) 
identified from full, valid numeric dates with total dose > 0 from study medication CRFs. This 
date is used to identify treated participants, define study and analysis periods, and assess time 
on study therapy. [This is the numeric version of SDTM DM.RFSTDTC, which is the same as 
DM.RFXSTDTC for this study.]
•
End date of study therapy is the latest start or stop date of any drug in the regimen (i.e., DCV 
or SOF) identified from full, valid numeric dates with total dose > 0 from study medication 
CRFs. This date is used to assess time on study therapy. [This is the numeric version of SDTM 
DM.RFXENDTC.]
•
Last date of study therapy is the end date of study therapy derived only for participants who 
completed or did not complete the treatment period based on the end of treatment subject status 
CRF. This date is used to define study and analysis periods, and assess time on study therapy. 
[This is the numeric version of SDTM DM.RFENDTC.]
•
Last contact date is the death date, if it exists, or the latest of the following numeric dates: 
randomization; study therapy start or end; AE imputed onset or resolution; diagnostic 
procedure start; HCV RNA collection; laboratory test (safety, pregnancy) collection; last 
contact from end of treatment or end of study subject status; medical procedure start or stop; 
neurologic exam; vital signs; non-study medication imputed start or stop; palatability 
assessment; acceptability assessment; physical measurement; physical exam; viral genotype 
collection; vital phenotype collection.
•
Start date of anti-HCV therapy on treatment or during follow-up is the earliest imputed 
concomitant or post-treatment numeric start date among anti-HCV medications (approved 
antiviral or immunomodulating agent; investigational antiviral or immunomodulating agent; 
see Section 7.4.5 and APPENDIX 1). 
7.4
Domain-Specific Conventions
7.4.1
AEs
Missing and partial adverse event onset dates are imputed according to the AE Domain 
Requirements Specifications9,10 in place at the start of programming.  Imputed dates are used to 
classify AEs into study and analysis periods. Counting rules for AEs, including those for exposure-
adjusted multiple AEs, also follow these specifications.
7.4.2
Exposure
Derivations are based on study medication CRFs.
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Start and end dates of individual study drugs (DCV and SOF) and formulations are derived 
analogously for participants with full, valid numeric dates with total dose > 0 (see Section 7.3).  
The following conventions are applied to dosing calculations for each drug/formulation:
•
Distinct records with non-missing numeric dose start date, total dose, and generic drug name 
are selected.
•
Missing dose stop dates are imputed. The missing stop date of a dosing record is set to 1 day 
before the start date of the next available dosing record. If the participant started drug and was 
lost to follow-up (i.e., has only 1 record), the missing end date is set to the start date, thus 
crediting the participant with 1 day of dosing.
•
Overlapping dose dates are modified.  If the start date of a dosing record is equal to or before 
the end date of the previous dosing record, then the start date is set to 1 day after the previous 
end date.
•
Total dose for a dosing record is calculated as the total dose recorded.
•
Duration for a dosing record is calculated as stop date - start date + 1.
•
Total amount of drug taken is the sum of total dose x duration across dosing records.
Interruptions of individual study drugs (DCV and SOF) are identified from records with full, valid 
numeric start and stop dates, and total daily dose of 0. For participants who discontinued study 
therapy, only records with start dates before the last date of study therapy are selected, and end 
dates after the last date of study therapy are set to the last date of study therapy.
Dose adherence to a study drug (DCV or DOF) is defined as 100*minimum(average daily dose 
/target daily dose, 1):
•
DCV: Target daily dose = 20 mg if Day 1 weight < 30 kg; 40 mg if 30 ≤ Day 1 weight < 45 
kg; 60 mg if Day 1 weight ≥ 45 kg;
•
SOF: Target daily dose = 400 mg for Cohort 1; TBD for Cohorts 2 and 3.
Day 1 weight is determined from IRT (see Section 6.3.2.3).
7.4.3
Human Genotyping
SNP genotype is considered missing if either allele is not A, C, G, T, DEL or INS.
7.4.4
Laboratory Test Results
Toxicity grades are based on standard values, standard lower limit of normal (LLN), and standard 
ULN, as applicable. If a laboratory value that is graded as a multiple of the ULN or LLN falls 
between 2 toxicity grades, then the higher toxicity grade is assigned (e.g., an ALT value that is 
2.53 x ULN is classified as Grade 2, not Grade 1).
7.4.5
Non-Study Medications
Non-study medications are coded using the BMS WHO dictionary. Missing and partial non-study 
medication start and stop dates (including unknown and continuing) are imputed according to the 
Non-Study Medication Domain Requirements Specifications
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programming.11 Imputed dates are used to classify medications as previous, current, concomitant 
or post-treatment.
7.4.6
Viral Genotyping and Phenotyping
If there are multiple records on the same collection day, then the last record assayed is selected. 
Only records from the central laboratory are used.
7.4.7
Virology
The central laboratory uses the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v2.0 
to measure HCV RNA level. This assay has limit of detection = 15 IU/mL, LLOQ = 15 IU/mL,
and upper limit of quantification (ULOQ) = 1.0 x 108 IU/mL.
HCV RNA viral loads are reported by the central laboratory and listed as follows: 
•
(1) Actual numeric values for detectable virus within LLOQ and ULOQ;  
•
(2) “> ULOQ” for detectable virus above ULOQ; 
•
(3) “< LLOQ, HCV RNA detected” for detectable virus below LLOQ; 
•
(4) “No HCV RNA detected” for undetectable virus.
Analyses of HCV RNA < LLOQ TND use data corresponding to item 4 above. Analyses of HCV 
RNA < LLOQ TD or TND use data corresponding to items 3 and 4 above.
For analyses of HCV RNA as a continuous parameter, HCV RNA values in the original scale of 
IU/mL are imputed with a value of 1 more (or 1 less) if an inequality “>” (“<”) is present (items 2 
and 3 above), and a value of LLOQ - 1 if undetectable (item 4 above). These values are then 
transformed to the log10 scale.  
If there are multiple values on the same collection day, then the first value assayed is selected. 
Only records from the central laboratory are used.
8
CONTENT OF REPORTS
The timing of interim analyses will depend on the availability of Day 10 PK results. An interim 
analysis will be performed when the first 5 participants in each age cohort complete the Day 10 
PK sample collection.
If the median plasma exposure in a cohort is outside the predefined therapeutic range, then dose 
modification will be performed using pediatric formulations of DCV, and an additional 5 
participants will be enrolled. Another interim analysis will be performed when these additional 
participants complete the Day 10 PK sample collection in order to confirm the exposure at the 
modified dose. All Day 10 PK interim analyses will focus on PK and select safety listings (e.g.,
AEs, laboratory tests, end of treatment subject status). In each cohort, enrollment will continue in 
order to achieve at least 8 evaluable participants per cohort.
Additional interim analyses will be performed when all participants in an age cohort complete the 
Follow-up Week 12 visit and when all participants complete the Follow-up Week 12 visit in order 
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to assess the primary and secondary endpoints. All endpoints except PK and durability of virologic 
response will be assessed.
The final analysis will be conducted when all participants complete long-term follow-up to assess 
long-term efficacy endpoints (
, durability of virologic response, and virologic 
resistance) and follow-up safety endpoints.
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS
Relevant protocol deviations are summarized as categorical parameters for treated participants.
Eligibility Deviations
Eligibility deviations are based on those occurring during the pre-treatment period for the 
following categories:
•
Inclusion criterion 2a: HCV genotype other than GT-1 to GT-6, including mixtures, during 
screening;
•
Inclusion criterion 2b: HCV RNA < 1,000 IU/mL during screening;
•
Inclusion criterion 2e: Presence of cirrhosis as defined in protocol. 
−
A participant is considered to be non-cirrhotic if any one of the following criteria is met:
♦Liver biopsy results with F0-F3 stage of fibrosis by Metavir within 3 years before 
screening. Determined from the Fibrosis Staging CRF;
♦Fibroscan measurement < 12.5 kPa within 1 year before Day 1. Determined from the 
Fibrosis Staging CRF;
♦APRI ≤ 0.5 during screening. Determined from the laboratory test.  
−
A participant is considered to be cirrhotic if any one of the following criteria is met:
♦Liver biopsy results with F4 stage of fibrosis by Metavir at any time before screening. 
Determined from the Fibrosis Staging CRF;
♦Fibroscan measurement ≥ 12.5 kPa within 1 year before Day 1. Determined from the 
Fibrosis Staging CRF;
♦APRI > 0.5 during screening. Determined from the laboratory test.
If fibrosis stage data are available from several sources, then the liver biopsy supersedes
Fibroscan, and Fibroscan supersedes APRI.
•
Inclusion criterion 2f: Baseline weight < 10 kg;
•
Inclusion criterion 3a: Age < 3 or > 18 years at enrollment;
•
Exclusion criterion 1a: Positive serological test for HBV or HIV infection during screening. 
Defined as positive HBsAg, HIV-1 antibody, or HIV-2 antibody.
•
Exclusion criterion 1e: Pre-treatment HCC. Identified from general medical history specify 
details (#) or fibrosis staging finding;
•
Exclusion criterion 1i: Confirmed HbA1c ≥ 0.085 or ≥ 8.5% during screening. Confirmed is 
defined as at least 2 consecutive measurements;
•
Exclusion criterion 2a: Use of prohibited prior non-study medication (#). Defined as any of the 
following:
−
Any HCV NS5A inhibitor or SOF;
−
Any approved anti-HCV therapy < 12 weeks before Day 1;
Generic drug names are presented alphabetically as subcategories.
•
Exclusion criteria 3b to 3i: Laboratory test findings during screening, with the following 
subcategories:
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-
Exclusion criterion 3b: ALT or AST > 10 x ULN
-
Exclusion criterion 3c: Albumin < 35 g/L or < 3.5 g/dL
-
Exclusion criterion 3d: Total bilirubin > 19 μmol/L or > 1.1 mg/dL without history of 
Gilbert syndrome. Gilbert syndrome is identified from general medical history specify 
details (#);
-
Exclusion criterion 3e: Alpha fetoprotein > 50 ng/mL or > 50 μg/L
-
Exclusion criterion 3f: ANC < 1.5 x 109 cells/L or < 1.5 x 103 cells/μL
-
Exclusion criterion 3g: Hemoglobin < 100 g/L or < 10 g/dL
-
Exclusion criterion 3h: Platelets < 100 x 109 cells/L
-
Exclusion criterion 3i: Creatinine clearance < 1 mL/s/m2 or < 60 mL/min/1.73m2, using 
the Schwartz formula.
(#) Non-study medications and medical conditions marked above with # are identified by a BMS 
physician prior to database lock.
The screening portion of the pre-treatment analysis period begins at informed consent and ends
before the start of study therapy (Day 1). 
A participant with multiple pre-treatment measurements (e.g., HCV RNA) is considered to have 
an eligibility deviation only if all pre-treatment measurements meet the deviation criterion.
Participant Management Deviations
Participant management deviations are evaluated during the on-treatment or follow-up analysis 
period for the following categories:
•
At least 2 consecutive missed doses of DCV before Day 10 PK sampling, or at least 1 missed 
dose of DCV within 2 days before Day 10 PK sampling. Missed doses of DCV are identified 
from interruptions or gaps between dosing records;
•
At least twice of DCV target daily dose taken within 2 days before Day 10 PK sampling;
•
DCV or SOF average daily dose < 80% of target daily dose;
•
DCV or SOF interruption > 7 consecutive days;
•
Continuation of study therapy after having virologic breakthrough;
•
Use of prohibited non-study concomitant medication for more than 1 day, including anti-HCV 
medications (#). Generic drug names are presented alphabetically as subcategories;
•
Use of non-study anti-HCV medication during follow-up (#). Generic drug names are 
presented alphabetically as subcategories;
(#) Non-study medications marked above with # are identified by a BMS physician prior to 
database lock.
 
 
 
 
 
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Anti-HCV Medications
Currently, the following non-study generic drugs are approved for HCV treatment: 
BOCEPREVIR, 
BROCE/INTA/RIBAV, 
BROCE/INTAB/RIBAV, 
DACLATASVIR*, 
DASABUVIR, DASAB/OMBIT/PARIT/RIBAV/RITON*, DASAB/OMBIT/PARIT/RITON*, 
ELBASVIR*, 
ELBVIR/GRAZO*, 
GLECAPREVIR, 
GLECA/PIBRE, 
GRAZOPREVIR, 
INTERFERON, INTERFERON ALFA, INTERFERON ALFA 1B, INTERFERON ALFA 2A, 
INTERFERON ALFA 2B, INTERFERON ALFA N1, INTERFERON ALFA N3, INTERFERON 
ALFACON, INTERFERON ALFACON 1, INTERFERON BETA, INTERFERON BETA 1A, 
INTERFERON BETA 1B, INTERFERON GAMMA, INTERFERON GAMMA
1B, 
INTA/RIBAV, INTA/RIBAV/TELAP, INTAA/RIBAV, INTAB/RIBAV, INTFER/RIBAV, 
LEDIPASVIR*, 
LEDIP/RIBAV/SOFO*, 
LEDIP/SOFO*, 
OMBITASVIR*, 
OMBIT/PARIT/RITON*, PARITAPREVIR, PIBRENTASVIR*, RIBAVIRIN, RIBAV/SOFO, 
SIMEPREVIR, 
SIMPRE/SOFO, 
SOFOSBUVIR, 
SOFO/VELPAT*, 
SOFO/VELPAT/VOXILA*, TELAPREVIR, VELPATASVIR*. The drugs asterisked (“*”) are or 
contain NS5A inhibitors. 
Other non-study medications that may be considered to have anti-HCV activity (depending on the 
reported name) are the following generic drug names: INVESTIGATIONAL ANTIVIRAL, 
INVESTIGATIONAL 
IMMUNOMODULATING 
AGENT, 
IMMUNOMODULATING 
AGENT. 
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APPENDIX 2
NS5A AND NS5B KEY GENOTYPIC SUBSTITUTIONS
All NS5A genotypic substitutions at amino acid positions 24, 28, 29, 30, 31, 32, 58, 62, 92, and 
93 are noted if they differ from the reference sequence for each HCV genotype (see table below).
APP 2-1:
NS5A Reference Sequence at Key Amino Acid Positions
HCV 
Genotype
Sequence 
Accession 
Number
Reference
Strain
Amino Acid Position Reference
24
28
29
30
31
32
58
62
92
93
1a
AF009606
H77
K
M
P
Q
L
P
H
E
A
Y
1b
AJ238799
Con1
Q
L
P
R
L
P
P
Q
A
Y
2
AB047639
GT2
T
F
P
K
L
P
P
N
C
Y
3
GU814263
GT3
S
M
P
A
L
P
P
S
E
Y
4
GU814265
GT4
K
L
P
L
M
P
P
D
A
Y
5
AF064490
GT5
Q
L
P
Q
L
P
P
T
A
T
6
Y12083
GT6
Q
F
P
R
L
P
T
V
A
T
The following NS5B key substitutions are noted, regardless of HCV genotype: D61G; A112T; 
L159F; E237G; S282T or S282R; C316N; L320F, L320I, or L320V; V321A or V321I; S473T.
Mixture substitutions are denoted by Monogram with a slash separating each amino acid in the 
mixture (e.g., “V321A/I/V”). Each amino acid of the mixture is assessed when determining 
persistence or replacement of substitutions.
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