Clinical trial NCT02486406
Conditions: Chronic Hepatitis C Infection
Keywords: Hepatitis C Virus Hepatitis C Genotype 1 Hepatitis C Genotype 4 Pediatric
Sponsor: AbbVie
Start date: 2015-10-28; Completion date: 2020-11-19
Enrollment: 64 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a Phase 2/3, open-label, multicenter study to evaluate the pharmacokinetics (PK), efficacy, and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/RTV) with or without dasabuvir (DSV) and with or without ribavirin (RBV) in Hepatitis C virus (HCV) genotype 1 or 4 (GT1 or GT4)-infected pediatric participants of ≥ 3 to 17 years of age.

Detailed description:
The study population for Part 1, the PK study, included GT1-infected participants who were noncirrhotic and treatment-naïve (TN). Part 2, the safety and efficacy study, included GT1 or GT4-infected participants who were TN or interferon (\[IFN\] or Pegylated-interferon alfa-2a or 2b \[pegIFN\] with or without RBV) treatment-experienced (TE) without cirrhosis or with compensated cirrhosis. In Part 1 and Part 2, the treatment regimen and duration were dependent on HCV GT, GT1 subtype, and cirrhosis status.

Arms: arm 1: Participants with HCV GT1b without cirrhosis received the adult 3-DAA (OBV/PTV/RTV and DSV) regimen: two 12.5 mg ombitasvir /75 mg paritaprevir /50 mg ritonavir tablets taken orally every morning (QD) and one dasabuvir 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis received 12-week treatment with the adult 3-DAA regimen and ribavirin 200 mg tablets were administered orally per local label. arm 2: Participants with HCV GT1b received the adult 3-DAA (OBV/PTV/RTV and DSV) regimen: two 12.5 mg ombitasvir /75mg paritaprevir /50 mg ritonavir tablets taken orally every morning (QD) and one dasabuvir 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis received 12-week treatment with the adult 3-DAA regimen and ribavirin 200 mg tablets were administered orally per local label. Participants with HCV GT1a with compensated cirrhosis received 24-week treatment with the adult 3-DAA regimen and ribavirin 200 mg tablets were administered orally per local label. Participants with HCV GT4 received 12-week treatment with the OBV/PTV/RTV formulation and ribavirin 200 mg tablets were administered orally per local label. arm 3: Participants with HCV GT1b without cirrhosis were to receive the mini-tablet 3-DAA (OBV, PTV, RTV, and DSV) regimen for 12 weeks: ombitasvir 0.3 mg, paritaprevir 1.0 mg, and ritonavir 1.0 mg mini-tablets administered orally QD based on body weight and dasabuvir taken orally BID as 3.08 mg mini-tablets based on body weight. Participants with HCV GT1a without cirrhosis received 12-week treatment with the mini-tablet 3-DAA regimen and ribavirin was provided as a 40 mg/mL oral solution and administered per local label. arm 4: Participants with HCV GT1b without cirrhosis were to receive the mini-tablet 3-DAA (OBV, PTV, RTV, and DSV) regimen for 12 weeks: ombitasvir 0.3 mg, paritaprevir 1.0 mg, and ritonavir 1.0 mg mini-tablets administered orally QD based on body weight and dasabuvir taken orally BID as 3.08 mg mini-tablets based on body weight. Participants with HCV GT1a without cirrhosis received 12-week treatment with the mini-tablet 3-DAA regimen and ribavirin was provided as a 40 mg/mL oral solution and administered per local label.
Interventions: intervention 1: Ombitasvir/paritaprevir/ritonavir intervention 2: Dasabuvir intervention 3: Ribavirin intervention 4: Ombitasvir mini tablet intervention 5: Paritaprevir mini tablet intervention 6: Ritonavir mini tablet intervention 7: Dasabuvir mini tablet intervention 8: Ribavirin solution
Intervention descriptions: intervention 1: Film-coated tablet for oral use intervention 2: Film-coated tablet for oral use intervention 3: Film-coated tablet for oral use intervention 4: Film-coated tablet for oral use intervention 5: Film-coated tablet for oral use intervention 6: Film-coated tablet for oral use intervention 7: Film-coated tablet for oral use intervention 8: Oral solution

Protocol documents:
Prot_000.pdf: 
Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir
M14-748 Protocol Amendment 3
EudraCT 2015-000111-41
1
1.0
Title Page
Clinical Study Protocol M14-748
An Open-Label, Multicenter Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of 
Ombitasvir (OBV), Paritaprevir (PTV), Ritonavir (RTV) 
With or Without Dasabuvir (DSV) and With or Without 
Ribavirin (RBV) in Pediatric Subjects With 
Genotype 1 or 4 Chronic Hepatitis C Virus (HCV) 
Infection (ZIRCON)
Incorporating Administrative Change 1 
Amendments 1, 1.01, 2 and 3
AbbVie Investigational
  Product:
Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir
Date:
21 August 2017
Development Phase:
Part 1:  Phase 2
Part 2:  Phase 3
Study Design:
Open-label combination drug study
EudraCT Number:
2015-000111-41
Investigators:
Multicenter.  Investigator information is on file at AbbVie.
Sponsor:
AbbVie Inc.*
NCT02486406




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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
15 March 2015
Amendment 1
23 July 2015
Amendment 1.01
28 January 2016
Administrative Change 1
20 May 2016
Amendment 2
07 July 2016
The purpose of this amendment is to:
●
Remove pellets formulation from the study, and change all endpoints to 
remove the pellet formulation.
Rationale:  The inclusion of the pellet formulation introduces additional 
variability into the analysis of therapeutic exposure by age and weight among 
a relatively small number of subjects in each age and weight group, so it is 
preferable to establish the PK, safety and efficacy using one formulation.
●
Remove APRI from study procedures.
Rationale:  Liver fibrosis is determined with Fibrotest, Fibroscan or liver 
biopsy.  APRI measurement is redundant to the test mentioned above and 
therefore has been removed.
●
Update contraceptive language in the protocol further.
Rationale:  Contraceptive recommendations were edited to align with 
regulatory guidance and to ensure patient safety.  Section 5.2.1, Inclusion 
Criteria, Criterion 3 and 4 updated to add contraceptive practices.  Inclusion 
criteria clarify which female subjects require pregnancy testing for 
participation in the study.  Section 5.2.2, Exclusion Criteria, Criterion 1 and 
11 define acceptable approaches for women who plan pregnancy and males 
who should refrain from sperm donation during the trial.  Section 5.2.4, 
Contraception Recommendations and Pregnancy Testing, added to provide 
greater detail regarding contraceptive practice, in alignment with regulatory 
guidance.


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●
Addition of Exclusion Criterion 12 in Section 5.2.2, Exclusion Criteria.
Rationale:  Exclusion Criterion 12 has been added to the protocol to clarify 
weight limit for subjects in the 3 to 8 year old age group.  Children weighing 
<15 kg represent a very small subpopulation in the 3 to 8 year old age group.  
In this population, drug dosing is particularly challenging, and the variability 
in dosing can lead to a higher level variability in PK.  In addition, there is a 
lack of significant urgency for treating the HCV infection in younger children.  
The alternative of allowing subjects to grow to a higher weight prior to 
treatment offers more benefit.   
●
Update Virologic Failure criteria.
Rationale:  Due to the high sensitivity of the COBAS® AmpliPrep/COBAS®
TaqMan® HCV Test, v2.0 assay currently used in Study M14-748, the LLOQ is 
15 IU/mL.  A small fluctuation of the HCV RNA level around LLOQ, for  
example, a current value of 16 IU/mL after previously achieving <15 IU/mL, 
may occur within the assay variability.  Therefore, the current virologic 
breakthrough criteria of "HCV RNA ≥ LLOQ after achieving LLOQ 
previously" may include subjects, who have responded to treatment.  In 
addition, using virologic breakthrough criteria of "HCV RNA ≥ 100 IU/mL 
after previously achieved LLOQ" is consistent with the recent AbbVie HCV 
studies, where the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 
assay was used to define LLOQ.
●
Reduction of Long Term Follow Up period.
Rationale:  In accordance with EMA guidance "Report of the paediatric 
hepatitis C therapy expert meeting" document, thus the study long term period 
has been simplified in the frequency of visits and the total duration reduced.
●
Correct inconsistencies and typographical errors throughout the protocol.
An itemized list of all changes made to this protocol amendment can be found in 
Appendix F.


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-748
Name of Study Drug:  ombitasvir, paritaprevir, 
ritonavir, dasabuvir, ribavirin
Phase of Development:  2/3
Name of Active Ingredient:  ombitasvir, 
paritaprevir, ritonavir, dasabuvir, ribavirin
Date of Protocol Synopsis:  21 August 2017
Protocol Title:  An Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Ombitasvir (OBV), Paritaprevir (PTV), Ritonavir (RTV) With or Without Dasabuvir (DSV) 
and With or Without Ribavirin (RBV) in Pediatric Subjects With Genotype 1 or 4 Chronic Hepatitis C 
Virus (HCV) Infection (ZIRCON)
Objectives:  
To assess the pharmacokinetics of OBV, PTV, RTV, and DSV with or without RBV in treatment-naïve, 
non-cirrhotic, HCV GT1-infected pediatric subjects in Part 1.
To assess the efficacy (percentage of subjects achieving SVR12 [defined as HCV RNA < LLOQ 12 weeks 
after the last actual dose of study drug]) or SVR24 [defined as HCV RNA < LLOQ 24 weeks after the last 
actual dose of study drug]) and safety of OBV, PTV, RTV with or without DSV and with or without 
RBV for 12 or 24 weeks in HCV genotype 1 (GT1) or genotype 4 (GT4)-infected treatment-naïve and 
prior IFN (IFN or peg-IFN with or without RBV) treatment-experienced, cirrhotic and non-cirrhotic 
pediatric subjects in Part 1 and Part 2.
To assess the durability of response for subjects who achieved SVR, to assess the emergence and 
persistence of specific HCV amino acid variants associated with drug resistance in subjects who 
experienced virologic failure, and to assess the impact of OBV, PTV, RTV with or without DSV and with 
or without RBV on growth and development in Part 3, the long-term follow-up of approximately 
2.5 years.
Investigator:  Global, multicenter trial:  Investigator information is on file at AbbVie.
Study Sites:  Up to 30 sites globally.
Study Population:  
Part 1:  Treatment-naïve, non-cirrhotic, GT1-infected pediatric patients ≥ 3 to 17 years of age 
Part 2:  Treatment-naïve and IFN (IFN or peg-IFN with or without RBV) treatment-experienced HCV 
GT1 or GT4-infected pediatric subjects ≥ 12 to 17 years of age with or without compensated cirrhosis
Part 3 (Long-term follow-up):  All subjects who take at least one dose of study drug and complete the 
Post-Treatment (PT) Week 24 visit in Part 1 or Part 2.
Number of Subjects to be Enrolled:  
Approximately 62 subjects will be enrolled in total into two Parts.  Part 1:  Approximately 
36 treatment-naïve, non-cirrhotic, GT1 subjects.  Part 2:  Approximately 26 subjects ≥ 12 to 17 years of 
age treatment-naïve or prior IFN treatment-experienced, cirrhotic or non-cirrhotic with GT1 or GT4 HCV 
infection.


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Methodology:
The study aims to assess three formulations in the pediatric population.  The approved adult 3D 
(OBV/PTV/RTV and DSV) regimen formulation and the approved adult 2D (OBV/PTV/RTV) regimen 
formulation will be administrated in subjects who are in the ≥ 12 to 17 years old age group with weight 
greater than 45 kg and willing to swallow the adult formulation.  The mini-tablet formulation will be 
administered in subjects who are in the ≥ 3 – 8 and ≥ 9 – 11 age groups to identify the optimal or final 
doses.  
Part 1 mini-tablet is designed to allow for dose adjustment on an ongoing basis, based on available 
pharmacokinetic and clinical data to achieve therapeutic exposures that have been safe and efficacious in 
adult subjects.  Area under the concentration curve (AUC) from the intensive PK sampling at Week 2 
will be the primary measure for dose adjustment, which will be compared with the range of the geometric 
means and the range of individual values across Phase 1/2/3 studies in adults that had intensive PK data 
(see Section 5.1).  Cmax and Ctrough will be considered for safety and efficacy using the same rules.  Part 2 
(Safety and Efficacy) will use the adult formulation if the results from the adult formulation in Part 1 are 
satisfactory.  In Part 1 and Part 2, the treatment duration is either 12 weeks or 24 weeks and all pediatric 
subjects who receive at least 1 dose of study drug will be followed for 24 weeks in the post-treatment 
period after completing or prematurely discontinuing the study treatment.  All pediatric subjects who 
complete the Post-Treatment (PT) Week 24 visit in either Part 1 or Part 2 will be followed in Part 3 
(Long-term Follow-up) for 144 weeks.
Part 1 (Pharmacokinetic Study):
Approximately 36 treatment-naïve, non-cirrhotic, HCV GT1-infected pediatric subjects will be enrolled.  
In the ≥ 12 to 17 year age group, 12 subjects will receive the standard adult formulation; in the ≥ 3 to 8 
and ≥ 9 to 11 year age groups, at least 12 subjects will receive the mini-tablet formulation.  Up to 
12 additional subjects may be enrolled to receive the mini-tablet formulation in Part 1 if needed to 
adequately characterize the pharmacokinetics of a particular age group or subgroup.  Subjects in the ≥ 12 
to 17 year age group who are ≥ 45 kg and willing to swallow the adult formulations will begin enrollment 
before subjects in the younger age groups.  The starting drug regimen is defined by HCV sub-genotype.  
All HCV sub-genotype 1b (GT1b) subjects will receive study medication (OBV/PTV/RTV and DSV)
without RBV for 12 weeks as shown below.  All subjects with a HCV GT1 non-b infection will receive 
study medication with weight based RBV for 12 weeks. 


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Methodology (Continued):
Part 1 (Pharmacokinetic Study) (Continued):
Patient Population
Treatment
Duration
Genotype 1b, 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir 
12 weeks
Genotype 1a,* 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + ribavirin
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, and Week 12.  At Week 2 and 
Week 8, the morning dose of study drug will be administered in the clinic at approximately 24 hours after 
the prior morning dose.  At Week 2, the evening doses will be administered in the clinic following the 
12 hour PK draw and the morning doses at Week 2 + 1 day will be administered in the clinic following 
the 24 hour PK draw.  PT visits will occur at PT Weeks 4, 12, and 24.
PK samples will be collected at the following timepoints from each subject:
!
Day 1:  4 hours postdose (the morning doses will be administered in the clinic)
!
Week 2:  2, 4, 8, 12 and 24 hours postdose (the morning doses, the evening doses following the 
12 hour PK draw and the morning doses following the 24 hour PK draw will be administered in the 
clinic)
!
Week 4: a PK sample (regardless of the dosing time)
!
Week 8: a trough PK sample (i.e., prior to the morning dose, which will be administered in the 
clinic)
!
Week 12: a PK sample (regardless of the dosing time)
Based on assessment of Week 2 intensive pharmacokinetic and clinical data, dose adjustments and/or 
dose adjustments for subsequently enrolled subjects may be performed.
Part 2 (Safety/Efficacy Study):
Approximately 16 HCV GT1-infected and approximately 10 HCV GT4-infected treatment-naïve or IFN 
(IFN or pegIFN with or without RBV) treatment-experienced pediatric subjects in the ≥ 12 to 17 age 
group will be enrolled.  
Subjects with GT1 infection will receive the 3D tablet formulation approved for adults (with or without 
RBV) and the subjects with GT4 infection will receive the 2D tablet formulation approved for adults with 
RBV.  RBV will be administered weight based as tablets or as solution per local RBV label.  The 
regimen and duration will be determined according to HCV genotype, sub-genotype and cirrhosis status.


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Methodology (Continued):
Part 2 (Safety/Efficacy Study) (Continued):
Patient Population
Treatment
Duration
Genotype 1b with or 
without compensated 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir 
(approved adult 3D formulation)
12 weeks
Genotype 1a,* without 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
12 weeks
Genotype 1a,* with 
compensated cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
24 weeks
Genotype 4 with or 
without compensated
cirrhosis
ombitasvir + paritaprevir + ritonavir + ribavirin 
(approved adult 2D formulation plus RBV)
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and 
Week 24.  The latter 3 visits at Weeks 16, 20 and 24 are required for subjects with compensated cirrhosis 
taking study drug for 24 weeks.  PT visits will occur at PT Weeks 4, 12, and 24.
One PK sample (regardless of the dosing time) will be collected at each visit for each subject in Part 2.
The following criteria will be considered evidence of virologic failure during treatment.  Pediatric 
subjects demonstrating any of the following should be discontinued from study drug:
!
Confirmed increase from nadir (defined as 2 consecutive HCV RNA measurements 
> 1 log10 IU/mL above nadir) in HCV RNA at any time point
!
Confirmed HCV RNA ≥ 100 IU/ml (defined as 2 consecutive HCV RNA measurements 
≥100 IU/ml) at any point after achieving HCV RNA < LLOQ
Confirmatory testing should be completed as soon as possible.  If any of the above criteria are met, the 
subject will discontinue study treatment, if applicable.  If the Investigator feels that a subject who meets 
one of these criteria should still remain on study treatment, the subject would only be allowed to remain 
on treatment with approval of the AbbVie Study TA SD/TA MD.
Part 3 (Long-Term Follow-Up):
All subjects who have completed Post-Treatment Week 24 in either Part 1 or Part 2 of the study will be 
followed to assess the durability of viral response, for the emergence and persistence of resistant viral 
variants, and for SAEs related to study drug for an additional 120 weeks in the Long-term Follow-up 
period.  Study visits will occur at Post-Treatment Weeks 36, 48, 96, and 144.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female ≥ 3 to 17 years of age and weight ≥ 15 kg at time of enrollment.
2.
Willingness to participate in the study for up to 42 months.
3.
HCV infection demonstrated by positive anti-HCV Ab and HCV RNA ≥ 1000 IU/mL at the time of 
screening.
4.
Screening laboratory results indicating HCV genotype 1 for enrollment into Part 1 and genotype 1 or 
4 for enrollment into Part 2.
5.
Parent or legal guardian with the willingness and ability to provide written informed consent and 
subject willing and able to give assent, as appropriate for age and country.
Main Exclusion:  
1.
Women who are pregnant, breastfeeding, or are considering becoming pregnant.
2.
Use of known strong inducers and inhibitors (e.g., gemfibrozil) of cytochrome P450 2C8 (CYP2C8) 
in subjects receiving dasabuvir, or strong or moderate inducers of CYP3A, within 2 weeks or 
10 half-lives, whichever is longer, of the respective medication/supplement prior to study drug 
administration.
3.
Positive test result for Hepatitis B surface antigen (HbsAg) or anti-HIV antibody (HIV Ab) test.
4.
Current enrollment in another interventional clinical study, previous enrollment in this study, prior or 
current use of any investigational or commercially available anti-HCV agents other than IFNs or 
RBV or receipt of any investigational product within 6 weeks prior to study drug administration.
Investigational Products:
Weight < 45 kg or eligible but not willing to swallow the adult 
formulations:  Part 1
paritaprevir
1.0 mg mini-tablet
ritonavir
1.0 mg mini-tablet
ombitasvir
0.3 mg mini-tablet
dasabuvir 
3.08 mg mini-tablet
ribavirin 
40 mg/mL oral solution 
Weight ≥ 45 kg who are ≥ 12 to 17 years old and willing to swallow 
the adult formulations:
ombitasvir/paritaprevir/r  
12.5/75/50 mg tablet
dasabuvir  
250 mg tablet
Ribavirin
200 mg tablet
  


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Doses:
Part 1 Mini-Tablet:
Initial dosing based on body weight at time of Screening:
≥ 15 to 29 kg
≥ 30 to 44 kg
≥ 45 kg
paritaprevir (QD) 
50 mg
100 mg
150 mg
ritonavir (QD)
35 mg
70 mg
100 mg
ombitasvir (QD)
10 mg
15 mg
25 mg
dasabuvir (BID)
100 mg
150 mg
250 mg
Ribavirin solution
Per local label
Part 2:
Only adult formulation and RBV tablets if required will be provided to 
subjects who are in the ≥ 12 – 17 year old age group with weight equal 
and greater than 45 kg and willing to swallow the adult formulations.
Mode of Administration:
Oral
Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  
Part 1: Pediatric subjects will receive OBV, PTV, RTV, DSV with or without RBV for 12 weeks. 
Part 2: Pediatric subjects will receive OBV, PTV, RTV with or without DSV and with or without RBV 
for 12 weeks or 24 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each treatment and Post-Treatment Period visit in all 
three parts of the study.
Pharmacokinetic:
Plasma concentrations of OBV, possible OBV metabolites, PTV, possible PTV metabolites, DSV, DSV 
M1 metabolite, other possible DSV metabolites, RTV and RBV (if applicable) will be determined at each 
study visit for each subject for the treatment periods of Part 1 and Part 2.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests and vital signs.  Growth and development will be assessed relative to age specific norms.


Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir
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Statistical Methods:
The pharmacokinetic analysis will be performed separately for Part 1 and Part 2.  For population 
pharmacokinetic analyses, data from Part 1 and Part 2 will be combined if needed.  All efficacy, safety, 
growth and development outcomes will be assessed across Parts 1 and 2 of the study with summaries by 
formulation, age and weight group, totaled across all subjects, and totaled across adult formulations 
(OBV/PTV/RTV + RBV and OBV/PTV/RTV and DSV ± RBV).  Analyses on durability of response, 
resistance, growth and development outcomes, and patient-reported outcomes will be performed through 
Post-Treatment Week 24 in Parts 1 and 2 and after Post-Treatment Week 24 for all subjects in Part 3. 
An interim analysis will occur once all subjects complete PT Week 12 or prematurely discontinue from 
the study.  Final analysis will occur after the completion of the whole study.
Efficacy:
The primary pharmacokinetic endpoints are Cmax and AUC following dosing on Week 2, and trough 
concentration (Ctrough) following dosing on Week 2 and Week 8 for OBV, PTV, DSV, and RTV.
The primary efficacy endpoint is the percentage of subjects with SVR12 among all subjects.  The 
percentage of subjects achieving SVR12 will be calculated along with the 2-sided 95% confidence 
interval.  The lower bound of the 2-sided 95% confidence interval of the percentage of subjects with 
SVR12 across all subjects must be greater than 67% to show superiority to pegIFN and RBV as described 
in Section 8.2.


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Statistical Methods (Continued):
Efficacy (Continued):
The main secondary endpoints are:
1.
The percentage of subjects who achieve SVR12 summarized by formulation, age and weight group 
and across all subjects. 
2.
The percentage of subjects who achieve SVR24 by formulation, age and weight group, across all the 
subjects, and across all subjects on the adult formulations;
3.
The percentage of subjects with ALT normalization during treatment, defined as ALT ≤ ULN at the 
final treatment visit for subjects with ALT > ULN at baseline, by formulation, age and weight group, 
across all subjects, and across all subjects on the adult formulations.
For the secondary efficacy endpoints, the simple percentage will be calculated along with the 2-sided 
95% confidence interval.  For both primary and secondary endpoints, the normal approximation to the 
binomial distribution will be used if the rate is not 0% or 100%, otherwise the Wilson's score method will 
be used to calculate the confidence interval.  The lower bound of the 2-sided 95% confidence interval of 
the SVR24 rate across all subjects in the study will also be compared to 67%.
Resistance: 
For subjects with virologic failure and HCV RNA > 1000 IU/mL, the variants at each amino acid position 
(by population, deep, and/or clonal nucleotide sequencing) at available post baseline time points 
compared to baseline and prototypic reference standard sequences will be summarized by DAA target 
genes and accompanying listings will be provided. 
Safety:
All safety analysis will be done by age and weight group separately for each formulation, for all subjects, 
and for all subjects on the adult formulations.
The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
MedDRA system organ class and preferred term.  Tabulations will also be provided in which the number 
of subjects reporting an adverse event (MedDRA preferred term) is presented by grade (Grades 1 – 5) 
and relationship to study drugs.
Change from baseline in laboratory tests and vital sign measurements to each time point of collection will 
be summarized descriptively.  Laboratory test and vital sign values that are potentially clinically 
significant, according to predefined criteria, will be identified and the number and percentage of subjects 
with potentially clinically significant values during treatment will be calculated.
Growth and Development: 
All growth and development analyses will be done by age group separately for each formulation, for all 
subjects, and for all subjects on the adult formulations.  The following growth and development 
endpoints will be calculated at applicable study visits.
!
Growth rate at each post baseline visit (defined as change in height over change in age from the 
previous visit)
!
Height z score
!
Waist circumference
!
Tanner staging


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Statistical Methods (Continued):
Pharmacokinetic:
Plasma concentrations and pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 metabolite, RTV 
and RBV, if applicable, will be tabulated for each subject and summarized as appropriate by formulation, 
weight range or age group.
Individual plasma concentrations or pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 
metabolite, RTV and RBV may be used for safety or efficacy evaluation if needed.
Additional analyses may be conducted as needed.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
2D
Ombitasvir, Paritaprevir, Ritonavir
3D
Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AUC
Area under the concentration curve
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BID
Twice Daily
BMI
Body mass index
BUN
Blood urea nitrogen
CI
Confidence interval
CrCl
Creatinine clearance
CRF
Case report form
CYP3A
Cytochrome P450 3A
DAA
Direct-acting antiviral agent
DDI
Drug-drug interaction
DNA
Deoxyribonucleic acid
DSV
Dasabuvir
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GT
Genotype
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropic


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HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HIV Ab
Human immunodeficiency virus antibody
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IFN
Interferon
IL28B
Interleukin 28B
IMP
Investigational Medical Product
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to treat
IU
International units
IUD
Intrauterine Device
LCB
Lower confidence bound
LLN
Lower limit of normal
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LTFU
Long-Term Follow-up
MedDRA
Medical Dictionary for Regulatory Activities
ND
New Drug
NS3
Nonstructural viral protein 3
NS4A
Nonstructural viral protein 4A
NS5A
Nonstructural viral protein 5A
NS5B
Nonstructural viral protein 5B
OATP1B1
Organic anion transporting polypeptide 1B1
OBV
Ombitasvir
PCR
Polymerase chain reaction
pegIFN
Pegylated-interferon alfa-2a or 2b
PIP
Pediatric Investigational Plan
PK
Pharmacokinetic
POR
Proof of Receipt
PRO
Patient Reported Outcomes
PSP
Pediatric Study Plan


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PT
Post-Treatment
PTV
Paritaprevir
QD
Once daily
RBC
Red blood cells
RBV
Ribavirin
RNA
Ribonucleic acid
RT-PCR
Reverse transcriptase PCR
RTV
Ritonavir
SAE
Serious adverse event
SAS
Statistical Analysis System
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained virologic response
SVR12
Sustained virologic response 12 weeks Post-Treatment
SVR24
Sustained virologic response 24 weeks Post-Treatment
TA MD
Therapeutic Area Medical Director 
TA SD
Therapeutic Area Scientific Director
ULN
Upper limit of normal
USPI
United States Proscribing Information
WBC
White blood cells
WOCBP
Women of Childbearing Potential
Definition of Terms
Study Drugs
Ombitasvir, Paritaprevir, Ritonavir, ± Dasabuvir, ± RBV 
Screening Period
Up to 42 days prior to Study Day 1
Study Day 1
First day a subject takes study drugs
Treatment Period (TP)
Baseline/Study Day 1 through last dose of study drugs
Post-Treatment Period (PTP)
Day after the last dose of study drugs through Post-Treatment 
Week 24 
Long-Term Follow-Up (LTFU)
Day after Post-Treatment Week 24 visit through Post-Treatment 
Week 144 or Post-Treatment Discontinuation


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 3
1.2
Synopsis................................................................................................. 5
1.3
List of Abbreviations and Definition of Terms...................................... 14
2.0
Table of Contents ................................................................ 17
3.0
Introduction......................................................................... 22
3.1
Differences Statement .......................................................................... 31
3.2
Benefits and Risks................................................................................ 32
3.3
Pediatric Study Plan and Pediatric Investigational Plan......................... 33
4.0
Study Objective ................................................................... 34
5.0
Investigational Plan.............................................................34
5.1
Overall Study Design and Plan:  Description ........................................ 34
5.1.1
Screening ............................................................................................. 41
5.1.1.1
Rescreening.......................................................................................... 41
5.1.2
Treatment Period (TP).......................................................................... 42
5.1.3
Post-Treatment Period of Part 1 and Part 2 ........................................... 44
5.1.4
Long-Term Follow-Up Period .............................................................. 44
5.2
Selection of Study Population............................................................... 45
5.2.1
Inclusion Criteria.................................................................................. 45
5.2.2
Exclusion Criteria................................................................................. 46
5.2.3
Prior and Concomitant Therapy............................................................ 49
5.2.3.1
Prior HCV Therapy .............................................................................. 50
5.2.3.2
Concomitant Therapy........................................................................... 50
5.2.3.3
Prohibited Therapy............................................................................... 51
5.2.4
Contraception Recommendations and Pregnancy Testing ..................... 52
5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables ......................................................................... 54
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 54
5.3.1.1
Study Procedures.................................................................................. 54
5.3.1.2
Blood Samples for Pharmacogenetic Analysis ...................................... 66
5.3.1.3
Meals and Dietary Requirement............................................................ 67


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5.3.2
Drug Concentration Measurements....................................................... 67
5.3.2.1
Collection of Samples for Analysis....................................................... 67
5.3.2.2
Handling/Processing of Samples........................................................... 69
5.3.2.3
Disposition of Samples......................................................................... 69
5.3.2.4
Measurement Methods ......................................................................... 70
5.3.3
Efficacy Variables................................................................................ 70
5.3.3.1
Primary Variables................................................................................. 70
5.3.3.2
Secondary Variables............................................................................. 71
5.3.4
Safety Variables ................................................................................... 71
5.3.5
Pharmacokinetic Variables ................................................................... 71
5.3.6
Pharmacogenetic Variables................................................................... 72
5.4
Removal of Subjects from Therapy or Assessment ............................... 72
5.4.1
Discontinuation of Individual Subjects ................................................. 72
5.4.2
Discontinuation of Entire Study............................................................ 73
5.4.3
Discontinuation of Subjects Meeting Virologic Failure Criteria ............ 74
5.5
Treatments ........................................................................................... 75
5.5.1
Treatments Administered...................................................................... 75
5.5.2
Identity of Investigational Products ...................................................... 76
5.5.2.1
Packaging and Labeling........................................................................ 77
5.5.2.2
Storage and Disposition of Study Drugs ............................................... 77
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 78
5.5.4
Selection and Timing of Dose for Each Subject.................................... 79
5.5.5
Blinding ............................................................................................... 80
5.5.6
Treatment Compliance ......................................................................... 80
5.5.7
Drug Accountability ............................................................................. 80
5.6
Discussion and Justification of Study Design........................................ 82
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 82
5.6.2
Appropriateness of Measurements........................................................ 83
5.6.3
Justification of Primary and Secondary Endpoint Success Criteria........ 83
5.6.4
Suitability of Subject Population .......................................................... 83
5.6.5
Selection of Doses in the Study ............................................................ 84
5.6.6
Maximum Dose.................................................................................... 85
6.0
Complaints........................................................................... 86


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6.1
Medical Complaints ............................................................................. 86
6.1.1
Definitions ........................................................................................... 86
6.1.1.1
Adverse Event...................................................................................... 86
6.1.1.2
Serious Adverse Events........................................................................ 87
6.1.2
Adverse Event Severity ........................................................................ 88
6.1.3
Relationship to Study Drug................................................................... 89
6.1.4
Adverse Event Collection Period.......................................................... 90
6.1.5
Adverse Event Reporting...................................................................... 91
6.1.6
Pregnancy............................................................................................. 92
6.1.7
Toxicity Management........................................................................... 93
6.1.7.1
Grade 1 or 2 Laboratory Abnormalities and Mild or Moderate 
Adverse Events..................................................................................... 94
6.1.7.2
Grade 3 or 4 Laboratory Abnormalities ................................................ 94
6.1.7.3
Severe Adverse Events or Serious Adverse Events ............................... 95
6.1.7.4
Management of Decreases in Hemoglobin............................................ 96
6.1.7.5
Management of ALT Elevations........................................................... 97
6.1.7.6
Creatinine Clearance ............................................................................ 98
7.0
Protocol Deviations ............................................................. 99
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 100
8.1
Statistical and Analytical Plans............................................................100
8.1.1
Demographics .....................................................................................102
8.1.2
Efficacy...............................................................................................103
8.1.2.1
Primary Efficacy Endpoint Across Parts 1 and 2..................................103
8.1.2.2
Secondary Efficacy Endpoints Across Parts 1 and 2 ............................103
8.1.2.3
Additional Efficacy Endpoints Across Parts 1 and 2 ............................104
8.1.2.4
Subgroup Analysis of Parts 1 and 2 .....................................................105
8.1.2.5
Treatment Failures...............................................................................106
8.1.3
Growth and Development....................................................................106
8.1.4
Patient Reported Outcomes .................................................................107
8.1.5
Acceptability Questionnaire.................................................................108
8.1.6
Safety..................................................................................................108
8.1.6.1
Adverse Events....................................................................................108


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8.1.6.2
Clinical Laboratory Data .....................................................................109
8.1.6.3
Vital Signs Data ..................................................................................109
8.1.7
Resistance Analysis.............................................................................109
8.1.8
Pharmacokinetic and Exposure-Response Analyses.............................112
8.2
Determination of Sample Size .............................................................113
8.3
Randomization Methods......................................................................114
9.0
Ethics.................................................................................. 114
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................114
9.2
Ethical Conduct of the Study...............................................................115
9.3
Subject Information and Consent.........................................................115
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 116
10.1
Source Documents...............................................................................116
10.2
Case Report Forms..............................................................................116
11.0
Data Quality Assurance .................................................... 118
12.0
Use of Information ............................................................ 118
13.0
Completion of the Study ................................................... 118
14.0
Investigator's Agreement.................................................. 120
15.0
Reference List.................................................................... 121
List of Tables
Table 1.
SVR12 for HCV Genotype 1a-Infected Subjects Without Cirrhosis 
Who Were Treatment-Naïve or Previously Treated With 
PegIFN/RBV........................................................................................ 25
Table 2.
SVR12 for HCV Genotype 1b-Infected Subjects Without Cirrhosis 
Who Were Treatment-Naïve or Previously Treated With 
PegIFN/RBV........................................................................................ 26
Table 3.
SVR12 for HCV Genotype 1-Infected Subjects with Cirrhosis 
Who Were Treatment-Naïve or Previously Treated with 
pegIFN/RBV ........................................................................................ 27
Table 4.
Baseline Fibrosis Stage......................................................................... 39
Table 5.
Treatment Regimen and Duration – Part 1............................................ 42


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Table 6.
Treatment Regimen and Duration – Part 2 (For Subjects ≥ 12 –  
17 Years of Age) .................................................................................. 43
Table 7.
Medications Contraindicated for Use with the Study Drug 
Regimen............................................................................................... 47
Table 8.
Clinical Laboratory Tests ..................................................................... 58
Table 9.
Child-Pugh Classification of Severity of Cirrhosis................................ 63
Table 10.
Identity of Investigational Products ...................................................... 77
Table 11.
Proposed DAA and Ritonavir Doses for Subjects Administered 
the Adult Formulation or Mini Tablet Formulation ............................... 85
Table 12.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases......................................................................... 97
List of Figures
Figure 1.
Study Schematic................................................................................... 40
Figure 2.
Adverse Event Collection..................................................................... 91
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................124
Appendix B.
List of Protocol Signatories .................................................................126
Appendix C.
Study Activities...................................................................................127
Appendix D.
Estimated Blood Loss for Pediatric Subjects........................................134
Appendix E.
Tanner Pubertal Stage..........................................................................136
Appendix F.
Protocol Amendment:  List of Changes ...............................................137


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3.0
Introduction
Hepatitis C viral (HCV) infection is a global health problem, with 170 million individuals 
chronically infected worldwide and at risk of developing liver cirrhosis, hepatocellular 
carcinoma, or both.2  Children represent only a small proportion of the hepatitis C virus 
(HCV) infected population.  Nevertheless, a substantial number of children have chronic 
HCV infection and are at risk for complications.  According to a recent report which 
approximated 115 million HCV infected persons in the world, 11 million of them were 
younger than 15 years of age.  It has been estimated that the global health care costs for 
HCV-infected children and their families are hundreds of millions of dollars annually.3
In pediatric populations, the natural history of disease varies based on factors such as the 
route of transmission, age at time of infection, and the presence of comorbidities such as 
hematologic malignancy or immunosuppression.  The 3 most important routes of HCV 
infection for pediatric patients are vertical transmission, transfusion of contaminated 
blood products, and injection drug use.  As infection via contaminated blood products has 
essentially disappeared in countries with adequate hygienic facilities due to improvements 
to the safety of the blood supply in the early 1990s and injection drug use in the pediatric 
population occurs among adolescents and young adults, vertical transmission has become 
the predominant mode of HCV transmission to pediatric patients in the developed world.4  
The rate of perinatal transmission presently ranges from 5% to 13% in children born to 
HCV-infected mothers.5-9
Spontaneous viral clearance in vertically infected children seems to be dependent on 
genotype and was found to range from 2.4% – 25%.10,11  Beyond the age of 4 years, 
spontaneous viral clearance seems to become rather unlikely.10  Patients who do not clear 
the virus within the first years of life will develop chronic hepatitis C.  Overall, the 
cumulative probability of progression to chronicity is approximately 80%.12,13
Chronic hepatitis C appears as a mild, indolent infection in most pediatric patients, with 
low rates of disease progression over 10 to 35 years.11,14,15  Of perinatally-infected 
children, approximately 20% experience spontaneous viral clearance, 50% develop 


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chronic asymptomatic infection (with intermittent viremia, usually normal alanine 
aminotransferase [ALT] levels, and rare hepatomegaly), and 30% develop chronic active 
infection.13  The most severe sequelae of chronic HCV, including progressive hepatic 
fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma (HCC) occur significantly 
less frequently in pediatric patients than in adults with chronic HCV infection.  The 
frequency of advanced fibrosis and cirrhosis appear to increase with increasing age, and 
both are uncommon in younger children.14,16 In a study of 359 viremic untreated 
HCV-infected pediatric patients, progression to advanced liver disease occurred in 1.8% 
of the 332 patients with persistent viremia, at a mean of 9.6 years.10  HCC has rarely been 
reported in adolescents.17  Cirrhosis has been reported in pediatric series at frequencies 
ranging from < 2%10,14,16 to as high as 8%; however, the latter rate was reported from a 
quaternary referral center in the US, which likely over-represents the prevalence of 
advanced disease in the pediatric population.18  Cirrhosis appears to be extremely 
uncommon in patients less than 6 years of age.10,11,14,16,18,19
Currently available treatments for pediatric chronic hepatitis C are interferon-α (IFN) or 
pegylated interferon-α (pegIFN) and ribavirin (RBV).  SVR rates of pegIFN in 
combination with ribavirin in patients with genotype 1 have been reported in several 
pediatric studies and ranged from 44% to 59%.  Achieving SVR in children with 
genotype 2 and 3 was very successful and yielded rates of more than 90%. 
Combinations of direct-acting antiviral agents (DAAs) targeting different steps of viral 
replication have been shown to significantly improve HCV treatment compared to 
interferon-containing regimens for HCV genotype 1 infection by increasing SVR rates, 
increasing the safety and tolerability of treatment, shortening duration of therapy and 
simplifying the treatment algorithm.  In addition, wider application of DAA therapy and 
better responses with combination DAA regimens are expected to significantly reduce the 
public health burden of this disease.  However, limitations still exist particularly in 
patients with comorbid conditions and in difficult-to-cure patients with advanced liver 
disease including those with cirrhosis.  None of the DAA combination therapies are 
currently approved for pediatric patients.


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AbbVie's Ombitasvir/Paritaprevir/r (OBV/PTV/RTV) and Dasabuvir (DSV), Also 
Known as the 3D Regimen
AbbVie's IFN-free 3D regimen for the treatment of chronic HCV GT 1 infection includes 
3 DAAs targeting different steps in HCV replication.  Ombitasvir is a nonstructural 
protein 5A (NS5A) inhibitor; paritaprevir is a NS3/NS4A protease inhibitor co-
administered with the pharmacokinetic enhancer, ritonavir (paritaprevir/r); and dasabuvir 
is a NS5B non-nucleoside polymerase inhibitor.  
The safety and efficacy of OBV/PTV/RTV 25/150/100 mg once daily and DSV 250 mg 
twice daily was evaluated in six Phase 3 randomized, multicenter, clinical trials 
(Studies M11-646, M13-098, M13-389, M13-961, M14-002 and M13-099) in more than 
2,300 adult subjects with chronic HCV GT1 infection who received the 3D regimen with 
or without ribavirin for 12 or 24 weeks, including one trial exclusively in subjects with 
compensated cirrhosis.
Subjects with HCV GT1a infection without cirrhosis treated with the 3D regimen with 
RBV for 12 weeks in Studies M11-646, M13-098 and M14-002 had a median age of 
53 years (range:  18 to 70); 63% of the subjects were male; 90% were White; 7% were 
Black/African American; 8% were Hispanic or Latino; 72% had IL28B non-CC genotype; 
85% had baseline HCV RNA levels of at least 800,000 IU/mL.  The efficacy results from 
Studies M11-646, M13-098 and M14-002 are listed in Table 1.


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Table 1.
SVR12 for HCV Genotype 1a-Infected Subjects Without Cirrhosis 
Who Were Treatment-Naïve or Previously Treated With 
PegIFN/RBV
3D + RBV for 12 Weeks % (n/N)
GT1a Treatment-Naïve
M11-646 (SAPPHIRE-I) SVR12
96% (308/322)
Outcome for subjects without SVR12
On treatment virologic failure
< 1% (1/322)
Relapse
2% (6/314)
Other
2% (7/322)
M14-002 (PEARL IV) SVR12
97% (97/100)
Outcome for subjects without SVR12
On treatment virologic failure
1% (1/100)
Relapse
1% (1/98)
Other
1% (1/100)
GT1a Treatment-Experienced
M13-098 (SAPPHIRE-II) SVR12
96% (166/173)
Outcome for subjects without SVR12
On treatment virologic failure
0% (0/173)
Relapse
3% (5/172)
Other
1% (2/173)
SVR12 by Prior pegIFN/RBV Experience
Null Responder
95% (83/87)
Partial Responder
100% (36/36)
Relapser
94% (47/50)
Subjects with HCV GT1b infection without cirrhosis were treated with the 3D regimen 
with or without RBV for 12 weeks in Studies M13-389 and M13-961.  Subjects had a 
median age of 52 years (range:  22 to 70); 47% of the subjects were male; 93% were 
White; 5% were Black/African American; 2% were Hispanic or Latino; 83% had IL28B 
non-CC genotype; 77% had baseline HCV RNA levels of at least 800,000 IU/mL.  The 
efficacy results for subjects treated with the 3D regimen without RBV from 
Studies M13-389 and M13-961 are listed in Table 2.


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Table 2.
SVR12 for HCV Genotype 1b-Infected Subjects Without Cirrhosis 
Who Were Treatment-Naïve or Previously Treated With 
PegIFN/RBV
3D for 12 Weeks % (n/N)
GT1b Treatment-Naïve
M13-961 (PEARL-III) SVR12
100% (209/209)
Outcome for subjects without SVR12
On treatment virologic failure
0% (0/210)
Relapse
0% (0/210)
Other
0% (0/210)
GT1b Treatment-Experienced
M13-389 (PEARL-II) SVR12
100% (91/91)
Outcome for subjects without SVR12
On treatment virologic failure
0% (0/91)
Relapse
0% (0/91)
Other
0% (0/91)
SVR12 by Prior pegIFN/RBV Experience
Null Responder
100% (32/32)
Partial Responder
100% (26/26)
Relapser
100% (33/33)
The 3D regimen in combination with RBV was evaluated in Study M13-099 in 380 HCV 
GT1a and 1b-infected subjects with compensated cirrhosis who were either treatment-
naïve or did not achieve SVR with prior treatment with pegIFN/RBV.  Subjects were 
randomized to receive 3D + RBV for either 12 or 24 weeks.  Treated subjects had a 
median age of 58 years (range:  21 to 71); 70% of the subjects were male; 95% were 
White; 3% were Black/African American; 12% were Hispanic or Latino; 82% had IL28B 
non-CC genotype; 86% had baseline HCV RNA levels of at least 800,000 IU/mL; 15% 
had platelet counts of less than 90 × 109/L; 50% had albumin less than 4.0 mg/dL.  The 
efficacy results from Study M13-099 are presented in Table 3.
The safety and efficacy of the 3D regimen without RBV for 12 weeks was evaluated in 
Study M14-490 (TURQUOISE-III) in 60 HCV GT1b-infected subjects with compensated 


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cirrhosis, who were either treatment-naïve or prior pegIFN/RBV treatment-experienced.  
All subjects (100%) achieved SVR12.  No patients discontinued treatment due to adverse 
events.  Based on these results treatment guidelines from AASLD have been updated to 
recommend the 3D regimen without RBV for 12 weeks in GT1b-infected subjects with 
compensated cirrhosis, and the US label was updated accordingly (Table 3).
Table 3.
SVR12 for HCV Genotype 1-Infected Subjects with Cirrhosis Who 
Were Treatment-Naïve or Previously Treated with pegIFN/RBV 
GT 1a
GT 1b
M13-099 (TURQUOISE-II) and 
M14-490 (TURQUISE-III)
3D + RBV for 
24 Weeks 
% (n/N)
3D + RBV for 
12 Weeks 
% (n/N)
3D + RBV 
for 12 Weeks 
% (n/N)
3D Without 
RBV for 
12 Weeks 
% (n/N)
SVR12
95% (115/121)
89% (124/140)
99% (67/68)
100% (60/60)
Outcome for subjects without 
SVR12
On treatment virologic failure
2% (3/121)
< 1% (1/140)
0% (0/68)
0% (0/60)
Relapse
1% (1/116)
8% (11/135)
1% (1/68)
0% (0/60)
Other
2% (2/121)
3% (4/140)
0% (0/68)
0% (0/60)
SVR12 for Treatment-naive
95% (53/56)
92% (59/64)
100% (22/22)
100% (27/27)
SVR12 by Prior pegIFN/RBV 
Experience
100% (33/33)
Null Responder
93% (39/42)
80% (40/50)
100% (25/25)
100% (25/25)
Partial Responder
100% (10/10)
100% (11/11)
86% (6/7)
100% (5/5)
Relapser
100% (13/13)
93% (14/15)
100% (14/14)
100% (3/3)
Other Failures+
-
-
-
100% (18/18)
+
Other types of pegIFN/RBV failures includes non-response, relapse/breakthrough, and other pegIFN failures.
The safety of 3D + RBV was assessed in 770 subjects in two placebo-controlled trials 
(Studies M11-646 and M13-098).  Adverse reactions that occurred more often in subjects 
treated with 3D + RBV compared to placebo were fatigue, nausea, pruritus, other skin 
reactions, insomnia, and asthenia.  The majority of the adverse reactions were mild in 
severity.  Two percent of subjects experienced a serious adverse event (SAE) and the 


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proportion of subjects who permanently discontinued treatment due to adverse reactions 
was less than 1%.
The safety of the 3D regimen with and without RBV was assessed in 401 and 
509 subjects, respectively, in three clinical trials (Studies M13-389, M13-961 and 
M14-002).  Pruritus, nausea, insomnia, and asthenia were identified as adverse events 
occurring more often in subjects treated with 3D + RBV.  The majority of adverse events 
were mild to moderate in severity.  The proportion of subjects who permanently 
discontinued treatment due to adverse events was less than 1% for both 3D + RBV and 
3D alone. 
The safety of 3D + RBV was assessed in 380 subjects with compensated cirrhosis who 
were treated for 12 (n = 208) or 24 (n = 172) weeks duration in Study M13-099.  The type 
and severity of adverse events in subjects with compensated cirrhosis was comparable to 
non-cirrhotic subjects in other Phase 3 trials.  Fatigue, skin reactions and dyspnea 
occurred at least 5% more often in subjects treated for 24 weeks.  The majority of adverse 
events occurred during the first 12 weeks of dosing in both treatment arms.  Most of the 
adverse events were mild to moderate in severity.  The proportion of subjects treated with 
3D + RBV for 12 and 24 weeks with SAEs was 6% and 5%, respectively and 2% of 
subjects permanently discontinued treatment due to adverse events in each treatment arm.
Approximately 1% of subjects treated with the 3D regimen with and without RBV in 
Phase 3 studies experienced post-baseline serum ALT levels greater than 5 times the 
upper limit of normal (ULN) after starting treatment.  The incidence increased to 25% 
(4/16) among women taking a concomitant ethinyl estradiol-containing medication.  The 
incidence of ALT elevations greater than 5 times ULN among women using estrogens 
other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone 
replacement therapy, was 1.7% (1/59).  ALT elevations were typically asymptomatic, 
generally occurred during the first 4 weeks of treatment (mean time 20 days, range: 
8 – 57 days) and most resolved with ongoing therapy.  Elevations in ALT were generally 
not associated with bilirubin elevations. 


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Post-baseline elevations in bilirubin at least 2 × ULN were observed in 15% of subjects 
who received 3D + RBV compared to 2% in those who received 3D alone.  These 
bilirubin increases were predominately indirect and related to the inhibition of the 
bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis.  
Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and 
generally resolved with ongoing therapy.  Bilirubin elevations were not associated with 
serum ALT elevations.
In summary, the 3D regimen, with or without RBV, was well tolerated with a low 
discontinuation rate.  Adverse events were typically mild, and many of the adverse events 
and laboratory abnormalities observed were attributable to the presence of RBV.  
Transient, asymptomatic serum ALT elevations were observed at a low rate, were not 
associated with hepatic dysfunction and generally resolved with ongoing treatment.
A detailed discussion of the preclinical toxicology, metabolism, pharmacokinetics and 
drug-drug interactions can be found in the Investigator's Brochures and prescribing 
information for ombitasvir/paritaprevir/r and dasabuvir, and prescribing information for 
ribavirin.
AbbVie's Ombitasvir/Paritaprevir/r (OBV/PTV/RTV), Also Known as the 2D 
Regimen
AbbVie's IFN-free 2D regimen includes ombitasvir and paritaprevir/r.  The 2D program is 
composed of one Phase 2b trial for HCV sub-genotype 1b and genotype 4 in the US and 
Europe (Study M13-393, also known as PEARL-I), one Phase 2a trial for genotypes 1, 2, 
and 3 in the US (Study M12-998), one Japanese Phase 2b trial for HCV sub-genotype 1b 
and genotype 2 (Study M12-536), and two Japanese Phase 3 trials for HCV sub-genotype 
1b and genotype 2 (Studies M13-004 and M14-153). 
HCV Genotype 4
While GT4 infection accounts for only approximately 1% of HCV infections in the United 
States (US), in parts of Europe the prevalence of GT4 among all HCV-infected people is 


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as high as 10% to 24% in some areas.20-24  HCV GT4 infection is common in the Middle 
East and Sub-Saharan Africa.  In Egypt, it is responsible for almost 90% of HCV 
infections.20-25
Efficacy and safety data are available from the cohorts of non-cirrhotic 
genotype 4-infected adult subjects participating in the Phase 2 Study M13-393 (PEARL-I) 
who were administered ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg once 
daily with or without RBV for 12 weeks.  SVR12 rates of 91% were observed among 
non-cirrhotic genotype 4-infected treatment-naïve subjects who received the 2D without 
RBV regimen for 12 weeks.  When non-cirrhotic HCV genotype 4-infected treatment-
naïve subjects were administered the 2D regimen with RBV, SVR12 rates of 100% were 
achieved.  Among non-cirrhotic HCV genotype 4-treatment-experienced subjects 
receiving the 2D regimen with RBV for 12 weeks, the SVR12 rate was 100%. 
Safety data from these cohorts of non-cirrhotic genotype 4-infected subjects demonstrate 
the 12-week 2D regimen with or without RBV was generally well tolerated, with no 
subject discontinuing study drug due to a treatment-emergent adverse event.  The only 
treatment-emergent adverse events that occurred in ≥ 10.0% of subjects in all 3 treatment 
groups were asthenia and headache.  This adverse event profile is consistent with the more 
robust placebo-controlled and regimen-controlled analysis sets of the Phase 3 3D + RBV 
treatment regimen from which asthenia, nausea, fatigue, insomnia, and pruritus were 
identified as adverse drug reactions.
Overall, the percentage of HCV genotype 4-infected subjects in any treatment group who 
experienced a protocol defined potentially clinically significant or Grade 3 hematology or 
chemistry value was low.  These findings are also consistent with the observations from 
the Phase 3 studies evaluating the 3D + RBV treatment regimen.
The 2D regimen was subsequently evaluated in genotype 4-infected treatment-naïve or 
prior pegIFN/RBV treatment-experienced cirrhotic adult subjects following 12 weeks, 
16 weeks and 24 weeks treatment durations (Study M11-665, AGATE-I).  High SVR12
rates of 97% and 98% were achieved for the 12 week and 16 week treatment arms, 


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suggesting no added benefit to SVR observed with an additional 4 weeks of treatment for 
the 16-week arm.  The regimen was generally well tolerated, with no patient discontinuing 
treatment due to adverse events.
Hepatic Decompensation
In late 2015, several cases of hepatic decompensation were reported in patients treated 
post-marketing with 2D or 3D with or without RBV, some of which resulted in fatalities 
or necessitated liver transplants.  These occurrences were observed in patients who 
already had advanced or decompensated cirrhosis prior to starting treatment.  Although 
complete information on baseline clinical status and laboratory values was infrequently 
available, patients with severe outcomes of death or liver transplantation generally had 
evidence of more advanced cirrhosis and portal hypertension.  Laboratory findings (when 
available) associated with events of hepatic decompensation and hepatic failure were 
characterized by the acute onset of rising direct serum bilirubin levels with additional 
clinical signs and symptoms of hepatic decompensation, typically without associated ALT 
elevations.  The label was subsequently updated to contraindicate 3D and 2D in patients 
with decompensated cirrhosis (i.e., CPB or CPC).  The current study is intended to 
evaluate the pharmacokinetics, safety, efficacy and the long-term outcomes of ombitasvir, 
paritaprevir, ritonavir with or without dasabuvir and with or without ribavirin in pediatric 
subjects with genotype 1 or 4 chronic hepatitis C with or without compensated cirrhosis.  
Subjects with current evidence or a prior history of liver decompensation are excluded 
from this study.
3.1
Differences Statement
The combination of OBV/PTV/RTV with or without DSV and with or without RBV has 
been thoroughly studied and is approved in the US and several countries in EU for the 
treatment of HCV GT1 and GT4-infected adults.  This is the first study to evaluate the 
pharmacokinetics, efficacy and safety of OBV/PTV/RTV with or without DSV and with 
or without RBV in HCV-infected pediatric subjects (under age 18).  The study population 
for Part 1, the pharmacokinetic study, will include GT1-infected subjects who are 


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non-cirrhotic and treatment-naïve.  Part 2, the safety and efficacy study, will include GT1 
and GT4 subjects who are treatment-naïve or IFN (IFN or pegIFN with or without RBV) 
treatment-experienced with or without compensated cirrhosis.  In Part 3, long-term safety 
and efficacy will be evaluated for 144 weeks.
3.2
Benefits and Risks
Part 1 of this study is a Phase 2 study in which eligible HCV GT1-infected pediatric 
subjects will receive OBV, PTV, RTV and DSV with or without RBV for 12 weeks.  
Part 2 of this study is a Phase 3 study in which eligible genotype 1 or 4-infected subjects 
will receive OBV/PTV/RTV with or without DSV and with or without RBV for 12 or 
24 weeks depending on HCV genotype, sub-genotype and cirrhosis status.  
OBV/PTV/RTV and DSV with or without RBV was evaluated in > 2300 adult subjects 
with HCV GT1 infection in six Phase 3 studies.  OBV/PTV/RTV and DSV with or 
without RBV achieved SVR12 greater than 97% overall in HCV GT1-infected subjects, 
including those with compensated cirrhosis, with the label recommended regimens.  
OBV/PTV/RTV with or without RBV was evaluated in 135 adult subjects with HCV 
GT4 infection in a Phase 2 study.  Similarly high SVR12 rates (100%) were observed in 
this study with OBV/PTV/RTV with RBV.  
OBV/PTV/RTV and DSV with or without RBV was well tolerated in the Phase 3 studies 
in genotype 1-infected adults with discontinuation due to AEs approximately 1%.  
Adverse events that are known and those not previously described, may occur as detailed 
in the informed consent and assent for this study.  In addition, subjects may experience 
inconvenience or discomfort related to the study visits or study procedures.
Post-marketing cases of hepatic decompensation were reported in patients treated with 
OBV/PTV/RTV with or without DSV with or without RBV, some of which resulted in 
fatalities or necessitated liver transplants.  These occurrences were observed in patients 
who already had highly advanced or decompensated cirrhosis prior to starting treatment.  
In this study, patients with a history of or existing decompensation will not be included in 
the study.  Other risks associated with OBV/PTV/RTV with or without DSV and with or 


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without RBV include the risks of toxicity and virologic failure.  Adverse events associated 
with treatment have been limited and manageable based on the results from the Phase 2/3 
studies.  Given the potential high rate of cure in HCV GT1 and GT4-infected subjects, the 
risk-benefit profile is favorable.
3.3
Pediatric Study Plan and Pediatric Investigational Plan
The original Study M14-748 study design was developed in accordance with the Pediatric 
Study Plan (PSP) and Pediatric Investigational Plan (PIP) for OBV/PTV/RTV and DSV 
for the treatment of Hepatitis C virus infection.6,20,27
The Pediatric Committee (PDCO) of the European Medicines Agency (EMA) issued a 
positive opinion on the PIP for the OBV/PTV/RTV and DSV on November 08, 2013.  
Upon AbbVie request, a waiver was granted for the pediatric population younger than 
3 years of age "on the grounds that the specific medicinal product does not represent a 
significant benefit over existing treatment for pediatric patients" in this age group.  In 
addition, both the PK and safety and efficacy study were granted deferrals to begin after 
approval of OBV/PTV/RTV and DSV in adults with GT1 infection.
Similarly, the initial PSP for OBV/PTV/RTV and DSV, dated December 19, 2013, 
provided a waiver for the pediatric population younger than 3 years of age and a deferral 
to begin the PK and safety/efficacy studies in pediatric populations after the approval of 
OBV/PTV/RTV and DSV in adults with GT1 infection.  The initial PSP was revised to 
include GT4-infected subjects and agreed upon by the FDA on December 19, 2014.  This 
revision also included a waiver for the pediatric population younger than 3 years of age 
and a deferral of pediatric assessments in the pediatric population younger than 18 years 
of age for the 2D regimen until after approval of the NDA for GT4 infection.


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4.0
Study Objective
Primary Objective(s):
●
To assess the pharmacokinetics of different OBV, PTV, RTV and DSV 
formulations with or without RBV in treatment-naïve, non-cirrhotic, GT 1 
HCV-infected pediatric subjects in Part 1. 
●
To assess the efficacy (percentage of subjects with SVR12) and safety of 
OBV/PTV/RTV with or without DSV and with or without RBV for 12 or 
24 weeks in HCV GT1 or GT4-infected treatment-naïve and treatment-
experienced pediatric subjects with and without compensated cirrhosis in 
Part 1 and Part 2.
Secondary Objective(s):
●
To evaluate the percentage of subjects with SVR12 by formulation, age and 
weight group and across all subjects on the adult formulations.
●
To evaluate the percentage of subjects with SVR24 and the percentage of 
subjects with ALT normalization by the end of treatment, by formulation, age 
and weight group, across all subjects, and across all subjects on the adult 
formulations.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
In Part 1 of this study eligible HCV GT1-infected, treatment-naïve, non-cirrhotic pediatric 
subjects will receive OBV, PTV, RTV with DSV and with or without RBV for 12 weeks.  
Part 2 of this study is a Phase 3 study in which eligible GT1 or 4-infected treatment-naïve 
or prior IFN (or IFN or pegIFN with or without RBV) treatment-experienced pediatric 
subjects without cirrhosis or with compensated cirrhosis will receive OBV/PTV/RTV 
with or without DSV and with or without RBV for 12 or 24 weeks depending on HCV 
genotype, sub-genotype and cirrhosis status.  Part 1 is designed to allow for dose 
adjustment (details are provided below in Dose Adjustment Considerations for Part 1 


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[Pharmacokinetic Study]) on an ongoing basis based on available pharmacokinetic and 
clinical data to achieve therapeutic exposures that have been demonstrated to be safe and 
efficacious in adult subjects.  Part 2 will evaluate the adult formulations in treatment-
naïve and IFN treatment-experienced HCV GT1 or GT4-infected adolescents with or 
without compensated cirrhosis.  Both Parts 1 and 2 will consist of a Screening Period 
(Section 5.1.1), a Treatment Period (Section 5.1.2), and a 24-week Post-Treatment Period 
(Section 5.1.3) (Section 5.1.4).  Subjects who prematurely discontinue study treatment in 
Part 1 will be followed in the Post-Treatment Period in Part 1.  Similarly subjects who 
prematurely discontinue study treatment in Part 2 will be followed in the Post-Treatment 
Period in Part 2.  After completing the Post-Treatment Period in Part 1 or Part 2, the 
subjects will be followed in Part 3 for 144 weeks.  Subjects who prematurely discontinue 
from the Post-Treatment Period in Part 1 or Part 2 or from Part 3 will be discontinued 
from the study.
Part 1
In Part 1, the primary objectives are to assess the pharmacokinetics, efficacy and safety of 
OBV, PTV, RTV and DSV with or without RBV in HCV GT1-infected, treatment-naive 
pediatric subjects.  Part 1 will include approximately 36 subjects.  At least 12 subjects will 
enroll in each of the 3 age year groups, ≥ 3 to 8, ≥ 9 to 11, and ≥ 12 to 17.  Enrollment 
will begin with pediatric subjects ≥ 12 to 17 years old who are ≥ 45 kg and willing to 
swallow the OBV/PTV/RTV and DSV adult formulations.  After acceptable 
pharmacokinetic, efficacy and safety data are available from at least 6 subjects from the 
≥12 to 17 age group who receive the adult regimen, subjects ages ≥ 9 to 11 will begin 
enrollment to be administered the mini-tablet formulations.  After acceptable 
pharmacokinetic, efficacy and safety data are available from at least 6 subjects from the 
≥9 to 11 age group (at least 4 of which have a body weight of 15 to 44 kg) subjects ages 
≥ 3 to 8 will be enrolled and administered the mini-tablets.  In the ≥ 3 to 8 year age group, 
at least 2 subjects each from subgroups ≥ 3 to 5 and ≥ 6 to 8 years old will be enrolled to 
ensure that there is adequate information for dosing recommendations for the entire ≥ 3 to 
8 age group.  Up to approximately 12 additional pediatric subjects may be enrolled to 


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receive the mini-tablet formulation in Part 1 if needed to adequately characterize the 
pharmacokinetics and determine the final dose strength for a particular age group or 
subgroup.  Subjects will be followed in Part 1 of the study through Post-Treatment 
Week 24.
In summary, children who are ≥ 12 to 17 years old with weight ≥ 45 kg and willing to 
swallow the adult formulations will use the adult formulations of OBV/PTV/RTV with 
DSV.  All other children ≥ 3 to 11 years of age will be dosed with the pediatric mini-tablet 
formulation.  For subjects that are not willing to swallow the RBV tablets and are not 
taking the adult formulations of the DAAs, RBV will be provided as a 40 mg/mL oral 
solution.
Dose Adjustment Considerations for Part 1
For each subject, the initial dose of DAAs will be based on the subject's body weight at 
Screening.  No dose adjustments of DAAs or RBV will be made as a consequence of 
weight change during the treatment period.  Dose adjustments may be implemented 
during the treatment period based on available data and enrollment.  When preliminary 
pharmacokinetic and clinical data (following Week 2 intensive PK sampling or Week 8 
trough sample) from approximately 6 subjects in the age group are available, these data 
will be used to adjust doses, if needed, for subjects who have been enrolled and for 
subjects who are subsequently enrolled in the respective age group.  The data from age 
groups of ≥ 3 to 8 and ≥ 9 to 11 years old may be combined for final analyses if exposures 
from these 2 groups are comparable to each other.
For each of the analytes (OBV, PTV, RTV, or DSV), the geometric mean and individual 
values of AUC from these pediatric subjects from the Week 2 intensive PK sampling will 
be compared with the range of geometric means and the range of individual AUCs across 
Phase 1/2/3 studies in adults that had intensive pharmacokinetic data.  Dose adjustments 
may be made for each component of the DAA regimen if the respective geometric mean 
AUC in pediatric subjects is outside the geometric mean range in adults and/or at least 2 
of 6 pediatric subjects have individual AUCs outside of the individual range in adults.  In 


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addition, if data are available from fewer than 6 subjects and if at least 2 of these subjects 
have individual AUCs outside of the individual range in adults, dose adjustment might be 
considered for the age group.
AUC will be the primary measure for dose adjustment.  Cmax and Ctrough will be considered 
for safety and efficacy using the same rules.
Additional criteria may be considered for making dose adjustment decisions for Part 1 to 
ensure safe and efficacious exposures.  Subjects who take at least one dose of the study 
drug will be followed in Part 1 of the study through Post-Treatment Week 24 to assess 
SVR12 and SVR24.
Part 2
In Part 2, the primary objectives are to further evaluate the safety and efficacy (percentage 
of treatment-naïve or treatment-experienced subjects achieving SVR12) of 
OBV/PTV/RTV and DSV with or without RBV in HCV GT1-infected pediatric subjects 
and OBV/PTV/RTV in GT4-infected pediatric subjects with or without compensated 
cirrhosis.  Part 2 will enroll approximately 16 HCV GT1infected and 10 GT4 infected, 
treatment-naïve or IFN (IFN or pegIFN with or without RBV) treatment-experienced 
pediatric subjects ages ≥ 12 to 17 years of age.  Enrollment in Part 2 will begin once 
dosing recommendations of OBV, PTV, RTV and DSV are available for the ≥ 12 to 
17 year-old age group based on the pharmacokinetic and clinical data from Part 1 of the 
study.  Subjects who take at least one dose of the study drug will be followed in Part 2 of 
the study through Post-Treatment Week 24 to assess SVR12 and SVR24.
Part 3 (Long-Term Follow-Up Period)
In Part 3, the objectives are to assess the durability of response for subjects who achieved 
SVR, to assess the persistence of specific HCV amino acid variants associated with drug 
resistance in subjects who experienced virologic failure and to assess the impact of 
OBV/PTV/RTV with or without DSV co-administered with or without RBV on growth 
and development.  All pediatric subjects who complete the PT Week 24 visit in Part 1 or 


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Part 2 will be automatically enrolled into Part 3 and followed for up to 144 weeks.  
Subjects will return to their study site for their scheduled visits on an outpatient basis.  
Subjects with virologic failure are allowed to use any other approved treatments for their 
HCV infection, if appropriate, while participating in the Long-term Follow-up study; 
however that therapy would be provided outside the context of this study and needs to be 
captured in source documents and entered into EDC by site personnel.
Fibrosis Assessment
An assessment of liver fibrosis is mandatory prior to enrollment.  Subjects, with no 
history of cirrhosis, who have not had a liver biopsy or FibroScan within 24 months prior 
to screening, will undergo a non-invasive FibroTest to determine presence or absence of 
cirrhosis.  
Subjects will be considered to be non-cirrhotic based on a liver biopsy within 24 months 
prior to screening demonstrating the absence of cirrhosis (e.g., a Metavir Score of 3 or 
less, Ishak score of 4 or less) or, if a liver biopsy is unavailable, a historical Fibroscan®
result < 14.6 kPa within 24 months prior to screening.  If neither historical result is 
available, a screening FibroTest score of < 0.75 can be used to demonstrate absence of 
cirrhosis. 
Subjects will be considered to have cirrhosis based on previous histologic diagnosis of 
cirrhosis on a liver biopsy at any time prior to screening (e.g., Metavir Score of 
> 3 [including 3 – 4 or 3/4], Ishak score of > 4) or, if a liver biopsy is unavailable, a 
historical FibroScan score ≥ 14.6 kPa or a screening FibroTest ≥ 0.75 (Table 4).


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Table 4.
Baseline Fibrosis Stage
Baseline Fibrosis 
Stage, Metavir 
Equivalents
Liver Biopsy Metavir, 
Batts-Ludwig, 
Knodell, IASL, 
Scheuer, or Laennec 
Score
Liver Biopsy 
Ishak Score
FibroScan (kPa)
FibroTest 
F0 – F1
0 or 1
0, 1, or 2
< 8.8
< 0.49
F2
2
3
≥ 8.8 to < 9.6
0.49 to < 0.59
F3
3
4
≥ 9.6 to < 14.6
0.59 to < 0.75
F4
4
5 or 6
≥ 14.6
≥ 0.75
The resulting fibrosis status (F0-F3 noncirrhotic, F4 cirrhotic) and HCV 
genotype/sub-genotype will be documented via recording in the Interactive Response 
Technology (IRT) system for each subject to determine the duration and regimen of the 
study drug for each subject.
Subjects will be considered treatment-naïve if they have never received any antiviral 
treatment for hepatitis C virus infection.
Subjects will be considered treatment-experienced if they have received prior IFN (IFN or 
pegIFN with or without RBV) excluding DAAs.  Subjects with prior treatment with IFN 
will be categorized as one of the following:
●
Non-responder:  HCV RNA detected at the end of a prior IFN, IFN/RBV or 
pegIFN/RBV treatment course (except for breakthrough, which is captured 
separately).  These subjects are further categorized as:
○
Null-responder:  failed to achieve a 1 log10 IU/mL reduction in HCV RNA 
by Week 4 or a 2 log10 IU/mL reduction in HCV RNA by Week 12 during 
a prior IFN, IFN/RBV or pegIFN/RBV treatment course;
○
Partial responder:  achieved at least 2 log10 IU/mL reduction in HCV RNA 
by Week 12 during a prior IFN, IFN/RBV or pegIFN/RBV treatment 
course but failed to achieve HCV RNA undetectable at the end of 
treatment;


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○
Unknown or unable to specify:  insufficient data to categorize as null or 
partial responder. 
●
Breakthrough:  confirmed ≥ 1 log10 IU/mL increase from nadir or achieved 
HCV RNA undetectable (or unquantifiable) during a prior IFN, IFN/RBV or 
pegIFN/RBV treatment course but HCV RNA was quantifiable during or at 
the end of treatment.
●
Relapser:  achieved HCV RNA undetectable at the end of a prior IFN, 
IFN/RBV or pegIFN/RBV treatment course but HCV RNA was detectable 
following cessation of therapy.
●
Unknown/other IFN-experienced:  subject received a prior IFN, IFN/RBV or 
pegIFN/RBV treatment course and reason for not achieving SVR is unknown 
or other than above.
After meeting the eligibility criteria, subjects will be enrolled to 12 weeks of treatment in 
Part 1 or either 12 or 24 weeks of treatment in Part 2.
Figure 1.
Study Schematic
The study is designed to enroll approximately 62 subjects to meet scientific, regulatory 
and clinical objectives without enrolling an undue number of subjects in alignment with 


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ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
5.1.1
Screening
At the Screening Visit for Part 1 or Part 2, parent(s)/guardian(s) must provide written 
(signed and dated) informed consent and the subject must provide assent (as appropriate 
for age and country) respectively, prior to any study specific procedures on the subject.
Subjects will receive a unique subject number via the IRT system and will undergo the 
study procedures identified in Section 5.3.1 associated with the Screening Visit.  The 
investigator or his/her designated and qualified representatives will evaluate whether the 
subject meets all of the eligibility criteria specified in Section 5.2.1 and Section 5.2.2 for 
the Part in which they are enrolling during the period from the Screening Visit through 
Study Day 1 prior to dosing and record the results of this assessment and the details of the 
informed consent and assent process in the subject's medical records.
Eligible subjects have up to 42 days following the Screening Visit to enroll into Part 1 or 
Part 2 of the study.  There is no screening period for Part 3 (Long-term Follow-up).  Part 3 
will start the day after the PT Week 24 Visit in Part 1 or Part 2.
5.1.1.1
Rescreening
Subjects who have any of the following results are ineligible to rescreen or have other 
exclusionary laboratory parameters retested:  an exclusionary HCV genotype, a positive 
hepatitis B surface antigen (HBsAg), positive human immunodeficiency virus (HIV) 
antibody or confirmed pregnancy.
Subjects who meet all eligibility criteria with the exception of up to 
three (3) exclusionary laboratory parameters may repeat laboratory testing once within 
the 42-day screening period without prior AbbVie approval. Subjects being retested 
because of exclusionary laboratory parameter(s) must have the related panel(s) repeated 


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(e.g., bilirubin requires a repeat chemistry panel) within the same screening period and all 
eligibility criteria must be met on the repeated panels.
Subjects may be rescreened only once as follows:
●
Subjects who have more than 3 exclusionary laboratory results require 
approval from the AbbVie Therapeutic Area Medical Director prior to 
rescreening.
●
Eligible subjects who fail to enroll within 42 days of screening, regardless of 
the reason for falling outside the 42-day screening window.
For subjects who do not meet the study eligibility criteria, the site personnel must register 
the subject as a screen failure in both IRT and electronic data capture (EDC) systems.
5.1.2
Treatment Period (TP)
After meeting all the eligibility criteria, subjects will be enrolled to a study regimen 
according to their HCV sub-genotype for Part 1 (Table 5) or to a study regimen and study 
duration according to their HCV genotype, sub-genotype and cirrhosis status in Part 2 
(Table 6).
Table 5.
Treatment Regimen and Duration – Part 1
Patient Population
Treatment
Duration
Genotype 1b, 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir
12 weeks
Genotype 1a,* 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + ribavirin
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
In Part 1, treatment-naïve HCV GT1-infected subjects without cirrhosis will receive OBV, 
PTV, RTV and DSV with or without RBV for 12 weeks according to Table 5.  In Part 2, 
HCV GT1 and GT4-infected subjects with and without compensated cirrhosis who are 
either treatment-naïve or previously treated with IFN (IFN or pegIFN with or without 


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RBV) will receive OBV/PTV/RTV with or without DSV and with or without RBV 
according to Table 6.  The treatment duration will be 12 or 24 weeks depending on their 
genotype, subgenotype and cirrhosis status.  Details regarding enrollment in Part 1 and 
Part 2 are outlined in Section 5.1 (Overall Study Design and Plan:  Description).
Table 6.
Treatment Regimen and Duration – Part 2 (For Subjects ≥ 12 –
17 Years of Age)
Patient Population
Treatment
Duration
Genotype 1b with or 
without compensated 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir
12 weeks
Genotype 1a,* without 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + ribavirin
12 weeks
Genotype 1a,* with 
compensated cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + ribavirin
24 weeks
Genotype 4 with or 
without compensated 
cirrhosis
ombitasvir + paritaprevir + ritonavir + ribavirin
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
The site will enter subject's genotype and sub-genotype (GT1b/GT1 non-b/GT4) and 
fibrosis stage in the IRT system in order to obtain the subject's treatment regimen and 
duration.
OBV, PTV, RTV, DSV (if applicable) and RBV (if applicable) will be administered as 
described in Section 5.5.1 (Treatments Administered).  Subjects and their 
parent(s)/guardian(s) will receive instructions about the study drugs at the Day 1 Visit.  
The study drugs will be dispensed at the visits as indicated in Appendix C.
After enrollment, all subjects will continue to return to the site on an outpatient basis for 
the study visits and procedures as identified in Appendix C.  Subjects could also return to 
the site for an unscheduled study visit for additional safety assessments if the investigator 
feels it is necessary.  Sites should ensure that subjects adhere to the study visits listed in 
Appendix C.  Subjects who cannot complete their study visit per the visit schedule should 


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ensure they do not run out of study drug prior to their next study visit.  Compliance is 
critical to ensure adequate drug exposure. 
Virologic failure criteria will be evaluated and applied by the Investigator as detailed in 
Section 5.4.3.
Subjects who prematurely discontinue from the Treatment Period should return for a 
Treatment Discontinuation Visit and undergo the study procedures as outlined in 
Appendix C and as described in Section 5.3.1.1.  Ideally, this should occur on the day of 
study drug discontinuation, but is recommended to be no later than 2 days after their final 
dose of study drug and prior to the initiation of any other anti-HCV therapy if applicable.  
Following completion or premature discontinuation of study drug treatment, all subjects 
in either Part 1 or Part 2 will be followed in the associated Post-Treatment Period of 
Part 1 or Part 2.
5.1.3
Post-Treatment Period of Part 1 and Part 2
All subjects who receive at least one dose of the study drug will enter into the 
Post-Treatment Period of Part 1 or Part 2.  The 24-week Post-Treatment Period of Parts 1 
and 2 will include the visits through Post-Treatment Week 24 as outlined in Appendix C.  
Subjects who prematurely discontinue during the Post-Treatment Period should return to 
the site for a discontinuation visit and undergo the study procedures as outlined in 
Appendix C. 
5.1.4
Long-Term Follow-Up Period
All subjects who complete the Post-Treatment Week 24 visit will automatically be 
enrolled into Part 3 – the Long-term Follow-up Period and return to the site on an 
outpatient basis for the study visits and procedures as identified in Appendix C.  The 
Long-term Follow-up Period will begin the day following the Post-Treatment Week 24 
visit and last for 144 weeks as outlined in Appendix C.  Subjects may also return to the 
site for an unscheduled study visit for additional safety assessments if the investigator 
feels it is necessary. 


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The Long-term Follow-up Period will assess safety, antiviral response, and growth and 
development.
Growth and development will be assessed using waist circumference, Tanner Pubertal 
Staging, height standardized score, and growth rate defined as the change in height over 
change in age from the previous visit.
5.2
Selection of Study Population
The study population in Part 1 consists of HCV genotype 1-infected pediatric subjects 
without cirrhosis who are naïve to HCV treatment.  The study population in Part 2 
consists of HCV genotype 1- or 4-infected pediatric subjects with or without compensated 
cirrhosis, who are treatment-naïve or IFN (IFN or pegIFN with or without RBV) 
treatment-experienced.
Subjects who meet the inclusion criteria and who do not meet any of the exclusion criteria 
will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
1.
Male or female ≥ 3 to 17 years of age with weight ≥ 15 kg at time of enrollment.
2.
Willingness to participate in the study for up to 42 months.
3.
If female, subject must either be pre-menarche and not sexually active, 
permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy) OR for Women of Childbearing Potential (WOCBP) practicing at 
least one protocol specified method of birth control (Section 5.2.4), starting at 
Study Day 1 (or earlier) through at least 30 days after stopping study drug (if not 
receiving RBV), or for up to 6 months after stopping study drug if receiving RBV 
(or as directed by local RBV label).
4.
If male subject and sexually active with female partner(s) of childbearing potential, 
subject must agree to practice the protocol specified contraception (Section 5.2.4), 
from Study Day 1 and for up to 9 months after stopping study drug (or as directed 


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by the local RBV label if receiving RBV) or from Study Day 1 through 30 days 
after last dose of study drug for subjects whose study regimen does not include 
RBV.
5.
HCV infection demonstrated by positive anti-HCV Ab and HCV RNA 
≥1000 IU/mL at the time of screening. 
6.
Screening laboratory results indicating HCV genotype 1 for enrollment into Part 1 
and genotype 1 or 4 for enrollment into Part 2.
7.
Subject has never received antiviral treatment (including IFN or pegIFN with or 
without RBV) for hepatitis C infection (treatment-naïve subjects) for Part 1 or 
Part 2, or subject must have completed their IFN based (IFN or pegIFN with or 
without RBV only) hepatitis C treatment at least 6 months prior to enrollment into 
Part 2.
8.
Parent or legal guardian with the willingness and ability to provide written 
informed consent and subject willing and able to give assent, as appropriate for age 
and country. 
9.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at Study Day 1.  Females of non-
childbearing potential (as defined above) at Screening do not require pregnancy 
testing.
Rationale for Inclusion Criteria
1, 2, 5 – 7
To select the appropriate subject population with sufficient disease 
severity for evaluation
3, 4, 9
RBV has known teratogenic effects
8
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will be excluded from the study if he/she meets any of the following criteria:


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1.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after stopping study drug (if not 
receiving RBV), or for up to 6 months after stopping study drug if receiving RBV 
(or as directed by local RBV label).
2.
Use of known strong inducers and inhibitors (e.g., gemfibrozil) of cytochrome
P450 2C8 (CYP2C8) in subjects receiving dasabuvir, or strong or moderate 
inducers of CYP3A, medications listed below, or medications contraindicated for 
ritonavir or RBV (for those that receive RBV), within 2 weeks or 10 half-lives, 
whichever is longer, of the respective medication prior to study drug administration 
including but not limited to:
Table 7.
Medications Contraindicated for Use with the Study Drug Regimen
Alfuzosin
Astemizole
Atorvastatin
Blonanserin
Carbamazepine
Cisapride
Colchicinec
Dihydroergotamine
Dronedarone
Efavirenz
Ergotamine
Ergonovine
Ethinyl estradiol-containing 
medications
Fusidic Acid
Gemfibrozila
Lovastatin
Lurasidone
Methylergonovine
Midazolam (oral) 
Phenobarbital
Phenytoin
Pimozide
Ranolazine
Rifampin
Salmeterol
Sildenafilb
Simvastatin
St. John's Wort
Terfenadine
Triazolam
a.
Strong CYP2C8 inhibitors (e.g., gemfibrozil) and CYP2C8 inducers are not contraindicated with ombitasvir, 
paritaprevir and ritonavir (for GT4 subjects).
b.
When used for the treatment of pulmonary arterial hypertension.
c.
When used in patients with renal or hepatic impairment.
Note: Not all medications contraindicated with ribavirin are listed above.  Refer to the most current package inserts or 
product labeling of ribavirin for a complete list of contraindicated medications.


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For medications contraindicated with AbbVie's 2D and 3D regimen, refer to the 
recommended prescribing information section of the approved local product labels in 
countries where the regimen contained in this study (i.e., ombitasvir/paritaprevir/ritonavir 
with or without dasabuvir) has received marketing authorization.  If locally approved 
labels are not available, refer to the following Contraindicated Medication list:
3.
Clinically significant abnormalities or co-morbidities, other than HCV infection 
that make the subject an unsuitable candidate for this study or treatment with RBV 
(if applicable) in the opinion of the investigator.
4.
Positive test result for Hepatitis B surface antigen (HbsAg) or anti-HIV antibody
(HIV Ab) test.
5.
Current enrollment in another interventional clinical study, previous enrollment in 
this study, prior or current use of any investigational or commercially available 
anti-HCV agents other than IFNs or RBV or receipt of any investigational product 
within 6 weeks prior to study drug administration.
6.
History of solid organ transplant.
7.
Prior or current use of any investigational or commercially available anti-HCV 
agents other than IFN, pegIFN or RBV, including telaprevir, boceprevir, 
sofosbuvir, ombitasvir, dasabuvir, paritaprevir, ledipasvir, daclatasvir, simeprevir, 
elbasvir, grazoprevir or an investigational DAA. 
8.
Screening laboratory analyses showing any of the following abnormal laboratory 
results:
●
Albumin < 2.8 g/dL
●
Hemoglobin < 10 g/dL
●
Platelets < 25,000 cells per mm3
●
Total bilirubin > 3.0 mg/dL


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9.
Any current or past clinical evidence of Child-Pugh B or C Classification 
(Child-Pugh Score ≥ 7) or clinical history of liver decompensation such as ascites 
(noted on physical exam), variceal bleeding or hepatic encephalopathy.
10.
Confirmed presence of hepatocellular carcinoma indicated on imaging techniques 
such as computed tomography (CT) scan or magnetic resonance imaging (MRI) 
within 3 months prior to Screening or on an ultrasound performed at Screening for 
subjects with cirrhosis (a positive ultrasound result will be confirmed with CT scan 
or MRI).
11.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 120 days after stopping study drug if receiving DAAs 
only, or for up to 9 months after stopping study drug if receiving RBV (or as 
directed by local RBV label).
Rationale for Exclusion Criteria
1, 3, 7, 8, 
10, 11
To ensure safety of the subjects throughout the study
2
To avoid bias for the evaluation of efficacy and safety by concomitant use 
of other medications
4 – 6, 9
To avoid bias for the evaluation of efficacy and safety
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from 2 weeks prior to 
enrollment through 30 days post-dosing, must be recorded along with the reason for use, 
date(s) of administration including start and end dates, and dosage information including 
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During the Post-Treatment Period, all medications taken will be recorded until 30 days 
following the last dose of study drugs.  Only medications taken for SAEs assessed as 
related to the study drugs and treatment of HCV will be recorded thereafter.
The AbbVie Therapeutic Area Medical Director should be contacted if there are any 
questions regarding concomitant or prior therapies.
5.2.3.1
Prior HCV Therapy
Part 1 will include only subjects that are treatment-naïve.  For Part 2, prior or current use 
of any investigational or commercially available anti-HCV agents other than IFN, pegIFN 
or RBV, including telaprevir, boceprevir, sofosbuvir, ombitasvir, dasabuvir, paritaprevir, 
ledipasvir, daclatasvir, simeprevir, elbasvir, grazoprevir or an investigational DAA 
excludes a subject from this study.  Subjects who previously participated in trials of 
investigational anti-HCV agents may be enrolled if they can produce documentation that 
they received only placebo.
Treatment experienced subjects must have discontinued previous therapy at least 
6 months prior to the Screening Visit in order to be eligible for the study.
5.2.3.2
Concomitant Therapy
Subjects must be able to safely discontinue any prohibited medications within 2 weeks or 
10 half-lives of the medication, whichever is longer, prior to initial study drug 
administration and through 2 weeks following discontinuation of study drugs.  
Parent(s)/legal guardian(s) and the pediatric subject must review and sign the informed 
consent and assent respectively prior to discontinuing any prohibited medications for the 
purpose of meeting study enrollment criteria.
The investigator or a qualified designee should confirm that a concomitant medication can 
be safely administered with DAAs (including ritonavir) and RBV (if applicable).  Some 
medications may require dose adjustments due to potential for drug-drug interactions.


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The investigator or qualified designee should review concomitant medication(s) label(s), 
the locally approved labels for ombitasvir, paritaprevir, ritonavir, dasabuvir (if applicable) 
and ribavirin (if applicable) and http://www.hep-druginteractions.org/ to screen 
concomitant medications at each visit for potential drug-drug interactions (DDI) with 
study drugs.  Additionally, the site should document their DDI review in the subject's 
source.
Subjects using systemic ethinyl estradiol-containing contraceptive therapy have a higher 
risk for elevated ALT levels.  Subjects using these kinds of medications must discontinue 
them at least 2 weeks prior to initial study drug administration.  Subjects may replace the 
systemic ethinyl estradiol-containing contraceptive with a highly effective progestin-only 
hormonal contraceptive method or with another highly effective contraceptive method.
During the Post-Treatment Period, investigators should reassess concomitant medications.  
Subjects may resume previously prohibited medications or revert to pre-study doses, at a 
minimum of 2 weeks following discontinuation of study drugs, if applicable.
5.2.3.3
Prohibited Therapy
In addition to the medications listed in Table 7, use of known strong or moderate inducers 
of CYP3A (for GT1 and GT4 subjects receiving OBV/PTV/RTV with or without DSV), 
or strong inducers and inhibitors of CYP2C8 (only for GT1 subjects receiving 
OBV/PTV/RTV with DSV) are prohibited within 2 weeks or 10 half-lives of the 
medication, whichever is longer, prior to the initial dose of study drugs and through the 
first 2 weeks after the subject has completed study drugs in the Treatment Period.
Subjects must be able to safely discontinue any prohibited medications.  Subjects must be 
consented prior to discontinuing any prohibited medications for the purpose of meeting 
study enrollment criteria.  During the Post-Treatment Periods of Part 1 and Part 2, 
investigators should reassess prohibited medications and subjects may resume previously 
prohibited medications or revert to pre-study doses, at a minimum of 2 weeks following 
discontinuation of study drugs, if applicable.


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5.2.4
Contraception Recommendations and Pregnancy Testing
The contraception recommendations in this paragraph are summarized in relation to the 
potential risk of the investigational products used in this study.  All female subjects who 
are experiencing menses or are nearing sexual maturation in the opinion of the Principal 
Investigator, or who are of child-bearing potential should undergo pregnancy testing 
according to Section 5.3.1.1.
If female, subject must be:
●
Pre-menarche and not sexually active, or 
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy), or
●
Practicing at least one of the following methods of birth control, on Study 
Day 1 (or earlier) through at least 30 days after stopping study drug (if not 
receiving RBV), or for up to 6 months after stopping study drug if receiving 
RBV (or as directed by local RBV label).
○
Progestogen-only hormonal contraception (injectable or implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
Study Day 1.
○
Bilateral tubal occlusion/ligation.
○
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of 
the WOCBP trial participant.
○
Intrauterine device (IUD).
○
Intrauterine hormone-releasing system (IUS).
○
True abstinence:  Refraining from heterosexual intercourse when this is in 
line with the preferred and usual lifestyle of the subject (periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable).


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Listed methods of contraception achieve a failure rate of less than 1% per year when used 
perfectly (consistently and correctly).  For oral hormonal contraceptives, failure rates can 
increase up to 9% with typical use (including inconsistent or incorrect use).  
Note:  Contraceptive methods with low user dependency are implantable progesterone 
only hormonal contraception, IUD, IUS, bilateral tubal occlusion, and vasectomized 
partner.
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
If male, subjects must be 
●
Prepubertal and not sexually active, or
●
surgically sterile (vasectomy with medical assessment confirming surgical 
success), or
●
have a female partner who is postmenopausal or permanently sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy), or
●
if sexually active with female partner(s) of childbearing potential must agree to 
practice contraception with a method listed below from Study Day 1 and for up 
to 9 months after stopping study drug (or as directed by the local RBV label if 
receiving RBV) or from Study Day 1 and continue for 120 days after last dose 
of study drug for subjects whose study regimen does not include RBV.
●
Condom use in combination with one additional birth control method.
●
True abstinence:  Refraining from heterosexual intercourse – when this is in 
line with the preferred and usual lifestyle of the subject.  (Note:  Periodic
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
120 days after the end of treatment if taking DAAs only, or for 9 months after the last 
dose of RBV (or per local RBV label).


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5.3
Efficacy Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
The study procedures outlined in Appendix C are discussed in detail in this section with 
the exception of the assessment of concomitant medications (Section 5.2.3), and the 
collection of adverse event information (Section 6.1.4).  All study data will be recorded in 
the subject's source documentation and then on the appropriate eCRFs, with the exception 
of laboratory data which will be provided to the Sponsor electronically from the 
laboratory(ies).
Informed Consent/Assent 
Signed study-specific informed consent and assent (as appropriate for age and country) 
will be obtained from the parent(s)/guardian(s) and subject before any study procedures 
are performed.  If a subject becomes of legal age during the course of the study, the 
subject will need to be consented using the approved informed consent form.  Details 
about how informed consent and assent will be obtained and documented are provided in 
Section 9.3.
RBV Information
Subjects taking RBV will be given the RBV Medication Guide (where applicable/locally 
available). 
Medical History
A complete medical history, including history of tobacco, nicotine containing products 
and alcohol use, will be taken from each subject during the Screening Visit.  An updated 


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medical history will be obtained prior to study drug administration and will serve as the 
baseline for clinical assessment.
Physical Examination
A complete physical examination will be performed at visits specified in Appendix C.  A 
symptom-directed physical examination may be performed at any other visit, when 
necessary.
The physical examination performed on Study Day 1 will serve as the baseline physical 
examination for clinical assessment.  Any significant physical examination findings after 
the first dose will be recorded as adverse events.
Vital Signs, Weight, Height and Waist Circumference
Body temperature, blood pressure, pulse, body weight, height, and waist circumference 
will be measured at the visits specified in Appendix C, or upon subject discontinuation.  
Blood pressure and pulse rate will be measured after the subject has been sitting for at 
least 3 minutes.  The vital signs performed on Study Day 1 will serve as the baseline for 
clinical assessment.  Height will be measured standing without shoes using a stadiometer.  
Waist circumference will be measured using a flexible tape at the level of the iliac crest at 
the end of expiration.
12-Lead Electrocardiogram
The ECG obtained at Screening will serve as the baseline assessment.  The ECG should 
be performed prior to blood collection.  An ECG can be performed at subsequent visits if 
deemed clinically.  
The ECGs will be evaluated by an appropriately trained physician at the site ("local 
reader").  The local reader from the site will sign, and date ECG tracings and will provide 
his/her global interpretation as a written comment on the tracing using the following 
categories:


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●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the 
subject's source.  The automatic machine reading (i.e., machine-generated measurements 
and interpretation that are automatically printed on the ECG tracing) will not be collected.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 8
at the visits indicated in Appendix C.
An overview about the volume of blood drawn for each of the study visits is listed in 
Appendix D of this protocol.  The Investigator/designee should refer to the local 
recommendations on blood drawn in pediatric patients (e.g., the guide on "Ethical 
Considerations for Clinical Trials on Medical Products With the Paediatric Population" 
or "Blood Drawing For Human Subject Research" by Duke University).  The 
Investigator/designee should document exceptions to the local blood loss 
recommendations in the subject's source along with a justification as appropriate.
At the Study Day 1 visit, a blood sample is to be collected prior to the first dose of study 
drug which is to be administered during the visit.  Subjects should be reminded to eat 
prior to their first dose of study drug after the sample is collected (e.g., suggest they bring 
a light snack).  Fasting status will be recorded in the source documents and on the 
laboratory requisition.  The baseline laboratory test results for clinical assessment for a 
particular test will be defined as the last measurement prior to the initial dose of study 
drug.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  Instructions regarding the collection, processing, and shipping of these 
samples will be provided by the central laboratory chosen for this study.  The certified 


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laboratory chosen for this study is Covance.  Samples will be sent to the following 
address: 
North and South American sites:
Covance Central Laboratory Services
8211 SciCor Drive
Indianapolis, IN  46214-2985 USA
Tel.   (317) 271-1200
Fax:  (317) 273-4030
European sites:
Covance Central Laboratory Services
Rue Moïse-Marcinhes 7
1217 Meyrin/Genève-CH
Tel: +41 58-822-7000
Fax: +41 58-822-6999


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Table 8.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Additional Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands, if detected
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
ANC
Prothrombin Time/INR
Activated partial thromboplastin 
time (aPTT)
Reticulocyte count
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubina,b
Direct and indirect bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT) 
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumina
Chloride
Bicarbonate
Magnesium
Gamma-glutamyl transferase (GGT)a
Creatinine clearance (Cockcroft Gault 
calculation for subjects ≥12 years old 
and Schwartz formula for those
       < 12 years old)
Alpha2-macroglobulinb
Haptoglobinb
Apolipoprotein A1b
HBsAgc
Anti-HCV Abc
Anti-HIV Abc
FSHc
Urine and Serum 
Human Chorionic 
Gonadotropin (hCG)d
HCV RNA
IL28Bc
HCV genotype and sub-genotypec
Pharmacogenetic sample 
(optional)
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocyte esterase
Microscopic (reflex)
a.
Also a component of the Child-Pugh Assessment.
b.
Also a component of FibroTest.
c.
Performed only at Screening.  FSH will be taken for female subjects aged ≥ 9 to 17 years old.
d.
Serum and urine pregnancy testing only required for female subjects who are experiencing menses or are nearing 
sexual maturation in the opinion of the PI, or who are of child-bearing potential.
Acceptability Questionnaire
For each subject who is taking the mini-tablet formulation, the parent(s)/guardian(s) of the 
subject will complete an Acceptability Questionnaire to provide feedback on the 
perception of the dosage form.  The parent(s)/guardian(s) of the subject will be asked of 
their overall impression towards the dosage form and the administration via dosing 


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vehicle to the subject; such as duration of administration, volume of dosing vehicle, 
swallowability, and the convenience of administration.  
The questionnaire will be completed at the visits as indicated in Appendix C.  The 
parent(s)/guardian(s) will indicate their answers on the questionnaire, which will be kept 
as part of the study record and copied into EDC by site personnel.  Site personnel will 
encourage completion of the questionnaire at all applicable visits and will ensure that a 
response is entered for all items. 
Pregnancy Test 
Females of non-childbearing potential (either pre-menarche and not sexually active or 
permanently surgically sterile as defined above in Section 5.2.4) at Screening do not 
require pregnancy testing.  All female subjects who are experiencing menses or are 
nearing sexual maturation in the opinion of the Principal Investigator, or who are of child-
bearing potential:
●
A serum pregnancy test will be performed at the Screening visit only and 
analyzed by the central laboratory.
●
Pregnancy testing will be performed as specified in Appendix C regardless of 
treatment regimen.
●
Subjects that receive a RBV containing regimen will have pregnancy tests 
performed monthly throughout the Treatment Period and through Post-
Treatment Week 16 or 4 months after the discontinuation of RBV, or 
according to the local RBV label and/or local treatment guidelines for RBV.
●
Subjects receiving DAAs only should have urine pregnancy testing done 
through Post-Treatment Week 4.
●
Urine pregnancy testing will be performed on-site during the study visit if 
there is a scheduled visit.  The pregnancy result will be captured in the source 
document and recorded in the eCRF by site personnel.  If there is not a 
scheduled study visit, subjects may either have pregnancy testing performed at 
the site as an unscheduled study visit or a urine pregnancy test may be 
conducted by the subject at home with a pregnancy test kit provided by the 


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site.  If a urine pregnancy test is performed at home, site personnel should 
contact these female study subjects to capture the results of any study-related 
pregnancy tests in the source records only.
●
If a urine pregnancy result is positive, a confirmatory hCG serum test should 
be collected and sent to the central lab.
Concomitant Medication Assessment
Use of medications (prescription or over-the-counter, including vitamins, herbal 
supplements, and vaccines) from the time of signing the consent, through the Treatment 
Period and 30 days after study drugs are stopped must be recorded in the source and eCRF 
at each study visit indicated in Appendix C (Treatment Period and Post-Treatment 
Period).  Thereafter, only medications taken for SAEs assessed as related to study drugs 
and treatment of HCV will be recorded in the eCRF at each study visit indicated in 
Appendix C (Post-Treatment Period).  The investigator or his/her designated and qualified 
representatives should review concomitant medication(s) label(s), the locally approved 
labels for ombitasvir, paritaprevir, ritonavir, dasabuvir (if applicable), and ribavirin (if 
applicable) and http://www.hep-druginteractions.org/ to screen concomitant medications 
at each visit for potential drug interaction with study drugs.  The site should document 
their DDI review in the source and maintain it in the subject's study file.  The sites should 
refer to Section 5.2.3 (Prior, Concomitant, and Prohibited Therapy).
Hepatitis and HIV Screen
HBsAg (hepatitis B surface antigen), anti-HCV Ab and anti-HIV Ab will be performed at 
Screening.  A positive anti-HIV Ab test must be confirmed.  The investigator or his/her 
representatives must discuss any local reporting requirements to local health agencies with 
the subject's parent(s)/legal guardian(s).  The site will report these results per local 
regulations, if necessary.


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HCV Genotype and Sub-Genotype
Plasma samples for HCV genotype and sub-genotype will be collected at Screening.  
Genotype and sub-genotype will be assessed using the Versant HCV Genotyping assay 
(LiPA 2.0).  If the Versant LiPA 2.0 assay is resulted as "unable to genotype" then the 
HCV genotype will be determined by Sanger sequencing of NS5B region on Applied 
Biosystems 3500XL.
HCV RNA Levels
Plasma samples for HCV RNA levels will be collected as indicated in Appendix C and 
analyzed using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0.  For this 
assay, the lower limit of quantification (LLOQ) is 15 IU/mL.
Historical Liver Biopsy or FibroScan or Screening Fibro Test
An assessment of liver fibrosis is mandatory prior to enrollment.  Subjects with no history 
of cirrhosis who have not had a liver biopsy or Fibroscan within 24 months prior to 
screening, will undergo a non-invasive FibroTest at Screening to determine presence or 
absence of cirrhosis.
Subjects will be considered to be non-cirrhotic based on a liver biopsy within 24 months 
prior to screening demonstrating the absence of cirrhosis (e.g., a Metavir Score of 3 or 
less, Ishak score of 4 or less) or, if a liver biopsy is unavailable, a historical Fibroscan®
result < 14.6 kPa within 24 months prior to screening.  If neither historical result is 
available, a screening FibroTest score of < 0.75 can be used to demonstrate absence of 
cirrhosis. 
Subjects will be considered to have cirrhosis based on previous histologic diagnosis of 
cirrhosis on a liver biopsy (e.g., Metavir Score of > 3 [including 3 – 4 or 3/4], Ishak score 
of > 4) or a historical FibroScan score of  ≥ 14.6 kPa or a screening FibroTest result of 
≥0.75. 


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Longitudinal Fibrotest
All subjects will undergo assessment of FibroTest at Screening or Day 1 and FibroTest at 
PT Weeks 24, and 144.  Any subject that does not have a FibroTest performed during 
Screening will have them performed at Day 1.
Child-Pugh Score and Category
The Child-Pugh score will be calculated and documented prior to Day 1 Visit for cirrhotic 
subjects only.  Subjects who were considered to be non-cirrhotic at the screening visit but 
identified as cirrhotic (according to definitions listed here) during the screening process 
will return to the site prior to the baseline visit for Child-Pugh assessment.
The Child-Pugh score uses five clinical measures of liver disease (3 laboratory parameters 
and 2 clinical assessments).  Child-Pugh score will be determined at the screening visit as 
indicated in Appendix C.  The Child-Pugh score will be automatically calculated prior to 
Day 1 by EDC RAVE once the investigator or designated site personnel enters the 
subject's parameters (as listed in Table 9).  A total score of 5 – 6 is considered Class A 
(compensated disease); 7 – 9 is Class B (significant functional compromise); and 10 – 15 
is Class C (decompensated disease).


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Table 9.
Child-Pugh Classification of Severity of Cirrhosis
Points Assigned for Observed Findings
1
2
3
Total bilirubin, μmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites*
None
Slight
Moderate to severe
Hepatic encephalopathy**
None
Grade 1 or 2 
(or suppressed with 
medication)
Grade 3 or 4
(or refractory)
*
None.
Slight ascites = Ascites detectable only by ultrasound examination.
Moderate ascites = Ascites manifested by moderate symmetrical distension of the abdomen.
Severe ascites = Large or gross ascites with marked abdominal distension.
**
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2: lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
Hepatocellular Carcinoma Screening:  Liver Ultrasound
In order to monitor for the presence of hepatocellular carcinoma (HCC), an ultrasound of 
the liver will be performed as indicated in Appendix C for subjects with compensated 
cirrhosis only.
Subjects with a historical negative liver ultrasound, CT or MRI (within 3 months prior to 
screening) are not required to undergo a screening ultrasound.
A positive ultrasound result suspicious for HCC during the treatment or Post-Treatment 
Period will be confirmed with CT scan or MRI.


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HCV Resistance Testing Plasma Sample
A plasma sample for baseline HCV resistance testing will be collected on Day 1.  HCV 
resistance testing is required for all subjects who meet virologic failure criteria at the 
visits indicated in Appendix C.  Specific instructions for preparation and storage of the 
samples will be provided by the central laboratory, the Sponsor, or its designee.
Tanner Pubertal Stage
The Tanner Pubertal Stage will be calculated for all subjects ages ≥ 9 to 17 and 
documented at the visits indicated in Appendix C.  Boys will be rated on a 5-point scale 
(Tanner Stage 1 – 5) for genital development and pubic hair growth.  Girls will be rated 
on a 5-point scale (Tanner Stage 1 – 5) for breast development as well as pubic hair 
growth (Appendix E).  Once a child reaches Tanner Stage 5, the test will not be repeated.
Patient Reported Outcomes (PRO) Instrument (EQ-5D-3L with EQ VAS)
Subjects will complete the PRO instrument, EQ-5D-3L with EQ VAS, with the assistance 
of a parent/guardian (where allowed per local regulatory guidelines) on the study days 
specified in Appendix C.  The PRO should be administered as the first procedure at each 
visit.  Subjects will be instructed to follow the instructions provided with the instrument 
and to provide the best possible response to each item.  Site personnel shall not provide 
interpretation or assistance to subjects other than encouragement to complete the tasks.  
Subjects who are unable (too young) to read or understand the instrument may have their 
parent(s)/guardian(s) read the questionnaire to them.  Site personnel will encourage 
completion of each instrument at all applicable visits and will ensure that a response is 
entered for all items.
The EQ-5D-3L is a health state instrument that evaluates preference for health status 
(utility).  The 5 items in the EQ-5D-3L comprise 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression), each of which are rated on 3 levels of 
severity.  Subjects also rate their perception of their overall health on a separate visual 
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situation at the time of completion.  Completion of the EQ-5D-3L should require 
approximately 5 minutes.  Subjects who are older than 7-years of age (at Day 1) and are 
able to read and understand the questions should complete the questionnaire by 
themselves.  For subjects who are 7-years of age or younger (at Day 1) or who are not 
comfortable with reading the questions, their parent(s)/guardian(s) should read the 
questionnaires to them and record their response for each item.
Assignment of Subject Numbers
A subject number is assigned at screening via IRT system.  Subject numbers will be 
unique 5-digit numbers and will begin with 11001, with the first digit representing the 
part of initial enrollment (Part 1 or Part 2); the next 2 digits will represent the 
investigative site and the last 2 digits representing the subjects at that site.  Enrolled 
subjects will keep their subject number throughout the study.
Study Drug Dispensation
Study drugs will be dispensed at the visits as indicated in Appendix C.
Study Drug Dosing Card
Study drug dosing cards will be dispensed to subjects in Part 1 and Part 2 at the study 
visits indicated in Appendix C.  Parent(s)/legal guardian(s) and the subject will be 
instructed by the site to record the date and time (to the nearest minute) of the 2 study 
drug doses prior to each scheduled visit in the treatment periods including evening dose 
(other than Day 1).  The subject must bring the completed study drug dosing card with 
them to each visit.  Site personnel will record the information from the completed dosing 
card into the eCRF and file the completed dosing card in the subject's source documents.  
In the event that the dosing card is not available, the site may obtain dosing information 
via parent(s)/legal guardian(s) and/or subject interview and record this information into 
the eCRF and into the subject's source documents.


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Ribavirin Diary
At Day 1, the principal investigator or designee will provide the parent(s)/legal 
guardian(s) with a Ribavirin Diary in case the subject is taking the RBV solution 
formulation.  The principal investigator or designee will complete the header of the RBV 
diary and instruct the parent(s)/legal guardian(s) on the completion of the diary.  The 
parent(s)/legal guardian(s) must bring the completed RBV diary to each of the study 
visits.  The principal investigator or designee will transcribe the information from the 
RBV diary into the RAVE system.
Study Drug Compliance
At the Study Drug accountability visits noted in Appendix C, the returned study drug 
including RBV will be accounted for by the study site and recorded electronically.  
Additional information regarding treatment compliance can be found in Section 5.5.6.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis
IL28B Sample
One (required) 2 mL whole blood sample for deoxyribonucleic acid (DNA) isolation will 
be collected from each subject at screening for Interleukin 28B (IL28B) pharmacogenetic 
analysis and related markers.  If the sample is not collected at this visit, it may be 
collected at any time throughout the study.  This sample will not be used for any testing 
other than IL28B genotypes.
Specific instructions for sample collection and storage will be provided by the central 
laboratory, the Sponsor, or its designee. 
Optional Sample for Pharmacogenetic DNA Analysis
One 3 mL whole blood sample for DNA isolation will be collected on Day 1 (Treatment 
Periods Part 1 and Part 2) from each subject who signed the assent form (as per local 
requirements) and whose parent(s)/guardian(s) have signed the informed consent to 
provide the optional sample for pharmacogenetic analysis.  If the optional 


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pharmacogenetic sample is not collected at Day 1, it may be collected at any other visit 
during the study.  The Investigator/designee should follow their local recommendations 
on blood drawn for the PG sample collection during the Treatment Period.  The procedure 
for obtaining and documenting informed consent is discussed in Section 9.3.  The sample 
collection tubes will minimally be labeled with "PG-DNA," protocol number and subject 
number.  Samples will be shipped frozen to AbbVie or a designated laboratory for DNA 
extraction and long-term storage.  Specific instructions for preparation and storage of 
archive pharmacogenetic samples will be provided by the central laboratory, AbbVie, or 
its designee.  AbbVie will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on OBV, 
PTV, DSV, (or drugs for the treatment of HCV) continues but no longer than 20 years.
5.3.1.3
Meals and Dietary Requirement
Subjects should be reminded that, in order to maximize absorption, each dose of the study 
drugs should be taken with food.  Subjects whose visits occur prior to the morning dose of 
study drugs should be instructed to not have a full meal before the visits, so that study 
drugs can be taken with food during the visits.
All study drugs should be dosed together and administered with food, i.e., the morning 
dose of OBV, PTV, RTV, DSV (if applicable) and RBV( if applicable) should be taken 
together with food and the evening dose of DSV (if applicable) and RBV (if applicable) 
should be taken together with food.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of OBV, possible OBV metabolites, PTV, 
possible PTV metabolites, DSV, DSV M1 metabolite, other possible DSV metabolites, as 
well as RTV and RBV (if applicable) will be collected by venipuncture at each study visit 
indicated in Appendix C.


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Part 1
Subjects enrolled into Part 1 may undergo dose adjustments based on available 
pharmacokinetic and clinical data.  Study treatment visits will occur at Day 1, Week 2, 
Week 4, Week 8, and Week 12.  At Week 2 and Week 8, the morning dose of study drug 
will be administered in the clinic at approximately 24 hours after the prior morning dose.  
At Week 2, the evening doses of DSV and RBV (if applicable) will be administered in the 
clinic following the 12 hour PK draw and the Week 2 + 1 day morning doses of study 
drug will be administered in the clinic following the 24 hour PK draw.  PK samples will 
be collected at the following timepoints for each subject:
●
Day 1:  4 hours post-dose (the morning doses will be administered in the 
clinic)
●
Week 2:  2, 4, 8, 12 and 24 hours post-dose (the morning doses, the evening 
doses following the 12 hour PK draw and the morning doses following the 
24 hour PK draw will be administered in the clinic)
●
Week 4:  a PK sample (regardless of the dosing time)
●
Week 8:  a trough PK sample (i.e., prior to the morning dose, which will be 
administered in the clinic)
●
Week 12:  a PK sample (regardless of the dosing time)
The time that each blood sample is collected will be recorded to the nearest minute on the 
lab requisitions. 
Part 2
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, Week 12, Week 16, 
Week 20 and Week 24.  The latter 3 visits, Weeks 16, 20 and 24, are required for subjects 
with GT1a HCV infection and compensated cirrhosis receiving 24 weeks of treatment.  
One PK sample (regardless of the dosing time) will be collected at each treatment visit for 
each subject in Part 2.


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The time that each blood sample is collected will be recorded to the nearest minute on the 
lab requisitions. 
For Part 1, the maximum amount of blood drawn will be approximately 18.3 mL during a 
24-hour period (at Week 2) and approximately 55.8 mL during a 30-day period (from 
Day 1 to Week 4) as indicated in Appendix D.
For Part 2, the maximum amount of blood drawn after Day 1 (25.8 mL) will be 
approximately 11.7 mL during any 24-hour period and approximately 49.2 mL during a 
30-day period (from Day 1 to Week 4) as indicated in Appendix D.
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the plasma samples for the pharmacokinetic assays of OBV, possible OBV 
metabolites, PTV, possible PTV metabolites, DSV, DSV M1 metabolite, other possible 
DSV metabolites, RTV and RBV will be provided by the central laboratory, the Sponsor, 
or its designee.  
5.3.2.3
Disposition of Samples
The frozen plasma samples for the pharmacokinetic assays of OBV, possible OBV 
metabolites, PTV, possible PTV metabolites, DSV, DSV M1 metabolite, other possible 
DSV metabolites, RTV and RBV will be packed in dry ice sufficient to last during 
transport, and transferred from the study site to the central laboratory.
Specific instructions for shipping to the analytical lab from the central laboratory will be 
provided by the central laboratory, the Sponsor, or its designee. 


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The central laboratory will then ship the plasma samples to:
Sample Receiving
Dept. R43F, Bldg. AP13A, Room 2310
c/o:  Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL  60085
Phone:
(847) 937-0889
Fax:
(847) 938-9898
Email:
sample.receiving@abbvie.com
An inventory of the samples included will accompany the package and an electronic copy 
of the Manifests (including subject number, study day, the time of sample collection and 
barcode) will be sent to the contact person at sample.receiving@abbvie.com.
5.3.2.4
Measurement Methods
Plasma concentrations of OBV, PTV, DSV, DSV M1 metabolite, RTV and RBV will be 
determined using validated analytical methods under the supervision of the Drug Analysis 
Department at AbbVie.  Plasma concentrations of possible metabolites of OBV, PTV, and 
other metabolites of DSV may also be determined using validated or non-validated 
methods.  
5.3.3
Efficacy Variables
5.3.3.1
Primary Variables
The primary PK endpoints from Part 1 are:
●
Cmax and AUC following dosing on Week 2, and trough concentration 
following dosing on Week 2 and Week 8 for OBV, PTV, DSV, and RTV.
The primary efficacy endpoint is:
●
The percentage of subjects with SVR12 among all subjects.


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5.3.3.2
Secondary Variables
The secondary efficacy endpoints in Parts 1 and 2 are:
●
The percentage of subjects with SVR12 by formulation, age and weight group 
and across all subjects on the adult formulations.
●
The percentage of subjects with SVR24 by formulation, age and weight group, 
across all subjects, and across all subjects on the adult formulations.
●
The percentage of treatment-naïve subjects with ALT normalization during 
treatment, defined as ALT ≤ ULN at the final treatment visit for subjects with 
ALT > ULN at baseline by formulation, age and weight group, across all 
subjects, and across all subjects on the adult formulations.
5.3.4
Safety Variables
The following safety evaluations will be analyzed during the study:  adverse event 
monitoring and vital signs, physical examination, and laboratory test assessments.  
Growth and development outcomes of growth rate, height relative to age, waist 
circumference and Tanner stage will also be assessed.
5.3.5
Pharmacokinetic Variables
Individual plasma concentrations of OBV, PTV, DSV, DSV M1 metabolite, RTV and 
RBV (if applicable) will be measured for Part 1 and Part 2.  
Values for the pharmacokinetic parameters of OBV, PTV, RTV, DSV, DSV 
M1 metabolite, and RBV (if applicable) including the Cmax, Tmax, Ctrough, and area under 
the concentration curve (AUC) will be determined by noncompartmental methods using 
data from subjects in Part 1.  
Additional parameters may be determined if useful in the interpretation of the data.


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5.3.6
Pharmacogenetic Variables
IL28B status will be determined for each subject and analyzed as a factor contributing to 
the subject's response to study treatment.  These IL28B genotype results may be analyzed 
as part of a multi-study assessment of IL28B and response to study drug treatment.  The 
results may also be used for the development of diagnostic tests related to IL28B and 
study treatment, or drugs of these classes.
DNA samples from subjects, where the subject has provided assent (per local regulations) 
and subject's parent(s)/guardian(s) have signed the informed consent to additional 
pharmacogenetic analysis, may be sequenced and data analyzed for genetic factors 
contributing to the disease or to the subject's response to OBV, PTV, DSV in terms of 
pharmacokinetics, efficacy, tolerability, and safety.  Such genetic factors may include 
genes for drug metabolizing enzymes, drug transport proteins, genes within the target 
pathway, genes believed to be related to the disease or to drug response.  Some genes 
currently insufficiently characterized or unknown may be understood to be important at 
the time of analysis.  The samples may be analyzed as part of a multi-study assessment of 
genetic factors involved in the response to OBV, PTV, DSV, drugs of this class, or the 
disease state.  The samples may also be used for the development of diagnostic tests 
related to OBV, PTV, DSV, drugs of this class, or the disease state.  The results of 
pharmacogenetic analyses may not be reported with the study summary.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
If a subject prematurely discontinues during the Treatment Period, Post-Treatment Period 
or the Long-term Follow-up Period, the procedures outlined for the applicable Premature 


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D/C Visit should be completed as defined in Appendix C.  Ideally for study drug 
discontinuation, this should occur on the day of study drug discontinuation, but no later 
than 2 days after their final dose of study drug and prior to the initiation of any other 
anti-HCV therapy.  However, these procedures should not interfere with the initiation of 
any new treatments or therapeutic modalities that the investigator feels are necessary to 
treat the subject's condition.  Following discontinuation of study drug, the subject will be 
treated in accordance with the investigator's best clinical judgment.  The last dose of any 
study drug and reason for discontinuation from the Treatment Period will be recorded in 
the EDC system.
If a subject has an ongoing adverse event or an unresolved laboratory result that is 
significantly outside of the reference range at the time of study drug discontinuation, the 
investigator will attempt to provide follow-up until a satisfactory clinical resolution of the 
laboratory result or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of RBV (if 
applicable) to that subject must be discontinued immediately and DAAs may be continued 
at the principal investigator's discretion after discussion with the subject and 
parent(s)/guardian(s), if the benefit of continuing DAAs is felt to outweigh the potential 
risk.  Specific instructions regarding subject pregnancy can be found in Section 6.1.6.  
Subjects will be monitored for SVR in the Post-Treatment Period as described in 
Section 5.1.3.  The investigator is also encouraged to report the pregnancy information to 
the voluntary RBV Pregnancy Registry, if applicable.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  


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Advance notice is not required by either party if the study is stopped due to safety 
concerns. 
If AbbVie terminates the study for safety reasons, AbbVie will immediately notify the 
investigator by telephone and subsequently provide written instructions for study 
termination.
5.4.3
Discontinuation of Subjects Meeting Virologic Failure 
Criteria
The following criteria will be considered evidence of virologic failure during the study 
treatment period.  Pediatric subjects demonstrating any of the following should be 
discontinued from study drug:
●
Confirmed increase from nadir (defined as 2 consecutive HCV RNA 
measurements > 1 log10 IU/mL above nadir) in HCV RNA at any time point
●
Confirmed HCV RNA ≥ 100 IU/ml (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/ml) at any point after achieving HCV RNA < LLOQ
Confirmatory testing, where required, should be completed as soon as possible.  Also, 
when confirmation is required, the subject should remain on study treatment until the 
virologic failure has been confirmed.
If any of the above criteria are met during the study treatment period, the subject should 
discontinue study treatment but continue in the PT Period.  If the investigator believes the 
virologic failure is due to study drug interruption and/or is compliance related, the 
AbbVie Study TA SD/TA MD should be contacted to discuss alternative management.


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5.5
Treatments
5.5.1
Treatments Administered
Each dose of open-label DAA study drugs (ombitasvir, paritaprevir, ritonavir and 
dasabuvir) and ribavirin will be dispensed in the form of tablets, mini-tablets, or as an oral 
solution (RBV only).  Study drugs will be dispensed at the visits listed in Appendix C.
Adult Formulations:
Ombitasvir/paritaprevir/r will be provided by the Sponsor as 12.5 mg/75 mg/50 mg 
tablets.  Ombitasvir/paritaprevir/r will be taken orally as 2 tablets every morning which 
corresponds to an ombitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg dose QD.
Dasabuvir will be provided by the Sponsor as 250 mg tablets.  Dasabuvir will be taken 
orally as 1 tablet twice daily, which corresponds to a 250 mg dose BID.
RBV:  Parts 1 and 2
RBV will also be provided to the investigator by the Sponsor for use in this study.  RBV 
will be provided as 200 mg tablets for subjects that are willing to swallow those tablets.  
For subjects that are not willing to swallow the RBV tablets and not taking the adult 
formulations of the DAAs, RBV will be provided as a 40 mg/mL oral solution.  
Management of RBV in renally impaired patients (CrCl < 50 mL/min) will be left to the 
physician's discretion in consultation with the Therapeutic Area Medical Director.
Part 1 Mini-Tablet:
Ombitasvir, paritaprevir and ritonavir will be provided by the Sponsor as separate 0.3 mg, 
1.0 mg, and 1.0 mg mini-tablets.  Ombitasvir, paritaprevir and ritonavir will be taken 
orally and will be dosed QD based on body weight.
Dasabuvir will be provided by the Sponsor as 3.08 mg mini-tablet.  Dasabuvir will be 
taken orally and will be dosed BID based on body weight.


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The mini-tablets are packed in unit doses and are to be administered at once.  The legal 
guardian(s) should be counselled by site to check that the study drug bottles have been 
emptied completely into the dosing vehicle to assure the complete dose is taken by the 
subject.  Ombitasvir, Paritaprevir, Ritonavir will be taken orally and will be dosed QD 
based on body weight.  Dasabuvir will be taken orally and will be dosed BID based on 
body weight.
On the morning of Study Day 1, at the site, subjects will be administered study drugs by 
the study site personnel and receive instructions for self-administration of all study drugs 
from the Day 1 evening dose of dasabuvir or Study Day 2 through Study Week 12 of the 
Treatment Period.  The date and time of administration of the first dose of each drug will 
be recorded in the source and eCRF.
Following enrollment, the site will use the IRT system for drug dispensation. Study drugs 
must not be dispensed without contacting the IRT system, and only for subjects enrolled 
in the study through the IRT system.
All subjects who receive at least one dose of study drugs who fail to achieve virologic 
suppression, or who experience virologic breakthrough on DAA therapy will be 
discontinued from treatment and enter the Post-Treatment Period, unless alternative 
management is agreed to with AbbVie Study TA SD/TA MD.  The investigator can 
prescribe another regimen, as deemed appropriate, which will not be provided or 
reimbursed by AbbVie.
5.5.2
Identity of Investigational Products
Information regarding the study drugs to be used in this study is presented in Table 10.


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Table 10.
Identity of Investigational Products
Part
Investigational 
Product
Manufacturer
Mode of 
Administration
Formulation
Strength
1 & 2
Ombitasvir/paritaprevir/ 
ritonavir
AbbVie
Oral
Tablets
12.5/75/50 mg
1 & 2
Dasabuvir
AbbVie
Oral
Tablets
250 mg
1
Ombitasvir
AbbVie
Oral
Mini-tablets
0.3 mg
1
Paritaprevir
AbbVie
Oral
Mini-tablets
1.0 mg
1
Ritonavir
AbbVie
Oral
Mini-tablets
1.0 mg
1 
Dasabuvir
AbbVie
Oral
Mini-tablets
3.08 mg
1 & 2
Ribavirin
Kadmon/ AbbVie
Oral
Tablets
200 mg
1
Ribavirin
Merck
Oral
Solution
40 mg/mL
2
Ribavirin
MSD Sharp & Dohme
Oral
Solution
40 mg/mL
5.5.2.1
Packaging and Labeling
Part 1:  Ombitasvir/paritaprevir/ritonavir tablets, dasabuvir tablets, all mini-tablets, RBV 
tablets or oral solution will all be provided in bottles.  Each bottle will be labeled as 
required per country requirement.  Labels must remain affixed to the bottles.
Part 2:  Adult formulation ombitasvir/paritaprevir/ritonavir tablets and dasabuvir tablets 
will be provided in bottles.  Ribavirin tablets and oral solution will be provided in bottles.  
All products will be labeled as required per country requirement and labels must remain 
affixed.
All blank spaces (if applicable) on the study drug labels should be completed by site staff 
prior to dispensing to subjects.
5.5.2.2
Storage and Disposition of Study Drugs
All study drugs, with the exception of the ribavirin oral solution, must be stored at 
controlled room temperature (15° to 25°C/59° to 77°F) according to labeled storage 
conditions.  Ribavirin oral solution should be stored at refrigerated or controlled room 
temperature (2° to 30°C/36° to 86°F).


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Part 1:  Ombitasvir 0.3 mg, paritaprevir 1.0 mg, ritonavir 1.0 mg and dasabuvir 3.08 mg 
mini-tablets will be supplied to the site in bottles.
Mini-tablets can be administered in a dosing vehicle (e.g., applesauce, see dosing card for 
instructions).
RBV for both Part 1 and 2:  RBV tablets and solution will be administered according to 
the local RBV label and provided by the sponsor to the sites.  A dosing syringe for the 
RBV solution intake will be provided by the sponsor to the sites.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to the AbbVie.  Upon receipt of study drugs, 
the site will acknowledge receipt within the IRT system.
5.5.3
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the 
use of IRT.  For subjects who do not meet the study selection criteria (or who are unable 
to enroll before enrollment has closed), the site personnel must contact the IRT system 
and identify the subject as a screen failure.
First, the subjects in the ≥ 12 to 17 year age group of Part 1 who are ≥ 45 kg and willing 
to swallow the adult formulations will be enrolled, then sequential enrollment into the 
other age groups of Part 1 will start (Section 5.1).  Enrollment in Part 2 will begin once 
dosing recommendations of OBV, PTV, RTV and DSV are available for the ≥ 12 to 
17 year-old age group based on the pharmacokinetic and clinical data from Part 1 of the 
study (Section 5.1).  Subjects who are enrolled will retain their subject number assigned at 
the Screening Visit throughout the study.  For enrollment of eligible subjects into the 
study, the site will utilize the IRT system in order to receive unique study drug kit 
numbers according to the regimen assigned (Table 5 and Table 6).  In Part 1, the study 
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computer-generated before the start of the study by the AbbVie Data and Statistical 
Sciences Department.
In Part 1 of the study, caps on the number of subjects in each group in IRT will be 
employed to ensure that approximately 12 subjects in each age group are enrolled.
In Part 2 of the study, caps on GT1 and GT4 subjects will be employed in IRT to ensure 
that approximately 10 genotype 4-infected subjects regardless of prior treatment 
experience and cirrhotic status are enrolled.
Contact information and user guidelines for IRT use will be provided to each site.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.5.  The daily dose assigned 
to each subject in Part 1 will be assigned by IRT according to the formulation used and 
the weight of the subject.  In Part 2, the study drugs will be provided in unit doses and the 
number of unit doses to be administered per day will be assigned by IRT according to the 
formulation used (to be determined from Part 1) and the weight of the subject.
Study drug dosing will be initiated at the Study Day 1 Visit.  OBV, PTV, RTV will be 
dosed QD and DSV (if applicable) will be dosed BID.  Thus with normal dosing, 1 dose 
of OBV, PTV, RTV and DSV (if applicable) should be taken in the morning, and 1 dose 
of DSV should be taken in the evening.  RBV (if applicable) will be dosed according to 
the local label.  RBV dose modifications will be assessed by the Investigator following 
the RBV Dose Modification Guideline (Table 12), taking into account the subject's 
clinical and safety parameters in conjunction with the Therapeutic Area Medical Director.
All study drugs should be dosed together and administered with food at approximately the 
same time in the morning every day, i.e., the AM dose of OBV, PTV, RTV, DSV (if 
applicable) and RBV (if applicable) should be taken together with food and the PM dose 
of DSV (if applicable) and RBV (if applicable) should be taken together and with food.


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5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
All study drugs will be dispensed to subjects by study-site personnel under the direction 
of the investigator.  At the start of the study, each subject along with their 
parent(s)/guardian(s) should receive counseling regarding the importance of dosing 
adherence with the treatment regimen with regard to virologic response and potential 
development of resistance.  The start and stop dates of all study drugs will be recorded in 
the source documents and eCRFs.  When dosing mini-tablets, the bottles should be 
checked thoroughly to ensure that no mini-tablets remained inside the bottle.
During the Treatment Period, subjects will be instructed to bring all study drug units (full, 
partial or empty) to the study site at each study visit.  The study site personnel will inspect 
the contents of the study drug bottles and account for the returned study drug 
electronically at each Study Drug Accountability visit indicated in Appendix C.  If poor 
adherence is noted, the subject and parent(s)/guardian(s) should be counseled and this 
should be documented in the subject's source document.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt (POR) or similar document and via recording in the IRT system.  A 
current (running) and accurate inventory of study drug will be kept per subject by the 
investigator.  An overall accountability of the study drug will be performed and verified 
by the AbbVie monitor throughout the Treatment Period.  The monitor will review study 


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drug accountability on an ongoing basis.  Final accountability will be verified by the 
monitor at the end of study drug treatment at the site.
During the study, should an enrolled subject misplace or damage a study drug unit, the 
IRT system must be contacted and informed of the misplaced or damaged study drug.  If 
the study drug unit is damaged, the subject will be requested to return the remaining study 
drug to the site.  Replacement study drug may only be dispensed to the subject by 
contacting the IRT system.  Study drug replacement(s) and an explanation of the reason 
for the misplaced or damaged study drug(s) will be documented within the subject's 
source.  Date of the first dose and the last dose of the regimen will be documented in the 
subject's source documents and recorded on the appropriate eCRF.
The return status of each study drug unit and the date of reconciliation will be documented 
at Study Drug Accountability Visits in Appendix C.
Detailed instructions regarding study drug accountability are provided below. 
Adult Formulations and RBV Tablets Part 1 and Part 2
The number of tablets of each type of study drug returned in each bottle will be noted in 
the IRT system and on a drug accountability log (if appropriate).  Labels must remain 
affixed to the bottles.
Mini-Tablet Formulation (Part 1)
The status of each returned mini-tablet bottle will be noted in the IRT system and on a 
drug accountability log (if appropriate).  The Investigator/designee must document the 
status of the returned bottles as full/sealed or empty or unsealed but not empty in the IRT 
system.  Labels must remain affixed to the bottles.
RBV Solution Part 1
The status of each returned RBV solution bottle will be noted in the IRT system and on a 
drug accountability log (if appropriate).  The Investigator/designee must document the 


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status of the returned RBV solution bottle as full/sealed or empty or unsealed but not 
empty in the IRT system.  Labels must remain affixed to the bottles.  Supporting drug 
accountability data will be transcribed by the Investigator/designee from the RBV solution 
diary into the EDC system.  
Upon completion of or discontinuation from the Treatment Period, all original study drug 
units (containing unused study drugs) will be returned to the Sponsor (or designee) or 
destroyed on site.  All destruction procedures will be according to instructions from the 
Sponsor and according to local regulations following completion of drug accountability 
procedures.  All empty original study drug units shall be disposed of onsite following 
completion of study drug accountability and reconciliation procedures.  Labels must 
remain attached to the study drug units.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The combination regimen of OBV, PTV, RTV, with DSV (GT1) or without DSV (GT4) 
and with RBV (GT1a and GT4) or without RBV (GT1b) for 12 or 24 weeks (GT1a 
cirrhotic subjects only) is currently approved in adults in several countries including the 
US and in the EU.  The dose, durations, and regimens have been optimized for a given 
HCV genotype/sub-genotype and cirrhosis/non-cirrhosis status in adults.  These same 
durations and regimens are anticipated to be similarly successful in children as long as the 
drug exposures are comparable, so further regimen/duration exploration is not warranted.  
In addition, no interferon-free regimens are approved for use in children; the approved 
standard of care (pegIFN/RBV) has notably lower efficacy rates and a worse safety profile 
than the interferon-free DAA regimens and requires a longer treatment duration, making a 
comparative study unethical and difficult to enroll.  A non-randomized parallel study 
design with regimens/duration and drug exposure comparable to the recommended adult 
regimens is the best method for evaluation.  


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5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  HCV RNA assays are standard and validated.  The EQ-5D-3L instrument is 
standard in the literature and thoroughly validated in studies of the pediatric population 
and in pediatric subjects who have chronic health conditions.
5.6.3
Justification of Primary and Secondary Endpoint Success 
Criteria
According to the Highlights of Prescribing Information of PEGASYS®, the SVR24 rate 
was 47% among 45 treatment-naïve pediatric subjects with HCV GT1 in the NV17424 
trial.1  To show that the DAA regimen is superior to this current standard of care by 20%, 
the lower bound of the 2-sided 95% confidence interval of the SVR12 rate across all 
subjects in the study must be greater than 67%.
For the secondary endpoints of the percentage of subjects with SVR12 by formulation, age 
and weight group, the percentage of subjects with SVR24, and the percentage of subjects 
with ALT normalization during treatment, the simple percentage will be calculated along 
with a 2-sided 95% confidence interval.  The lower bound of the 2-sided 95% confidence 
interval of the SVR24 rate across all subjects in the study will also be compared to 67%.  
ALT normalization is defined as the percentage of subjects with ALT at or below the 
upper limit of normal (ULN) at the final treatment visit among subjects with ALT > ULN 
at baseline, and will be presented along with a 2-sided 95% confidence interval.
5.6.4
Suitability of Subject Population
This study plans to enroll both HCV treatment-naïve and IFN (IFN and pegIFN with or 
without RBV) treatment-experienced subjects from ≥ 3 to 17 years old with genotype 1 or 
4 HCV infection as agreed upon in the PIP and PSP.  The older subjects who are willing 
to swallow the adult formulations and are ≥ 45 kg will be studied with the adult 
coformulated tablets.  For the younger children in the ≥ 3 to 8 and ≥ 9 to 11 year old age 
groups, a mini-tablet formulation of all the DAAs and RTV will be used for ease of 


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administration.  In addition, RBV oral solution will be available in the study for children 
who cannot take the RBV tablets.  
5.6.5
Selection of Doses in the Study
In the Pediatric Investigation Plans (PIP) and the Pediatric Study Plan (PSP) for 
ombitasvir/paritaprevir/ritonavir and dasabuvir, the proposed pediatric doses were based 
on providing comparable exposures to adult subjects.
AbbVie has recently developed separate mini-tablet formulations for ombitasvir, 
paritaprevir, ritonavir and dasabuvir for use in Part 1 of the present study.
The mg/kg doses as proposed in the PIP and PSP were used to calculate mg doses for a 
given weight range for each of the age groups.  While this approach involved some 
approximation of doses, it provides a simplified approach and is expected to help reduce 
potential dispensing and dosing errors while meeting the objectives of the weight based 
dosing.  This approach is further supported by the wide margin of safety/efficacy for each 
DAA.
In the global Phase 3 program, 30 adult HCV GT1-infected subjects had body weight 
ranging from 42 to 49 kg.  The exposures of ombitasvir, paritaprevir, ritonavir and 
dasabuvir in these subjects were within the ranges of exposures in subjects who had body 
weight of at least 50 kg.  The established safety and efficacy of the 3D regimen in adults 
would support the use of the same adult dose of ombitasvir/paritaprevir/ritonavir 
25/150/100 mg QD and dasabuvir 250 mg BID in children who weigh at least 42 kg.  For 
the present study, children who weigh at least 45 kg will be dosed with adult dose if they 
are willing to swallow the adult formulations.
For Part 1 of the present study, the proposed doses by body weight range for subjects 
administered the adult formulation or the mini tablet formulation are shown in Table 11.


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Table 11.
Proposed DAA and Ritonavir Doses for Subjects Administered the 
Adult Formulation or Mini Tablet Formulation
Body Weight
15 to 29 kg
30 to 44 kg
≥ 45 kg
Paritaprevir (QD) 
50 mg
100 mg
150 mg
Ritonavir (QD)
35 mg
70 mg
100 mg
Ombitasvir (QD)
10 mg
15 mg
25 mg
Dasabuvir (BID)
100 mg
150 mg
250 mg
For Part 1, enrollment will start with pediatric subjects ≥ 12 to 17 years old who are 
≥45 kg and willing to swallow the adult formulations.  The pharmacokinetic and clinical 
data will be used to confirm appropriate exposure in this age group.  Dose adjustments 
will be made if necessary to ensure safe and efficacious exposures that are comparable to 
the adult population.
Enrollment in Part 2 will only begin after the recommendations of adult 3D formulation 
are determined ≥ 12 to 17 years based on the pharmacokinetic, safety and efficacy data 
from Part 1 of the study. 
Details on the dose adjustment considerations for Part 1, the enrollment sequence in 
Part 1, and the considerations for enrollment in Part 2 are provided in Section 5.1.
5.6.6
Maximum Dose
For Part 1, the maximum dose of OBV, PTV and RTV will not exceed 25 mg, 150 mg, 
and 100 mg per day for 12 weeks.  The maximum dose of DSV will not exceed 500 mg 
per day for 12 weeks.  For subject receiving RBV, the maximum RBV dose will not 
exceed 1200 mg, divided twice daily for 12 weeks.
For Part 2, the maximum dose of OBV, PTV and RTV will not exceed 25 mg, 150 mg, 
and 100 mg per day for 12 or 24 weeks depending on HCV genotype, sub-genotype and 
cirrhosis status.  For HCV GT1-infected subjects, the maximum dose of DSV will not 


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exceed 500 mg per day for 12 or 24 weeks.  For subject receiving RBV, the maximum 
RBV dose will not exceed 1200 mg, divided twice daily for 12 or 24 weeks.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
For adverse events, please refer to Sections 6.1 through 6.1.7.6.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 


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be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (meets protocol specific criteria [see Section 6.1.7 regarding toxicity 
management]) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition or 
the surgery/procedure has been pre-planned prior to study entry.  However, if the
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.


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Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4).


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The table of clinical toxicity grades "National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4" is available from the Cancer Therapy Evaluation 
Program (CTEP) website at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf and is to be used in the grading of adverse events.  Below 
are the general grading categories.  However, the investigator should always search NCI 
CTC AE for a given diagnostic/symptomatic AE term to identify and apply specific 
grading details for that AE entity.
Grading System for Adverse Events (a semi-colon indicates 'or' within the description of 
the grade).
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
ADL = Activities of Daily Living
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of (OBV/PTV/RTV with or without DSV) and to the use of RBV (if 
applicable):
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.


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No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All serious adverse events as well as protocol-related nonserious adverse events 
(e.g., infection at venipuncture site) will be collected from the time the 
parent(s)/guardian(s) and subject signs the study-specific informed consent and assent (as 
appropriate for age and country) respectively until study drug administration.  From the 
time of study drug administration until 30 days following discontinuation of study drug 
treatment has elapsed, all adverse events and serious adverse events will be collected, 
whether solicited or spontaneously reported by the subject.  From 30 days following 
discontinuation of study drug administration until the end of study, only serious adverse 
events deemed related to study drug by the investigator will need to be collected.
Adverse event information will be collected as shown in Figure 2.


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Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a SAE, whether associated with study drug or not, the Investigator will 
notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the 
SAE by entering the SAE data into the electronic data capture (EDC) system.  For SAEs 
that occur prior to the site having access to the RAVE® system or if RAVE is not 
operable, the forms should be faxed or emailed to Clinical Pharmacovigilance within 
24 hours of the site being made aware of the SAE.
FAX to:  +1 (847) 938-0660
Email:   PPDINDPharmacovigilance@AbbVie.com
For safety concerns, contact the Antiviral Safety Team at:
Antiviral Safety Management
Dept. R48S, Bldg. AP30-3
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL  60064
Office:
(847) 938-1870
Email:
SafetyManagement_Virology@abbvie.com




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Pregnancy in a study subject must be reported to the AbbVie within 1 working day of the 
site becoming aware of the pregnancy.  Subjects who report a positive pregnancy test 
during the Treatment Period must be notified to stop RBV (if applicable) immediately.  
Administration of DAAs may be continued at the investigator's discretion after discussion 
with the subject, if the benefit of continuing therapy is felt to outweigh the potential risk 
(as allowed per local guidance) (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment with DAAs only, or through Post-Treatment Week 28 (or per local RBV label) 
after the last dose of RBV for treatment with DAAs plus RBV.  The investigator is 
encouraged to report the pregnancy information to the voluntary RBV Pregnancy 
Registry, if RBV is included within the regimen.
Subjects who discontinue study medications due to pregnancy will be monitored for SVR 
in the Post-Treatment Period as described in Section 5.4.1.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to the Sponsor within 24 hours of 
the site becoming aware of the event.
6.1.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.  All adverse events and 
laboratory abnormalities will be managed and followed to a satisfactory clinical 
resolution.  The table of clinical toxicity grades "National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4" is to be used in the grading of 
adverse events and laboratory abnormalities which is available on the Cancer Therapy 
Evaluation Program (CTEP) website at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.


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A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the investigator or the Sponsor as having a "reasonable possibility" 
of being related to the study drug (Section 6.1.3).  A toxicity is deemed "clinically 
significant" based on the medical judgment of the investigator.  Laboratory abnormalities 
will be managed as deemed clinically appropriate by the investigator until satisfactory 
resolution.
Investigators should avoid interrupting study drugs for more than 7 consecutive days.  The 
Investigator should ensure that any study drug interruptions or RBV (if applicable) dose 
modifications and associated adverse events are promptly entered into the appropriate 
eCRFs.
The toxicity management guidelines below should be followed throughout the Treatment 
Period of the study.
6.1.7.1
Grade 1 or 2 Laboratory Abnormalities and Mild or Moderate 
Adverse Events
Subjects who develop a mild or moderate adverse event or Grade 1 or 2 laboratory 
abnormality, other than those discussed separately in Section 6.1.7.4 (Management of 
Decreases in Hemoglobin) for subjects receiving RBV, Section 6.1.7.5 (Management of 
ALT Elevations), and Section 6.1.7.6 (Creatinine Clearance) may continue study drugs 
with follow-up per study protocol and in accordance with local standard of care.
6.1.7.2
Grade 3 or 4 Laboratory Abnormalities
With the exception of Grade 3 or higher abnormalities of total bilirubin, uric acid, 
phosphorus, total cholesterol, triglycerides, or glucose (in subjects with a history of 
diabetes), if a subject experiences a Grade 3 or greater abnormal laboratory parameter 
during the Treatment Period, the abnormal laboratory test should be repeated.  If the 
Grade 3 or greater abnormality is confirmed, the investigator should assess whether the 
abnormality can be managed medically without interruption of study drug, or whether 
study drugs should be interrupted and the laboratory parameter followed until it improves.  


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If study drugs are interrupted and restarted and the abnormality recurs, then study drugs 
should be permanently discontinued.
Decreases in serum hemoglobin or in calculated creatinine clearance or elevations of 
serum ALT should be managed according to the guidance in Section 6.1.7.4, 
Section 6.1.7.5, and Section 6.1.7.6 below.  Grade 3 or greater abnormalities of total 
bilirubin, uric acid, phosphorus, total cholesterol, triglycerides or glucose (in subjects with 
a history of diabetes) should be managed medically as appropriate and do not require 
confirmation or study drug interruption unless deemed necessary by the investigator.
6.1.7.3
Severe Adverse Events or Serious Adverse Events
If a subject experiences a severe adverse event (Grade 3+) or a serious adverse event that 
the investigator considers to have a reasonable possibility of relationship to study drug, 
the investigator should assess whether the adverse event can be managed medically 
without interruption of study drug, or whether study drugs should be interrupted until the 
event improves.  If study drugs are interrupted and restarted and the adverse event recurs, 
then study drugs should be permanently discontinued.
If a subject experiences a severe adverse event (Grade 3+) or serious adverse event that is 
considered unrelated (no reasonable possibility) to the study drugs, it is not necessary to 
interrupt study drugs unless an interruption is required because of the nature of the event 
(e.g., unable to take oral medications).
The investigator should ensure that all serious adverse events are reported to AbbVie 
within 24 hours of awareness.  Serious adverse event follow-up information, including 
associated dose interruptions (or discontinuations), must be reported to AbbVie within 
24 hours of awareness by entering updated SAE information into the appropriate eCRFs.
Severe adverse events and any associated dose interruptions (or discontinuations) should 
be entered into the appropriate eCRFs.


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6.1.7.4
Management of Decreases in Hemoglobin
For subjects not receiving ribavirin:
Hemoglobin decreases should be managed according to grade based on the guidance in 
Section 6.1.7.1 and Section 6.1.7.2 above.
For subjects receiving ribavirin:  
Decreases in hemoglobin are a well characterized side effect of ribavirin exposure.  If a 
subject receiving the standard dose of RBV experiences a hemoglobin decrease meeting 
one of the criteria outlined in Table 12, a confirmatory test should be performed.  If the 
hemoglobin decrease is confirmed, the management guidelines in Table 12 should be 
followed.  Management will be different for subjects without a history of known cardiac 
disease and subjects with known cardiac disease.  Subjects experiencing decreases in 
hemoglobin that do not meet the criteria outlined in Table 12 may need hemoglobin 
evaluations at more frequent intervals at the discretion of the investigator.  
In subjects with creatinine clearance less than 50 mL/min, RBV should be interrupted if 
subject experiences a confirmed decrease in hemoglobin to less than 10 g/dL.  In these 
subjects, decreases in hemoglobin should be managed at the discretion of the investigator 
and as medically appropriate.  
Use of hematologic growth factors (such as erythropoietin or filgrastim) or blood 
transfusions are permitted at the discretion of the investigator.  Management of 
hematologic growth factor therapy is the responsibility of the Investigator, and growth 
factors will not be provided by AbbVie.
Alternate management of hemoglobin decreases outside of these criteria is permitted with 
approval of the AbbVie Therapeutic Area Medical Director.


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Table 12.
Ribavirin Dose Modification Guidelines in Management of 
Hemoglobin Decreases
Subjects with Creatinine Clearance ≥ 50 mL/min
Reduce RBV Daily Dosea if:
Interrupt RBVb if:
Hemoglobin in Patients 
with No Cardiac Disease
< 10 g/dL
< 8.5 g/dL
Hemoglobin in Patients 
with History of Stable 
Cardiac Disease
≥ 2 g/dL decrease in hemoglobin during any 
4 week treatment period (permanent dose 
reduction)
< 12 g/dL despite 4 weeks at 
reduced RBV dose
a.
Reduce RBV daily dose in accordance with local RBV prescribing information/product label or per the discretion 
of the investigator. 
b.
If the abnormality is reversed, RBV may be restarted at the discretion of the investigator and in accordance with 
local RBV prescribing information/product label.
6.1.7.5
Management of ALT Elevations
Transient asymptomatic grades 3 – 4 ALT elevations have been observed in 
approximately 1% of subjects receiving paritaprevir/r-containing regimens.  If a subject 
experiences a post-baseline increase in ALT to > 5 × ULN that is increased from the 
previous measurement, the subject should have a confirmatory ALT measurement 
performed.
If the ALT increase is confirmed to be > 5 × ULN and increased from the previous 
measurement, the recommendations below should be followed:
●
Evaluate for alternative etiology of ALT elevation:  update medical history and 
concomitant medications eCRF (if applicable), and obtain additional testing as 
appropriate.
●
Manage the subject as medically appropriate.
●
Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and
●
INR within 1 week.  Repeat liver chemistries as indicated until resolution.
●
Consider discontinuing study drugs if ALT level is persistently > 10 × ULN.
●
Discontinue study drugs if the following is observed at any time:


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○
Increasing direct bilirubin, increasing INR, or onset of symptoms/signs of 
hepatitis.
Alternate management of ALT increases is permitted with approval of the AbbVie 
Therapeutic Area Medical Director.
6.1.7.6
Creatinine Clearance
If calculated creatinine clearance (by Schwartz formula for children aged 3 to < 12 years 
and Crockcroft-Gault formula for children ≥ 12 years)  is confirmed to have decreased to 
< 50 mL/minute, medical evaluation should include a full review of current medications, 
including those taken on an as needed basis, those which are sold over the counter and any 
dietary and herbal supplements, and appropriate dose reduction or discontinuation based 
on impaired renal function should be done (if applicable).  Ribavirin dose should be 
adjusted according to local RBV prescribing information/product label or per the 
discretion of the investigator.  Alternative management of RBV dose in the setting of 
reduced renal function will require approval of the AbbVie Therapeutic Area Medical 
Director.
Schwartz formula (children 3 to < 12 years old):
GFR Estimate = [Height (cm) × 0.55] /
[Serum creatinine (μmol/L) × 0.01131]
Crockcroft-Gault formula (Children ≥ 12 years old):
CrCl = [(140 – Age) × Mass (in kg) × (0.85 if female)] / 
[72 × Serum creatinine (in mg/dL)]
The investigator should also consider whether drug-drug interactions with concomitant 
medications may have contributed to the decrease in creatinine clearance, and whether 
discontinuation or substitution of the possible interacting drug might be needed.  For 
example, drug interactions between DAAs and some antihypertensive medications could 


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potentially increase exposures of the antihypertensive, which may lead to reduction in 
renal function.  If anti-hypertensive medications are adjusted, vital signs should be 
monitored to ensure appropriate blood pressure control.  Refer to Section 5.2.3 for 
additional information regarding drug-drug interactions.
If creatinine clearance improves, the site should perform all necessary readjustment of any 
dose modifications that have been made.  If creatinine clearance improves to above the 
level that triggered the RBV dose reduction, RBV dose may be increased accordingly.
The Investigator should ensure that any concomitant medication changes, RBV dose 
reductions, and study drug discontinuations, as well as consequent related adverse events 
are entered into the appropriate eCRFs.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), and the following AbbVie Clinical 
Personnel:




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SAS® (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all 
analyses.  All statistical tests and all confidence intervals will be two-sided with an α level 
of 0.05. 
The intention-to-treat populations, ITT will consist of all subjects who receive at least one 
dose of study drug in Part 1 or Part 2 of the study.  The intention-to-treat population for 
Part 3, ITT-3, will consist of all subjects who enter Part 3.
Efficacy endpoints and growth and development outcomes will be summarized across 
Parts 1 and 2 for the ITT population.  Growth outcomes including standardized height, 
waist circumference, Tanner pubertal stage, and growth rate as defined in protocol 
Section 5.3.1.1 will be summarized through Post-Treatment Week 24 in Parts 1 and 2 and 
through the end of Long-term Follow-up in Part 3, for ITT-3.  
No data will be imputed for any efficacy or safety analyses except for analyses of the 
SVR endpoints.  For EQ-5D-3L health state index, no imputation will be performed for 
missing items.
HCV RNA values will be selected for the SVR12 and SVR24 analyses based on defined 
visit windows.  When there is no HCV RNA value in a visit window based on defined 
visit windows, the closest values before and after the window, regardless of the value 
chosen for the subsequent and preceding window, will be used for the flanking imputation 
described below.
If a subject has a missing HCV RNA value at a post-baseline visit but with undetectable 
or unquantifiable HCV RNA levels at both the preceding value and succeeding value, the 
HCV RNA level will be considered undetectable or unquantifiable, respectively, at this 
visit for this subject.  For SVR12 and SVR24 analysis, if there is no value in the appropriate 
window but there is an HCV RNA value after the window, then it will be imputed into the 
SVR12 or SVR24 window, respectively.  Subsequent to this flanking imputation, if a 
subject is missing a value for the visit window associated with the analysis, the subject 
will be imputed as a visit failure (i.e., not undetectable or unquantifiable).


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The 95% confidence interval for any simple percentage (e.g., SVR12, SVR24, and 
percentage of subjects with ALT normalization) will be calculated using normal 
approximation to the binomial distribution if the percentage is not 0% or 100%; 
otherwise, Wilson's score method will be used.
Detailed statistical methods for all endpoints will be provided in the Statistical Analysis 
Plan (SAP).
8.1.1
Demographics
Demographics and baseline characteristics will be summarized by age and weight group 
separately for each formulation, for all subjects and for all subjects on the adult 
formulations in the ITT and ITT-3 populations.  The baseline value refers to the last non-
missing measurement collected before the first dose of study drug is received in Part 1 and 
on or before Day 1 in Part 2.  Demographics include age, birth year, weight, height, body 
mass index (BMI), height z score (height z score will be calculated using WHO published 
height-for-age z-score tables), waist circumference, gender, race, ethnicity, geographic 
region and country.  Baseline characteristics will include HCV genotype and sub-
genotype (1a, 1b, 1-other and 4 if applicable), IL28B genotype ([CC, CT, or TT] and [CC 
or non-CC]), IFN treatment history if applicable (treatment-naïve or IFN-based treatment-
experienced [prior non-responder {null responder, partial responder, or other unable to 
specify}, breakthrough, relapse, and interferon experienced-other]), baseline platelets 
(< 90 or ≥90 × 109/L), baseline albumin (< 35 or ≥ 35 g/L), baseline HCV RNA levels 
(continuous) and (< 800,000 IU/mL or ≥800,000 IU/mL, baseline fibrosis stage [F0-1, 
F2, F3, F4]), baseline Fibrotest score, baseline Child-Pugh score (non-cirrhotic, 5, 6, or 
> 6), tobacco use (user, ex-user, or non-user) status, alcohol use (drinker, ex-drinker, or 
non-drinker) status, and baseline Tanner pubertal staging – genital (males only), breast 
(females only), and pubic hair development.  Summary statistics (N, mean, median, SD, 
and range) will be generated for continuous variables (e.g., age and height z-score).  The 
number and percentage of subjects will be presented for categorical variables (e.g., gender 
and race).


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8.1.2
Efficacy
Efficacy analyses will be performed across Part 1 and Part 2 using the ITT population.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0.  For this 
assay, the lower limit of quantification (LLOQ) and the lower limit of detection are 
15 IU/mL.  HCV RNA results that are detectable but not quantifiable are reported as 
"HCV RNA is detected, less than 15 IU/mL HCV RNA."  HCV RNA results for which no 
HCV RNA is detected are reported as "HCV RNA not detected."
8.1.2.1
Primary Efficacy Endpoint Across Parts 1 and 2
The primary efficacy endpoint is the percentage of subjects with SVR12 among all 
subjects.  The 95% confidence interval for the SVR rate will be calculated.
To evaluate the hypothesis that the percentage of HCV pediatric subjects treated with 
ombitasvir/paritaprevir/r, with or without dasabuvir with or without RBV who achieve 
SVR12 is superior to the historical SVR rate for the pediatric population treated with 
pegIFN and RBV, the lower bound of the 2-sided 95% CI of the percentage of subjects 
with SVR12 must be greater than 67% (Section 5.6.3).
8.1.2.2
Secondary Efficacy Endpoints Across Parts 1 and 2
1.
The percentage of subjects who achieve SVR12 by formulation, age and weight 
group, and across all subjects on the adult formulations.
2.
The percentage of subjects who achieve SVR24 by formulation, age and weight 
group, across all subjects, and across all subjects on the adult formulations.
3.
The percentage of subjects with ALT normalization during treatment, defined as 
ALT ≤ ULN at the final treatment visit for subjects with ALT > ULN at baseline, 
by formulation, age, and weight group, across all subjects, and across all subjects 
on the adult formulations.


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The percentage of subjects with SVR12 or SVR24 and the percentage of subjects with ALT 
normalization during treatment, the simple percentage will be calculated along with the 
2-sided 95% confidence intervals.  The lower bound of the 2-sided 95% confidence 
interval of the SVR24 rate across all subjects in the study will also be compared to 67%.  
ALT normalization is defined as the percentage of subjects with ALT at or below the 
ULN at the final treatment visit among all treatment naïve subjects with ALT > ULN at 
baseline, and will be presented along with 95% confidence intervals.
8.1.2.3
Additional Efficacy Endpoints Across Parts 1 and 2
The following efficacy endpoints will be analyzed by formulation, age and weight group, 
across all subjects, and across all subjects on the adult formulations:
1.
The percentage of subjects with virologic failure during treatment; 
2.
The percentage of subjects with Post-Treatment relapse (including Relapse12 as 
defined at the end of this section);
3.
Change from baseline to all post-baseline visits in Fibrotest score.
If the dose of the mini-tablets is adjusted for any age or weight group during the study, 
any subjects administered the dose considered not acceptable will be removed in a 
sensitivity analysis of SVR12 among subjects administered acceptable doses of OBV, 
PTV, RTV and DSV.
All rates of SVR, ALT normalization, virologic failure on treatment and relapse will be 
presented with 2-sided 95% confidence intervals.
On-treatment virologic failure is breakthrough or failure to suppress during treatment.  
Breakthrough is defined as confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ 
during treatment, or confirmed increase from nadir in HCV RNA (two consecutive HCV 
RNA measurement > 1 log10 IU/mL above nadir) at any time point during treatment.  
Failure to suppress during treatment is defined as all on-treatment values of HCV RNA 


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≥LLOQ with at least 6 weeks (defined as active study drug duration ≥ 36 days) of 
treatment.
Relapse12 defined as confirmed HCV RNA ≥ LLOQ between end of treatment and 
12 weeks after last actual dose of active study drug (up to and including the SVR12
assessment time point) for a subject with HCV RNA < LLOQ at Final Treatment Visit 
who completes treatment.  Completion of treatment is defined as a study drug duration 
≥77 days for a subject assigned to 12 weeks of treatment and ≥ 154 days for a subject 
assigned to 24 weeks of treatment).
The change from baseline to each post baseline visit of collection for Fibrotest will be 
summarized descriptively.
8.1.2.4
Subgroup Analysis of Parts 1 and 2
The percentage of subjects with SVR12 will be presented along with the 2-sided 95% 
confidence interval for the following subgroups if applicable.
●
Age (≥ 3 – 8, ≥ 9 – 11, and ≥ 12 – 17 years);
●
HCV genotype and sub-genotype (1a, 1b, other 1, and 4);
●
Presence of compensated cirrhosis (yes/no);
●
Treatment IFN (IFN or pegIFN with or without RBV) experience if applicable 
(treatment naïve, prior non-responder, prior breakthrough, prior relapse, and 
interferon experienced-other);
●
IL28B genotype (CC or non-CC), (CC, CT, or TT);
●
Sex (male or female);
●
Baseline Child-Pugh Score (non-cirrhotic, 5 or ≥ 6);
●
Baseline fibrosis stage (F0-F1, F2, F3 or F4); 
●
Baseline HCV RNA level (< 800,000 IU/mL or ≥ 800,000 IU/mL);
●
Race (Black versus non-black);
●
Ethnicity (Hispanic/Latino versus none);
●
Height z-score (< –1, –1 to 1 or > 1);


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●
Drug compliance (< 80% versus ≥ 80%).
For cirrhotic subjects, the following subgroups will be presented:
●
Baseline platelets (< 90, ≥ 90 × 109/L)
●
Baseline albumin (< 35, ≥ 35 g/L)
●
Any of platelets < 90 × 109/L and albumin < 35 g/L
The two-sided 95% confidence intervals will be produced if there are at least 10 subjects 
in the subgroups.
8.1.2.5
Treatment Failures
Across Parts 1 and 2, the number and percentage of subjects overall, on the adult 
formulations, and on the mini-tablet formulation meeting each and any of the following 
SVR24 and SVR12 non-response categories will summarized.  The summary might also be 
subgrouped by age and weight group, and HCV genotypes/sub-genotypes.
1.
On-treatment virologic failure (breakthrough or fail to suppress)
2.
Relapse (with further breakdown by relapse vs reinfection based on HCV RNA 
population sequence)
3.
Premature study drug discontinuation with no on-treatment virologic failure
4.
Missing SVR data (SVR24 or SVR12)
5.
Other
8.1.3
Growth and Development
The following growth and development endpoints will be calculated through 
Post-Treatment Week 24 in Parts 1 and 2 for the ITT population, and in Part 3 for the 
ITT-3 population for later visits.


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●
Growth rate at each post baseline visit (defined as change in height over
change in age from the previous visit)
●
Height z score27
●
Waist circumference
●
Tanner staging
For growth rate and height z score, summary statistics (N, mean and SD together, median 
and range together) will be provided at each applicable post baseline visit for all and by 
gender for each pre-defined age group separately.  For height z score only, summary 
statistics of change from baseline (N, mean and SD together, median and range together) 
will be summarized over time at each applicable study visit for all and by gender for each 
pre-defined age group separately.  Change from baseline in waist circumference, weight 
and height will be summarized together with other vital signs such as temperature and 
blood pressure.  Listings of Tanner staging for each applicable subject over applicable 
timepoints will be produced.
8.1.4
Patient Reported Outcomes
During Treatment and Post-Treatment, health utility values will be assessed using the 
EQ-5D-3L instrument.  The health state data measured by EQ-5D-3L will not be analyzed 
until validated weights are available for pediatric subjects to convert health states to a 
single summary index.
For subjects enrolled in Part 1 and 2 (ITT), summary statistics at each visit and on the 
change from baseline to each visit (n, mean, SD, minimum and maximum) of EQ VAS 
score will be provided.  In particular, for each of the three visits – EOT, PT Week 12 and 
PT Week 24, the mean change from baseline in EQ VAS score, will be analyzed using 
ANCOVA with appropriate baseline fibrosis stage, gender, and age group as factors, and 
baseline EQ VAS score and SVR status as covariates.  For subjects enrolled in Part 3 
(ITT-3), summary statistics at each visit and the change from baseline to each applicable 
post-baseline visit (n, mean, SD, minimum and maximum) in EQ VAS score will be 
provided.


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8.1.5
Acceptability Questionnaire 
For each subject taking the mini-tablet formulation, the parent(s)/guardian(s) of the 
subject will complete an Acceptability Questionnaire to provide feedback on the 
perception of the dosage form at the visits indicated in Appendix C.
The number and percentage of subjects with each categorical answer marked will be 
presented for each question in the acceptability questionnaire at each applicable treatment 
visit overall, by age and weight group.  Listings of acceptability questionnaire results and 
comments for each applicable subject over applicable treatment visits will be produced.
8.1.6
Safety
All subjects who receive at least one dose of study drug will be included in the safety 
analyses.  The safety analysis will be carried out for all subjects by formulation, age and 
weight group, for all subjects on the adult formulation.  A listing of any SAEs recorded in 
Part 3 will be included.
8.1.6.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects with treatment-emergent adverse 
events (i.e., any event that begins or worsens in severity after initiation of study drug 
through 30 days post-study drug dosing) will be tabulated by primary MedDRA System 
Organ Class (SOC) and preferred term (PT).  The tabulation of the number of subjects 
with treatment-emergent adverse events by grade (Grades 1 – 5) and relationship to study 
drug also will be provided.
Additional analyses will be performed if useful and appropriate.


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8.1.6.2
Clinical Laboratory Data
Clinical laboratory tests will be summarized at each visit.  The baseline value will be the 
last measurement prior to the initial dose of study drug.  Mean changes from baseline to 
each post baseline visit will be summarized descriptively.
Laboratory data values collected during the Treatment Period will be categorized as low, 
normal, or high based on reference ranges of the laboratory used in this study.  The 
number and percentage of subjects who experience post-baseline shifts during treatment 
in clinical laboratory values from low/normal to high and high/normal to low based on the 
normal range will be summarized.
In addition, the number and percentage of subjects with post-baseline values meeting 
pre-specified criteria for Potentially Clinically Significant laboratory values during 
treatment will be summarized.  Additional analyses will be performed if useful and 
appropriate.
8.1.6.3
Vital Signs Data
Mean changes in temperature, systolic and diastolic blood pressure, pulse, weight, height, 
and waist circumference from Day 1 to each post baseline visit will be summarized 
descriptively.  Number and percentage of subjects with post-baseline values meeting 
pre-defined criteria for Potentially Clinically Significant vital signs values during 
treatment will be summarized.  
8.1.7
Resistance Analysis
All subjects who receive at least 1 dose of study drug in Part 1 or Part 2 will be followed 
to monitor the development and persistence of antiviral drug resistance by population, 
deep, and/or clonal sequencing (in subjects who experience virologic failure).
The genes of interest for sequencing in this study are those encoding NS3 amino acids 1 
to 181, NS5A amino acids 1 to 215, and (only in subjects receiving DSV) NS5B amino 
acids 300 to 591.  For each DAA target, resistance-associated signature amino acid 


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variants will be identified by AbbVie Clinical Virology.  Only samples with an HCV 
RNA level of ≥ 1000 IU/mL will undergo sequence analysis in order to allow accurate 
assessment of the products of amplification.  Therefore if the HCV RNA level at the time 
of virologic failure is < 1000 IU/mL, the sample closest in time after the failure with an 
HCV RNA level ≥ 1000 IU/mL will be used if available. 
The prototypic reference strains with their associated GenBank Accession IDs for 
sequence analyses are GT1a-H77 (NC_004102) and 1b-Con1 (AJ238799).  For 
genotype 4, ED43 (GenBank Accession ID GU814265) will be used for all samples
except those identified by phylogenetic analysis as sub-genotype 4d, for which 
genotype 4d strain QC382 (GenBank Accession ID FJ462437) will be used.  A 
329 nucleotide region of NS5B will be PCR amplified and sequenced from the baseline 
sample from all genotype 4-infected subjects.  Phylogenetic analysis will be conducted on 
the resulting sequences in order to accurately determine the genotype 4 sub-genotype.29
The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant (by population or deep sequencing) in a baseline 
sample determined by comparison of the amino acid sequence of the baseline 
sample to the appropriate prototypic reference amino acid sequence for a given 
DAA target (NS3, NS5A, or NS5B).
●
Post-baseline variant by population or deep sequencing:  an amino acid variant 
in a post-baseline time point sample that was not detected at baseline and is 
detectable by population or deep sequencing.
●
Post-baseline variant by clonal sequencing:  a variant at a signature resistance 
associated amino acid position that was not present by population or deep 
sequencing at baseline in a subject that is detected in a post-baseline sample by 
clonal sequencing in at least 2 clones from that sample (among the subset of 
subjects for whom clonal sequencing is performed).
●
Linked variant by population or deep sequencing:  variants at 2 or more 
signature resistance-associated amino acid amino acid positions identified 
within a target by population or deep sequencing, and no mixture of amino 
acids is detected at any of those positions.


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●
Post-baseline variant by clonal sequencing:  a variant at a signature 
resistance-associated amino acid position that was not present by population or 
deep sequencing at baseline in a subject that is detected in a post-baseline 
sample by clonal sequencing in at least 2 clones from that sample (among the 
subset of subjects for whom clonal sequencing is performed).
For subjects who have population or deep sequencing performed on baseline samples, a 
listing by subject of all baseline variants relative to the appropriate prototypic reference 
sequence at signature resistance-associated amino acid positions will be provided for each 
DAA target.  In addition, a summary of the number and percentage of subjects with each 
baseline variant at a signature resistance-associated amino acid position within each target 
by HCV sub-genotype out of the total number of baseline samples sequenced will also be 
provided.  
The following analyses will be performed on the samples from subjects who experience 
virologic failure and have post-baseline resistance data available. 
The HCV amino acid sequence as determined by population or deep sequencing at the 
time of virologic failure or the sample closest in time after virologic failure with an HCV 
RNA level of ≥ 1000 IU/mL will be compared with the baseline sequence and with the 
appropriate prototypic reference amino acid sequence.  A listing by subject of all 
post-baseline variants at signature resistance-associated amino acid positions detected by 
population or deep sequencing relative to the baseline amino acid sequences will be 
provided for each DAA target.  In addition, a listing by subject of all post-baseline 
variants (by population or deep sequencing) at signature resistance-associated amino acid 
positions relative to the appropriate prototypic reference amino acid sequences will be 
provided.
Linkage between variants at signature resistance-associated amino acid positions by 
population or deep sequencing will also be evaluated.  A listing by subject and time point 
of the linked variants will be provided.


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For the subset of samples for which clonal sequencing is performed, the amino acid 
variants determined by clonal sequencing will be summarized by counting the number of 
clones whose amino acid sequence at signature resistance-associated positions does not 
match that of the population baseline sequence by subject at each time point and amino 
acid position, out of the total number of clones analyzed.  Listings by subject of 
post-baseline variants at signature resistance-associated positions detected by clonal 
sequencing (≥ 2 clones per sample) will be provided for each DAA target.
For all subjects who experience virologic failure for whom resistance analyses are 
performed, the persistence of resistance-associated substitutions at signature resistance 
associated amino acid positions for each target will be assessed by population, deep, 
and/or clonal sequencing at Post-Treatment Week 24 and at various time points during the 
LTFU period.  However, if resistance-associated variants are not detected in a given target 
for a subject at the time of virologic failure, then that target may not be sequenced in 
subsequent samples from that subject.  Listings by subject and time point of all variants at 
signature resistance-associated amino acid positions relative to the baseline amino acid 
sequence will be provided for each DAA target.
All summaries may also be subgrouped by age group.
8.1.8
Pharmacokinetic and Exposure-Response Analyses
Plasma concentrations of OBV, PTV, DSV, DSV M1 metabolite, RTV and RBV will be 
tabulated and summarized as appropriate by formulation, weight range or age group for 
subjects in Part 1 and Part 2.
Values for the pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 metabolite, 
RTV and RBV including the Cmax, Tmax, Ctrough, and AUC will be tabulated and 
summarized formulation, weight range or age group for subjects in Part 1.  Additional 
parameters or summaries may be determined if useful in the interpretation of the data.
Plasma concentration data from Part 1 and Part 2 of this study may be combined with data 
from other studies and analyzed using the following general methodology.


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Population pharmacokinetic analyses may be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software.  The structure of the starting 
pharmacokinetic model will be based on the pharmacokinetic analysis of data from 
previous studies.  Apparent oral clearance (CL/F) and apparent volume of distribution 
(V/F) of the PK analytes will be the pharmacokinetic parameters of major interest in the 
NONMEM analyses.  If necessary, other parameters, including the parameters describing 
absorption characteristics, may be fixed if useful in the analysis.  
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.
Relationship between exposure and clinical observations (antiviral activity) will be 
explored.  Exposure-response relationships for primary and secondary efficacy variables 
and/or some safety measures of interest may also be explored.  
The relationship between exposure (e.g., population pharmacokinetic model predicted 
concentrations over time or average concentrations or AUC or trough concentrations of 
the individual model-predicted pharmacokinetic profiles, or some other appropriate 
measure of exposure) and antiviral activity will be explored using graphical and/or 
logistic regression analyses. 
Additionally, relationship between exposure and safety endpoints of interest may also be 
explored.  Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
The sample size of 36 subjects in Part 1 will adequately characterize the pharmacokinetics 
of the AbbVie DAAs to enable dose selection in pediatric subjects.
According to the Prescribing Information of PEGASYS, the SVR24 rate was 47% among 
45 treatment-naïve pediatric subjects with HCV GT1 in the NV17424 trial.  To show that 


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the DAA regimen is superior to this current standard of care by 20% in Parts 1 and 2, the 
lower bound of the 2-sided 95% confidence interval of the SVR12 rate across all subjects 
in the study must be greater than 67%.  For the primary efficacy endpoint of the 
percentage of subjects with SVR12, if it is assumed 90% subjects would achieve SVR12
then 50 or more subjects would have > 90% power to have a lower bound of 2-sided 
confidence interval based on normal approximation to the binomial distribution > 67%.
8.3
Randomization Methods
There is no randomization in this study.  Enrolled subjects will receive treatment per the 
planned study schematic outlined in Section 5.1.2.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent/assent and all other forms 
of subject information related to the study (e.g., advertisements used to recruit subjects) 
and any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will 
review the ethical, scientific and medical appropriateness of the study before it is 
conducted.  IEC/IRB approval of the protocol, informed consent/assent and subject 
information and/or advertising, as relevant, will be obtained prior to the authorization of 
drug shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 


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any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject's parent(s)/legal guardian(s) and answer all questions regarding this study.  
Pediatric subjects will be included in all the discussions in order to obtain written assent.  
Prior to any study-related screening procedures being performed on the subject, the 
informed consent statement will be reviewed and signed and dated by subject's 
parent(s)/legal guardian(s) and the person who administered the informed consent, and 
any other signatories according to local requirements.  Additionally, in keeping with each 
institution's IEC requirements, if applicable, an informed assent form will also be obtained 
by each subject, as appropriate for age and country, prior to any study-related procedures 
being performed.  If a subject becomes of legal age during the course of the study, that 
subject will need to be consented using the approved informed consent form. A copy of 
the informed consent form and assent form will be given to the subject and subject's 
parent(s)/legal guardian(s) and the originals will be placed in the subject's medical record.  
An entry must also be made in the subject's dated source documents to confirm that 
informed consent and assent (if applicable) were obtained prior to any study-related 
procedures and that the subject and parent(s)/legal guardian(s) received signed copies of 
the informed consent and assent forms.


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Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
Optional pharmacogenetic analysis will only be performed if the subject has provided 
assent, as appropriate for age and country, and the subject's parent(s)/guardian(s) have 
voluntarily signed and dated the pharmacogenetic informed consent, approved by an 
IRB/IEC, after the nature of the testing has been explained and the subject and their 
parent(s)/guardian(s) have had an opportunity to ask questions.  The subject's 
parent(s)/guardians(s) must have signed and dated the pharmacogenetic informed consent 
before the optional pharmacogenetic testing is performed.  If the parent(s)/guardian(s) do 
not provide consent or subject does not provide assent, as appropriate for age and country, 
to the optional pharmacogenetic testing, it will not impact the subject's participation in the 
study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 


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AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.


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11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any optional pharmacogenetic research that may be done using DNA samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision-making or patient management.  Hence, the investigator, the subject, nor the 
subject's physician (if different than the investigator) will be informed of individual 
subject optional pharmacogenetic results, should analyses be performed, nor will anyone 
not directly involved in this research.  Correspondingly, genetic researchers will have no 
access to subject identifiers.  Individual results will not be reported to anyone not directly 
involved in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.


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AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for Paritaprevir, 
Ritonavir, Ombitasvir, Dasabuvir and the product labeling for RBV.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
An Open-Label, Multicenter Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of Ombitasvir (OBV), 
Paritaprevir (PTV), Ritonavir (RTV) With or Without Dasabuvir 
(DSV) and With or Without Ribavirin (RBV) in Pediatric Subjects 
With Genotype 1 or 4 Chronic Hepatitis C Virus (HCV) Infection 
(ZIRCON)
Protocol Date:
21 August 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
PEGASYS® (peginterferon alfa-2a) [package insert].  San Francisco, CA; 
Genentech Inc., 2002.
2.
Gower E, Estes C, Blach S, et al.  Global epidemiology and genotype distribution 
of the hepatitis C virus infection.  J Hepatol.  2014;61 (1 Suppl):S45-57.
3.
El-Shabrawi MH, Kamal NM.  Burden of pediatric hepatitis C.  World J 
Gastroenterol.  2013;19(44):7880-8.
4.
Wirth S, Kelly D, Sokal E, et al.  Guidance for clinical trials for children and 
adolescents with chronic hepatitis C.  J Pediatr Gastroenterol Nutr.  
2011;52(2):233-7.
5.
Gibb DM, Goodall RL, Dunn DT, et al.  Mother-to-child transmission of 
hepatitis C virus:  evidence for preventable peripartum transmission.  Lancet.  
2000;356(9233):904-7.
6.
Zanetti AR, Tanzi E, Romanò L, et al.  A prospective study on mother-to-infant 
transmission of hepatitis C virus.  Intervirology.  1998;41(4-5):208-12.
7.
Tovo PA, Palomba E, Ferraris G, et al.  Increased risk of maternal-infant 
hepatitis C virus transmission for women coinfected with human 
immunodeficiency virus type 1.  Italian Study Group for HCV Infection in 
Children.  Clin Infect Dis.  1997;25(5):1121-4.
8.
Conte D, Fraquelli M, Prati D, et al.  Prevalence and clinical course of chronic 
hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort 
of 15,250 pregnant women.  Hepatology.  2000;31(3):751-5.
9.
Ceci O, Margiotta M, Marello F, et al.  Vertical transmission of hepatitis C virus in 
a cohort of 2,447 HIV-seronegative pregnant women:  a 24-month prospective 
study.  J Pediatr Gastroenterol Nutr.  2001;33(5):570-5.
10.
Bortolotti F, Verucchi G, Cammà C, et al.  Long-term course of chronic hepatitis C 
in children:  from viral clearance to end-stage liver disease.  Gastroenterology.  
2008;134(7):1900-7.


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11.
Iorio R, Giannattasio A, Sepe A, et al.  Chronic hepatitis C in childhood:  an 
18-year experience.  Clin Infect Dis.  2005;41(10):1431-7.
12.
Resti M, Jara P, Hierro L, et al.  Clinical features and progression of perinatally 
acquired hepatitis C virus infection.  J Med Virol.  2003;70(3):373-7.
13.
European Paediatric Hepatitis C Virus Network.  Three broad modalities in the 
natural history of vertically acquired hepatitis C virus infection.  Clin Infect Dis 
2005;41(1):45-51.
14.
Casiraghi MA, De Paschale M, Romanò L, et al.  Long-term outcome (35 years) of 
hepatitis C after acquisition of infection through mini transfusions of blood given at 
birth.  Hepatology.  2004;39(1):90-6.
15.
Jara P, Resti M, Hierro L, et al.  Chronic hepatitis C virus infection in childhood:  
clinical patterns and evolution in 224 white children.  Clin Infect Dis.  
2003;36(3):275-80.
16.
Guido M, Bortolotti F, Leandro G, et al.  Fibrosis in chronic hepatitis C acquired in 
infancy:  is it only a matter of time?  Am J Gastroenterol.  2003;98(3):660-3.
17.
Gonzalez-Peralta R, Langham MR, Mohan P, et al.  Hepatocellular carcinoma in 
two adolescents with cirrhosis secondary to hepatitis C infection.  J Pediatr 
Gastroenterol Nutr.  2003;37(3):380.
18.
Rumbo C, Fawaz RL, Emre SH, et al.  Hepatitis C in children:  a quaternary 
referral center perspective.  J Pediatr Gastroenterol Nutr.  2006;43(2):209-16.
19.
Goodman ZD, Makhlouf HR, Liu L, et al.  Pathology of chronic hepatitis C in 
children:  liver biopsy findings in the Peds-C trial.  Hepatology.  
2008;47(3):836-43.
20.
Zekry A, Whiting P, Crawford DH, et al.  Liver transplantation for HCV-associated
liver cirrhosis:  predictors of outcomes in a population with significant genotype 3 
and 4 distribution.  Liver Transpl.  2003;9(4):339-47.
21.
Wali MH, Heydtmann M, Harrison RF, et al.  Outcome of liver transplantation for 
patients infected by hepatitis C, including those infected by genotype.  Liver 
Transpl.  2003;9(8):796-804.


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22.
World Health Organization.  Guidelines for the screening, care and treatment of 
persons with hepatitis C infection.  April 2014.
23.
American Association for the Study of Liver Diseases. Recommendations for 
testing, managing, and treating hepatitis C.  19 December 2014.
24.
European Association for the Study of the Liver:  EASL recommendations on 
treatment of hepatitis C.  April 2014.
25.
Lawitz E, Mangia A, Wyles D, et al.  Sofosbuvir for previously untreated chronic 
hepatitis C infection.  N Engl J Med.  2013;368(20):1878-87.
26.
AbbVie, Inc.  Pediatric Study Plan.  19 December 2014.
27.
AbbVie, Inc.  Pediatric Investigation Plan.  08 November 2013.
28.
WHO.  Child Growth Standards.  27 April 2006.
29.
Koletzki D, Dumont S, Vermeiren H, et al.  Development and evaluation of an 
automated hepatitis C virus NS5B sequence-based subtyping assay.  Clin Chem 
Lab Med.  2010;48(8):1095-102.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Global Drug Supply
Clinical
Statistics
Clinical
Bioanalysis


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Appendix C.
Study Activities
Study Activities – Treatment Period – Parts 1 and 2
Treatment Period (TP)
Treatment Visits – All Subjects
Treatment Visits – 24-Week*
Premature 
D/C from 
Treatmentc
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
or 
EOTb
Wk 16
Wk 20
Wk 24 
(EOT)b
Informed Consentd
X
RBV medication guidee
X
Medical History
X
Xf
Physical Examg
X
X
X
X
X
X
X
Vital Signs, Weight, Height, Waist 
Circumference
X
Xh
X
X
X
X
X
X
X
X
ECG
X
Xi
Pregnancy Test (serum [s] urine [u])j
X (s)
X (u)
X (u)
X(u)
X (u)
X (u)
X (u)
X (u)
X (u)
Hematology/Chemistry/Urinalysis/Coagulation 
Panelk
X
X
X
X
X
X
X
X
X
X
FSHl
X
HBsAg, Anti-HCV Ab, Anti-HIV Ab
X
HCV Genotype and Sub-genotype
X
IL28B Sample
X


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Treatment Period (TP)
Treatment Visits – All Subjects
Treatment Visits – 24-Week*
Premature 
D/C from 
Treatmentc
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
or 
EOTb
Wk 16
Wk 20
Wk 24 
(EOT)b
Historical Liver Biopsy or FibroScan 
assessment or Screening FibroTest for liver 
cirrhosism
X
Longitudinal Fibrotest
Xn
Child Pugh Scoreo
X
HCC Assessment:  Liver ultrasoundp
X
X
Concomitant Medication Assessmentq
X
X
X
X
X
X
X
X
X
X
Adverse Event Assessmentr
X
X
X
X
X
X
X
X
X
X
Study Drugs Dispensations
X
X
Weeks 4, 6, 8, 
10
Xt
X
X
Dispense/Collect/Review Study Drug Dosing 
Cardu
X
X
X
X
X
X
X
X
X
Study Drug Accountability and/or Review of 
Study Drug Adherence
X
Weeks 4, 6, 8, 
10s
X
X
X
X
X
RBV Solution Diary Dispense/Collect/Recordv
X
X
Weeks 4, 6, 8, 
10
X
X
X
X
X
PK Samplingw
X
X
X
X
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
X
X
X
Assignment of Subject Number via IRTx
X
Enrollment
X


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Treatment Period (TP)
Treatment Visits – All Subjects
Treatment Visits – 24-Week*
Premature 
D/C from 
Treatmentc
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
or 
EOTb
Wk 16
Wk 20
Wk 24 
(EOT)b
HCV Resistance Sampley
X
Tanner Pubertal Stagez
X
Patient Reported Outcomeaa
X
X
X
X
X
X
X
X
X
Acceptability Questionnairebb
X
X
X
X
Pharmacogenetic Sample (optional)cc
X
Drug compliance reviewdd
X
X
X
X
X
X
D/C = Discontinuation; EOT (End of Treatment) = Final Treatment Visit; Day 1 = Baseline Visit 
*
Treatment for 24 weeks is applicable for all subjects with genotype 1 non-b compensated cirrhosis. 
a.
All procedures to be performed prior to first dose.
b.
Treatment Duration Study Visits:
!
Subjects assigned to 12 weeks of treatment will complete the procedures from the screening visit through the Week 12/EOT visit.
!
Subjects assigned to 24 weeks of treatment will complete the procedures from the screening visit through the Week 24/EOT.  Subjects will complete a Week 12 Study 
Visit as an interim visit.
c.
Subjects that prematurely discontinue from the Treatment Period should return to the site to complete the Premature D/C from Treatment visit procedures.
d.
Prior to performing any screening or study-specific procedures, parent(s)/guardian(s) will sign an informed consent for the study.  Additionally an assent from the subject will 
be obtained to meet the institution's IEC requirements, as applicable.
e.
Where applicable/locally available.
f.
Medical history will be updated at the Day 1 Visit prior to study drug administration and will serve as the Baseline for clinical assessment.
g.
A symptom-directed physical examination may be performed at any other visit, when necessary.
h.
Height and waist circumference will be measured at baseline only during treatment.


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i.
Part 1 only.
j.
A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for additional details.)  Females who are experiencing menses 
or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential who are receiving RBV should have urine pregnancy testing done monthly 
starting from Day 1 (Baseline) through PT Week 16 after RBV discontinuation or per local label.  Females who are experiencing menses or are nearing sexual maturation in 
the opinion of the PI or who are of childbearing potential who are receiving DAA only should have urine pregnancy testing done thru Post-Treatment Week 4.
k.
Non-cirrhotic subjects:  Coagulation panel performed only at Day 1 and as clinically indicated.
Cirrhotic subjects:  Coagulation panel is required at all treatment visits. 
l.
FSH for all female subjects aged ≥ 9 to 17 years old.
m.
Subjects with no history of cirrhosis who have not had a liver biopsy or Fibroscan within 24 months prior to screening, will have a screening FibroTest to determine the 
presence or absence of cirrhosis for the purpose of treatment assignment.  Subjects who have a liver biopsy or FibroScan indicating cirrhosis at any time in the past will not 
need a Fibrotest to be performed at screening as evidence of cirrhosis.
n.
Perform a Fibrotest at Day 1 for any subject who did not have a FibroTest done during Screening.
o.
Applies only to subjects with cirrhosis.  The Child-Pugh score will be calculated in the EDC RAVE system.  Subjects who were considered to be non-cirrhotic at the 
Screening visit but identified as cirrhotic (according to definitions listed in Section 5.3.1.1) during the screening period will return to the site prior to the baseline visit for 
Child-Pugh assessment.
p.
HCC assessment for subjects with compensated cirrhosis only:  Liver ultrasound will be performed at the screening visit.  Liver ultrasound testing will occur yearly after 
Day 1.
Subjects with a historical negative liver ultrasound, CT or MRI (within 3 months prior to screening) are not required to undergo a screening ultrasound.
q.
The local study drug labels and http://www hep-druginteractions.org/ should be utilized to evaluate concomitant medications for potential DDI.
r.
See specific information regarding the adverse event collection in Section 6.1.4.
s.
Part 1:  Study drugs will be dispensed every 2 weeks for subjects receiving the mini-tablets with study visit procedures occurring at Day 1, Weeks 2, 4, 6, 8 and 10.  Subjects 
receiving the adult formulation will have drug dispensed at Study Day 1 and Weeks 4 and 8 for 12-week treatment.
Part 2:  Study drug dispensed every 4 weeks at regularly scheduled visits at Day 1 and Weeks 4 and 8 for 12-week treatment and Day 1 and Weeks 4, 8, 12, 16, and 20 for 
24-week treatment.  Drug accountability will be performed at each drug dispensation visit as outlined for mini-tablet, pellet and adult formulations.
t.
Study drugs are only dispensed at Week 12 for subjects who will receive 24 weeks of treatment.
u.
Dosing card is filled out with date and time (to the nearest minutes) of the 2 doses before PK draws in Part 1 and Part 2.  Do not dispense the dosing card at Week 12 visit of 
Part 1 and at the Week 12 visit for subjects assigned to 12 weeks of treatment in Part 2 (Section 5.3.1.1).


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v.
Only for Subjects taking RBV Solution  
Part 1:  Dispensed/Collected every 2 weeks for subjects receiving the mini-tablets with RBV with study visit procedures occurring at Day 1, Weeks 2, 4, and 8. 
Part 2:  Dispensed/Collected every 4 weeks at regularly scheduled visits at Day 1 and Weeks 4 and 8 for 12-week treatment and Day 1 and Weeks 4, 8, 12, 16, and 20 for 
24-week treatment. 
w.
In Part 1, intensive PK sampling will be done at Week 2 and sparse PK sampling at other visits (Section 5.3.2.1), while sparse PK sampling will be done at all PK visits in 
Part 2 (Section 5.3.2.1).
x.
The Subject will retain the subject number throughout the course of the study. 
y.
Resistance sample will be collected at Day 1 and upon meeting virologic failure criteria.
z.
The Tanner Pubertal stage is assessed for subjects aged ≥ 9 to 17 years old.  Tanner staging will not be repeated once the child reaches Tanner Stage 5.
aa.
The PRO should be administered as the first study procedure at each visit. 
bb. Subjects taking the mini-tablet/pellet formulations only.
cc.
Parent(s) or legal guardian(s) and subjects must provide written informed consent and assent (as appropriate for age and country) respectively for the optional 
pharmacogenetic substudy.  If the optional pharmacogenetic DNA sample is not collected at Day 1, it may be collected at any other visit during the study.  The investigative 
site should follow the volume of blood drawn guidance as outlined in Section 5.3.1.1 for the PG sample collection.
dd. Sites will inspect the returned study drug containers at every visit to determine drug compliance.  Sites will counsel legal guardian(s) in case of non-drug compliance.  See 
Section 5.5.6 for more details.


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Study Activities – Post-Treatment – Parts 1, 2 and 3
Post-Treatment (PT)
Post-Treatment Period of 
Parts 1 and 2 (PTP)
Part 3:  Long-Term Follow-Up (LTFU)
Premature 
D/C
Activity
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96, and 144
Vital Signs, Weight, Height, Waist Circumferencesa
X
X
X
X
X
X
X
Urine Pregnancy Testb
X
(Weeks 12, 16)
X
Longitudinal Fibrotest
X
Xc
Hematology/Chemistry/Urinalysisd/Coagulation Panel
X
X
HCC Assessment:  Liver Ultrasounde
X
X
X
Concomitant Medication Assessmentf
X
X
X
X
X
X
X
Adverse Event Assessmentg
X
X
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
HCV Resistance Sampleh
Tanner Pubertal Stagei
X
X
Xj
X
Patient Reported Outcomek
X
X
X
X
X
X
X
D/C = Discontinuation
a.
Height and Waist circumference will be measured at PT Weeks 12, 36, 96 and 144 only.
b.
A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for additional details.)  Females who are experiencing menses 
or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential who are receiving DAAs only should have urine pregnancy testing done thru 
Post-Treatment Week 4.
Females who are experiencing menses or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential who are receiving RBV should have urine 
pregnancy testing done monthly starting from Day 1 (Baseline) through PT Week 16 after RBV discontinuation or per local label.


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At the PT Visit 16subjects may have an unscheduled office visit for pregnancy testing or elect to perform the tests at home with test kits provided by the site.  Additional 
testing may be required per local RBV label.
c.
FibroTest will be performed at PT Weeks 24 and 144.
d.
Urinalysis will not be conducted after the Post-Treatment Week 4 visit.
e.
HCC assessment for subjects with compensated cirrhosis only:  Liver ultrasound testing will occur yearly.
f.
Only medications taken for SAEs assessed as related to study drugs and treatment of HCV will be collected after 30 days post-dosing.
g.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  Only drug-related SAEs will be collected thereafter.  See Section 6.1.4.
h.
Resistance samples are only collected at the confirmation visit for patients that potentially meet virologic failure criteria.
i
The Tanner Pubertal stage is assessed for subjects aged ≥ 9 to 17 years old.  Tanner staging will not be repeated once the child reaches Tanner Stage 5.
j.
Tanner Pubertal Staging only performed at PT Weeks 12, 36, 96 and 144.
k.
The PRO should be administered as the first study procedure at each visit.


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Appendix D.
Estimated Blood Loss for Pediatric Subjects
Treatment Period – Part 1:  
Treatment Period (TP)
Treatment Visits – All Subjects
Premature D/C 
from Treatment
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Pediatric 
tubes
Screening
Day 1
Wk 2
Wk 4
Wk 8
Wk 12 or 
EOT
19.8
25.8
18.3
11.7
10.3
11.7
12.8
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Standard 
tubes
29.0
29.8
20.5
14.3
12.5
14.3
16.8


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Treatment Period – Part 2:  
Treatment Period (TP)
Treatment Visits – All Subjects
Premature D/C 
from 
Treatment
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Pediatric 
tubes
Screening
Day 1
Wk 2, 4, 8, 12, 
16 and 20
Wk 24 or 
EOT
19.8
25.8
11.7
12.8
12.8
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Standard 
tubes
29.0
29.8
14.3
16.8
16.8
Post-Treatment – Part 3:  
Post-Treatment (PT)
Post-Treatment Period of 
(PTP)
Part 3:  Long-Term Follow-Up 
(LTFU)
Premature 
D/C
Estimated 
Whole Blood 
Drawn (mL) –
using Pediatric 
tubes
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96*, and 144
8.7
6.0
20.7
16.0
17.1
20.7*/17.1
20.8
Estimated 
Whole Blood 
Drawn (mL) –
using 
Standard 
tubes
12.3
6.0
23.5
16.0
18.5
23.5*/18.5
24.8


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Appendix E.
Tanner Pubertal Stage
Boys – development of external genitalia
Stage 1:
Prepubertal
Stage 2:
Enlargement of scrotum and testes; scrotum skin reddens and changes in 
texture
Stage 3:
Enlargement of penis (length at first); further growth of testes
Stage 4:
Increased size of penis with growth in breadth and development of glans; 
testes and scrotum larger, scrotum skin darker
Stage 5:
Adult genitalia
Girls – breast development
Stage 1:
Prepubertal
Stage 2:
Breast bud stage with elevation of breast and papilla; enlargement of areola
Stage 3:
Further enlargement of breast and areola; no separation of their contour
Stage 4:
Areola and papilla form a secondary mound above level of breast
Stage 5:
Mature stage: projection of papilla only, related to recession of areola
Boys and girls – pubic hair
Stage 1:
Prepubertal (can see velus hair similar to abdominal wall)
Stage 2:
Sparse growth of long, slightly pigmented hair, straight or curled, at base of 
penis or along labia
Stage 3:
Darker, coarser and more curled hair, spreading sparsely over junction of 
pubes
Stage 4:
Hair adult in type, but covering smaller area than in adult; no spread to 
medial surface of thighs
Stage 5:
Adult in type and quantity, with horizontal distribution ("feminine")


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Appendix F.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-748
Name of Study Drug:  ombitasvir, paritaprevir, 
ritonavir, dasabuvir, ribavirin
Phase of Development:  2/3
Name of Active Ingredient:  ombitasvir, 
paritaprevir, ritonavir, dasabuvir, ribavirin
Date of Protocol Synopsis:  07 July 2016
Protocol Title:  An Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Ombitasvir (OBV), Paritaprevir (PTV), Ritonavir (RTV) With or Without Dasabuvir (DSV) 
and With or Without Ribavirin (RBV) in Pediatric Subjects With Genotype 1 or 4 Chronic Hepatitis C 
Virus (HCV) Infection (ZIRCON)
Objectives:  
To assess the pharmacokinetics of OBV, PTV, RTV, and DSV with or without RBV in treatment-naïve, 
non-cirrhotic, HCV GT1-infected pediatric subjects in Part 1.
To assess the efficacy (percentage of subjects achieving SVR12 [defined as HCV RNA < LLOQ 12 weeks 
after the last actual dose of study drug]) or SVR24 [defined as HCV RNA < LLOQ 24 weeks after the last 
actual dose of study drug]) and safety of OBV, PTV, RTV with or without DSV and with or without 
RBV for 12 or 24 weeks in HCV genotype 1 (GT1) or genotype 4 (GT4)-infected treatment-naïve and 
prior IFN (IFN or peg-IFN with or without RBV) treatment-experienced, cirrhotic and non-cirrhotic 
pediatric subjects in Part 1 and Part 2.
To assess the durability of response for subjects who achieved SVR, to assess the emergence and 
persistence of specific HCV amino acid variants associated with drug resistance in subjects who 
experienced virologic failure, and to assess the impact of OBV, PTV, RTV with or without DSV and with 
or without RBV on growth and development in Part 3, the long-term follow-up of approximately 
3.5 years.
Investigator:  Global, multicenter trial:  Investigator information is on file at AbbVie.
Study Sites:  Up to 30 sites globally.
Study Population:  
Part 1:  Treatment-naïve, non-cirrhotic, GT1-infected pediatric patients ≥ 3 to 17 years of age 
Part 2:  Treatment-naïve and IFN (interferon or pegylated-interferon with or without RBV) 
treatment-experienced HCV GT1 or GT4-infected pediatric subjects ≥ 12 to 17 years of age with or 
without compensated cirrhosis
Part 3 (Long-term follow-up):  All pediatric subjects who take at least one dose of study drug and 
complete the Post-Treatment (PT) Week 24 visit in Part 1 or Part 2.


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Number of Subjects to be Enrolled:  
Approximately 74 subjects will be enrolled in total into two Parts.  Part 1:  Approximately 
48 treatment-naïve, non-cirrhotic, GT1 subjects.  Part 2:  Approximately 26 treatment-naïve or prior IFN 
treatment-experienced, cirrhotic or non-cirrhotic subjects with GT1 or GT4.
Methodology:
The study aims to assess four formulations in the pediatric population.  The approved adult 3D regimen 
formulation and the approved adult 2D regimen formulation will be administrated in subjects who are in 
the 12 to 17 years old age group with weight greater than 45 kg and willing to swallow the adult 
formulation.  These formulations will be the final dose formulations for this age group if satisfactory 
safety and efficacy profiles are observed.  The mini-tablet formulation will be administered in subjects 
who are in the 3 – 8 and 9 – 11 age groups to identify the optimal or final doses.  The pellet formulation 
will be administrated also in these two age groups after final doses are identified.  The pellet formulation 
will be the final dose formulation for the two age groups if satisfactory safety and efficacy profile is 
observed.
Part 1 mini-tablet is designed to allow for dose adjustment on an ongoing basis, based on available 
pharmacokinetic and clinical data to achieve therapeutic exposures that have been safe and efficacious in 
adult subjects.  Area under the concentration curve (AUC) from the intensive PK sampling at Week 2 
will be the primary measure for dose adjustment, which will be compared with the range of the geometric 
means and the range of individual values across Phase 1/2/3 studies in adults that had intensive PK data 
(see Section 5.1).  Cmax and Ctrough will be considered for safety and efficacy using the same rules.  Part 2 
(Safety and Efficacy) will use the adult formulation if the results from the adult formulation in Part 1 are 
satisfactory.  In Part 1 and Part 2, the treatment duration is either 12 weeks or 24 weeks and all pediatric 
subjects who receive at least 1 dose of study drug will be followed for 24 weeks in the post-treatment 
period after completing or prematurely discontinuing the study treatment.  All pediatric subjects who 
complete the Post-Treatment (PT) Week 24 visit in either Part 1 or Part 2 will be followed in Part 3 
(Long-term Follow-up) for an additional 168 weeks.
Part 1 (Pharmacokinetic Study):
Approximately 48 treatment-naïve, non-cirrhotic, HCV GT1-infected pediatric subjects will be enrolled.  
In the ≥ 12 to 17 year age group, 12 subjects will receive the standard adult formulation; in the ≥ 3 to 8 
and ≥ 9 to 11 year age groups, at least 6 subjects will receive the mini-tablet formulation and at least 
6 subjects will receive the pellet formulation).  Up to 12 additional subjects may be enrolled to receive 
the mini-tablet formulation in Part 1 if needed to adequately characterize the pharmacokinetics of a 
particular age group or subgroup.  Subjects in the ≥ 12 to 17 year age group who are ≥ 45 kg and willing 
to swallow the adult formulations will begin enrollment before subjects in the younger age groups.  The 
starting drug regimen is defined by HCV sub-genotype.  All HCV sub-genotype 1b subjects will receive 
study medication without RBV for 12 weeks as shown below.  All subjects with a HCV GT1 non-b 
infection will receive study medication with weight based RBV for 12 weeks. 


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Methodology (Continued):
Part 1 (Pharmacokinetic Study) (Continued):
Patient Population
Treatment
Duration
Genotype 1b, 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir 
12 weeks
Genotype 1a,* 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + ribavirin
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, and Week 12.  At Week 2 and 
Week 8, the morning dose of study drug will be administered in the clinic at approximately 24 hours after 
the prior morning dose.  At Week 2, the evening doses will be administered in the clinic following the 
12 hour PK draw and the morning doses at Week 2 + 1 day will be administered in the clinic following 
the 24 hour PK draw.  PT visits will occur at PT Weeks 4, 12, and 24.
PK samples will be collected at the following timepoints from each subject:
!
Day 1:  4 hours postdose (the morning doses will be administered in the clinic)
!
Week 2:  2, 4, 8, 12 and 24 hours postdose (the morning doses, the evening doses following the 
12 hour PK draw and the morning doses following the 24 hour PK draw will be administered in the 
clinic)
!
Week 4: a PK sample (regardless of the dosing time)
!
Week 8: a trough PK sample (i.e., prior to the morning dose, which will be administered in the 
clinic)
!
Week 12: a PK sample (regardless of the dosing time)
Based on assessment of Week 2 intensive pharmacokinetic and clinical data, dose adjustments and/or 
dose adjustments for subsequently enrolled subjects may be performed.
Part 2 (Safety/Efficacy Study):
Approximately 16 HCV GT1-infected and approximately 10 HCV GT4-infected treatment-naïve or IFN 
(IFN or pegIFN with or without RBV) treatment-experienced pediatric subjects in the ≥ 12 to 17 age 
group will be enrolled.  
Subjects with GT1 infection will receive the 3D formulations approved for adults (with or without RBV) 
and the subjects with GT4 infection will received the 2D formulation approved for adults with RBV in 
Part 2.  RBV dosing will be weight-based at 1000 or 1200 mg divided twice daily or per local RBV label.  
The regimen and duration will be determined according to HCV genotype, sub-genotype and cirrhosis 
status.


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Methodology (Continued):
Part 2 (Safety/Efficacy Study) (Continued):
Patient Population
Treatment
Duration
Genotype 1b with or 
without compensated 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir 
(approved adult 3D formulation)
12 weeks
Genotype 1a,* without 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
12 weeks
Genotype 1a,* with 
compensated cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
24 weeks
Genotype 4 with or 
without compensated 
cirrhosis
ombitasvir + paritaprevir + ritonavir + ribavirin 
(approved adult 2D formulation plus RBV)
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and 
Week 24.  The latter 3 visits at Weeks 16, 20 and 24 are required for subjects with compensated cirrhosis 
taking study drug for 24 weeks.  PT visits will occur at PT Weeks 4, 12, and 24.
One PK sample (regardless of the dosing time) will be collected at each visit for each subject in Part 2.
The following criteria will be considered evidence of virologic failure during treatment.  Pediatric 
subjects demonstrating any of the following should be discontinued from study drug:
!
Confirmed increase from nadir (defined as 2 consecutive HCV RNA measurements 
> 1 log10 IU/mL above nadir) in HCV RNA at any time point
!
Confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA measurements ≥ LLOQ) at 
any point after achieving HCV RNA < LLOQ
!
Failure to achieve HCV RNA < LLOQ on or before Week 6
Confirmatory testing should be completed as soon as possible.  If any of the above criteria are met, the 
subject will discontinue study treatment, if applicable.  If the Investigator feels that a subject who meets 
one of these criteria should still remain on study treatment, the subject would only be allowed to remain 
on treatment with approval of the AbbVie Study TA SD/TA MD.
Part 3 (Long-Term Follow-Up):
All subjects who have completed Post-Treatment Week 24 in either Part 1 or Part 2 of the study will be 
followed to assess the durability of viral response, for the emergence and persistence of resistant viral 
variants, and for SAEs related to study drug for an additional 168 weeks in the Long-term Follow-up.  
Study visits will occur at Post-Treatment Weeks 36, 48, 72, 96, 120, 144, 168, and 192.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female ≥ 3 to 17 years of age at time of enrollment.
2.
Willingness to participate in the study for up to 50 months.
3.
HCV infection demonstrated by positive anti-HCV Ab and HCV RNA ≥ 1000 IU/mL at the time of 
screening.
4.
Screening laboratory results indicating HCV genotype 1 for enrollment into Part 1 and genotype 1 or 
4 for enrollment into Part 2.
5.
Parent or legal guardian with the willingness and ability to provide written informed consent and 
subject willing and able to give assent, as appropriate for age and country.
Main Exclusion:  
1.
Women who are pregnant, breastfeeding, or are considering becoming pregnant.
2.
Use of known strong inducers and inhibitors (e.g., gemfibrozil) of cytochrome P450 2C8 (CYP2C8) 
in subjects receiving dasabuvir, or strong or moderate inducers of CYP3A, within 2 weeks or 
10 half-lives, whichever is longer, of the respective medication/supplement prior to study drug 
administration.
3.
Positive test result for Hepatitis B surface antigen (HbsAg) or anti-HIV antibody (HIV Ab) test.
4.
Current enrollment in another interventional clinical study, previous enrollment in this study, prior or 
current use of any investigational or commercially available anti-HCV agents other than IFNs or 
RBV or receipt of any investigational product within 6 weeks prior to study drug administration.


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Investigational Products:
Weight < 45 kg or eligible but not willing to swallow the adult 
formulations:  Part 1
paritaprevir
1.0 mg mini-tablet
ritonavir
1.0 mg mini-tablet
ombitasvir
0.3 mg mini-tablet
dasabuvir 
3.08 mg mini-tablet
ribavirin 
40 mg/mL oral solution 
Weight < 45 kg:  Final pellet dosage strength:  Part 1
ombitasvir/paritaprevir/ritonavir
ombitasvir/paritaprevir/ritonavir 
X1/X2/X3 mg pellets
dasabuvir 
dasabuvir X4 mg pellets
ribavirin 
40 mg/mL oral solution 
Weight ≥ 45 kg who are ≥ 12 to 17 years old and willing to swallow 
the adult formulations:
ombitasvir/paritaprevir/r  
12.5/75/50 mg tablet
dasabuvir  
250 mg tablet
ribavirin
200 mg tablet
  
Doses:
Part 1:
Initial dosing based on body weight at time of Screening:
≤ 14 kg
15 to 29 kg
30 to 44 kg
≥ 45 kg
paritaprevir (QD) 
35 mg
50 mg
100 mg
150 mg
ritonavir (QD)
25 mg
35 mg
70 mg
100 mg
ombitasvir (QD)
5 mg
10 mg
15 mg
25 mg
dasabuvir (BID)
50 mg
100 mg
150 mg
250 mg
ribavirin
Per local label
The doses for ombitasvir/paritaprevir/r and dasabuvir pellet dosing in 
Part 1 will be determined from Part 1 mini-tablet dosing. 
Part 2:
Only adult formulation will be provided to subjects who are in the 12 –
17 year old age group with weight greater than 45 kg and willing to 
swallow the adult formulations.
Mode of Administration:
Oral


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Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  
Part 1: Pediatric subjects will receive OBV, PTV, RTV, DSV with or without RBV for 12 weeks. 
Part 2: Pediatric subjects will receive OBV, PTV, RTV with or without DSV and with or without RBV 
for 12 weeks or 24 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each treatment and Post-Treatment Period visit in all 
three parts of the study.
Pharmacokinetic:
Plasma concentrations of OBV, possible OBV metabolites, PTV, possible PTV metabolites, DSV, DSV 
M1 metabolite, other possible DSV metabolites, RTV and RBV (if applicable) will be determined at each 
study visit for each subject for the treatment periods of Part 1 and Part 2.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests and vital signs.  Growth and development will be assessed relative to age specific norms.
Statistical Methods:
The pharmacokinetic analysis will be performed separately for Part 1 and Part 2.  For population 
pharmacokinetic analyses, data from Part 1 and Part 2 will be combined if needed.  All efficacy, safety, 
growth and development outcomes will be assessed across Parts 1 and 2 of the study with summaries by 
formulation and age group, totaled across the final dose formulations (2D + RBV, 3D ± RBV, and 
pellets), and totaled across adult formulations (2D + RBV and 3D ± RBV).  Analyses on durability of 
response, resistance, growth and development outcomes, and patient-reported outcomes will be 
performed through Post-Treatment Week 24 in Parts 1 and 2 and after Post-Treatment Week 24 for all 
subjects in Part 3. 
An interim analysis will occur once all subjects complete PT Week 12 or prematurely discontinue from 
the study.  Final analysis will occur after the completion of the whole study.
Efficacy:
The primary pharmacokinetic endpoints are Cmax and AUC following dosing on Week 2, and trough 
concentration (Ctrough) following dosing on Week 2 and Week 8 for OBV, PTV, DSV, and RTV.
The primary efficacy endpoint is the percentage of subjects with SVR12 among the subjects who receive 
the final dose formulations.  The final dose formulations are the adult formulations used in either Part 1 
and/or Part 2 (3D ± RBV and 2D + RBV) and the coated pellet formulation to be used in Part 1 only.  
The percentage of subjects achieving SVR12 will be calculated across all subjects on the final dose 
formulations along with the 2-sided 95% confidence interval.  The lower bound of the 2-sided 95% 
confidence interval of the percentage of subjects with SVR12 on the final dose formulations must be 
greater than 67% to show superiority to pegIFN and RBV as described in Section 8.2.


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Statistical Methods (Continued):
Efficacy (Continued):
The main secondary endpoints are:
1.
The percentage of subjects who achieve SVR12 summarized by formulation and age group and across 
all subjects on the adult formulations. 
2.
The percentage of subjects who achieve SVR24 by formulation and age group, across all the subjects 
on the final dose formulations, and across all subjects on the adult formulations;
3.
The percentage of subjects with ALT normalization during treatment, defined as ALT ≤ ULN at the 
final treatment visit for subjects with ALT > ULN at baseline, by formulation and age group, across 
all subjects on the final dose formulations, and across all subjects on the adult formulations.
For the secondary efficacy endpoints, the simple percentage will be calculated along with the 2-sided 
95% confidence interval.  For both primary and secondary endpoints, the normal approximation to the 
binomial distribution will be used if the rate is not 0% or 100%, otherwise the Wilson's score method will 
be used to calculate the confidence interval.  The lower bound of the 2-sided 95% confidence interval of 
the SVR24 rate in subjects on the final dose formulations will also be compared to 67%.
Resistance: 
For subjects with virologic failure and HCV RNA > 1000 IU/mL, the variants at each amino acid position 
(by population, deep, and/or clonal nucleotide sequencing) at available post baseline time points 
compared to baseline and prototypic reference standard sequences will be summarized by DAA target 
genes and accompanying listings will be provided. 
Safety:
All safety analysis will be done by age group separately for each formulation, for all subjects on the final 
dose formulations, and for all subjects on the adult formulations.
The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
MedDRA system organ class and preferred term.  Tabulations will also be provided in which the number 
of subjects reporting an adverse event (MedDRA preferred term) is presented by grade (Grades 1 – 5) 
and relationship to study drugs.
Change from baseline in laboratory tests and vital sign measurements to each time point of collection will 
be summarized descriptively.  Laboratory test and vital sign values that are potentially clinically 
significant, according to predefined criteria, will be identified and the number and percentage of subjects 
with potentially clinically significant values during treatment will be calculated.
Growth and Development: 
All growth and development analyses will be done by age group separately for each formulation, for all 
subjects on the final dose formulations, and for all subjects on the adult formulations.  The following 
growth and development endpoints will be calculated at applicable study visits.
!
Growth rate at each post baseline visit (defined as change in height over change in age from the 
previous visit)
!
Height z score
!
Waist circumference
!
Tanner staging


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Statistical Methods (Continued):
Pharmacokinetic:
Plasma concentrations and pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 metabolite, RTV 
and RBV, if applicable, will be tabulated for each subject and summarized as appropriate by formulation, 
weight range or age group.
Individual plasma concentrations or pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 
metabolite, RTV and RBV may be used for safety or efficacy evaluation if needed.
Additional analyses may be conducted as needed.
Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-748
Name of Study Drug:  ombitasvir, paritaprevir, 
ritonavir, dasabuvir, ribavirin
Phase of Development:  2/3
Name of Active Ingredient:  ombitasvir, 
paritaprevir, ritonavir, dasabuvir, ribavirin
Date of Protocol Synopsis:  21 August 2017
Protocol Title:  An Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Ombitasvir (OBV), Paritaprevir (PTV), Ritonavir (RTV) With or Without Dasabuvir (DSV) 
and With or Without Ribavirin (RBV) in Pediatric Subjects With Genotype 1 or 4 Chronic Hepatitis C 
Virus (HCV) Infection (ZIRCON)
Objectives:  
To assess the pharmacokinetics of OBV, PTV, RTV, and DSV with or without RBV in treatment-naïve, 
non-cirrhotic, HCV GT1-infected pediatric subjects in Part 1.
To assess the efficacy (percentage of subjects achieving SVR12 [defined as HCV RNA < LLOQ 12 weeks 
after the last actual dose of study drug]) or SVR24 [defined as HCV RNA < LLOQ 24 weeks after the last
actual dose of study drug]) and safety of OBV, PTV, RTV with or without DSV and with or without 
RBV for 12 or 24 weeks in HCV genotype 1 (GT1) or genotype 4 (GT4)-infected treatment-naïve and 
prior IFN (IFN or peg-IFN with or without RBV) treatment-experienced, cirrhotic and non-cirrhotic 
pediatric subjects in Part 1 and Part 2.
To assess the durability of response for subjects who achieved SVR, to assess the emergence and 
persistence of specific HCV amino acid variants associated with drug resistance in subjects who 
experienced virologic failure, and to assess the impact of OBV, PTV, RTV with or without DSV and with 
or without RBV on growth and development in Part 3, the long-term follow-up of approximately 
2.5 years.
Investigator:  Global, multicenter trial:  Investigator information is on file at AbbVie.
Study Sites:  Up to 30 sites globally.


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Study Population:  
Part 1:  Treatment-naïve, non-cirrhotic, GT1-infected pediatric patients ≥ 3 to 17 years of age 
Part 2:  Treatment-naïve and IFN (IFN or peg-IFN with or without RBV) treatment-experienced HCV 
GT1 or GT4-infected pediatric subjects ≥ 12 to 17 years of age with or without compensated cirrhosis
Part 3 (Long-term follow-up):  All subjects who take at least one dose of study drug and complete the 
Post-Treatment (PT) Week 24 visit in Part 1 or Part 2.
Number of Subjects to be Enrolled:  
Approximately 62 subjects will be enrolled in total into two Parts.  Part 1:  Approximately 
36 treatment-naïve, non-cirrhotic, GT1 subjects.  Part 2:  Approximately 26 subjects ≥ 12 to 17 years of 
age treatment-naïve or prior IFN treatment-experienced, cirrhotic or non-cirrhotic with GT1 or GT4 HCV 
infection.
Methodology:
The study aims to assess three formulations in the pediatric population.  The approved adult 3D 
(OBV/PTV/RTV and DSV) regimen formulation and the approved adult 2D (OBV/PTV/RTV) regimen 
formulation will be administrated in subjects who are in the ≥ 12 to 17 years old age group with weight 
greater than 45 kg and willing to swallow the adult formulation.  The mini-tablet formulation will be 
administered in subjects who are in the ≥ 3 – 8 and ≥ 9 – 11 age groups to identify the optimal or final 
doses.  
Part 1 mini-tablet is designed to allow for dose adjustment on an ongoing basis, based on available 
pharmacokinetic and clinical data to achieve therapeutic exposures that have been safe and efficacious in 
adult subjects.  Area under the concentration curve (AUC) from the intensive PK sampling at Week 2 
will be the primary measure for dose adjustment, which will be compared with the range of the geometric 
means and the range of individual values across Phase 1/2/3 studies in adults that had intensive PK data 
(see Section 5.1).  Cmax and Ctrough will be considered for safety and efficacy using the same rules.  Part 2 
(Safety and Efficacy) will use the adult formulation if the results from the adult formulation in Part 1 are 
satisfactory.  In Part 1 and Part 2, the treatment duration is either 12 weeks or 24 weeks and all pediatric 
subjects who receive at least 1 dose of study drug will be followed for 24 weeks in the post-treatment 
period after completing or prematurely discontinuing the study treatment.  All pediatric subjects who 
complete the Post-Treatment (PT) Week 24 visit in either Part 1 or Part 2 will be followed in Part 3 
(Long-term Follow-up) for 144 weeks.
Part 1 (Pharmacokinetic Study):
Approximately 36 treatment-naïve, non-cirrhotic, HCV GT1-infected pediatric subjects will be enrolled.  
In the ≥ 12 to 17 year age group, 12 subjects will receive the standard adult formulation; in the ≥ 3 to 8 
and ≥ 9 to 11 year age groups, at least 12 subjects will receive the mini-tablet formulation.  Up to 
12 additional subjects may be enrolled to receive the mini-tablet formulation in Part 1 if needed to 
adequately characterize the pharmacokinetics of a particular age group or subgroup.  Subjects in the ≥ 12 
to 17 year age group who are ≥ 45 kg and willing to swallow the adult formulations will begin enrollment 
before subjects in the younger age groups.  The starting drug regimen is defined by HCV sub-genotype.  
All HCV sub-genotype 1b (GT1b) subjects will receive study medication (OBV/PTV/RTV and DSV)
without RBV for 12 weeks as shown below.  All subjects with a HCV GT1 non-b infection will receive 
study medication with weight based RBV for 12 weeks. 


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Methodology (Continued):
Part 1 (Pharmacokinetic Study) (Continued):
Patient Population
Treatment
Duration
Genotype 1b, 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir 
12 weeks
Genotype 1a,* 
without cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + ribavirin
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, and Week 12.  At Week 2 and 
Week 8, the morning dose of study drug will be administered in the clinic at approximately 24 hours after 
the prior morning dose.  At Week 2, the evening doses will be administered in the clinic following the 
12 hour PK draw and the morning doses at Week 2 + 1 day will be administered in the clinic following 
the 24 hour PK draw.  PT visits will occur at PT Weeks 4, 12, and 24.
PK samples will be collected at the following timepoints from each subject:
!
Day 1:  4 hours postdose (the morning doses will be administered in the clinic)
!
Week 2:  2, 4, 8, 12 and 24 hours postdose (the morning doses, the evening doses following the 
12 hour PK draw and the morning doses following the 24 hour PK draw will be administered in the 
clinic)
!
Week 4: a PK sample (regardless of the dosing time)
!
Week 8: a trough PK sample (i.e., prior to the morning dose, which will be administered in the 
clinic)
!
Week 12: a PK sample (regardless of the dosing time)
Based on assessment of Week 2 intensive pharmacokinetic and clinical data, dose adjustments and/or 
dose adjustments for subsequently enrolled subjects may be performed.
Part 2 (Safety/Efficacy Study):
Approximately 16 HCV GT1-infected and approximately 10 HCV GT4-infected treatment-naïve or IFN 
(IFN or pegIFN with or without RBV) treatment-experienced pediatric subjects in the ≥ 12 to 17 age 
group will be enrolled.  
Subjects with GT1 infection will receive the 3D tablet formulation approved for adults (with or without 
RBV) and the subjects with GT4 infection will receive the 2D tablet formulation approved for adults with 
RBV.  RBV will be administered weight based as tablets or as solution per local RBV label.  The 
regimen and duration will be determined according to HCV genotype, sub-genotype and cirrhosis status.


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Methodology (Continued):
Part 2 (Safety/Efficacy Study) (Continued):
Patient Population
Treatment
Duration
Genotype 1b with or 
without compensated 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir 
(approved adult 3D formulation)
12 weeks
Genotype 1a,* without 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
12 weeks
Genotype 1a,* with 
compensated cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
24 weeks
Genotype 4 with or 
without compensated 
cirrhosis
ombitasvir + paritaprevir + ritonavir + ribavirin 
(approved adult 2D formulation plus RBV)
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
Study treatment visits will occur at Day 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and 
Week 24.  The latter 3 visits at Weeks 16, 20 and 24 are required for subjects with compensated cirrhosis 
taking study drug for 24 weeks.  PT visits will occur at PT Weeks 4, 12, and 24.
One PK sample (regardless of the dosing time) will be collected at each visit for each subject in Part 2.
The following criteria will be considered evidence of virologic failure during treatment.  Pediatric 
subjects demonstrating any of the following should be discontinued from study drug:
!
Confirmed increase from nadir (defined as 2 consecutive HCV RNA measurements 
> 1 log10 IU/mL above nadir) in HCV RNA at any time point
!
Confirmed HCV RNA ≥ 100 IU/ml (defined as 2 consecutive HCV RNA measurements 
≥100 IU/ml) at any point after achieving HCV RNA < LLOQ
Confirmatory testing should be completed as soon as possible.  If any of the above criteria are met, the 
subject will discontinue study treatment, if applicable.  If the Investigator feels that a subject who meets 
one of these criteria should still remain on study treatment, the subject would only be allowed to remain 
on treatment with approval of the AbbVie Study TA SD/TA MD.
Part 3 (Long-Term Follow-Up):
All subjects who have completed Post-Treatment Week 24 in either Part 1 or Part 2 of the study will be 
followed to assess the durability of viral response, for the emergence and persistence of resistant viral 
variants, and for SAEs related to study drug for an additional 120 weeks in the Long-term Follow-up 
period.  Study visits will occur at Post-Treatment Weeks 36, 48, 96, and 144.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female ≥ 3 to 17 years of age and weight ≥ 15 kg at time of enrollment.
2.
Willingness to participate in the study for up to 42 months.
3.
HCV infection demonstrated by positive anti-HCV Ab and HCV RNA ≥ 1000 IU/mL at the time of 
screening.
4.
Screening laboratory results indicating HCV genotype 1 for enrollment into Part 1 and genotype 1 or 
4 for enrollment into Part 2.
5.
Parent or legal guardian with the willingness and ability to provide written informed consent and 
subject willing and able to give assent, as appropriate for age and country.
Main Exclusion:  
1.
Women who are pregnant, breastfeeding, or are considering becoming pregnant.
2.
Use of known strong inducers and inhibitors (e.g., gemfibrozil) of cytochrome P450 2C8 (CYP2C8) 
in subjects receiving dasabuvir, or strong or moderate inducers of CYP3A, within 2 weeks or 
10 half-lives, whichever is longer, of the respective medication/supplement prior to study drug 
administration.
3.
Positive test result for Hepatitis B surface antigen (HbsAg) or anti-HIV antibody (HIV Ab) test.
4.
Current enrollment in another interventional clinical study, previous enrollment in this study, prior or 
current use of any investigational or commercially available anti-HCV agents other than IFNs or 
RBV or receipt of any investigational product within 6 weeks prior to study drug administration.
Investigational Products:
Weight < 45 kg or eligible but not willing to swallow the adult 
formulations:  Part 1
paritaprevir
1.0 mg mini-tablet
ritonavir
1.0 mg mini-tablet
ombitasvir
0.3 mg mini-tablet
dasabuvir 
3.08 mg mini-tablet
ribavirin 
40 mg/mL oral solution 
Weight ≥ 45 kg who are ≥ 12 to 17 years old and willing to swallow 
the adult formulations:
ombitasvir/paritaprevir/r  
12.5/75/50 mg tablet
dasabuvir  
250 mg tablet
Ribavirin
200 mg tablet
  


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Doses:
Part 1 Mini-Tablet:
Initial dosing based on body weight at time of Screening:
≥ 15 to 29 kg
≥ 30 to 44 kg
≥ 45 kg
paritaprevir (QD) 
50 mg
100 mg
150 mg
ritonavir (QD)
35 mg
70 mg
100 mg
ombitasvir (QD)
10 mg
15 mg
25 mg
dasabuvir (BID)
100 mg
150 mg
250 mg
Ribavirin solution
Per local label
Part 2:
Only adult formulation and RBV tablets if required will be provided to 
subjects who are in the ≥ 12 – 17 year old age group with weight equal 
and greater than 45 kg and willing to swallow the adult formulations.
Mode of Administration:
Oral
Reference Therapy:
Not applicable
Dose:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  
Part 1: Pediatric subjects will receive OBV, PTV, RTV, DSV with or without RBV for 12 weeks. 
Part 2: Pediatric subjects will receive OBV, PTV, RTV with or without DSV and with or without RBV 
for 12 weeks or 24 weeks.
Criteria for Evaluation:
Efficacy:
Plasma HCV RNA (IU/mL) will be assessed at each treatment and Post-Treatment Period visit in all 
three parts of the study.
Pharmacokinetic:
Plasma concentrations of OBV, possible OBV metabolites, PTV, possible PTV metabolites, DSV, DSV 
M1 metabolite, other possible DSV metabolites, RTV and RBV (if applicable) will be determined at each 
study visit for each subject for the treatment periods of Part 1 and Part 2.
Safety:
Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical 
laboratory tests and vital signs.  Growth and development will be assessed relative to age specific norms.


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Statistical Methods:
The pharmacokinetic analysis will be performed separately for Part 1 and Part 2.  For population 
pharmacokinetic analyses, data from Part 1 and Part 2 will be combined if needed.  All efficacy, safety, 
growth and development outcomes will be assessed across Parts 1 and 2 of the study with summaries by 
formulation, age and weight group, totaled across all subjects, and totaled across adult formulations 
(OBV/PTV/RTV + RBV and OBV/PTV/RTV and DSV ± RBV).  Analyses on durability of response, 
resistance, growth and development outcomes, and patient-reported outcomes will be performed through 
Post-Treatment Week 24 in Parts 1 and 2 and after Post-Treatment Week 24 for all subjects in Part 3. 
An interim analysis will occur once all subjects complete PT Week 12 or prematurely discontinue from 
the study.  Final analysis will occur after the completion of the whole study.
Efficacy:
The primary pharmacokinetic endpoints are Cmax and AUC following dosing on Week 2, and trough 
concentration (Ctrough) following dosing on Week 2 and Week 8 for OBV, PTV, DSV, and RTV.
The primary efficacy endpoint is the percentage of subjects with SVR12 among all subjects.  The 
percentage of subjects achieving SVR12 will be calculated along with the 2-sided 95% confidence 
interval.  The lower bound of the 2-sided 95% confidence interval of the percentage of subjects with 
SVR12 across all subjects must be greater than 67% to show superiority to pegIFN and RBV as described 
in Section 8.2.
The main secondary endpoints are:
1.
The percentage of subjects who achieve SVR12 summarized by formulation, age and weight group 
and across all subjects. 
2.
The percentage of subjects who achieve SVR24 by formulation, age and weight group, across all the 
subjects, and across all subjects on the adult formulations;
3.
The percentage of subjects with ALT normalization during treatment, defined as ALT ≤ ULN at the 
final treatment visit for subjects with ALT > ULN at baseline, by formulation, age and weight group, 
across all subjects, and across all subjects on the adult formulations.
For the secondary efficacy endpoints, the simple percentage will be calculated along with the 2-sided 
95% confidence interval.  For both primary and secondary endpoints, the normal approximation to the 
binomial distribution will be used if the rate is not 0% or 100%, otherwise the Wilson's score method will 
be used to calculate the confidence interval.  The lower bound of the 2-sided 95% confidence interval of 
the SVR24 rate across all subjects in the study will also be compared to 67%.
Resistance: 
For subjects with virologic failure and HCV RNA > 1000 IU/mL, the variants at each amino acid position 
(by population, deep, and/or clonal nucleotide sequencing) at available post baseline time points 
compared to baseline and prototypic reference standard sequences will be summarized by DAA target 
genes and accompanying listings will be provided. 


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Statistical Methods (Continued):
Safety:
All safety analysis will be done by age and weight group separately for each formulation, for all subjects, 
and for all subjects on the adult formulations.
The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
MedDRA system organ class and preferred term.  Tabulations will also be provided in which the number 
of subjects reporting an adverse event (MedDRA preferred term) is presented by grade (Grades 1 – 5) 
and relationship to study drugs.
Change from baseline in laboratory tests and vital sign measurements to each time point of collection will 
be summarized descriptively.  Laboratory test and vital sign values that are potentially clinically 
significant, according to predefined criteria, will be identified and the number and percentage of subjects 
with potentially clinically significant values during treatment will be calculated.
Growth and Development: 
All growth and development analyses will be done by age group separately for each formulation, for all 
subjects, and for all subjects on the adult formulations.  The following growth and development 
endpoints will be calculated at applicable study visits.
!
Growth rate at each post baseline visit (defined as change in height over change in age from the 
previous visit)
!
Height z score
!
Waist circumference
!
Tanner staging
Pharmacokinetic:
Plasma concentrations and pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 metabolite, RTV 
and RBV, if applicable, will be tabulated for each subject and summarized as appropriate by formulation, 
weight range or age group.
Individual plasma concentrations or pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 
metabolite, RTV and RBV may be used for safety or efficacy evaluation if needed.
Additional analyses may be conducted as needed.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:  "APRI"
APRI
Aspartate Aminotransferase to Platelet Ratio Index
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Definition of Terms
"Long-Term Follow-Up (LTFU)" previously read:
Long-Term Follow-Up (LTFU)
Day after Post-Treatment Week 24 visit through Post-
Treatment Week 168 or Post-Treatment Discontinuation


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Has been changed to read:
Long-Term Follow-Up (LTFU)
Day after Post-Treatment Week 24 visit through Post-
Treatment Week 144 or Post-Treatment Discontinuation
Section 3.0  Introduction
Subsection AbbVie's 3D Regimen
Subsection title previously read:
AbbVie's 3D Regimen
Has been changed to read:
AbbVie's Ombitasvir/Paritaprevir/r (OBV/PTV/RTV) and Dasabuvir (DSV), Also Known 
as the 3D Regimen
Section 3.0  Introduction
Subsection AbbVie's 3D Regimen
Second paragraph previously read:
The safety and efficacy of ombitasvir/paritaprevir/r 25/150/100 mg once daily and 
dasabuvir 250 mg twice daily (3D regimen) was evaluated in six Phase 3 randomized, 
multicenter, clinical trials (Studies M11-646, M13-098, M13-389, M13-961, M14-002 
and M13-099) in more than 2,300 adult subjects with chronic HCV GT1 infection who 
received the 3D regimen with or without ribavirin for 12 or 24 weeks, including one trial 
exclusively in subjects with compensated cirrhosis.
Has been changed to read:
The safety and efficacy of OBV/PTV/RTV 25/150/100 mg once daily and DSV 250 mg 
twice daily was evaluated in six Phase 3 randomized, multicenter, clinical trials 
(Studies M11-646, M13-098, M13-389, M13-961, M14-002 and M13-099) in more than 
2,300 adult subjects with chronic HCV GT1 infection who received the 3D regimen with 
or without ribavirin for 12 or 24 weeks, including one trial exclusively in subjects with 
compensated cirrhosis.


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Section 3.0  Introduction
Subsection AbbVie's 2D Regimen
Subsection title previously read:
AbbVie's 2D Regimen
Has been changed to read:
AbbVie's Ombitasvir/Paritaprevir/r (OBV/PTV/RTV), Also Known as the 2D Regimen
Section 3.1  Differences Statement
Last sentence previously read:
In Part 3, long-term safety and efficacy will be evaluated in a 168-week long-term follow-
up period.
Has been changed to read:
In Part 3, long-term safety and efficacy will be evaluated for 144 weeks.
Section 3.3  Pediatric Study Plan and Pediatric Investigational Plan
Last paragraph, first sentence previously read:
Similarly, the initial PSP for 3D, dated December 19, 2013, provided a waiver for the 
pediatric population younger than 3 years of age and a deferral to begin the PK and 
safety/efficacy studies in pediatric populations after the approval of OBV/PTV/RTV and 
DSV in adults with GT1 infection.  
Has been changed to read:
Similarly, the initial PSP for OBV/PTV/RTV and DSV, dated December 19, 2013, 
provided a waiver for the pediatric population younger than 3 years of age and a deferral 
to begin the PK and safety/efficacy studies in pediatric populations after the approval of 
OBV/PTV/RTV and DSV in adults with GT1 infection.  


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Section 4.0  Study Objective
Subsection Secondary Objective(s):
Previously read:
●
To evaluate the percentage of subjects with SVR12 by formulation and age 
group and across all subjects on the adult formulations.
●
To evaluate the percentage of subjects with SVR24 and the percentage of 
subjects with ALT normalization by the end of treatment, by formulation and 
age group, across all subjects on the final dose formulations, and across all 
subjects on the adult formulations.
Has been changed to read:
●
To evaluate the percentage of subjects with SVR12 by formulation, age and 
weight group and across all subjects on the adult formulations.
●
To evaluate the percentage of subjects with SVR24 and the percentage of 
subjects with ALT normalization by the end of treatment, by formulation, age 
and weight group, across all subjects, and across all subjects on the adult 
formulations.
Section 5.1  Overall Study Design and Plan:  Description
First paragraph, first sentence previously read:
Part 1 of this study is a Phase 2 study in which eligible HCV GT1-infected, treatment-
naïve, non-cirrhotic pediatric subjects will receive OBV, PTV, RTV with DSV and with 
or without RBV for 12 weeks.
Has been changed to read:
In Part 1 of this study eligible HCV GT1-infected, treatment-naïve, non-cirrhotic pediatric 
subjects will receive OBV, PTV, RTV with DSV and with or without RBV for 12 weeks.


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Section 5.1  Overall Study Design and Plan:  Description
First paragraph, eighth sentence previously read:
After completing the Post-Treatment Period in Part 1 or Part 2, the subjects will be 
followed in Part 3 for 168 weeks.  
Has been changed to read:
After completing the Post-Treatment Period in Part 1 or Part 2, the subjects will be 
followed in Part 3 for 144 weeks.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Part 1
First paragraph previously read:
In Part 1, the primary objective is to assess the pharmacokinetics of OBV, PTV, RTV and 
DSV with or without RBV in HCV GT1-infected, treatment-naive pediatric subjects.  
Part 1 will include approximately 36 subjects.  At least 12 subjects will enroll in each of 
the 3 age year groups, ≥ 3 to 8, ≥ 9 to 11, and ≥ 12 to 17.  Enrollment will begin with 
pediatric subjects ≥ 12 to 17 years old who are ≥ 45 kg and willing to swallow the 3D 
adult formulations.  After acceptable pharmacokinetic and safety data are available from 
at least 6 subjects from the ≥ 12 to 17 age group who receive the adult 3D regimen, 
subjects ages ≥ 9 to 11 will begin enrollment to be administered the mini-tablet 
formulations.  After acceptable pharmacokinetic and safety data are available from at least 
6 subjects from the ≥ 9 to 11 age group (at least 4 of which have a body weight of 15 to 
44 kg) subjects ages ≥ 3 to 8 will be enrolled in the mini-tablets.  In the ≥ 3 to 8 year age 
group, at least 4 subjects each from subgroups ≥ 3 to 5 and ≥ 6 to 8 years old will be 
enrolled to ensure that there is adequate information for dosing recommendations for the 
entire ≥ 3 to 8 age group.  Up to 12 additional pediatric subjects may be enrolled in Part 1 
if needed to adequately characterize the pharmacokinetics and determine the final dose 
strength for a particular age group or subgroup.  After the doses are established for the ≥ 9 
to 11 and ≥ 3 to 8 age groups using the mini-tablets, at least 6 additional subjects in each 
of the age groups will be enrolled and administered the co-formulated pellet formulation if 


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available to establish the PK, safety and efficacy of this formulation.  Subjects will be 
followed in Part 1 of the study through Post-Treatment Week 24.
Has been changed to read:
In Part 1, the primary objectives are to assess the pharmacokinetics, efficacy and safety of 
OBV, PTV, RTV and DSV with or without RBV in HCV GT1-infected, treatment-naive 
pediatric subjects.  Part 1 will include approximately 36 subjects.  At least 12 subjects will 
enroll in each of the 3 age year groups, ≥ 3 to 8, ≥ 9 to 11, and ≥ 12 to 17.  Enrollment 
will begin with pediatric subjects ≥ 12 to 17 years old who are ≥ 45 kg and willing to 
swallow the OBV/PTV/RTV and DSV adult formulations.  After acceptable 
pharmacokinetic, efficacy and safety data are available from at least 6 subjects from the 
≥12 to 17 age group who receive the adult regimen, subjects ages ≥ 9 to 11 will begin 
enrollment to be administered the mini-tablet formulations.  After acceptable 
pharmacokinetic, efficacy and safety data are available from at least 6 subjects from the 
≥9 to 11 age group (at least 4 of which have a body weight of 15 to 44 kg) subjects ages 
≥ 3 to 8 will be enrolled and administered the mini-tablets.  In the ≥ 3 to 8 year age group, 
at least 2 subjects each from subgroups ≥ 3 to 5 and ≥ 6 to 8 years old will be enrolled to 
ensure that there is adequate information for dosing recommendations for the entire ≥ 3 to 
8 age group.  Up to approximately 12 additional pediatric subjects may be enrolled to 
receive the mini-tablet formulation in Part 1 if needed to adequately characterize the 
pharmacokinetics and determine the final dose strength for a particular age group or 
subgroup.  Subjects will be followed in Part 1 of the study through Post-Treatment 
Week 24.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Part 1
Second paragraph, second sentence previously read:
All other children < 12 years of age will be dosed with either a pediatric mini-tablet 
formulation or pediatric co-formulated pellets.  


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Has been changed to read:
All other children ≥ 3 to 11 years of age will be dosed with the pediatric mini-tablet 
formulation.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Part 1
Heading "Dose Adjustment Considerations for Part 1"
First paragraph, second sentence previously read:
No dose adjustments of DAAs will be made as a consequence of weight change during the 
treatment period.  
Has been changed to read:
No dose adjustments of DAAs or RBV will be made as a consequence of weight change 
during the treatment period.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Part 2
First sentence previously read:
In Part 2, the primary objectives are to evaluate the safety and efficacy (percentage of 
treatment-naïve or treatment-experienced subjects achieving SVR12) of OBV/PTV/RTV 
and DSV with or without RBV in HCV GT1-infected subjects and OBV/PTV/RTV in 
GT4-infected pediatric subjects with or without compensated cirrhosis.  
Has been changed to read:
In Part 2, the primary objectives are to further evaluate the safety and efficacy (percentage 
of treatment-naïve or treatment-experienced subjects achieving SVR12) of 
OBV/PTV/RTV and DSV with or without RBV in HCV GT1-infected pediatric subjects 
and OBV/PTV/RTV in GT4-infected pediatric subjects with or without compensated 
cirrhosis.  


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Part 3 (Long-Term Follow-Up Period)
Second sentence previously read:
All pediatric subjects who complete the PT Week 24 visit in Part 1 or Part 2 will be 
automatically enrolled into Part 3 and followed for up to 168 weeks.  
Has been changed to read:
All pediatric subjects who complete the PT Week 24 visit in Part 1 or Part 2 will be 
automatically enrolled into Part 3 and followed for up to 144 weeks.
Figure 1.  Study Schematic
Previously read:


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Has been changed to read:
Section 5.1  Overall Study Design and Plan:  Description
Subsection Fibrosis Assessment
Last paragraph, first sentence previously read:
The study is designed to enroll approximately 74 subjects to meet scientific, regulatory 
and clinical objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  
Has been changed to read:
The study is designed to enroll approximately 62 subjects to meet scientific, regulatory 
and clinical objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  
Table 6.  Treatment Regimen and Duration – Part 2
Table title previously read:
Treatment Regimen and Duration – Part 2


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Has been changed to read:
Treatment Regimen and Duration – Part 2 (For Subjects ≥ 12 – 17 Years of Age)
Section 5.1.4  Long-Term Follow-Up Period
First paragraph, second sentence previously read:
The Long-term Follow-up Period will begin the day following the Post-Treatment 
Week 24 visit and last for 168 weeks as outlined in Appendix C.
Has been changed to read:
The Long-term Follow-up Period will begin the day following the Post-Treatment 
Week 24 visit and last for 144 weeks as outlined in Appendix C.  
Section 5.2.1  Inclusion Criteria
Criterion 1, 2, 3 and 4 previously read:
1. Male or female ≥ 3 to 17 years of age at time of enrollment.
2. Willingness to participate in the study for up to 50 months.
3. If female, subject must either be pre-menarche and not sexually active, permanently 
surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) 
OR for Women of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control (Section 5.2.4), starting at Study Day 1 (or earlier) 
through at least 30 days after stopping study drug (if not receiving RBV), or for up to 
4 months after stopping study drug if receiving RBV (or as directed by local RBV 
label).
4. If male subject and sexually active with female partner(s) of childbearing potential, 
subject must agree to practice the protocol specified contraception (Section 5.2.4), 
from Study Day 1 and for up to 7 months after stopping study drug (or as directed by 
the local RBV label if receiving RBV) or from Study Day 1 through 30 days after last 
dose of study drug for subjects whose study regimen does not include RBV.


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Has been changed to read:
1. Male or female ≥ 3 to 17 years of age with weight ≥ 15 kg at time of enrollment.
2. Willingness to participate in the study for up to 42 months.
3. If female, subject must either be pre-menarche and not sexually active, permanently 
surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) 
OR for Women of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control (Section 5.2.4), starting at Study Day 1 (or earlier) 
through at least 30 days after stopping study drug (if not receiving RBV), or for up to 
6 months after stopping study drug if receiving RBV (or as directed by local RBV 
label).
4. If male subject and sexually active with female partner(s) of childbearing potential, 
subject must agree to practice the protocol specified contraception (Section 5.2.4), 
from Study Day 1 and for up to 9 months after stopping study drug (or as directed by 
the local RBV label if receiving RBV) or from Study Day 1 through 30 days after last 
dose of study drug for subjects whose study regimen does not include RBV.
Section 5.2.2  Exclusion Criteria
Criterion 1 previously read:
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after stopping study drug (if not receiving 
RBV), or for up to 4 months  after stopping study drug if receiving RBV (or as directed 
by local RBV label).
Has been changed to read:
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after stopping study drug (if not receiving 
RBV), or for up to 6 months after stopping study drug if receiving RBV (or as directed by 
local RBV label).


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Table 7.  Medications Contraindicated for Use with the Study Drug Regimen
Previously read:
Alfuzosin
Astemizole
Blonanserin
Carbamazepine
Cisapride
Dihydroergotamine
Efavirenz
Ergotamine
Ergonovine
Ethinyl estradiol-containing 
medications
Fusidic Acid
Gemfibrozila
Lovastatin
Methylergonovine
Midazolam (oral) 
Phenobarbital
Phenytoin
Pimozide
Rifampin
Salmeterol
Sildenafilb
Simvastatin
St. John's Wort
Terfenadine
Triazolam
a.
Strong CYP2C8 inhibitors (e.g., gemfibrozil) and CYP2C8 inducers are not contraindicated with ombitasvir, 
paritaprevir and ritonavir (for GT4 subjects).
b.
When used for the treatment of pulmonary arterial hypertension.
Note: Not all medications contraindicated with ribavirin are listed above.  Refer to the most current package inserts or 
product labeling of ribavirin for a complete list of contraindicated medications.
Has been changed to read:
Alfuzosin
Astemizole
Atorvastatin
Blonanserin
Carbamazepine
Cisapride
Colchicinec
Dihydroergotamine
Dronedarone
Efavirenz
Ergotamine
Ergonovine
Ethinyl estradiol-containing 
medications
Fusidic Acid
Gemfibrozila
Lovastatin
Lurasidone
Methylergonovine
Midazolam (oral) 
Phenobarbital
Phenytoin
Pimozide
Ranolazine
Rifampin
Salmeterol
Sildenafilb
Simvastatin
St. John's Wort
Terfenadine
Triazolam
a.
Strong CYP2C8 inhibitors (e.g., gemfibrozil) and CYP2C8 inducers are not contraindicated with ombitasvir, 
paritaprevir and ritonavir (for GT4 subjects).
b.
When used for the treatment of pulmonary arterial hypertension.
c.
When used in patients with renal or hepatic impairment.
Note: Not all medications contraindicated with ribavirin are listed above.  Refer to the most current package inserts or 
product labeling of ribavirin for a complete list of contraindicated medications.


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Section 5.2.2  Exclusion Criteria
Criterion 11 previously read:
Male subject who is considering fathering a child or donating sperm during the study or 
for approximately 120 days after stopping study drug if receiving DAAs only, or for up to 
7 months after stopping study drug if receiving RBV (or as directed by local RBV label).
Has been changed to read:
Male subject who is considering fathering a child or donating sperm during the study or 
for approximately 120 days after stopping study drug if receiving DAAs only, or for up to 
9 months after stopping study drug if receiving RBV (or as directed by local RBV label).
Section 5.2.4  Contraception Recommendations and Pregnancy Testing
Second paragraph, third bullet previously read:
Practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 30 days after stopping study drug (if not receiving RBV), or for up 
to 4 months after stopping study drug if receiving RBV (or as directed by local RBV 
label).
Has been changed to read:
Practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 30 days after stopping study drug (if not receiving RBV), or for up 
to 6 months after stopping study drug if receiving RBV (or as directed by local RBV 
label).
Section 5.2.4  Contraception Recommendations and Pregnancy Testing
Sixth paragraph, fourth bullet previously read:
if sexually active with female partner(s) of childbearing potential must agree to practice 
contraception with a method listed below from Study Day 1 and for up to 7 months after 
stopping study drug (or as directed by the local RBV label if receiving RBV) or from 


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Study Day 1 and continue for 120 days after last dose of study drug for subjects whose 
study regimen does not include RBV.
Has been changed to read:
if sexually active with female partner(s) of childbearing potential must agree to practice 
contraception with a method listed below from Study Day 1 and for up to 9 months after 
stopping study drug (or as directed by the local RBV label if receiving RBV) or from 
Study Day 1 and continue for 120 days after last dose of study drug for subjects whose 
study regimen does not include RBV.
Section 5.2.4  Contraception Recommendations and Pregnancy Testing
Last paragraph previously read:
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
120 days after the end of treatment if taking DAAs only, or for 7 months after the last 
dose of RBV (or per local RBV label).
Has been changed to read:
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
120 days after the end of treatment if taking DAAs only, or for 9 months after the last 
dose of RBV (or per local RBV label).
Table 8.  Clinical Laboratory Tests
Column "Clinical Chemistry"
Delete:
Alpha fetoprotein
Section 5.3.1.1  Study Procedures
Subsection Acceptability Questionnaires
Subsection title previously read:
Acceptability Questionnaires


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Has been changed to read:
Acceptability Questionnaire
Section 5.3.1.1  Study Procedures
Subsection Acceptability Questionnaires
First paragraph, first sentence previously read:
For each subject who is taking the mini-tablet or pellet formulations, the 
parent(s)/guardian(s) of the subject will complete an Acceptability Questionnaire to 
provide feedback on the perception of the dosage form.  
Has been changed to read:
For each subject who is taking the mini-tablet formulation, the parent(s)/guardian(s) of the 
subject will complete an Acceptability Questionnaire to provide feedback on the 
perception of the dosage form.
Section 5.3.1.1  Study Procedures
Subsection Historical Liver Biopsy or FibroScan or Screening Fibro Test
First paragraph, last sentence previously read:
Subjects with no history of cirrhosis who have not had a liver biopsy or Fibroscan within 
24 months prior to screening, will undergo a non-invasive FibroTest and APRI at 
Screening to determine presence or absence of cirrhosis.
Has been changed to read:
Subjects with no history of cirrhosis who have not had a liver biopsy or Fibroscan within 
24 months prior to screening, will undergo a non-invasive FibroTest at Screening to 
determine presence or absence of cirrhosis.


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Section 5.3.1.1  Study Procedures
Subsection Historical Liver Biopsy or FibroScan or Screening Fibro Test
Heading "Longitudinal Fibrotest and APRI"
Heading title and text previously read:
Longitudinal Fibrotest and APRI
All subjects will undergo assessment of FibroTest and APRI at Screening or Day 1 and 
FibroTest and APRI at PT Weeks 24, 96 and 192.  Any subject that does not have a 
FibroTest and APRI performed during Screening will have them performed at Day 1.
Has been changed to read:
Longitudinal Fibrotest
All subjects will undergo assessment of FibroTest at Screening or Day 1 and FibroTest at 
PT Weeks 24, and 144.  Any subject that does not have a FibroTest performed during 
Screening will have them performed at Day 1.
Section 5.3.1.1  Study Procedures
Subsection Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha 
Fetoprotein
Subsection title previously read:
Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha Fetoprotein
Has been changed to read:
Hepatocellular Carcinoma Screening:  Liver Ultrasound
Section 5.3.1.1  Study Procedures
Subsection Hepatocellular Carcinoma Screening:  Liver Ultrasound and Alpha 
Fetoprotein
First paragraph previously read:
In order to monitor for the presence of hepatocellular carcinoma (HCC), an ultrasound of 
the liver and alpha fetoprotein testing will be performed as indicated in Appendix C for 
subjects with compensated cirrhosis only.


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Has been changed to read:
In order to monitor for the presence of hepatocellular carcinoma (HCC), an ultrasound of 
the liver will be performed as indicated in Appendix C for subjects with compensated 
cirrhosis only.
Section 5.3.1.1  Study Procedures
Subsection Ribavirin Diary
Add:  new subsection title and text
Ribavirin Diary
At Day 1, the principal investigator or designee will provide the parent(s)/legal 
guardian(s) with a Ribavirin Diary in case the subject is taking the RBV solution 
formulation.  The principal investigator or designee will complete the header of the RBV 
diary and instruct the parent(s)/legal guardian(s) on the completion of the diary.  The 
parent(s)/legal guardian(s) must bring the completed RBV diary to each of the study 
visits.  The principal investigator or designee will transcribe the information from the 
RBV diary into the RAVE system.
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Part 2
Fourth and fifth paragraph previously read:
For Part 1, the maximum amount of blood drawn for pharmacokinetic samples will be 
approximately 10 mL during a 24-hour period (at Week 2) and approximately 14 mL 
during a 30-day period (from Day 1 to Week 4) as indicated in Appendix D.
For Part 2, the maximum amount of blood drawn for pharmacokinetic samples will be 
approximately 2 mL during any 24-hour period and approximately 6 mL during a 30-day 
period (from Day 1 to Week 4) as indicated in Appendix D.


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Has been changed to read:
For Part 1, the maximum amount of blood drawn will be approximately 18.3 mL during a 
24-hour period (at Week 2) and approximately 55.8 mL during a 30-day period (from 
Day 1 to Week 4) as indicated in Appendix D.
For Part 2, the maximum amount of blood drawn after Day 1 (25.8 mL) will be 
approximately 11.7 mL during any 24-hour period and approximately 49.2 mL during a 
30-day period (from Day 1 to Week 4) as indicated in Appendix D.
Section 5.3.3.1  Primary Variables
Last paragraph and bullet list previously read:
The primary efficacy endpoint from Parts 1 and 2 is:
●
The percentage of treatment-naïve subjects with SVR12 among subjects on the 
final dose formulations.
Has been changed to read:
The primary efficacy endpoint is:
●
The percentage of subjects with SVR12 among all subjects.
Section 5.3.3.2  Secondary Variables
Bullet list previously read:
●
The percentage of subjects with SVR12 by formulation and age group and 
across all subjects on the adult formulations.
●
The percentage of subjects with SVR24 by formulation and age group, across 
all subjects on the final dose formulations, and across all subjects on the adult 
formulations.
●
The percentage of treatment-naïve subjects with ALT normalization during 
treatment, defined as ALT ≤ ULN at the final treatment visit for subjects with 
ALT > ULN at baseline by formulation and age group, across all subjects on 
the final dose formulations, and across all subjects the an adult formulations.


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Has been changed to read:
●
The percentage of subjects with SVR12 by formulation, age and weight group 
and across all subjects on the adult formulations.
●
The percentage of subjects with SVR24 by formulation, age and weight group, 
across all subjects, and across all subjects on the adult formulations.
●
The percentage of treatment-naïve subjects with ALT normalization during 
treatment, defined as ALT ≤ ULN at the final treatment visit for subjects with 
ALT > ULN at baseline by formulation, age and weight group, across all 
subjects, and across all subjects on the adult formulations.
Section 5.4.3  Discontinuation of Subjects Meeting Virologic Failure Criteria
Second and third bullet previously read:
●
Confirmed HCV RNA ≥ LLOQ (defined as 2 consecutive HCV RNA 
measurements ≥LLOQ) at any point after achieving HCV RNA < LLOQ
●
Failure to achieve HCV RNA < LLOQ on or before Week 6
Has been changed to read:
●
Confirmed HCV RNA ≥ 100 IU/ml (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/ml) at any point after achieving HCV RNA < LLOQ
Section 5.4.3  Discontinuation of Subjects Meeting Virologic Failure Criteria
Delete:  second paragraph
The sites should contact the subjects who have HCV RNA ≥ LLOQ at the Week 4 visit 
and have them return to the site at Week 6 for an unscheduled visit for HCV RNA testing.  
Only subjects with HCV RNA ≥ LLOQ at the Week 4 visit need to return to the site for an 
unscheduled blood draw for HCV RNA at Week 6.  If an inadequate virologic response at 
Week 6 is due to noncompliance or incorrect dosing or there is no evidence of virologic 
breakthrough, the study investigator may consider continuing treatment with the 
permission of the Study TA SD/TA MD.


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Section 5.5.1  Treatments Administered
First and second paragraph previously read:
Each dose of open-label DAA study drugs (ombitasvir, paritaprevir, ritonavir and 
dasabuvir) and ribavirin will be dispensed in the form of tablets, mini-tablets, pellets, or as 
an oral solution (RBV only).  Study drugs will be dispensed at the visits listed in 
Appendix C.
Note on dosage form nomenclature:  In the iPSPs and Study M14-748 protocol, the 
pediatric dosage form was previously referred to as either mini-tablets or granules.  
AbbVie has now determined the correct nomenclature for the pediatric dosage form to be 
"mini-tablets" for the administration of separate, individual components of the 3D 
regimen (ombitasvir, paritaprevir, ritonavir and dasabuvir) and "pellets" for the 
administration of co-formulated ombitasvir/paritaprevir/r with dasabuvir and will use this 
terminology for all new documents, but legacy documents or legacy investigational drug 
product labeling will not be revised.
Has been changed to read:
Each dose of open-label DAA study drugs (ombitasvir, paritaprevir, ritonavir and 
dasabuvir) and ribavirin will be dispensed in the form of tablets, mini-tablets, or as an oral 
solution (RBV only).  Study drugs will be dispensed at the visits listed in Appendix C.
Section 5.5.1  Treatments Administered
Subsection Part 1 Mini-Tablet and Pellet Formulations:
Subsection title previously read:
Part 1 Mini-Tablet and Pellet Formulations:
Has been changed to read:
Part 1 Mini-Tablet:


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Section 5.5.1  Treatments Administered
Subsection Part 1 Mini-Tablet and Pellet Formulations:
Add:  new third paragraph
The mini-tablets are packed in unit doses and are to be administered at once.  The legal 
guardian(s) should be counselled by site to check that the study drug bottles have been 
emptied completely into the dosing vehicle to assure the complete dose is taken by the 
subject.  Ombitasvir, Paritaprevir, Ritonavir will be taken orally and will be dosed QD 
based on body weight.  Dasabuvir will be taken orally and will be dosed BID based on 
body weight.
Section 5.5.1  Treatments Administered
Subsection Part 1 Mini-Tablet and Pellet Formulations:
Delete:  fifth paragraph
Once the final dose strength for the mini-tablets has been determined, enrollment into 
pellet dosing will be open upon sponsor notification.
Section 5.5.1  Treatments Administered
Subsection Part 1 Mini-Tablet and Pellet Formulations:
Delete:  seventh and eighth paragraph previously read:
A fixed dose pellet combination formulation containing ombitasvir/paritaprevir/r and a 
dasabuvir pellet formulation will be provided by the Sponsor as pellets per unit dose 
packaging.  The unit dose strength of ombitasvir/paritaprevir/r and dasabuvir will be 
determined with dose selection based on mini-tablet dosing in Part 1.  
Ombitasvir/paritaprevir/r will be taken orally and will be dosed QD based on body 
weight.
Dasabuvir will be taken orally and will be dosed BID based on body weight.
Section 5.5.2   Identity of Investigational Products
Previously read:
Information regarding the study drugs to be used in this study is presented in Table 10.


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Table 10.
Identity of Investigational Products
Part
Investigational Product
Manufacturer
Mode of 
Administration
Formulation
Strength
1 & 2
Ombitasvir/paritaprevir/ 
ritonavir
AbbVie
Oral
Tablets
12.5/75/50 mg
1 & 2
Dasabuvir
AbbVie
Oral
Tablets
250 mg
1
Ombitasvir
AbbVie
Oral
Mini-tablets
0.3 mg
1
Paritaprevir
AbbVie
Oral
Mini-tablets
1.0 mg
1
Ritonavir
AbbVie
Oral
Mini-tablets
1.0 mg
1 
Dasabuvir
AbbVie
Oral
Mini-tablets
3.08 mg
1
Ombitasvir/paritaprevir/ 
ritonavir
AbbVie
Oral
Pellets
X1/X2/X3 mg*
1
Dasabuvir
AbbVie
Oral
Pellets
X4* mg
1 & 2
Ribavirin
Kadmon/ 
AbbVie
Oral
Tablets
200 mg
1
Ribavirin
Merck
Oral
Solution
40 mg/mL
2
Ribavirin
MSD Sharp & 
Dohme
Oral
Solution
40 mg/mL
*
The unit dose strength of ombitasvir, paritaprevir, ritonavir and dasabuvir will be determined with dose selection 
based on Part 1.
Has been changed to read:
Information regarding the study drugs to be used in this study is presented in Table 10.


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Table 10.
Identity of Investigational Products
Part
Investigational 
Product
Manufacturer
Mode of 
Administration
Formulation
Strength
1 & 2
Ombitasvir/paritaprevir/ 
ritonavir
AbbVie
Oral
Tablets
12.5/75/50 mg
1 & 2
Dasabuvir
AbbVie
Oral
Tablets
250 mg
1
Ombitasvir
AbbVie
Oral
Mini-tablets
0.3 mg
1
Paritaprevir
AbbVie
Oral
Mini-tablets
1.0 mg
1
Ritonavir
AbbVie
Oral
Mini-tablets
1.0 mg
1 
Dasabuvir
AbbVie
Oral
Mini-tablets
3.08 mg
1 & 2
Ribavirin
Kadmon/ AbbVie
Oral
Tablets
200 mg
1
Ribavirin
Merck
Oral
Solution
40 mg/mL
2
Ribavirin
MSD Sharp & Dohme
Oral
Solution
40 mg/mL
Section 5.5.2.1  Packaging and Labeling
First paragraph
Delete:  third sentence
Pellets will be provided in unit dose packaging.
Section 5.5.2.1  Packaging and Labeling
Last paragraph previously read:
All blank spaces on the study drug labels should be completed by site staff prior to 
dispensing to subjects.
Has been changed to read:
All blank spaces (if applicable) on the study drug labels should be completed by site staff 
prior to dispensing to subjects.
Section 5.5.2.2  Storage and Disposition of Study Drugs
Third and fourth paragraph previously read:
Ombitasvir/paritaprevir/r pellets and dasabuvir pellets will be supplied to the sites in unit 
dose packaging.


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Mini-tablets and pellets can be administered in a dosing vehicle (e.g., applesauce, see 
dosing card for instructions).
Has been changed to read:
Mini-tablets can be administered in a dosing vehicle (e.g., applesauce, see dosing card for 
instructions).
Section 5.5.3  Method of Assigning Subjects to Treatment Groups
Second paragraph, first sentence previously read:
First, the subjects in the ≥ 12 to 17 year age group of Part 1 who are ≥ 45 kg and willing 
to swallow the adult formulations will be enrolled, then other groups of Part 1 will be 
enrolled (Section 5.1).
Has been changed to read:
First, the subjects in the ≥ 12 to 17 year age group of Part 1 who are ≥ 45 kg and willing 
to swallow the adult formulations will be enrolled, then sequential enrollment into the 
other age groups of Part 1 will start (Section 5.1).  
Section 5.5.6  Treatment Compliance
Second paragraph
Add:  new last sentence
When dosing mini-tablets, the bottles should be checked thoroughly to ensure that no 
mini-tablets remained inside the bottle.
Section 5.5.6  Treatment Compliance
Last paragraph, second sentence previously read:
The study site personnel will inspect the contents of the study drug units and account for 
the returned study drug electronically at each Study Drug Accountability visit indicated in 
Appendix C.  


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Has been changed to read:
The study site personnel will inspect the contents of the study drug bottles and account for 
the returned study drug electronically at each Study Drug Accountability visit indicated in 
Appendix C.  
Section 5.5.7  Drug Accountability
Subsection Adult Formulation and RBV Tablets Part 1 and Part 2
Subsection title previously read:
Adult Formulation and RBV Tablets Part 1 and Part 2
Has been changed to read:
Adult Formulations and RBV Tablets Part 1 and Part 2
Section 5.5.7  Drug Accountability
Subsection Mini-Tablets and Pellets (Part 1)
Subsection title and text previously read:
Mini-Tablets and Pellets (Part 1)
The status of each returned mini-tablet and pellet container will be noted in the IRT 
system and on a drug accountability log (if appropriate).  The Investigator/designee must 
document the status of the returned containers as full/sealed or empty or unsealed but not 
empty in the IRT system.  Labels must remain affixed to the bottles.
Has been changed to read:
Mini-Tablet Formulation (Part 1)
The status of each returned mini-tablet bottle will be noted in the IRT system and on a 
drug accountability log (if appropriate).  The Investigator/designee must document the 
status of the returned bottles as full/sealed or empty or unsealed but not empty in the IRT 
system.  Labels must remain affixed to the bottles.


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Section 5.6.3  Justification of Primary and Secondary Endpoint Success Criteria
Previously read:
According to the Highlights of Prescribing Information of PEGASYS®, the SVR24 rate 
was 47% among 45 treatment-naïve pediatric subjects with HCV GT1 in the NV17424 
trial.1 To show that the DAA regimen is superior to this current standard of care by 20%, 
the lower bound of the 2-sided 95% confidence interval of the SVR12 rate in subjects on 
the final dose formulations in the study must be greater than 67%.
For the secondary endpoints of the percentage of subjects with SVR12, the percentage of 
subjects with SVR24, and the percentage of subjects with ALT normalization during 
treatment, the simple percentage will be calculated along with a 2-sided 95% confidence 
interval.  The lower bound of the 2-sided 95% confidence interval of the SVR24 rate in 
subjects treated with a final dose formulation in the study will also be compared to 67%.  
ALT normalization is defined as the percentage of subjects with ALT at or below the 
upper limit of normal (ULN) at the final treatment visit among subjects with ALT > ULN 
at baseline, and will be presented along with a 2-sided 95% confidence interval.
Has been changed to read:
According to the Highlights of Prescribing Information of PEGASYS®, the SVR24 rate 
was 47% among 45 treatment-naïve pediatric subjects with HCV GT1 in the NV17424 
trial.1  To show that the DAA regimen is superior to this current standard of care by 20%, 
the lower bound of the 2-sided 95% confidence interval of the SVR12 rate across all 
subjects in the study must be greater than 67%.
For the secondary endpoints of the percentage of subjects with SVR12 by formulation, age 
and weight group, the percentage of subjects with SVR24, and the percentage of subjects 
with ALT normalization during treatment, the simple percentage will be calculated along 
with a 2-sided 95% confidence interval.  The lower bound of the 2-sided 95% confidence 
interval of the SVR24 rate across all subjects in the study will also be compared to 67%.  
ALT normalization is defined as the percentage of subjects with ALT at or below the 


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upper limit of normal (ULN) at the final treatment visit among subjects with ALT > ULN 
at baseline, and will be presented along with a 2-sided 95% confidence interval.
Section 5.6.4  Suitability of Subject Population
Third sentence previously read:
For the younger children in the ≥ 3 to 8 and ≥ 9 to 11 year old age groups, a mini-tablet or 
pellet formulation of all the DAAs and RTV will be used for ease of administration.  
Has been changed to read:
For the younger children in the ≥ 3 to 8 and ≥ 9 to 11 year old age groups, a mini-tablet 
formulation of all the DAAs and RTV will be used for ease of administration.  
Section 5.6.5  Selection of Doses in the Study
Fifth paragraph previously read:
For Part 1 of the present study, the proposed doses by body weight range are shown in 
Table 11.
Has been changed to read:
For Part 1 of the present study, the proposed doses by body weight range for subjects 
administered the adult formulation or the mini tablet formulation are shown in Table 11.
Table 11.  Proposed DAA and Ritonavir Doses for Pediatric Population
Table title and table previously read:
Table 11.
Proposed DAA and Ritonavir Doses for Pediatric Population
Body Weight
≤ 14 kg
15 to 29 kg
30 to 44 kg
≥ 45 kg
Paritaprevir (QD) 
35 mg
50 mg
100 mg
150 mg
Ritonavir (QD)
25 mg
35 mg
70 mg
100 mg
Ombitasvir (QD)
5 mg
10 mg
15 mg
25 mg
Dasabuvir (BID)
50 mg
100 mg
150 mg
250 mg


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Has been changed to read:
Table 12.
Proposed DAA and Ritonavir Doses for Subjects Administered the 
Adult Formulation or Mini Tablet Formulation
Body Weight
15 to 29 kg
30 to 44 kg
≥ 45 kg
Paritaprevir (QD) 
50 mg
100 mg
150 mg
Ritonavir (QD)
35 mg
70 mg
100 mg
Ombitasvir (QD)
10 mg
15 mg
25 mg
Dasabuvir (BID)
100 mg
150 mg
250 mg
Section 6.1.6  Pregnancy
First paragraph previously read:
Subjects and their partners should avoid pregnancy and males should avoid sperm 
donation throughout the course of the study, starting with Study Day 1 and for 30 days 
after the end of treatment with DAAs only, or for 7 months after the last dose of RBV (or 
per local RBV label) for males or through Post-Treatment Week 28 (or per local RBV 
label) for WOCBP and/or consistent with local treatment guidelines for RBV.
Has been changed to read:
Subjects and their partners should avoid pregnancy and males should avoid sperm 
donation throughout the course of the study, which is defined as from Study Day 1 until 
30 days after the last dose of study drug if subjects do not take RBV, or from Study Day 1 
until 6 months for WOCBP and 9 months for males after the last dose of the study drug 
containing RBV (or per local RBV label).




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Has been changed to read:
Demographics and baseline characteristics will be summarized by age and weight group 
separately for each formulation, for all subjects and for all subjects on the adult 
formulations in the ITT and ITT-3 populations.  
Section 8.1.1  Demographics
Fourth sentence previously read:
Baseline characteristics will include HCV genotype and sub-genotype (1a, 1b, 1-other and 
4 if applicable), IL28B genotype ([CC, CT, or TT] and [CC or non-CC]), IFN treatment 
history if applicable (treatment-naïve or IFN-based treatment-experienced [prior 
non-responder {null responder, partial responder, or other unable to specify}, 
breakthrough, relapse, and interferon experienced-other]), baseline platelets (< 90 or 
≥90 × 109/L), baseline albumin (< 35 or ≥ 35 g/L), baseline alpha fetoprotein (< 20 or 
≥20 ng/mL), baseline HCV RNA levels (continuous) and (< 800,000 IU/mL or 
≥800,000 IU/mL, baseline fibrosis stage [F0-1, F2, F3, F4]), baseline Fibrotest score, 
baseline APRI, baseline Child-Pugh score (non-cirrhotic, 5, 6, or > 6), tobacco use (user, 
ex-user, or non-user) status, alcohol use (drinker, ex-drinker, or non-drinker) status, and 
baseline Tanner pubertal staging – genital (males only), breast (females only), and pubic 
hair development.  Summary statistics (N, mean, median, SD, and range) will be 
generated for continuous variables (e.g., age and height z-score).  
Has been changed to read:
Baseline characteristics will include HCV genotype and sub-genotype (1a, 1b, 1-other and 
4 if applicable), IL28B genotype ([CC, CT, or TT] and [CC or non-CC]), IFN treatment 
history if applicable (treatment-naïve or IFN-based treatment-experienced [prior 
non-responder {null responder, partial responder, or other unable to specify}, 
breakthrough, relapse, and interferon experienced-other]), baseline platelets (< 90 or 
≥90 × 109/L), baseline albumin (< 35 or ≥ 35 g/L), baseline HCV RNA levels 
(continuous) and (< 800,000 IU/mL or ≥800,000 IU/mL, baseline fibrosis stage [F0-1, 
F2, F3, F4]), baseline Fibrotest score, baseline Child-Pugh score (non-cirrhotic, 5, 6, or 


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> 6), tobacco use (user, ex-user, or non-user) status, alcohol use (drinker, ex-drinker, or 
non-drinker) status, and baseline Tanner pubertal staging – genital (males only), breast 
(females only), and pubic hair development.  Summary statistics (N, mean, median, SD, 
and range) will be generated for continuous variables (e.g., age and height z-score)
Section 8.1.2.1  Primary Efficacy Endpoint Across Parts 1 and 2
First paragraph, first sentence previously read:
The primary efficacy endpoint is the percentage of subjects with SVR12 among all 
subjects on the final dose formulations.  
Has been changed to read:
The primary efficacy endpoint is the percentage of subjects with SVR12 among all 
subjects.
Section 8.1.2.2  Secondary Efficacy Endpoints Across Parts 1 and 2
Numbered list previously read:
1. The percentage of subjects who achieve SVR12 by formulation and age group, and 
across all subjects on the adult formulations.
2. The percentage of subjects who achieve SVR24 by formulation and age group, across 
all subjects on the final dose formulations and across all subjects on the adult 
formulations.
3. The percentage of subjects with ALT normalization during treatment, defined as ALT 
≤ ULN at the final treatment visit for subjects with ALT > ULN at baseline, by 
formulation and age group, across all subjects on the final dose formulations and 
across all subjects on the adult formulations.
Has been changed to read:
1. The percentage of subjects who achieve SVR12 by formulation, age and weight group, 
and across all subjects on the adult formulations.


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2. The percentage of subjects who achieve SVR24 by formulation, age and weight group, 
across all subjects, and across all subjects on the adult formulations.
3. The percentage of subjects with ALT normalization during treatment, defined as ALT 
≤ ULN at the final treatment visit for subjects with ALT > ULN at baseline, by 
formulation, age, and weight group, across all subjects, and across all subjects on the 
adult formulations.
Section 8.1.2.2  Secondary Efficacy Endpoints Across Parts 1 and 2
Last paragraph, second sentence previously read:
The lower bound of the 2-sided 95% confidence interval of the SVR24 rate across all 
subjects on the final dose formulations in the study will also be compared to 67%.  
Has been changed to read:
The lower bound of the 2-sided 95% confidence interval of the SVR24 rate across all 
subjects in the study will also be compared to 67%.  
Section 8.1.2.3  Additional Efficacy Endpoints Across Parts 1 and 2
First paragraph previously read:
The following efficacy endpoints will be analyzed by formulation and age group, across 
all subjects on the final dose formulations and across all subjects on the adult 
formulations:
Has been changed to read:
The following efficacy endpoints will be analyzed by formulation, age and weight group, 
across all subjects, and across all subjects on the adult formulations:
Section 8.1.2.3  Additional Efficacy Endpoints Across Parts 1 and 2
Item 3 previously read:
3. Change from baseline to all post-baseline visits in Fibrotest score and APRI.


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Has been changed to read:
3. Change from baseline to all post-baseline visits in Fibrotest score.
If the dose of the mini-tablets is adjusted for any age or weight group during the study, 
any subjects administered the dose considered not acceptable will be removed in a 
sensitivity analysis of SVR12 among subjects administered acceptable doses of OBV, 
PTV, RTV and DSV.
Section 8.1.2.3  Additional Efficacy Endpoints Across Parts 1 and 2
Third paragraph, second sentence previously read:
Breakthrough is defined as confirmed HCV RNA ≥ LLOQ after HCV RNA < LLOQ 
during treatment, or confirmed increase from nadir in HCV RNA (two consecutive HCV 
RNA measurement > 1 log10 IU/mL above nadir) at any time point during treatment.  
Has been changed to read:
Breakthrough is defined as confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ 
during treatment, or confirmed increase from nadir in HCV RNA (two consecutive HCV 
RNA measurement > 1 log10 IU/mL above nadir) at any time point during treatment.  
Section 8.1.2.3  Additional Efficacy Endpoints Across Parts 1 and 2
Last paragraph previously read:
The change from baseline to each post baseline visit of collection for Fibrotest and APRI 
will be summarized descriptively.
Has been changed to read:
The change from baseline to each post baseline visit of collection for Fibrotest will be 
summarized descriptively.


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Section 8.1.2.4  Subgroup Analysis of Parts 1 and 2
First paragraph previously read:
For subjects on the final dose formulations the number and percentage of subjects with 
SVR12 will be presented along with the 2-sided 95% confidence interval for the following 
subgroups if applicable.
Has been changed to read:
The percentage of subjects with SVR12 will be presented along with the 2-sided 95% 
confidence interval for the following subgroups if applicable.
Section 8.1.2.4  Subgroup Analysis of Parts 1 and 2
Second paragraph, third and fourth bullet previously read:
●
Baseline alpha fetoprotein (< 20, ≥ 20 ng/mL)
●
Any of platelets < 90 × 109/L, albumin < 35 g/L, or alpha fetoprotein 
≥20 ng/mL, or none of the three
Has been changed to read:
●
Any of platelets < 90 × 109/L and albumin < 35 g/L
Section 8.1.2.5  Treatment Failures
First paragraph previously read:
Across Parts 1 and 2, the number and percentage of subjects on final dose formulations, 
on the adult formulations and on the mini-tablet formulation meeting each and any of the 
following SVR24 and SVR12 non-response categories will summarized.  The summary 
might also be subgrouped by age group and HCV genotypes/sub-genotypes.
Has been changed to read:
Across Parts 1 and 2, the number and percentage of subjects overall, on the adult 
formulations, and on the mini-tablet formulation meeting each and any of the following 


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SVR24 and SVR12 non-response categories will summarized.  The summary might also be 
subgrouped by age and weight group, and HCV genotypes/sub-genotypes.
Section 8.1.5  Acceptability Questionnaire
Previously read:
For each subject taking the mini-tablet/pellet formulations, the parent(s)/guardian(s) of the 
subject will complete an Acceptability Questionnaire to provide feedback on the 
perception of the dosage form at the visits indicated in Appendix C.
Separately for mini-tablet and pellet formulations, the number and percentage of subjects 
with each categorical answer marked will be presented for each question in the 
acceptability questionnaire at each applicable treatment visit overall, by age group, and by 
weight group.  Listings of acceptability questionnaire results and comments for each 
applicable subject over applicable treatment visits will be produced separately for each 
part.
Has been changed to read:
For each subject taking the mini-tablet formulation, the parent(s)/guardian(s) of the 
subject will complete an Acceptability Questionnaire to provide feedback on the 
perception of the dosage form at the visits indicated in Appendix C.
The number and percentage of subjects with each categorical answer marked will be 
presented for each question in the acceptability questionnaire at each applicable treatment 
visit overall, by age and weight group.  Listings of acceptability questionnaire results and 
comments for each applicable subject over applicable treatment visits will be produced.
Section 8.1.6  Safety
Second sentence previously read:
The safety analysis will be carried out for all subjects in Parts 1 and 2 by formulation and 
age group, for all subjects on the final dose formulations, for all subjects on the adult 
formulations, and for all subjects on the mini-tablet formulation.  


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Has been changed to read:
The safety analysis will be carried out for all subjects by formulation, age and weight 
group, for all subjects on the adult formulation.
Section 8.1.8  Pharmacokinetic and Exposure-Response Analyses
First, second and third paragraph previously read:
Plasma concentrations of OBV, PTV, DSV, DSV M1 metabolite, RTV and RBV will be 
tabulated and summarized for subjects in Part 1 and Part 2 by age group and overall.
Values for the pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 metabolite, 
RTV and RBV including the Cmax, Tmax, Ctrough, and AUC will be tabulated and 
summarized for subjects in Part 1 by age group and overall.  Additional parameters or 
summaries may be determined if useful in the interpretation of the data.
Plasma concentration data from Part 1 and Part 2 of this study may be combined with data 
from other studies and analyzed using the following general methodology.
Has been changed to read:
Plasma concentrations of OBV, PTV, DSV, DSV M1 metabolite, RTV and RBV will be 
tabulated and summarized as appropriate by formulation, weight range or age group for 
subjects in Part 1 and Part 2.
Values for the pharmacokinetic parameters of OBV, PTV, DSV, DSV M1 metabolite, 
RTV and RBV including the Cmax, Tmax, Ctrough, and AUC will be tabulated and 
summarized formulation, weight range or age group for subjects in Part 1.  Additional 
parameters or summaries may be determined if useful in the interpretation of the data.
Section 8.2  Determination of Sample Size
Last paragraph, second and third sentence previously read:
To show that the DAA regimen is superior to this current standard of care by 20% in 
Parts 1 and 2, the lower bound of the 2-sided 95% confidence interval of the SVR12 rate in 


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subjects treated with a final dose formulation in the study must be greater than 67%.  For 
the primary efficacy endpoint of the percentage of subjects with SVR12 out of all subjects 
dosed with a final dose formulation, if it is assumed 90% subjects would achieve SVR12
then 50 subjects would have > 90% power to have a lower bound of 2-sided confidence 
interval based on normal approximation to the binomial distribution > 67%.
Has been changed to read:
To show that the DAA regimen is superior to this current standard of care by 20% in 
Parts 1 and 2, the lower bound of the 2-sided 95% confidence interval of the SVR12 rate 
across all subjects in the study must be greater than 67%.  For the primary efficacy 
endpoint of the percentage of subjects with SVR12, if it is assumed 90% subjects would 
achieve SVR12 then 50 or more subjects would have > 90% power to have a lower bound 
of 2-sided confidence interval based on normal approximation to the binomial distribution 
> 67%.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Global Drug Supply
Clinical
Statistics
Clinical
Bioanalysis


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Has been changed to read:
Name
Title
Functional Area
Pharmacokinetics
Clinical
Clinical
Global Drug Supply
Clinical
Statistics
Clinical
Bioanalysis
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Activity "Longitudinal Fibrotest & APRI" previously read:
Longitudinal Fibrotest & APRI
Has been changed to read:
Longitudinal Fibrotest


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Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Delete:  Activity "HCC Assessment:  Alpha fetoproteinp"
Treatment Period (TP)
Treatment Visits – All Subjects
Treatment Visits – 24-Week*
Premature 
D/C from 
Treatmentc
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
or 
EOTb
Wk 16
Wk 20
Wk 24 
(EOT)b
HCC Assessment:  Alpha fetoproteinp
X
X
X
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Activity "HCV RNA Samples" previously read:
Treatment Period (TP)
Treatment Visits – All Subjects
Treatment Visits – 24-Week*
Premature 
D/C from 
Treatmentc
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
or 
EOTb
Wk 16
Wk 20
Wk 24 
(EOT)b
HCV RNA Samples
X
X
X
Xx
X
X
X
X
X
X


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Has been changed to read:
Treatment Period (TP)
Treatment Visits – All Subjects
Treatment Visits – 24-Week*
Premature 
D/C from 
Treatmentc
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
or 
EOTb
Wk 16
Wk 20
Wk 24 
(EOT)b
HCV RNA Samples
X
X
X
X
X
X
X
X
X
X
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Add:  Activity "Drug compliance reviewdd"
Treatment Period (TP)
Treatment Visits – All Subjects
Treatment Visits – 24-Week*
Premature 
D/C from 
Treatmentc
Activity
Screening
Day 1a
Wk 2
Wk 4
Wk 8
Wk 12 
or 
EOTb
Wk 16
Wk 20
Wk 24 
(EOT)b
Drug compliance reviewdd
X
X
X
X
X
X


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Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Table note "m." and "n." previously read:
m.
Subjects with no history of cirrhosis who have not had a liver biopsy or Fibroscan within 24 months prior to 
screening, will have a screening FibroTest and APRI to determine the presence or absence of cirrhosis for the 
purpose of treatment assignment.  Subjects who have a liver biopsy or FibroScan indicating cirrhosis at any time in 
the past will not need a Fibrotest and APRI to be performed at screening as evidence of cirrhosis.
n.
Perform a Fibrotest and APRI at Day 1 for any subject who did not have a FibroTest and APRI done during 
Screening.
Has been changed to read:
m.
Subjects with no history of cirrhosis who have not had a liver biopsy or Fibroscan within 24 months prior to 
screening, will have a screening FibroTest to determine the presence or absence of cirrhosis for the purpose of 
treatment assignment.  Subjects who have a liver biopsy or FibroScan indicating cirrhosis at any time in the past 
will not need a Fibrotest to be performed at screening as evidence of cirrhosis.
n.
Perform a Fibrotest at Day 1 for any subject who did not have a FibroTest done during Screening.
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Table note "p.," first paragraph
Delete:  last sentence
Alpha fetoprotein testing will occur every 6 months.
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Table note "s.," first paragraph
First sentence previously read:
Part 1:  Study drugs will be dispensed every 2 weeks for subjects receiving the mini-
tablets or pellets with study visit procedures occurring at Day 1, Weeks 2, 4, 6, 8 and 10.  
Has been changed to read:
Part 1:  Study drugs will be dispensed every 2 weeks for subjects receiving the mini-
tablets with study visit procedures occurring at Day 1, Weeks 2, 4, 6, 8 and 10.  


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Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Table note "v.," second paragraph previously read: 
Part 1:  Dispensed/Collected every 2 weeks for subjects receiving the pellets with RBV 
with study visit procedures occurring at Day 1, Weeks 2, 4, and 8.
Has been changed to read:
Part 1:  Dispensed/Collected every 2 weeks for subjects receiving the mini-tablets with 
RBV with study visit procedures occurring at Day 1, Weeks 2, 4, and 8.
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Delete:  table note "x."
Subjects who fail to achieve HCV RNA < LLOQ at Week 4 will return at Week 6 for an 
unscheduled visit to assess HCV RNA.
Appendix C.  Study Activities
Subsection Study Activities – Treatment Period – Parts 1 and 2
Add:  table note "dd."
Sites will inspect the returned study drug containers at every visit to determine drug 
compliance.  Sites will counsel legal guardian(s) in case of non-drug compliance.  See 
Section 5.5.6 for more details.


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Appendix C.  Study Activities
Subsection Study Activities – Post-Treatment – Parts 1, 2 and 3
Previously read:
Post-Treatment (PT)
Post-Treatment Period of 
Parts 1 and 2 (PTP)
Part 3:  Long-Term Follow-Up (LTFU)
Premature 
D/C
Activity
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 72, 96, 120, 
144, 168, and 192
Vital Signs, Weight, Height, Waist Circumferencesa
X
X
X
X
X
X
X
Urine Pregnancy Testb
X
(Weeks 12, 16)
X
Longitudinal Fibrotest and APRI
X
Xc
Hematology/Chemistry/Urinalysisd/Coagulation Panel
X
X
HCC Assessment:  Liver Ultrasounde
X
X
X
HCC Assessment:  Alpha fetoproteine
X
X
X
X
Concomitant Medication Assessmentf
X
X
X
X
X
X
X
Adverse Event Assessmentg
X
X
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
HCV Resistance Sampleh
X
X
X
X
X
Tanner Pubertal Stagei
X
X
Xj
X
Patient Reported Outcomek
X
X
X
X
X
X
X
D/C = Discontinuation
a.
Height and Waist circumference will be measured at PT Weeks 12, 36, 72, 120, and 192 only. 


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b.
A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for additional details.)  Females who are experiencing menses 
or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential who are receiving DAAs only should have urine pregnancy testing done thru 
Post-Treatment Week 4.
c.
Females who are experiencing menses or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential who are receiving RBV should have urine 
pregnancy testing done monthly starting from Day 1 (Baseline) through PT Week 16 after RBV discontinuation or per local label.
d.
At the PT Visit 16subjects may have an unscheduled office visit for pregnancy testing or elect to perform the tests at home with test kits provided by the site.  Additional 
testing may be required per local RBV label.
e.
FibroTest and APRI will be performed at PT Weeks 96 and 192.
f.
Urinalysis will not be conducted after the Post-Treatment Week 4 visit.
g.
HCC assessment for subjects with compensated cirrhosis only:  Liver ultrasound testing will occur yearly.  Alpha fetoprotein testing will occur every 6 months.
h.
Only medications taken for SAEs assessed as related to study drugs and treatment of HCV will be collected after 30 days post-dosing.
i.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  Only drug-related SAEs will be collected thereafter.  See Section 6.1.4.
j.
Resistance samples are only collected for patients that meet virologic failure criteria.
k.
The Tanner Pubertal stage is assessed for subjects aged ≥ 9 to 17 years old.  Tanner staging will not be repeated once the child reaches Tanner Stage 5.
l.
Tanner Pubertal Staging only performed at PT Weeks 72, 120 and 192.
m.
The PRO should be administered as the first study procedure at each visit.


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Has been changed to read:
Post-Treatment (PT)
Post-Treatment Period of 
Parts 1 and 2 (PTP)
Part 3:  Long-Term Follow-Up (LTFU)
Premature 
D/C
Activity
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96, and 144
Vital Signs, Weight, Height, Waist Circumferencesa
X
X
X
X
X
X
X
Urine Pregnancy Testb
X
(Weeks 12, 16)
X
Longitudinal Fibrotest
X
Xc
Hematology/Chemistry/Urinalysisd/Coagulation Panel
X
X
HCC Assessment:  Liver Ultrasounde
X
X
X
Concomitant Medication Assessmentf
X
X
X
X
X
X
X
Adverse Event Assessmentg
X
X
X
X
X
X
X
HCV RNA Samples
X
X
X
X
X
X
X
HCV Resistance Sampleh
Tanner Pubertal Stagei
X
X
Xj
X
Patient Reported Outcomek
X
X
X
X
X
X
X
D/C = Discontinuation
a.
Height and Waist circumference will be measured at PT Weeks 12, 36, 96 and 144 only.
b.
A positive urine pregnancy test requires a confirmatory serum test.  (Refer to Section 5.3.1.1 [Pregnancy Test] for additional details.)  Females who are experiencing menses 
or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential who are receiving DAAs only should have urine pregnancy testing done thru 
Post-Treatment Week 4.
Females who are experiencing menses or are nearing sexual maturation in the opinion of the PI or who are of childbearing potential who are receiving RBV should have urine 
pregnancy testing done monthly starting from Day 1 (Baseline) through PT Week 16 after RBV discontinuation or per local label.


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At the PT Visit 16subjects may have an unscheduled office visit for pregnancy testing or elect to perform the tests at home with test kits provided by the site.  Additional 
testing may be required per local RBV label.
c.
FibroTest will be performed at PT Weeks 24 and 144.
d.
Urinalysis will not be conducted after the Post-Treatment Week 4 visit.
e.
HCC assessment for subjects with compensated cirrhosis only:  Liver ultrasound testing will occur yearly.
f.
Only medications taken for SAEs assessed as related to study drugs and treatment of HCV will be collected after 30 days post-dosing.
g.
Nonserious AEs and all SAEs will be collected until 30 days post dosing.  Only drug-related SAEs will be collected thereafter.  See Section 6.1.4.
h.
Resistance samples are only collected at the confirmation visit for patients that potentially meet virologic failure criteria.
i
The Tanner Pubertal stage is assessed for subjects aged ≥ 9 to 17 years old.  Tanner staging will not be repeated once the child reaches Tanner Stage 5.
j.
Tanner Pubertal Staging only performed at PT Weeks 12, 36, 96 and 144.
k.
The PRO should be administered as the first study procedure at each visit.


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Appendix D.  Estimated Blood Loss for Pediatric Subjects
Previously read:
Treatment Period – Part 1:  
Treatment Period (TP)
Treatment Visits – All Subjects
Premature D/C 
from Treatment
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Pediatric 
tubes
Screening
Day 1
Wk 2
Wk 4
Wk 6
Wk 8
Wk 12 
or EOT
21.2
29.2
38.3
23.7
6.0
22.3
23.7
24.8
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Standard 
tubes
29.0
31.8
40.5
26.3
6.0
24.05
26.3
28.8
Post-Treatment – Parts 1 and 3:  
Post-Treatment (PT)
Post-Treatment Period of 
Parts 1 (PTP)
Part 3:  Long-Term Follow-Up 
(LTFU)
Premature 
D/C
Estimated 
Whole Blood 
Drawn (mL) –
using Pediatric 
tubes
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 72, 96*, 120, 
144, 168, and 192*
19.7
16.0
20.7
16.0
17.1
17.1/*20.7
20.8
Estimated 
Whole Blood 
Drawn (mL) –
using 
Standard 
tubes
22.3
16.0
23.5
16.0
18.5
18.5/*23.5
24.8


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Has been changed to read:
Treatment Period – Part 1:  
Treatment Period (TP)
Treatment Visits – All Subjects
Premature D/C 
from Treatment
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Pediatric 
tubes
Screening
Day 1
Wk 2
Wk 4
Wk 8
Wk 12 or 
EOT
19.8
25.8
18.3
11.7
10.3
11.7
12.8
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Standard 
tubes
29.0
29.8
20.5
14.3
12.5
14.3
16.8


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Treatment Period – Part 2:  
Treatment Period (TP)
Treatment Visits – All Subjects
Premature D/C 
from 
Treatment
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Pediatric 
tubes
Screening
Day 1
Wk 2, 4, 8, 12, 
16 and 20
Wk 24 or 
EOT
19.8
25.8
11.7
12.8
12.8
Estimated 
Whole 
Blood 
Drawn 
(mL) –
using 
Standard 
tubes
29.0
29.8
14.3
16.8
16.8
Post-Treatment – Part 3:  
Post-Treatment (PT)
Post-Treatment Period of 
(PTP)
Part 3:  Long-Term Follow-Up 
(LTFU)
Premature 
D/C
Estimated 
Whole Blood 
Drawn (mL) –
using Pediatric 
tubes
PT 
Wk 4
PT 
Wk 12
PT 
Wk 24
PT 
Wk 36
PT 
Wk 48
PT 
Wks 96*, and 144
8.7
6.0
20.7
16.0
17.1
20.7*/17.1
20.8
Estimated 
Whole Blood 
Drawn (mL) –
using 
Standard 
tubes
12.3
6.0
23.5
16.0
18.5
23.5*/18.5
24.8

SAP_001.pdf: 
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir
M14-748 – Statistical Analysis Plan
Version 1.0 – 31 May 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M14-748
An Open-Label, Multicenter Study to Evaluate the 
Pharmacokinetics, Safety, and Efficacy of 
Ombitasvir (OBV), Paritaprevir (PTV), Ritonavir (RTV) 
With or Without Dasabuvir (DSV) and With or Without 
Ribavirin (RBV) in Pediatric Subjects With 
Genotype 1 or 4 Chronic Hepatitis C Virus (HCV) 
Infection (ZIRCON)
Date:  31 May 2018
Version 1.0
NCT02486406


Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir
M14-748 – Statistical Analysis Plan
Version 1.0 – 31 May 2018
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 9
4.4
Planned Analysis.................................................................................. 10
5.0
Analysis Populations ........................................................... 10
5.1
Definition for Analysis Populations ...................................................... 10
5.1.1
Intention-to-Treat (ITT) Population ...................................................... 10
5.1.2
Safety Population ................................................................................. 11
5.2
Variables Used for Stratification of Randomization.............................. 12
6.0
Analysis Conventions .......................................................... 12
6.1
Baseline and Final Value...................................................................... 12
6.1.1
Baseline................................................................................................ 12
6.1.2
Study Days........................................................................................... 12
6.1.3
Study Drug End Days........................................................................... 13
6.1.4
Final Treatment Value.......................................................................... 13
6.1.5
Final Post-Treatment Value .................................................................. 13
6.2
Analysis Windows................................................................................ 13
6.3
Missing Data Imputation ...................................................................... 18
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............19
7.1
Demographic and Baseline Characteristics ........................................... 20
7.2
Medical History.................................................................................... 21
7.3
Previous Treatment and Concomitant Medications ............................... 21
8.0
Patient Disposition............................................................... 22
9.0
Study Drug Exposure and Compliance.............................. 23
9.1
Exposure .............................................................................................. 23
9.2
Compliance .......................................................................................... 24


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10.0
Efficacy Analysis .................................................................24
10.1
General Considerations......................................................................... 24
10.2
Handling of Multiplicity....................................................................... 29
10.3
Primary PK and Primary Efficacy Analysis .......................................... 29
10.3.1
Primary PK Analysis ............................................................................ 29
10.3.2
Primary Efficacy Analysis Across Parts 1 and 2. .................................. 30
10.4
Secondary Efficacy Analyses Across Parts 1 and 2............................... 30
10.5
Efficacy Subgroup Analysis ................................................................. 31
10.6
Sensitivity Analysis for the Efficacy Endpoint of SVR12....................... 33
10.7
Additional Efficacy Analyses ............................................................... 33
10.8
Treatment Failures................................................................................ 34
10.9
Growth and Development..................................................................... 34
10.10
Resistance Analyses ............................................................................. 35
10.11
Patient Reported Outcomes .................................................................. 38
10.12
Acceptability Questionnaires................................................................ 38
11.0
Safety Analysis.....................................................................39
11.1
General Considerations......................................................................... 39
11.2
Analysis of Adverse Events.................................................................. 39
11.2.1
Treatment-Emergent Adverse Events.................................................... 39
11.2.1.1
Tabulations of Treatment-Emergent Adverse Events ............................ 39
11.2.2
Listing of Adverse Event...................................................................... 43
11.3
Analysis of Laboratory Data................................................................. 43
11.3.1
Variables and Criteria Defining Abnormality........................................ 43
11.3.2
Statistical Methods ............................................................................... 47
11.4
Analysis of Vital Signs and Weight ...................................................... 50
11.4.1
Variables and Criteria Defining Abnormality (if Applicable)................ 50
11.4.2
Statistical Methods ............................................................................... 50
12.0
References............................................................................50
List of Tables
Table 1.
Treatment Regimen and Duration by HCV Genotype, Subtype, 
and Cirrhosis Status................................................................................ 8


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Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Treatment Period) ............................................................................... 14
Table 3.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period) ....................................................................... 15
Table 4.
Analysis Time Windows for Laboratory Data, Vital Sign (Except 
Height, Waist circumference, and the Calculation of Growth rate), 
and PRO Instruments............................................................................ 16
Table 5.
Analysis Time Windows for Height, Waist Circumference, the 
Calculation of Growth Rate, and Tanner Pubertal Stage........................ 17
Table 6.
Analysis Time Windows for Acceptability Questionnaire 
(Treatment Period Only)....................................................................... 18
Table 7.
Analysis Time Windows for Fibrotest .................................................. 18
Table 8.
Criteria for Potentially Clinically Significant Hematology Values ........ 45
Table 9.
Criteria for Potentially Clinically Significant Chemistry Values ........... 46
Table 10.
Definitions of CTCAE Grades 1, 2, 3, and 4......................................... 48
List of Figures
Figure 1.
Study Schematic..................................................................................... 7


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Version 1.0 – 31 May 2018
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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
AbbVie Statistics and Statistical Programming for Study Protocol M14-748.  
Study M14-748 is designed to evaluate the pharmacokinetics, safety, and efficacy of 
ombitasvir (OBV), paritaprevir (PTV), ritonavir (RTV) with or without dasabuvir (DSV) 
and with or without ribavirin (RBV) in pediatric subjects with genotype 1 or 4 chronic 
hepatitis C virus (HCV) infection.
The SAP provides details to guide the analyses for baseline, efficacy, and safety variables 
and describes the populations and variables that will be analyzed and the statistical 
methods that will be utilized.  An interim analysis (after all subjects reach Post-Treatment 
[PT] Week 12 or prematurely discontinue the study) and an end of study analysis will be 
conducted for Study M14-748.  Analyses will be performed using SAS® Version 9.3 
(SAS Institute, Inc., Cary, NC) or later under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are to assess the pharmacokinetics of different OBV, 
PTV, RTV and DSV formulations with or without RBV in treatment-naïve, non-cirrhotic, 
GT 1 HCV-infected pediatric subjects in Part 1 and to assess the efficacy (percentage of 
subjects with SVR12 of all subjects) and safety of OBV/PTV/RTV with or without DSV 
and with or without RBV for 12 or 24 weeks in HCV GT1 or GT4-infected 
treatment-naïve and treatment-experienced pediatric subjects with and without 
compensated cirrhosis in Part 1 and Part 2.
The secondary objectives of this study are to evaluate the percentage of subjects with 
SVR12 by formulation, age and weight group and across all subjects on the adult 
formulation and to evaluate the percentage of subjects with SVR24 and the percentage of 
subjects with ALT normalization by the end of treatment, by formulation, age and weight 
group, and across all subjects on the adult formulation.


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4.2
Design Diagram
The study aims to assess three formulations in the pediatric population.  The approved 
adult 3D regimen formulation and the approved adult 2D regimen formulation will be 
administrated in subjects who are in the ≥ 12 to 17 age year group, weigh 45 kg or greater, 
and willing to swallow the adult formulation.  The mini-tablet formulation will be 
administered in subjects who are in ≥ 3 to 8 and ≥ 9 to 11 age year groups in order to 
identify the optimal doses or final dose.
The study consists of three parts.  In Part 1, a Phase 2 study, 36 or more eligible HCV 
GT1-infected, treatment-naïve, non-cirrhotic pediatric subjects will receive 12 weeks 
treatment with OBV/PTV/RTV with DSV and with or without RBV depending on HCV 
sub-genotype.  At least 12 subjects in the ≥ 12 to 17 age year group who are ≥ 45 kg and 
willing to swallow the 3D adult formulation will be enrolled first to receive the 3D adult 
formulation.  At least 12 subjects per each of the ≥ 9 to 11 and ≥ 3 to 8 age year groups 
will be enrolled to receive the mini-tablet formulation.  Up to 12 additional pediatric 
subjects may be enrolled to receive mini-tablet in Part 1 if needed to adequately 
characterize the pharmacokinetics and determine the final dose strength for a particular 
age group or subgroup. 
In Part 2, a Phase 3 study, eligible genotype 1 or 4-infected subjects will receive 
OBV/PTV/RTV with or without DSV and with or without RBV for 12 or 24 weeks 
treatment depending on HCV genotype, sub-genotype and cirrhosis status.  Part 2 will 
evaluate the adult formulation in treatment-naïve and IFN treatment-experienced HCV 
GT1 or GT4-infected adolescents with or without compensated cirrhosis.  Approximately 
16 GT1 and 10 GT4 infected adolescents will be enrolled in Part 2.
In both Parts 1 and 2, if RBV is included in the treatment regimen, RBV will be provided 
as tablets to subjects who receive the adult formulation, and as 40 mg/ml oral solution to 
subjects who receive the mini-tablet.


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Both Parts 1 and 2 will consist of a Screening Period, a Treatment Period, and a 24-week 
Post-Treatment Period.  Subjects who take at least one dose of the study drug will be 
followed in the Post-Treatment Period.  Subjects who prematurely discontinue study 
treatment in Part 1 will be followed in the Post-Treatment Period in Part 1.  Similarly 
subjects who prematurely discontinue study treatment in Part 2 will be followed in the 
Post-Treatment Period in Part 2.  After completing the Post-Treatment Period in Part 1 or 
Part 2, subjects will be followed in Part 3 the long-term follow-up period for another 
120 weeks.  Subjects who prematurely discontinue from the Post-Treatment Period in 
Part 1 or Part 2 or from Part 3 will be discontinued from the study.
After meeting the eligibility criteria, a total of approximately 62 subjects will be enrolled 
to 12 weeks of treatment in Part 1 or either 12 or 24 weeks of treatment in Part 2.
Figure 1.
Study Schematic
The treatment duration will be 12 weeks for all subjects except HCV GT1a-infected 
subjects with cirrhosis; these subjects will receive treatment for 24 weeks.
The duration of the study will be 156 weeks (for subjects receiving a 12-week treatment) 
or 168 weeks (for subjects receiving a 24-week treatment), not including a screening 


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period of up to 42 days, consisting of a 12-week or 24-week Treatment Period and a 
Post-Treatment (PT) Period of 144 weeks in total for all subjects who receive at least 
one dose of study drug.
Subjects who meet the eligibility criteria will be enrolled in Part 1 or Part 2 to either 12 or 
24 weeks of combination therapy with or without RBV based on HCV genotype, subtype, 
and cirrhosis status as described in Table 1.
Treatment Period
Table 1.
Treatment Regimen and Duration by HCV Genotype, Subtype, and 
Cirrhosis Status
Patient Population
Treatment
Duration
Genotype 1b with or without 
compensated cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir 
(approved adult 3D formulation)
12 weeks
Genotype 1a,* without 
cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
12 weeks
Genotype 1a,* with 
compensated cirrhosis
ombitasvir + paritaprevir + ritonavir + dasabuvir + 
ribavirin (approved adult 3D formulation plus RBV)
24 weeks
Genotype 4 with or without 
compensated cirrhosis
ombitasvir + paritaprevir + ritonavir + ribavirin 
(approved adult 2D formulation plus RBV)
12 weeks
*
Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 sub-genotype or with 
mixed genotype 1 infection.
All GT1- and GT4-infected adolescent subjects in Part 1 and Part 2 will receive 
OBV/PTV/r 25/150/100 mg once daily (QD) and GT1-infected adolescent subjects in 
Part 2 will receive also DSV 250 mg twice daily (BID).  All adolescent subjects with 
HCV GT1a or GT4 infection will also receive RBV 1000 mg BID if weight is less than or 
equal to 75 kg or 1200 mg BID if weight is above 75 kg. 
For subjects receiving mini-tablet formulation in Part 1, the doses will be dependent on 
the weight group (15 to 24 kg, 25 to 29 kg, 30 to 44 kg, ≥ 45 kg) at enrollment.
The Treatment Period will include assessment of PK, antiviral response, growth and 
development outcomes (assessed by height and Tanner pubertal stage), patient reported 


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M14-748 – Statistical Analysis Plan
Version 1.0 – 31 May 2018
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outcomes (assessed by EuroQol 5 Dimensions 3 Levels Health State Instrument [EQ-5D-
3L] questionnaire), HCC (assessed by liver ultrasound only in subjects with cirrhosis), 
acceptability questionnaires (for subjects receiving the min-tablet formulation only), and 
progression of liver disease (assessed by Fibrotest).
Post-Treatment Period
All subjects who receive at least one dose of study drugs will be monitored for an 
additional 24 weeks following the last dose of study drugs in Part 1 or Part 2.  All subjects 
who complete the PT Week 24 visit in Part 1 or Part 2 will be followed till PT Week 144 
in Part 3.
The Post-Treatment (PT) Period will include assessment of antiviral response, growth and 
development outcomes (assessed by height and tanner pubertal stage), patient reported 
outcomes (assessed by EuroQol 5 Dimensions 3 Levels Health State Instrument [EQ-5D-
3L] questionnaire), HCC (assessed by liver ultrasound only for subjects with cirrhosis), 
and progression of liver disease (assessed by Fibrotest).
The PT Period will begin the day following the last dose of study drug treatment.
4.3
Sample Size
The sample size of 36 subjects in Part 1 will adequately characterize the pharmacokinetics 
of the AbbVie DAAs to enable dose selection in pediatric subjects.
According to the Prescribing Information of PEGASYS, the SVR24 rate in the NV17424 
trial was 47% among 45 treatment-naïve pediatric subjects with HCV GT1.  To show that 
the DAA regimen is superior to this standard of care by 20% in Parts 1 and 2, the lower 
bound of the 2-sided 95% confidence interval of the SVR12 rate across all subjects in the 
study must be greater than 67%.  For the primary efficacy endpoint of the percentage of 
subjects with SVR12, if it is assumed that 90% of subjects would achieve SVR12 then 
50 or more subjects would have > 90% power to have a lower bound of 2-sided 
confidence interval based on normal approximation to the binomial distribution > 67%.


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4.4
Planned Analysis
An interim analysis will occur after all subjects in Part 1 or Part 2 have completed the PT 
Week 12 Visit or prematurely discontinued from study.  The database will be versioned 
after performing appropriate data cleaning.  Final data through PT Week 144 will be 
locked in a later version of the database.  SAS® (SAS Institute, Inc., Cary, NC) for the 
UNIX operating system will be used for all analyses.  All statistical tests and all 
confidence intervals will be two-sided with an α level of 0.05.
All analyses will be conducted by statisticians and statistical programmers at AbbVie or 
their designees according to the methodologies specified in this SAP.
There is no intention of changing the study design based on efficacy findings from the PT 
Week 12 interim analysis.  The intention is to follow all subjects who receive study drug 
for at least 144 weeks following treatment.  There will be no statistical adjustment 
employed due to this interim analysis.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
5.1.1
Intention-to-Treat (ITT) Population
The intention-to-treat (ITT) population will consist of all subjects who receive at least
one dose of study drug in Part 1 or Part 2 of the study.  All data from Part 1, Part 2, and 
Part 3 will be combined together, as appropriate, for statistical analyses specified in the 
SAP.
Demographic, baseline characteristic, exposure, concomitant medication and medical 
history analyses will be performed in the ITT population by age and weight group and 
overall among subjects on the mini-tablet formulation (ITT mini-tablet table with 
6 columns), and in summary tables, by Part 1 vs Part 2 and overall for subjects on the 
adult formulation and overall among subjects on the mini-tablet formulation, and overall 
among all subjects (ITT summary table with 5 columns).  Efficacy endpoints, growth and 


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development outcomes, and patient reported outcomes will be summarized in the ITT 
population.  Acceptability questionnaire will be summarized overall and by age group 
among subject on the mini-tablet formulation in the ITT population.
In addition, sensitivity analyses of the percentage of subjects with SVR12, will be 
performed on the Modified Intent-to-Treat Genotype (mITT-GT) population, and 
Modified Intent-to-Treat Genotype and Virologic Failure (mITT-GT-VF) population, 
respectively, as defined below.
The mITT-GT population includes subjects who receive at least 1 dose of study drug in 
Part 1 or Part 2 but excludes the subjects in Part 1 who are not of HCV GT1 infection and 
subjects in Part 2 who are not of HCV GT1 or GT4 infection.  The mITT-GT population 
is used to reduce the risk of bias that could occur due to enrolled population deviating 
from the treatment regimen as specified by the protocol.
The mITT-GT-VF population includes all subjects who receive at least 1 dose of study 
drug but excludes the subjects in Part 1 who are not of HCV GT1 infection and the 
subjects in Part 2 who are not of HCV GT1 or GT4 infection and in either part excludes 
subjects who did not achieve SVR12 for reasons other than on treatment virologic failure 
or relapse.  The mITT-GT-VF population is used to reduce the risk of bias that could 
occur due to either discordant HCV genotype or failures unrelated to study drug.
5.1.2
Safety Population
All subjects who receive at least one dose of study drug in Part 1 or Part 2 will be 
included in the safety population, which will be the same as the ITT population for this 
study.
Safety analyses will be performed on the safety population by age group and overall 
among subjects on the mini-tablet formulation, by Part 1 vs Part 2 and overall among 
subjects on the adult formulation, and overall among all subjects (Safety Summary 
7 column table).


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5.2
Variables Used for Stratification of Randomization
Approximately 62 subjects will be enrolled to receive ombitasvir, paritaprevir, ritonavir 
with or without dasabuvir and with or without RBV for 12 or 24 weeks depending on their 
HCV genotype, subtype, and cirrhotic status as shown in Table 1.  No other stratification 
of enrollment will be used for this study, although dose will depends on age group and 
weight group that a subject falls in.
6.0
Analysis Conventions
6.1
Baseline and Final Value
6.1.1
Baseline
The baseline value refers to the last non-missing measurement collected before the 
first dose of study drug received in Part 1 or Part 2.  All assessments on Study Day 1 
should be performed prior to administering the first dose of study drug, in accordance 
with the protocol.  The baseline value is therefore determined by the last non-missing 
measurement collected on or before the first day of study drug administration.
If multiple measurements are recorded on the same day, the last measurement recorded 
prior to dosing will be used as the baseline value.  If these multiple measurements occur at 
the same time or time is not available, then the average of these measurements (for 
continuous data) or the worst among these measurements (for categorical data) will be 
considered as the baseline value.  This same baseline value will be used for Treatment and 
PT Periods.
Safety assessments that are collected due to a serious adverse event that occurs on the 
first dose day are excluded when applying this algorithm.
6.1.2
Study Days
Study Days (days relative to the first dose of study drug) are calculated for each time 
point relative to the first dose of study drug.  Study Days are negative values when the 
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values when the time point of interest is after the first study drug dose day.  There is no 
Study Day 0.  Study Day 1 is the day of the first dose of study drug.
6.1.3
Study Drug End Days
For all subjects who receive at least one dose of study drug, study drug end days (days 
relative to the last dose of study drug) are calculated relative to the last dose of study drug.  
The last day of study drug is defined as Study Drug End Day 0.  Days before it have 
negative study drug end days and days after it have positive study drug end days.
6.1.4
Final Treatment Value
The final treatment value for each subject is the last measurement collected after Study 
Day 1 and on or before Study Drug End Day 2.
6.1.5
Final Post-Treatment Value
The final post-treatment value for each subject is the last measurement collected after 
Study Drug End Day 2.
6.2
Analysis Windows
For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 2
and Table 3 describe how HCV RNA and resistance data are assigned to protocol-
specified time points during the Treatment and PT Periods, respectively.  All time points 
and corresponding time windows are defined based on the blood sample collection date.
For safety laboratory data, vital signs (except height and waist circumference and the 
calculation of growth rate), and health-related quality of life (QoL) PROs collected 
throughout the study, the time windows specified in Table 4 will be used.
For height, waist circumference, the calculation of growth rate, and Tanner pubertal stage 
collected throughout the study, the time windows specified in Table 5 will be used.  The 
growth rate will be calculated at each visit as the change in height (millimeter) over 
change in age (years) from the previous visit.


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For acceptability questionnaire, the time windows specified in Table 6 describes how data 
are assigned to protocol specified time points during the treatment period.
For Fibrotest collected throughout the study, the time windows specified in Table 7 will 
be used.
If more than one assessment is included in a time window, the assessment closest to the 
nominal time will be used.  If there are two observations equally distant to the nominal 
time, the latest one will be used in analyses.  The only exception to this is for the SVR 
windows (e.g., SVR4, SVR12, and SVR24); for these windows, the last value in the 
window will be used.
If multiple measurements are made on the same day for a safety laboratory parameter or a 
vital sign parameter, the average of the values will be used in analyses.  For summaries of 
shifts from baseline and potentially significant values, multiple values on the same day 
will not be averaged; all values will be considered for these analyses.
Table 2.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Treatment Period)
Scheduled Visit
Nominal Day
(Study Day)
Time Window
(Study Day Range)
Day 1/Baselinea
1a
≤ 1a
Week 2
14
2 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Week 12
84
71 to 98
Week 16b
112
99 to 126
Week 20b
140
127 to 154
Week 24b
168
155 to 182
Final Treatment Visitc
2 to ≤ 2 days after last dose of study drug
a.
Day of first dose of study drug.
b.
Applicable to subjects with 24 weeks of treatment.
c.
The last value within the window will be used to define the Final Treatment visit value.
Note:
Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.


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Table 3.
Analysis Time Windows for HCV RNA and Resistance Endpoints 
(Post-Treatment Period)
Scheduled Visita
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Day Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 210
Post-Treatment Week 36
252
211 to 294
Post-Treatment Week 48
336
295 to 504
Post-Treatment Week 96
672
505 to 840
Post-Treatment Week 144
1,008
841 to 1,176
SVR4
b
28
3 to 56
SVR12
b
84
57 to 126
SVR24
b
168
127 to 210
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
For SVR windows, the last value in the window will be used.
Note:
The result closest to the scheduled time point will be used, except for SVR4, SVR12, and SVR24.  Data must 
also have Study Drug End Day > 2 for all windows.  Study Drug End Day 0 is defined as the day of the last 
dose of study drug.


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Table 4.
Analysis Time Windows for Laboratory Data, Vital Sign (Except 
Height, Waist circumference, and the Calculation of Growth rate), 
and PRO Instruments
Scheduled Visita
Nominal Day
(Study Day)
Time Window
(Study Days Range)
Day 1/Baseline
1b
≤ 1b
Week 2
14
2 to 21
Week 4
28
22 to 42
Week 8
56
43 to 70
Week 12
84
71 to 98
Week 16c
112
99 to 126
Week 20c
140
127 to 154
Week 24c
168
155 to 182
Final Treatment Visitd
2 to ≤ 2 days after last dose of study drug
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 4
28
3 to 56
Post-Treatment Week 12
84
57 to 126
Post-Treatment Week 24
168
127 to 210
Post-Treatment Week 36
252
211 to 294
Post-Treatment Week 48
336
295 to 504
Post-Treatment Week 96
672
505 to 840
Post-Treatment Week 144
1,008
841 to 1,176
Final Post-Treatment Visite
> 2 days after last dose of study drug
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
Day of first dose of study drug.
c.
Applicable to subjects with 24 weeks of treatment.
d.
The last value within the window will be used to define the Final Treatment visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
e.
The last value within the Post-Treatment Period window will be used to define the Final Post-Treatment visit 
value.  The lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  For visits through Treatment Week 24, data must 
also be within 2 days after the last dose of study drug.  For post-treatment visits, data must also have Study 
Drug End Day > 2 where Study Drug End Day 0 is defined as the day of the last dose of study drug.
Lab data are collected only through Post-Treatment Week 4. 
Acceptability questionnaire is collected on Treatment Weeks 2, 12, and 24 if applicable for subjects taking the 
min-tablet formulation only.


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Table 5.
Analysis Time Windows for Height, Waist Circumference, the 
Calculation of Growth Rate, and Tanner Pubertal Stage
Scheduled Visita
Nominal Day
(Study Day)
Time Window
(Study Days Range)
Day 1/Baseline
1b
≤ 1b
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 12
84
3 to 168
Post-Treatment Week 36
252
169 to 462
Post-Treatment Week 96
672
463 to 840
Post-Treatment Week 144
1,008
841 to 1,176
Final Post-Treatment Visitc
> 2 days after last dose of study drug
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
Day of first dose of study drug.
c.
The last value within the Post-Treatment Period window will be used to define the Final Post-Treatment visit 
value.  The lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  For post-treatment visits, data must also have Study 
Drug End Day > 2 where Study Drug End Day 0 is defined as the day of the last dose of study drug.
Tanner pubertal stage is collected for all subjects with age ≥ 9 to 17 year old.  If a subject turns 9 year old 
during the study, the test will start to be performed after the subject turns 9 year old.  Once a child reaches 
Tanner Stage 5, the test will not be repeated.
For the calculation of growth rate only, height will be assigned to a visit as described in the table above, then 
growth rate will be calculated as the change in height (millimeter) over the change in age (years) from the 
previous visit.  If height is missing at a visit and/or the previous visit, then growth rate will be missing for the 
visit.


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Table 6.
Analysis Time Windows for Acceptability Questionnaire 
(Treatment Period Only)
Scheduled Visit
Nominal Day (Study Day)
Time Window (Study Day Range)
Week 2
14
2 to 35
Week 12 
84
57 to 126
Week 24a
84
127 to 182
Final Treatment Visitb
2 to ≤ 2 days after last dose of study drug
a.
For 24-week treatment only.
b.
The last value within the window will be used to define the Final Treatment Visit value.  The upper bound of this 
Final window is Study Drug End Day ≤ 2.
Note: Data must also have Study Drug End Day ≤ 2 for all windows.  The result closest to the scheduled time point 
will be used.  Palatability questionnaire are administrated to subjects in Part 2 at Week 2 and End of Treatment 
Visit or premature discontinuation visit.
Table 7.
Analysis Time Windows for Fibrotest
Scheduled Visita
Nominal Day
(Study Day)
Time Window
(Study Days Range)
Day 1/Baseline
1b
≤ 1b
Scheduled Visit
Nominal Day
(Study Drug End Day)
Time Window
(Study Drug End Days Range)
Post-Treatment Week 24
168
3 to 420
Post-Treatment Week 96
672
421 to 840
Post-Treatment Week 144
1,008
841 to 1,176
Final Post-Treatment Visitc
> 2 days after last dose of study drug
a.
Post-Treatment Visits are applicable for subjects who received at least one dose of study drug.
b.
Day of first dose of study drug.
c.
The last value within the Post-Treatment Period window will be used to define the Final Post-Treatment visit 
value.  The lower bound of this Final window is Study Drug End Day 3.
Note:
The result closest to the scheduled time point will be used.  For post-treatment visits, data must also have Study 
Drug End Day > 2 where Study Drug End Day 0 is defined as the day of the last dose of study drug.
6.3
Missing Data Imputation
No data will be imputed for any efficacy or safety analyses except for analyses of the
HCV RNA endpoints.


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Missing Data Imputation for SVR
HCV RNA values will be selected for analysis based on the analysis windows defined in 
Section 6.3.
For analyses of SVR, subjects' missing visit values will have backward imputation 
applied, if possible.  For backward imputation, if the nearest HCV RNA value after the 
SVR window is unquantifiable or undetectable, then it will be used to impute the HCV 
RNA value in the SVR window.  If a subject is missing an HCV RNA value within the 
appropriate SVR window after performing backward imputation, then this value will be 
imputed with an HCV RNA value from a local laboratory if present; otherwise, the HCV 
RNA value will be missing.  Subjects with missing HCV RNA data in the analysis 
window, after imputations, will be imputed as a failure.
Regardless of the imputation method described above, if a subject starts another treatment 
for HCV, then all HCV RNA values for this subject measured on or after the start date of 
the new HCV treatment will be excluded from analyses.  The subject will be considered a 
failure for summaries of viral response at all time points after the start of the new HCV 
treatment. 
Missing Data Imputation for Virologic Failure
If HCV RNA values from the central laboratory are missing but a local laboratory value is 
present in the appropriate time period, then the local laboratory value will be used to 
assess post-treatment relapse and on-treatment virologic failure. 
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
The ITT population and 2 ITT population table formats will be used to summarize 
demographics, baseline characteristics, medical history and previous, concomitant, and 
post-treatment medications; i.e., data will be summarized by age and weight group and 
overall among all subjects on the mini-tablet formulation; and by Part 1 vs Part 2 and 


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overall among subjects on the adult formulation, and overall among subjects on mini-
tablet formulation and overall among all subjects. 
7.1
Demographic and Baseline Characteristics
Demographics include age, birth year, weight, height, BMI, height z score (height z score 
will be calculated using WHO published height-for-age z-score tables),6 and waist 
circumference as continuous variables, and sex, race, ethnicity, geographic region and 
country, age category ([≥ 3 - 8 year old group], [≥ 9 - 11 year old group], and [≥ 12 -
17 year old group]), weight category 15 to 29 kg, 30 to 44 kg, ≥ 45 kg), and height z-score 
category (< –1, –1 to 1, > 1).
Baseline characteristics will include:  HCV genotype subtype (1a, 1b, 1-other, and 4; 
using central laboratory results and final genotype/subtype results, see Section 10.10), 
IL28B genotype ([CC, CT, or TT] and [CC or non CC]), ]), prior IFN treatment history 
(treatment-naïve or IFN-based treatment-experienced), response to prior IFN treatment 
(prior non responder {null responder, partial responder, or other unable to specify}, 
breakthrough, relapse, unknown and interferon experienced-other), baseline platelet count 
(continuous and [< 90 × 109/L, ≥ 90 × 109/L], baseline albumin (continuous and [< 35, 
≥35 g/L]), baseline creatinine clearance using the Schwartz method for subjects from 3 to 
< 12 years old (continuous and [< 30, ≥ 30 to < 60, ≥ 60 to < 90, ≥ 90 mL/min/1.73 m2]) 
and using the CC&G method for subjects at least 12 years old (continuous; and 
[< 30 mL/min, ≥ 30 – < 50 mL/min, ≥ 50 – 8 < 90 mL/min, ≥ 90 mL/min]) baseline HCV 
RNA levels ([continuous (use log10 HCV RNA)] and [< 800,000 IU/mL or ≥ 
800,000 IU/mL]), baseline fibrosis stage (F0 - 1, F2, F3, F4), baseline Fibrotest score 
(continuous and [< 0.49, 0.49 – 0.58, 0.59 – 0.74, ≥ 0.75]), baseline Child-Pugh score 
(non-cirrhotic, 5, 6, or > 6), tobacco use (current, former, never or unknown) status, 
alcohol use (current, former, never or unknown) status, and baseline Tanner pubertal 
staging – genital (males only) (stages 1 - 5), breast (females only) (stages 1 - 5), and pubic 
hair development (stages 1 - 5).


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Subjects' HCV genotype and subtype may be assessed based on the Inno-LiPA 2.0 Assay 
used by the Central lab (Covance), the HCV genotype determination by Sanger 
sequencing a region of NS5B by the Central lab (Covance) and/or from phylogenetic 
analysis of the full length NS3/4A, NS5A, and/or NS5B sequences performed by AbbVie.  
If the phylogenetic analysis is available it will be used to determine the subject's final 
HCV genotype and subtype.  If it is not available, then the Sanger assay result will be 
used to determine the subject's HCV genotype and subtype, if available.  Finally, if 
neither the phylogenetic analysis result nor the Sanger assay results are available, then the 
Inno-LIPA assay results will be used to categorize the subject.
Subjects' baseline fibrosis stage will be assessed by investigator during the screening 
period and categorized as F0 - 1, F2, F3, or F4.
Summary statistics (N, mean, median, standard deviation [SD], and range) will be 
generated for continuous variables (e.g., age and BMI) and the number and percentage of 
subjects will be presented for categorical variables (e.g., sex and race).
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.
7.3
Previous Treatment and Concomitant Medications
Prior and concomitant medications will be summarized.  A prior medication is defined as 
any medication taken prior to the date of the first dose of study drug.  A concomitant 
medication is defined as any medication that started prior to the date of the first dose of 
study drug and continued to be taken after the first dose of study drug or any medication 


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that started on or after the date of the first dose of study drug, but not after the date of the 
last (maximum) dose of study drug.  The number and percentage of subjects taking prior 
or concomitant medications will be summarized by generic drug name based on the WHO 
Drug Dictionary.  Note that prior HCV medications (IFN and RBV) will be summarized 
separately from other prior medications.
Medications for the treatment of HCV taken in the PT Period will be collected and will be 
summarized by generic drug name.  A post-treatment medication for the treatment of 
HCV is defined as any medication taken on or after the last dose of study drug and entered 
as "Post treatment HCV medications" on the eCRF.
8.0
Patient Disposition
All patient disposition summaries will be performed in the safety population using the 
safety population table format.  The number of subjects for each of the following 
categories will be summarized.
●
Enrolled Subjects;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who discontinued from study drug;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued from the study.
●
Subjects ongoing in the Post-Treatment Period (if applicable at the time of the 
interim analysis);
The number and percentage of subjects who discontinued study drug will be summarized 
by reason (all reasons) and by primary reason (per eCRF).  Similar summaries will be 
provided for discontinuations from the study.
The number and percentage of subjects will be summarized for:
●
Subjects with interruptions of all study drugs for toxicity management;


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●
Subjects with any RBV dose modification;
○
Subjects with RBV dose modification due to decrease in hemoglobin;
○
Subjects with RBV dose modification due to decrease in creatinine 
clearance;
○
Subjects with RBV dose modification due to weight change;
○
Subjects with RBV dose modification due to other reasons;
●
Subjects with any RBV dose modification to 0 mg (i.e., RBV interruptions).
Reasons for study drug interruption and RBV dose modifications will be presented in the 
CSR listings.
The number and percentage of screened subjects who screen failed will be calculated, and 
the reasons for screen failure (inclusion/exclusion criteria, withdrew consent, lost to 
follow-up, and/or other) will be summarized.  A listing of reasons for screen failure will 
be provided for all subjects who screen failed.
9.0
Study Drug Exposure and Compliance
Exposure and compliance will be summarized in the safety population using the safety 
population format.
9.1
Exposure
Duration of exposure is defined for each subject as the last study drug dose date minus the 
first study drug dose date plus 1 day.
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be presented.  
Study drug duration also will be summarized with frequencies and percentages using the 
following categories depending on the treatment duration:
●
12 weeks of treatment:  1 to 15 days, 16 to 30 days, 31 to 45 days, 46 to 
60 days, 61 to 76 days, and > 76 days.
●
24 weeks of treatment:  1 to 15 days, 16 to 30 days, 31 to 60 days, 61 to 
90 days, 91 to 120 days, 121 to 153 days, and > 153 days.


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9.2
Compliance
For ombitasvir/paritaprevir/r tablet, dasabuvir tablet, and RBV tablet, tablet is the dose 
unit for drug accountability.  For mini-tablets, bottle is the dose unit for drug 
accountability and the return status for each dose unit is recorded as either full/sealed, 
empty, or unsealed but not empty.  A mini-tablet bottle is considered to be taken only if 
the return status is empty.  For RBV solution, mL is the dose unit for drug accountability.
At each protocol-specified visit, the total number of dose units dispensed and returned is
recorded for each type of study drug.  The compliance for each type of dose unit within 
the Treatment Period will be calculated as the percentage of dose units taken or returned 
empty relative to the total number of dose units expected to be taken.  The total number of 
dose units expected to be taken will be equal to the total number of dose units that should 
have been taken per the protocol for the duration that the subject was in the Treatment 
Period (date of last dose – date of first dose + 1 day).  If a mini-tablet bottle is returned 
unsealed but not empty or if any dosing unit of study drug is not returned for 
reconciliation, then study drug compliance for that drug will not be calculated for that 
subject.  Study drug interruptions due to an adverse event or other planned interruptions 
for toxicity management recorded on the eCRF will be subtracted from the duration.  For 
compliance to RBV, RBV dose modifications due to adverse events, toxicity 
management, or weight changes as recorded on the RBV Dose Modifications eCRF will 
be used to modify the total number of unit that should have been taken.  A subject is 
considered to be compliant if the percentage is between 80% and 120%.  Compliance will 
be calculated for each subject and each type of dose unit and will be summarized with the 
N, mean, standard deviation, median, minimum, and maximum.  In addition, the 
percentage of compliant subjects will be calculated for each study drug. 
10.0
Efficacy Analysis
10.1
General Considerations
All efficacy analyses will be performed in the ITT population, unless otherwise specified. 


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Missing data will be imputed as described in Section 6.3 for analyses of the HCV RNA 
endpoints of SVR.
Plasma HCV RNA levels will be determined for each sample collected by the central 
laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative 
Test, v2.0.  The lower limit of detection (LLOD) and lower limit of quantification 
(LLOQ) for this assay (regardless of genotype) are both 15 IU/mL.
HCV RNA results that are detectable but not quantifiable are reported as "< 15 IU/ML 
HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA 
NOT DETECTED" in the database.
The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values 
< 15 IU/mL, including values reported as "HCV RNA NOT DETECTED" or 
"< 15 IU/ML HCV RNA DETECTED."  HCV RNA ≥ LLOQ are all quantifiable values 
of 15 IU/mL or greater.
Definitions for HCV RNA Efficacy Endpoints
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.
A confirmed quantifiable value during treatment is defined as any two consecutive HCV 
RNA measurements ≥ LLOQ (or 100 IU/mL for Breakthrough), either both during 
treatment or at the final treatment measurement and the next consecutive post-treatment 
measurement.  A confirmed quantifiable post-treatment value is defined as any 
two consecutive post-treatment HCV RNA measurements ≥ LLOQ.
Breakthrough = confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during 
the Treatment Period; or confirmed increase from nadir in HCV RNA (two consecutive 


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HCV RNA measurements > 1 log10 IU/mL above nadir) at any time point during the 
Treatment Period.  A single breakthrough value (≥ 100 IU/mL or > 1 log10 above nadir) 
followed by lost to follow-up also will be considered a breakthrough (i.e., will not require 
confirmation).
EOT failure = HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment, 
where the HCV RNA value must be collected on or after Study Drug Day 36 and study 
drug duration ≥ 36 days.
On-treatment virologic failure = Breakthrough or EOT failure; if a subject meets both 
definitions of Breakthrough and EOT failure, he or she will be categorized as 
Breakthrough only. 
SVR4 = HCV RNA < LLOQ in the SVR4 window (4 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
SVR12 = HCV RNA < LLOQ in the SVR12 window (12 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window. 
SVR24 = HCV RNA < LLOQ in the SVR24 window (24 weeks after the last actual dose of 
study drug) without any confirmed quantifiable (≥ LLOQ) post-treatment value before or 
during that SVR window.
Relapse12 = confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after 
last actual dose of study drug (up to and including the SVR12 window) for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completed treatment excluding 
reinfection as described below. 
Relapse24 = confirmed HCV RNA ≥ LLOQ within the SVR24 window for a subject who 
achieved SVR12 and has HCV RNA data available in the SVR24 window, excluding 
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Relapseoverall = confirmed HCV RNA ≥ LLOQ between end of treatment and up to and 
including the last HCV RNA measurement collected in the PT Period for a subject with 
HCV RNA < LLOQ at Final Treatment Visit who completed treatment excluding 
reinfection.
Virologic failure = On-treatment virologic failure or Relapseoverall.
Only subjects who have at least one post-treatment HCV RNA value will be included in 
analyses of relapse.  For the analysis of relapse, completion of treatment is defined as a 
study drug duration of 77 days or greater for subjects assigned to 12 weeks of treatment, 
and 154 days or greater for subjects assigned to 24 weeks of treatment.  If the last 
available post-treatment value is ≥ LLOQ, then the subject will be considered a relapse 
(i.e., will not require confirmation).
HCV reinfection is defined as confirmed HCV RNA ≥ LLOQ after the end of treatment in 
a subject who had HCV RNA < LLOQ at Final Treatment Visit, along with the 
post-treatment detection of a different HCV genotype, subtype, or clade compared with 
baseline, as determined by phylogenetic analysis of the NS3 or NS5A, and/or NS5B gene 
sequences.  Reinfection in the case of the same HCV subtype is defined as a clade switch, 
as indicated by the lack of clustering between the baseline and post-treatment sequences 
by phylogenetic analysis.  If phylogenetic analysis is not possible due to technical 
difficulties, HCV reinfection may be determined with a confirmed HCV genotype or 
subgenotype switch by the Versant HCV Genotype Inno-LiPA Assay v2.0 or Sanger 
assay.
Post-treatment relapse is defined as described earlier (Relapse12, Relapse24, 
Relapseoverall), and no genotype, subtype, or clade switch compared with baseline as 
determined by phylogenetic analysis of the NS3 or NS5A gene sequences.  If 
phylogenetic analysis is not possible due to technical difficulties, the subject will be 
defined as having a post-treatment relapse unless an HCV genotype or subtype switch is 
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Reasons for SVR12 Non-Response
Subjects who do not achieve SVR12 (SVR12 non-responders) will be categorized as 
having:
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
HCV reinfection (see definition described earlier);
3.
Relapse12;
4.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR12 non-responder who prematurely discontinued study drug 
[study drug duration < 77 days for subjects assigned to 12 weeks of treatment or 
duration < 154 days for subjects assigned to 24 weeks of treatment] and did not 
meet the On-treatment virologic failure or HCV reinfection definitions); 
5.
Missing follow-up data in the SVR12 window (defined as any subject who 
completed study drug without data in the SVR12 window after applying the 
imputation rules and not meeting the definitions of [1], [2], [3], or [4]);
6.
Other (defined as SVR12 non-responder not meeting the definitions of [1] – [5]).
Reasons for SVR24 Non-Response
Subjects who do not achieve SVR24 (SVR24 non-responders) will be categorized as 
having: 
1.
On-treatment virologic failure (see On-treatment virologic failure definition);
2.
HCV re-infection;
3.
Relapse12;
4.
Relapse24;
5.
Prematurely discontinued study drug with no on-treatment virologic failure 
(defined as any SVR24 non-responder who prematurely discontinued study drug 


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[study drug duration < 77 days for subjects assigned to 12 weeks of treatment or 
duration < 154 days for subjects assigned to 24 weeks of treatment] and did not 
meet the On-treatment virologic failure, HCV reinfection, Relapse12, or 
Relapse24 definitions);
6.
Missing follow-up data in the SVR24 window (defined as any subject who 
completed study drug without data in the SVR24 window after applying the 
imputation rules, and not meeting the definitions of [1], [2], [3], [4], or [5]);
7.
Other (defined as SVR24 non-responder not meeting the definitions of [1] – [6]).
For the reasons for SVR12 and SVR24 nonresponse defined above, subjects are only to be 
counted in 1 category.  Specifically, subjects who were SVR12 or SVR24 nonresponders 
meeting the definition of HCV reinfection will be counted in the reinfection category 
regardless of whether they meet the definition of prematurely discontinued study drug, 
relapse12 or relapse24.
10.2
Handling of Multiplicity
This study will proceed using a sequential testing procedure from testing the hypothesis 
for the primary efficacy endpoint that the SVR12 rate is 20% > than the pre-specified 
historical control rate of 47% to the hypothesis for the secondary efficacy endpoint that 
the SVR24 rate is 20% > than the pre-specified historical control rate of 47%.  Thus, the 
testing of the secondary hypothesis regarding SVR24 will only be performed in the lower 
confidence bound of the 2-sided 95% confidence interval of the SVR12 rate is > 67%.
10.3
Primary PK and Primary Efficacy Analysis
10.3.1
Primary PK Analysis
The primary PK endpoints from Part 1 are:
●
Cmax and AUC following dosing on Week 2, and trough concentration 
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For the intensive PK data at Week 2, the pharmacokinetic parameters of Cmax, Tmax and 
AUC will be calculated and summarized for each analyte (paritaprevir, ombitasvir, 
ritonavir, dasabuvir, and dasabuvir M1 metabolite, and RBV, as applicable based on DAA 
regimen).
The trough concentrations at Week 8 will be summarized for each analyte.
10.3.2
Primary Efficacy Analysis Across Parts 1 and 2.
The primary efficacy endpoint across Parts 1 and 2 is:
●
The percentage of subjects with SVR12 among all subjects.
The SVR12 rate and corresponding 2-sided 95% confidence interval will be presented.
For both the primary and secondary efficacy endpoints, the Wilson's score method will be 
used to calculate the confidence interval.
According to the Highlights of Prescribing Information of PEGASYS®, the SVR24 rate 
was 47% among 45 treatment-naïve pediatric subjects with HCV GT1 in the NV17424 
trial.6  To show that the DAA regimen is superior to this current standard of care by 20%, 
the lower bound of the 2-sided 95% confidence interval of the SVR12 rate across all 
subjects in the study must be greater than 67%.
10.4
Secondary Efficacy Analyses Across Parts 1 and 2
The secondary efficacy endpoints calculated across subjects in Parts 1 and 2 are:
1.
The percentage of subjects who achieve SVR12 by formulation, age and weight 
group, and across all subjects on the adult formulation.
2.
The percentage of subjects who achieve SVR24 by formulation, age and weight 
group, and across all subjects on the adult formulation.
3.
The percentage of subjects with ALT normalization during treatment, defined as 
ALT ≤ ULN at the final treatment visit for subjects with ALT > ULN at baseline, 


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by formulation, age and weight group, and across all subjects on the adult 
formulation.
For the percentage of subjects with SVR12 or SVR24 and the percentage of subjects with 
ALT normalization during treatment, the simple percentage will be calculated along with 
the 2-sided 95% confidence intervals.
To test the hypothesis that the percentage of HCV pediatric subjects treated with 
ombitasvir/paritaprevir/r, with or without dasabuvir with or without RBV who achieve 
SVR24 is superior to the historical SVR rate of 47% for the pediatric population treated 
with pegIFN and RBV by 20%, the lower bound of the 2-sided 95% confidence interval 
of the SVR24 rate across all subjects in the study will also be compared to 67%.
ALT normalization is defined as the percentage of subjects with ALT at or below the 
ULN at the final treatment visit among subjects with ALT > ULN at baseline, and will be 
presented along with 95% confidence intervals.
The concordance between SVR12 and SVR24 will be assessed by agreement between 
SVR12 and SVR24 and by the positive predictive value (PPV) and the negative predictive 
value (NPV) of SVR12 on SVR24.  The agreement between SVR12 and SVR24 is defined as 
the number of subjects achieving both SVR12 and SVR24 and the number of subjects not 
achieving both SVR12 and SVR24 out of all subjects in the ITT population.  The PPV of 
SVR12 on SVR24 is the proportion of subjects who achieve SVR24 out of all subjects who 
achieved SVR12.  The NPV of SVR12 on SVR24 is the proportion of subjects who do not 
achieve SVR24 out of all subjects who do not achieve SVR12.
10.5
Efficacy Subgroup Analysis
The number and percentage of subjects with SVR12 across all subjects in the ITT 
population will be presented by the following subgroups:
●
Age group (≥ 3 – 8, ≥ 9 – 11, and ≥ 12 – 17 years) and weight group (15 to 
29 kg, 30 to 44 kg, ≥ 45 kg) at enrollment;


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●
HCV genotype and sub-genotype (1a, 1b, other 1, and 4);
●
Prior HCV Treatment Experience (naïve, IFN-experienced)
●
Prior IFN treatment response (among experienced) (prior non-responder, prior 
breakthrough, prior relapse, unknown, and interferon experienced-other);
●
IL28B genotype (CC or non-CC), (CC, CT, or TT);
●
Sex (male or female);
●
Baseline fibrosis stage (F0-F1, F2, F3 or F4); 
●
Baseline HCV RNA level (< 800,000 IU/mL or ≥ 800,000 IU/mL; < median or 
≥ median);
●
Race (Black versus non-black);
●
Ethnicity (Hispanic/Latino versus none);
●
Baseline height z-score (< –1, –1 to 1 or > 1);
●
Drug compliance (< 80% versus ≥ 80%).
●
Baseline creatinine clearance using the CC&G method for subjects at least 
12 years old (< 50 mL/min, ≥ 50 mL/min); 
●
Baseline creatinine clearance using the Schwartz method for subjects from 3 to 
< 12 years old (< 60 mL/min/1.73 m2, ≥ 60 mL/min/1.73 m2)
●
RBV dose modifications (yes/no).
The 2-sided 95% Wilson score confidence interval will be produced for each subgroup 
with at least 10 subjects. 
In addition, stepwise logistic regression will be performed on virologic failure (on-
treatment virologic failure or relapse) using subgroup variables as described above, if 
there are sufficient number of virologic failures.  Some variables may be treated as 
continuous to decrease the chance of separation or quasi-separation and some variables 
may be eliminated if missing for too many subjects.


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10.6
Sensitivity Analysis for the Efficacy Endpoint of SVR12
In addition to presenting the primary efficacy endpoint of SVR12 as described in 
Section 10.4, two sensitivity analyses of SVR12 will be presented using the two modified 
populations – mITT-GT and mITT-GT-VF.
10.7
Additional Efficacy Analyses
The following efficacy endpoints will be analyzed by formulation, age and weight group, 
and across all subjects on the adult formulation:
1.
The percentage of subjects with virologic failure during treatment; 
2.
The percentage of subjects with Post-Treatment relapse (including Relapse12 as 
defined at the end of this section);
3.
The percentage of subjects who relapsed after achieving SVR12 (Relapse24).
4.
The percentage of subjects with HCV RNA < LLOQ at each post baseline visit 
during the Treatment Period (using data as observed);
5.
The change from baseline to all post-baseline visits in Fibrotest score.
All rates of SVR, ALT normalization, virologic failure on treatment and relapse will be 
presented with 2-sided 95% confidence intervals using the Wilson's method.  Imputations 
for missing data will be performed as described in Section 6.3 for analysis of SVR and 
relapse.  All other endpoints will be presented using data as observed.
A summary of the subjects who completed treatment and relapsed (defined as 
Relapseoverall) will be prepared displaying the number of subjects relapsing overall and by 
SVR visit window (within the SVR4, SVR12, SVR24 windows or after SVR24 window), 
including the subject number and the SVR visit window corresponding to the first HCV 
RNA value of those indicating the occurrence of relapse.  A similar listing will be 
prepared for subjects who prematurely discontinued treatment and relapsed after having 
HCV RNA < LLOQ at their Final Treatment Visit.  A listing of subjects in the ITT 


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population excluded from the relapse denominator (e.g., study drug duration < 77 days for 
subjects assigned to 12 weeks of treatment) will be provided, as applicable.
Summary statistics (n, mean, SD, median, minimum and maximum) at each applicable 
visit and for change from baseline to each applicable visit will be provided by fibrosis 
stage and SVR12 for Fibrotest score. 
10.8
Treatment Failures
The number and percentage of subjects meeting each and any of the SVR24 and SVR12
non-response categories as defined in Section 10.1 will summarized by formulation, age 
and weight group, and across all subjects on the adult formulation along with the 2-sided 
95% confidence interval using the Wilson's score method and a corresponding list of the 
subjects numbers. 
10.9
Growth and Development
The following growth and development endpoints will be calculated at applicable study 
visits. 
●
Growth rate at each post baseline visit (defined as change in height over 
change in age from the previous visit)
●
Height z score6
●
Waist circumference
●
Tanner staging
For growth rate, summary statistics (N, mean and SD together, median and range 
together) will be provided at each applicable post baseline visit for all and by gender for 
each pre-defined age group separately.  For height z score, summary statistics (N, mean 
and SD together, median and range together) of height z score and summary statistics (N, 
mean and SD together, median and range together) of change from baseline will be 
provided over time at each applicable study visit for all and by gender each for 
pre-defined age group separately.  Change from baseline in waist circumference, weight 


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and height will be summarized together with other vital signs such as temperature and 
blood pressure.  Listings of Tanner staging for each applicable subject over applicable 
timepoints will be produced.
10.10
Resistance Analyses
If possible, subjects treated with study drug during the Treatment Period who experience 
virologic failure will have resistance testing conducted if 1) they have on-treatment 
breakthrough; 2) if they have post-treatment relapse, with a study drug duration ≥ 77 days 
for subjects assigned to 12 weeks of treatment or with a study drug duration ≥ 154 days 
for subjects assigned to 24 weeks of treatment; or 3) if they have at least 6 weeks of 
treatment and fail to suppress by Week 6 (i.e., meet virologic stopping criteria).  Subjects 
meeting one of these criteria will be referred to as subjects in the primary virologic failure 
(PVF) population, and a listing by subject that includes HCV subtype, IL28B genotype, 
reason for non-response, time point(s) sequenced as closest to time of VF, and HCV RNA 
value at the VF time point(s) will be produced for these subjects.  In addition, all listings 
described below will display HCV subtype and reason for non-response in the subject 
identifier for each subject.  A separate listing will delineate all subjects in the PVF 
population for whom no sequencing was performed (e.g., lost to follow-up while HCV 
RNA ≤ 1000 IU/mL).
Only samples with an HCV RNA level of ≥ 1000 IU/mL will undergo sequence analysis 
in order to allow accurate assessment of products of amplification.  Therefore if the HCV 
RNA level at the time of virologic failure (VF) is < 1000 IU/mL, the sample closest in 
time after the failure with an HCV RNA level ≥ 1000 IU/mL will be used if available.
The regions of interest for population sequencing from all evaluated time points in this 
study are those encoding full length NS3/4A, NS5A, and NS5B.  The prototypic reference 
sequences used for analysis will be H77 for genotype 1a or Con1 for genotype 1b.
For each DAA target, resistance-associated signature amino acid variants will be 
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associated variants have been identified in vitro and/or in vivo are 1) for ABT-450:  36, 
43, 55, 56, 80, 155, 156, and 168 in NS3 for genotype 1a; 55, 56, 155, 156, and 168 in 
NS3 for genotype 1b; 56, 155, 156, and 168 for genotype 4; 2) for ABT-267:  24, 28, 29, 
30, 31, 32, 58, 62, 92, and 93 in NS5A for genotype 1a; 24, 28, 29, 30, 31, 32, 58, 62, 92, 
and 93 in NS5A for genotype 1b; 28, 30, 31, 58, and 93 for genotype 4; and 3) for 
ABT-333:  316, 414, 446, 448, 451, 553, 554, 555, 556, 558, 559, and 561 in NS5B for 
genotype 1a; 316, 368, 411, 414, 445, 448, 553, 556, and 559 in NS5B for genotype 1b.  
The final list of amino acid positions where resistance-associated variants have been 
identified will be included in the CSR.
The following definitions will be used in the resistance analyses:
●
Baseline variant:  a variant (by population sequencing) in a baseline sample 
determined by comparison of the amino acid sequence of the baseline sample 
to the appropriate prototypic reference amino acid sequence for a given DAA 
target (NS3, NS5A, or NS5B).
●
Post-baseline variant by population sequencing:  an amino acid variant in a 
post baseline time point sample that was not detected at baseline in the subject 
and is detectable by population sequencing.
●
Emerged variant by population sequencing:  a post-baseline variant that is 
observed in 2 or more subjects of the same subtype by population sequencing.
●
Linked variant by population sequencing:  2 or more signature resistance 
associated or emerged amino acid variants identified within a target by 
population sequencing, and no mixture of amino acids is detected at either 
position.
The following analyses will be performed on the samples from subjects who are in the 
PVF population and have baseline and post-baseline resistance data available. 
The HCV amino acid sequence as determined by population sequencing at baseline will 
be compared to the appropriate prototypic reference amino acid sequence.  A listing by 
subject of all baseline variants relative to prototypic reference sequence at signature 


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resistance-associated amino acid positions will be provided for each DAA target (NS3, 
NS5A, and NS5B – genotype 1 only).
The HCV amino acid sequence as determined by population sequencing at the time of VF 
or the sample closest in time after VF with an HCV RNA level of ≥ 1000 IU/mL will be 
compared to the baseline and appropriate prototypic reference amino acid sequences.  A 
listing by subject and time point of all post-baseline variants relative to the baseline amino 
acid sequences will be provided across all DAA targets (NS3, NS5A, and NS5B).  In 
addition, a listing by subject and time point of all post-baseline variants at signature 
resistance amino acid positions relative to the appropriate reference sequence will be 
provided across all DAA targets (NS3, NS5A, and NS5B – genotype 1 only).
The number and percentage of subjects with post-baseline variants at signature amino acid 
positions or emerged variants at non-signature amino acid positions by population 
sequencing, listed by amino acid position and variant within a DAA target at the time of 
VF compared to baseline will be summarized, along with the number of subjects within a 
DAA target and overall.  The analyses will be grouped by HCV subtype and DAA target 
(NS3, NS5A, or NS5B – genotype 1 only) and will list the numbers of subjects with each 
variant.  The number of subjects with resistance variants in 3 targets – (genotype 1 only), 
2 targets or 1 target will also be provided. 
Linkage between emerged or signature variants by population sequencing will also be 
evaluated.  A listing by subject and time point of the linked variants by population 
sequencing for each target will be provided.
For all subjects who experience VF, the persistence of resistance-associated variants for 
each target (NS3, NS5A, and NS5B – genotype 1 only) will be assessed by population 
sequencing at Post-Treatment Week 24.  Listings by subject of all treatment emergent 
variants at signature resistance-associated positions will be provided for each DAA target. 


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10.11
Patient Reported Outcomes
During Treatment and Post-Treatment, health utility values will be assessed using the 
EQ-5D-3L instrument.  The health state data measured by EQ-5D-3L will be analyzed 
using adult weights until validated weights are available for pediatric subjects to convert 
health states to a single summary index.
Subject's responses to the EQ-5D-3L will be combined into a unique health state using a 
5-digit code with 1 digit from each of the 5 dimensions.  The EQ-5D-3L states will be 
converted into a single preference-weighted health utility index score by applying 
country-specific weights (if available) or US weights (if not available).  The VAS score 
will be analyzed separately.
For subjects enrolled in Part 1 and 2 (ITT), summary statistics at each visit and on the 
change from baseline to each visit (n, mean, SD, median, minimum and maximum) of EQ 
VAS score will be provided overall and by age group.  In particular, for each of the 
three visits – EOT, PT Week 12 and PT Week 24, the mean change from baseline in EQ 
VAS score, will be compared between subjects who achieve SVR12 and those who do not 
using ANCOVA with SVR12 status as a factor, and appropriate baseline fibrosis stage, 
gender, age group, and EQ VAS score as covariates.  Point estimate of the mean 
difference and 95% confidence intervals will be provided using the subjects who do not 
achieve SVR12 as the reference group.  For subjects enrolled in Part 3 (ITT-3), summary 
statistics at each visit after PT Week 24 and the change from baseline to each applicable 
visit after PT Week 24 (n, mean, SD, minimum and maximum) in EQ VAS score will be 
provided.  The ANCOVA analyses will be performed only if there is a sufficient number 
of subjects who didn't achieve SVR12.
10.12
Acceptability Questionnaires
The analyses of acceptability questionnaires will be performed among subjects who 
received the mini-tablet in the ITT population.


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The number and percentage of subjects with each categorical answer marked will be 
presented for each question in the acceptability questionnaire at each applicable treatment 
visit overall, and by age and weight group.  Listings of acceptability questionnaire results 
and comments for each applicable subject over applicable treatment visits will be 
produced separately for each formulation.
11.0
Safety Analysis
11.1
General Considerations
The safety analysis will be carried out for all subjects in the safety population using the 
safety population table format.
11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent adverse events are defined as any event that begins or 
worsens in severity after initiation of study drug through 30 days after the last dose of 
study drug.  Events where the onset date is the same as the study drug start date are 
assumed to be treatment-emergent.  If an incomplete onset date was collected for an 
adverse event, the event will be assumed to be treatment-emergent, unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the study drug start date).
11.2.1.1
Tabulations of Treatment-Emergent Adverse Events
Adverse event data will be summarized and presented using primary MedDRA system 
organ classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the clinical study report.  The 
system organ classes will be presented in alphabetical order and the preferred terms will 
be presented in alphabetical order within each system organ class.


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Adverse Event Overview
An overview of adverse events will be presented consisting of the number and percentage 
of subjects experiencing at least one event for the following adverse event categories:
●
Any treatment-emergent adverse event;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to RBV;
●
Treatment-emergent adverse events of grade 3 or higher;
●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to DAAs
●
Serious treatment-emergent adverse events;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to RBV dose modifications;
●
Treatment-emergent adverse events leading to death;
●
Deaths.
Adverse Event by SOC and PT
The following summaries of adverse events will be generated:
●
Treatment-emergent adverse events;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to DAAs;
●
Treatment-emergent adverse events with a "reasonable possibility" of being 
related to RBV;
●
Serious treatment-emergent adverse events;
●
Grade 3 or higher treatment-emergent adverse events;


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●
Treatment-emergent adverse events of Grade 3 or higher with a "reasonable 
possibility" of being related to DAA;
●
Treatment-emergent adverse events leading to discontinuation of study drug;
●
Treatment-emergent adverse events leading to interruption of study drug;
●
Treatment-emergent adverse events leading to RBV dose modifications;
●
Treatment-emergent adverse events leading to death;
●
Treatment-emergent adverse events leading to concomitant medication use 
(events with other action taken of "concomitant medication prescribed").
For all adverse event summaries, the number and percentage of subjects experiencing 
treatment-emergent adverse events will be tabulated according to SOC and PT.  Subjects 
reporting more than one adverse event for a given PT will be counted only once for that 
term (most severe incident for the severity tables and most related incident for the 
relationship tables).  Subjects reporting more than one adverse event within a SOC will be 
counted only once for that SOC.  Subjects reporting more than one adverse event will be 
counted only once in the overall total. 
A listing of treatment-emergent adverse events grouped by body system and preferred 
term with subject numbers will be created.
Adverse Event by PT
The number and percentage of subject experiencing treatment-emergent adverse events 
will be tabulated according to preferred term and sorted by overall frequency.  Similar 
summaries will be provided for Grade 3 or higher treatment-emergent adverse events, 
DAA related treatment-emergent adverse events, and treatment-emergent adverse events 
of Grade 3 or higher with a "reasonable possibility" of being related to DAA.
Adverse Event of Special Interest
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Adverse Event of Special 
Interest
Search Criteria
Time Frame
Hepatic decompensation and 
hepatic failure 
PMQ "Hepatic decompensation and 
hepatic failure"
Treatment-emergent
Hepatocellular carcinoma 
Cases will be identified by the following 
MedDRA preferred terms: hepatic 
cancer recurrent, hepatocellular 
carcinoma, hepatic neoplasm, hepatic 
cancer, and hepatic cancer metastatic
All post-baseline cases 
including both treatment 
emergent and non-
treatment emergent
Severe cutaneous reactions
SMQ "Severe cutaneous adverse 
reactions" (narrow search)
Treatment-emergent
For each AE of special interest, the number and percentage of subjects experiencing at 
least one adverse event of special interest will be presented by SOC and PT.  A listing of 
adverse events for subjects meeting the search criterion will be provided for each adverse 
event of special interest.
Adverse Event by Maximum Severity Grade Level
Treatment-emergent adverse events and DAA-related treatment emergent adverse events 
will be summarized by maximum severity grade level.  Each adverse event will be 
assigned a grade level (grade 1, 2, 3, 4, or 5) by the investigator.  If a subject has an AE 
with unknown severity, then the subject will be counted in the severity grade level 
category of "unknown," even if the subject has another occurrence of the same event with 
a severity present.  The only exception is if the subject has another occurrence of the same 
AE with the highest grade level (grade 5).  In this case, the subject will be counted under 
the "Grade 5" category.
Adverse Event by Maximum Relationship
Treatment-emergent adverse events also will be summarized by maximum relationship of 
each preferred term to DAA study drug and RBV, as assessed by the investigator.  If a 
subject has an adverse event with unknown relationship, then the subject will be counted 
in the relationship category of "unknown," even if the subject has another occurrence of 
the same event with a relationship present.  The only exception is if the subject has 


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another occurrence of the same adverse event with a relationship assessment of 
"Reasonable Possibility."  In this case, the subject will be counted under the "Reasonable 
Possibility" category.
11.2.2
Listing of Adverse Event
Listings of all serious adverse events (from the time the subject signed the study-specific 
informed consent until the end of the study), treatment-emergent serious adverse events, 
treatment-emergent adverse events leading to death, treatment-emergent adverse events 
leading to discontinuation of study drug, treatment-emergent adverse events leading to 
study drug interruptions, treatment-emergent adverse events leading to RBV dose 
modifications and treatment-emergent adverse events of special interest will be provided.
11.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional lab testing due to 
all SAE will be used in all analysis.
11.3.1
Variables and Criteria Defining Abnormality 
Hematology variables include:  hematocrit, hemoglobin, red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, bands, lymphocytes, monocytes, basophils, 
eosinophils, platelet count, absolute neutrophil count (ANC), reticulocyte count, 
prothrombin time, INR, and activated partial thromboplastin time (aPTT).
Chemistry variables include:  blood urea nitrogen (BUN), creatinine, total bilirubin, direct 
and indirect bilirubin, serum glutamic pyruvic transaminase (SGPT/ALT), serum glutamic 
oxaloacetic transaminase (SGOT/AST), alkaline phosphatase, sodium, potassium, 
calcium, inorganic phosphorus, uric acid, cholesterol, total protein, glucose, triglycerides, 
albumin, chloride, bicarbonate, magnesium, gamma glutamyl transferase (GGT), 
creatinine clearance (CC&G formula) for subjects at least 12 years old, and creatinine 
clearance adjusted for body surface area (BSA) using the Schwartz formula for subjects 
between 3 and < 12 years old.


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For subjects at least 12 years old, the central lab calculates the estimated creatinine 
clearance (CrCl) based on the following CC&G formula:
CrCl using CC&G formula (mL/min) = [(140 – age) × (weight in kg) × (0.85 if 
female)]/[serum creatinine (mg/dL) × 72].
For subjects between 3 and < 12 years old, the central lab calculates CrCl adjusted for 
BSA based on the following Schwartz formula:
CrCl using Schwartz formula (mL/min/1.73 m2) = 0.55 × (height in centimeter) / 
[serum creatinine (mg/dL)].
Urinalysis variables include:  specific gravity, ketones, pH, protein, blood, glucose, 
urobilinogen, bilirubin, leukocyte esterase, and microscopic (reflexly performed if other 
variables are abnormal).
The criteria for potentially clinically significant (PCS) laboratory findings are described in 
Table 8 and Table 9.


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Table 8.
Criteria for Potentially Clinically Significant Hematology Values
Test/Units
Agea Range (Years) and 
Gender if applicable
Very Low (VL)
Very High (VH)
Hemoglobin
(g/dL)
3 - 11
< 11.5
(g/dL)
12 - 17 Female
< 12.0
(g/dL)
12 - 17 Male
< 13.0
Platelets Count
(cells/mm3)
< 50,000
(cells/L)
< 50 × 109
White Blood Cell Count
(cells/mm3)
< 2000
> 20,000
(cells/L)
< 2.0 × 109
> 20 × 109
Absolute Neutrophil Count
(cells/mm3)
< 1000
(cells/L)
< 1 × 109
Lymphocyte Count
(cells/mm3)
< 500
(cells/L)
< 0.5 × 109
Eosinophil Count
(cells/mm3)
> 5000
(cells/L)
> 5 × 109
aPTT
> 2 × ULN
International Normalized Ratio
> 2 × ULN
a.
Use baseline age.
Note:
A post-baseline value must be more extreme than the baseline value to be considered a PCS finding.


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Table 9.
Criteria for Potentially Clinically Significant Chemistry Values
Test/Units
Very Low (VL)
Very High (VH)
ALT/SGPT
> 5 × ULN and ≥ 2 × baseline
AST/SGOT
> 5 × ULN and ≥ 2 × baseline
Alkaline Phosphatase
> 1.5 × ULN
Total Bilirubin (mg/dL)
≥ 2.0 × ULN
Creatinine
(mcmol/L)
≥ 132.605
(mg/dL)
≥ 1.5
Creatinine Clearance (mL/min)
< 50
BUN
> 5 × ULN
Uric Acid
(mcmol/L)
> 713.817
(mg/dL)
> 12.0
Phosphate
(mmol/L)
< 0.6
(mg/dL)
< 2.0
Calcium, Serum
(mmol/L)
< 1.75
> 3.1
(mg/dL)
< 7.0
> 12.5
Sodium (mmol/L)
< 130
> 155
Potassium (mmol/L)
< 3.0
> 6.0
Glucose
(mmol/L)
< 2.2
> 13.9
(mg/dL)
< 40
> 250
Albumin
(g/L)
< 20
(g/dL)
< 2
Protein
(g/L)
< 50
(g/dL)
< 5.0


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Table 9.
Criteria for Potentially Clinically Significant Chemistry Values 
(Continued)
Test/Units
Very Low (VL)
Very High (VH)
Cholesterol
(mmol/L)
> 10.34
(mg/dL)
> 400
Triglycerides
(mmol/L)
> 5.7
(mg/dL)
> 500
Note:
A post-baseline value must be more extreme than the baseline value to be considered a PCS finding.
11.3.2
Statistical Methods
The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study drug.  Values on Day 1 must also be before 
the time of first dose if time is available.  The same baseline value will be used for change 
to Treatment Period visits and change to Post-Treatment Period visits.
Mean changes from baseline to each post-baseline visit, including applicable post 
treatment visits, will be summarized.  Each protocol-specified laboratory parameter will 
be summarized with the sample size, baseline mean, visit mean, change from baseline 
mean, standard deviation, minimum, median, and maximum.
The number and percentage of subjects with post-baseline values during the Treatment 
Periods meeting the specified criteria for Potentially Clinically Significant (PCS) 
laboratory values (defined in Table 8 and Table 9) will be summarized.  A post-baseline 
value must be more extreme than the baseline value to be considered a PCS finding.  A 
separate listing will be provided that presents all lab values for the subjects meeting PCS 
criteria during treatment.
The laboratory parameters defined in Table 10 will be assigned a toxicity grade of 1, 2, 3, 
or 4 based on National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.  The number and percentage of subjects with a maximum toxicity 


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grade of 1, 2, 3 or 4 will be summarized.  The post-baseline value must be in a toxicity 
grade that is more extreme than the toxicity grade corresponding to the baseline value in 
order to be counted.  The summary will also include the number and percentage of 
subjects with a maximum of at least Grade 3 for all laboratory parameters in Table 10.  A 
listing of all relevant laboratory parameters will be provided for each subject who had an 
increase to Grade 2 or higher for all laboratory variables in Table 10.
Table 10.
Definitions of CTCAE Grades 1, 2, 3, and 4
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT/SGPT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST/SGOT
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total 
Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Hemoglobin 
Decreased
< LLN – 100 g/L
< 100 – 80 g/L
< 80 – 65 g/L
< 65 g/L
Assessment of Hepatic Laboratory Values
The number and percentage of subjects with post-nadir (preceding value is lower than the 
subsequent) on-treatment increases in ALT and/or post baseline increases in total bilirubin 
meeting the following criteria for potential hepatotoxicity will be summarized:
●
post nadir ALT > 5 × ULN (regardless of grade change);
●
total bilirubin ≥ 2 × ULN and > baseline
●
post nadir ALT > 3 × ULN and total bilirubin > 2 × ULN (Hy's law quadrant)
●
post nadir ALT > 3 × ULN and total bilirubin ≤ 2 × ULN (Temple's corollary 
quadrant)
The maximum ratio relative to the ULN will be used to determine if subjects meet the 
criteria listed above.  The ALT and total bilirubin values do not need to be concurrent in 
order to meet the defined criteria.  For ALT, the post-baseline value must represent an 


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increase from the first nadir (including baseline) to be counted.  First nadir is defined as 
the last value prior to the first increase.  For total bilirubin, a subject will be counted as 
meeting the specified criteria regardless of the baseline bilirubin value, except for the 
2nd bullet above where the post-baseline bilirubin value must be worse than the baseline 
bilirubin value.
Listings of liver function tests including ALT, AST, total, indirect and direct bilirubin, 
ratio of direct to total bilirubin, and alkaline phosphatase values will be provided for each 
subject who met any of the assessment of hepatic laboratory value criteria defined above.  
Hepatic Laboratory Abnormalities of Interest 
Among the labs assessed under "Assessment of Hepatic Laboratory Values" the following 
criteria are of interest.  The number and percentage of subjects with post-baseline values 
during the Treatment Period meeting the following criteria for hepatic laboratory 
parameters will be summarized:
●
confirmed post-nadir ALT > 5 × ULN;
●
post nadir ALT > 3 × ULN and a concurrent (determined by examination of 
listing) total bilirubin > 2 × ULN with direct bilirubin:total bilirubin ratio > 0.4 
This listing of the assessment of hepatic laboratory values will include all the cases of 
hepatic laboratory of abnormalities of interest. 
Confirmed post nadir ALT > 5 × ULN is defined as two consecutive ALT measurements 
> 5 × ULN after the nadir (which can be baseline value) at any time point during the 
Treatment Period.  If the first measurement is during treatment (Study Drug End Day ≤ 2) 
then the confirmatory value can be post treatment.  A single measurement > 5 × ULN 
followed by lost to follow-up also will be considered a confirmed (i.e., will not require 
confirmation).  The concurrent elevation of post nadir ALT and total bilirubin will be 
determined by review of the listing which will include post nadir ALT > 3 × ULN and 
total bilirubin > 2 × ULN with direct bilirubin:total bilirubin ratio > 0.4.


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11.4
Analysis of Vital Signs and Weight
11.4.1
Variables and Criteria Defining Abnormality (if Applicable)
Vital sign variables are body temperature (oral), sitting systolic blood pressure, sitting 
diastolic blood pressure, sitting pulse rate, body weight, height, and waist circumference.
11.4.2
Statistical Methods
Vital signs will be summarized at each visit during the Treatment Period.  The baseline 
value will be the last measurement on or before the day of the first dose of study drug.  
This same baseline value will be used for all change from baseline tables in the Treatment 
and Post-Treatment Periods.
Mean changes from baseline to each post-baseline visit, including applicable 
post-treatment visits, will be summarized for each vital sign parameter with the baseline 
mean, visit mean, change from baseline mean, standard deviation, minimum, median, and 
maximum.
12.0
References
1.
Julious SA.  Two-sided confidence intervals for the single proportion:  comparison 
of seven methods by Robert G. Newcombe, Statistics in Medicine 
1998; 17:857-872.  Stat Med.  2005;24(21):3383-4.
2.
Cella D, Webster K.  Linking outcomes management to quality-of-life 
measurement.  Oncology (Williston Park).  1997;11(11A):232-5.
3.
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health 
Survey.  2nd ed.  Lincoln, RI:  QualityMetric Incorporated; 2007.
4.
Szende A, Williams A, editors.  Measuring self-reported population health:  an 
international perspective based on EQ-5D-5L.  EuroQol Group Monographs 
Volume 1.  SpringMed, 2004.
5.
Rabin R, Oemar M, Oppe M, et al.  EQ-5D-5L user guide:  basic information on 
how to use the EQ-5D-5L instrument.  Version 1.0.  April 2011.


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6.
PEGASYS® (peginterferon alfa-2a) [package insert].  San Francisco, CA; 
Genentech Inc., 2002.
7.
WHO.  Child Growth Standards.  27 April 2006.