Clinical trial NCT03117569
Conditions: Hepatitis C, Chronic
Sponsor: Kirby Institute
Start date: 2017-08-21; Completion date: 2018-12-19
Enrollment: 380 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to determine if treatment monitoring schedule for chronic HCV patients treated with glecaprevir (300mg)/pibrentasvir (120mg) can be simplified.

Data has shown that direct acting antiviral (DAA) regimen of glecaprevir (300mg)/pibrentasvir (120mg), a protease inhibitor and NS5A inhibitor respectively , provides key features for HCV treatment simplification.

Eligible participants (naïve pre-cirrhosis chronic HCV patients) will be randomized (1:2) to the standard or simplified monitoring arm and will receive treatment for 8 weeks.

One post treatment visit will be conducted 12 weeks after the final dose of study medication to evaluate the proportion of patients with undetectable HCV RNA at this timepoint (SVR12).

Detailed description:
The capacity to scale-up interferon-free DAA therapy would be enhanced by simplified treatment monitoring strategies. The "next generation" DAA regimen of glecaprevir (300mg)/pibrentasvir (120mg), a protease inhibitor and NS5A inhibitor, provides key features for HCV treatment simplification, including on-treatment monitoring: 1) pangenotypic activity with extremely high efficacy (SVR\>95%); 2) no relationship between time to undetectable HCV RNA and SVR; 3) minimal drug-related toxicity; 4) ease of dosing (three pills once daily); and short duration (8 weeks in non-cirrhosis and 12 weeks in cirrhosis for treatment naïve patients). In phase II and III clinical trials in participants without cirrhosis, 8 weeks of glecaprevir (300mg)/pibrentasvir (120mg) has provided intention-to-treat SVR rates of 99.1%, 98%, 97%, and 93.1% in genotype 1, 2, 3, and 4-6 populations, respectively.

Current standard on-treatment monitoring in clinical trials involves clinic-based visits every 4 weeks. In the DAA era where treatments are highly tolerable, effective and short duration, this intensive monitoring strategy may no longer be required. A simplified on-treatment monitoring strategy is hypothesised to be non-inferior to the standard clinical trial on treatment monitoring strategy. If successful, a simplified on-treatment monitoring strategy is likely to be highly attractive to patients, clinicians and health care payers. It has the potential to improve the rapid scale up of treatment providing population level benefits in the reduction of global hepatitis C disease burden.

This study will be conducted as a Phase IIIb, randomised, controlled, multicentre, international trial.

There will be a maximum screening period of 6 weeks prior to Baseline. Eligible patients will be randomised into one of two on-treatment monitoring strategies; standard clinical trial monitoring (4-weekly on-treatment visits) vs simplified monitoring (no on-treatment visits). Randomisation will be 1:2 (standard vs simplified) and all participants will receive treatment with glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks.

All participants will attend the clinic for screening and baseline visit. Randomisation will occur at the baseline visit.

The two on-treatment monitoring strategies will differ as follows:

* Standard monitoring arm participants will have on-treatment clinic visits at weeks 4 and 8 (EoT).
* Simplified monitoring arm participants will have no on-treatment clinic visits.

Study nurse phone contact will also be made to participants in BOTH arms 1-2 days prior Week 4 and EoT (Week 8) visits to provide standardized reporting of adverse events, concomitant medication and adherence. One post treatment clinic visit will be conducted at SVR12 (week 20) for all participants.

Arms: arm 1: Participants will have on-treatment clinic visits at weeks 4 and 8. Participants have also phone contact-based visits at weeks 4 and 8 (1-2 days prior to scheduled clinic visits). arm 2: Participants will have no on-treatment clinic visits at weeks 4 and 8. Participants have phone contact-based visits at weeks 4 and 8.
Interventions: intervention 1: glecaprevir (300mg)/pibrentasvir (120mg)
Intervention descriptions: intervention 1: glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks

Protocol documents:
Prot_000.pdf: 
 
SMART-C 1701 Protocol Version 2.0 dated 14-Jun-17 
Page 1 of 40 
 
 
 
 
 
 
 
Simplified Monitoring - A Randomised Trial in hepatitis C 
 
 
 
A phase IIIb, open-label, multicentre, international randomised controlled trial of 
simplified treatment monitoring for 8 weeks glecaprevir (300mg)/pibrentasvir 
(120mg) in chronic HCV treatment naïve patients without cirrhosis 
 
Protocol number: 
VHCRP1701 
 
Protocol version: 
2.0 
 
 
Version date:  
14 June 2017 
EudraCT number: 
2017-000694-37 
 
Name of sponsor: 
Kirby Institute  
 
 
 
UNSW Sydney  
 
 
 
Wallace Wurth Building (C27) 
 
 
 
Sydney NSW 2052 
 
 
 
Australia 
 
Coordinating Principal Investigator (CPI):  
Medical Monitor: 
Professor Gregory Dore 
The Kirby Institute 
UNSW Sydney 
Wallace Wurth Building (C27) 
Sydney NSW 2052 
Australia 
E: gdore@kirby.unsw.edu.au 
P: +61 2 9385 0900 
F: +61 2 9385 9214 
A/Professor Gail Matthews 
The Kirby Institute 
UNSW Sydney 
Wallace Wurth Building (C27) 
Sydney NSW 2052 
Australia 
E: gmatthews@kirby.unsw.edu.au 
P: +61 2 9385 0900 
F: +61 2 9385 9214 
 
 
Signature: 
 
Print name: 
Date:  
 
 
Prof Gregory Dore 
14/Jun/17 


 
SMART-C 1701 Protocol Version 2.0 dated 14-Jun-17 
Page 2 of 40 
 
 
 
 
 
  
Table of contents 
 
Protocol Synopsis ............................................................................................................................................ 4 
Inclusion criteria .......................................................................................................................................... 5 
Exclusion criteria.......................................................................................................................................... 6 
Schedule of Assessments (Standard monitoring arm) .................................................................................. 10 
Schedule of Assessments (Simplified monitoring arm) ................................................................................. 11 
1.0 
Background and rationale ................................................................................................................. 12 
2.0 
Study objectives ................................................................................................................................. 13 
2.1 
Hypothesis ..................................................................................................................................... 13 
2.2 
Primary objective ........................................................................................................................... 13 
2.3 
Secondary objective(s) .................................................................................................................. 13 
2.4 
Exploratory objective ..................................................................................................................... 13 
3.0 
Participant population ....................................................................................................................... 13 
3.1 
Number of Participants and Participant Selection ........................................................................ 13 
3.2 
Inclusion criteria ............................................................................................................................ 14 
3.3 
Exclusion criteria ............................................................................................................................ 15 
4.0 
Study design ...................................................................................................................................... 16 
4.1 
Summary of study design .............................................................................................................. 16 
4.2 
Visit Schedule ................................................................................................................................ 17 
4.3 
Treatment Discontinuation Criteria............................................................................................... 18 
5.0 
Treatment of participants.................................................................................................................. 18 
5.1 
Method of Assigning Participants to Treatment Groups (Randomisation) ................................... 18 
5.2 
Study Drug and Study Visit Adherence .......................................................................................... 19 
5.3 
Prior and Concomitant Medications.............................................................................................. 19 
5.4 
Methods of contraception: ............................................................................................................ 21 
6.0 
Study procedures ............................................................................................................................... 22 
6.1 
Visits and Procedures .................................................................................................................... 22 
6.2 
Study Questionnaires .................................................................................................................... 26 
7.0 
Recording and reporting Adverse Events (AEs) and Product Complaints ......................................... 27 
7.1 
Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events ........................... 27 
7.1.1 
Adverse Event definition ........................................................................................................... 27 
7.1.2 
Serious Adverse Event (SAE) (including Serious Adverse Drug Reactions) ................................ 27 
7.2 
Assessment of Adverse Events and Serious Adverse Events ......................................................... 28 
7.2.1 
Assessment of Causality for Study Drugs and Procedures ........................................................ 28 
7.2.2 
Assessment of Severity .............................................................................................................. 28 
7.3 
Reporting Requirements ............................................................................................................... 28 
7.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .......................................................... 29 
7.5 Product Complaints ............................................................................................................................. 30 


 
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8.0 
Packaging, labelling, storage and accountability of clinical trial supplies ......................................... 30 
8.1 
Formulation ................................................................................................................................... 31 
8.2 
Packaging and labelling ................................................................................................................. 31 
8.3 
Storage and handling ..................................................................................................................... 31 
8.4 
Dosage and administration............................................................................................................ 31 
9.0 
Biological samples ............................................................................................................................. 32 
9.1 
Laboratory supplies and sample processing.................................................................................. 32 
9.2 
Shipping of biological samples ...................................................................................................... 32 
9.3 
Future use of biological samples ................................................................................................... 32 
10.0 
Statistics ............................................................................................................................................. 33 
10.1 
Sample Size .................................................................................................................................... 33 
10.2 
Assessments of efficacy ................................................................................................................. 33 
10.3 
Efficacy analysis ............................................................................................................................. 34 
10.4 
Assessments of safety ................................................................................................................... 34 
10.5 
Definition of Intent-to-treat Population ........................................................................................ 34 
10.6 
Definition and evaluation of HCV resistance ................................................................................. 34 
11.0 
Data Safety and Monitoring Board (DSMB) ....................................................................................... 35 
12.0 
Data collection, source documents and record retention ................................................................ 35 
12.1 
Submission of data ........................................................................................................................ 35 
12.2 
Archiving ........................................................................................................................................ 36 
13.0 
Ethics committee/regulatory approval and informed consent ......................................................... 36 
14.0 
Confidentiality of data ....................................................................................................................... 37 
15.0 
Governance ....................................................................................................................................... 38 
16.0 
Quality Control (QC) and Quality Assurance (QA) ............................................................................. 38 
17.0 
Publication Policy ............................................................................................................................... 38 
18.0 
List of References .............................................................................................................................. 39 
19.0 
Abbreviations List .............................................................................................................................. 40 
 
 
 


 
SMART-C 1701 Protocol Version 2.0 dated 14-Jun-17 
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Protocol Synopsis 
 
Title 
SMART-C 
A phase IIIb, open-label, multicentre, international randomised 
controlled trial of simplified treatment monitoring for 8 weeks 
glecaprevir (300mg)/pibrentasvir (120mg) in chronic HCV treatment 
naïve patients without cirrhosis 
Protocol registration no. 
 
ClinicalTrials.gov Identifier: NCT03117569 
Background and rationale 
 
 
The capacity to scale-up interferon-free DAA therapy would be enhanced 
by simplified treatment monitoring strategies. The “next generation” 
DAA regimen of glecaprevir (300mg)/pibrentasvir (120mg), a protease 
inhibitor and NS5A inhibitor, provides key features for HCV treatment 
simplification, including on-treatment monitoring: 1) pangenotypic 
activity with extremely high efficacy (SVR>95%); 2) no relationship 
between time to undetectable HCV RNA and SVR; 3) minimal drug-
related toxicity; 4) ease of dosing (three pills once daily); and short 
duration (8 weeks in non-cirrhosis and  12 weeks in cirrhosis for 
treatment naïve patients).1,2 In phase II and III clinical trials in participants 
without cirrhosis, 8 weeks of glecaprevir (300mg)/pibrentasvir (120mg) 
has provided intention-to-treat SVR rates of 99.1%, 98%, 97%, and 93.1%  
in genotype 1, 2, 3, and 4-6 populations, respectively.9,10,11 
Current standard on-treatment monitoring in clinical trials involves clinic-
based visits every 4 weeks. In the DAA era where treatments are highly 
tolerable, effective and short duration, this intensive monitoring strategy 
may no longer be required. A simplified on-treatment monitoring 
strategy is hypothesised to be non-inferior to the standard clinical trial on 
treatment monitoring strategy. If successful, a simplified on-treatment 
monitoring strategy is likely to be highly attractive to patients, clinicians 
and health care payers. It has the potential to improve the rapid scale up 
of treatment providing population level benefits in the reduction of 
global hepatitis C disease burden. 
Hypothesis 
 
In treatment naïve non-cirrhosis patients with chronic HCV (genotypes 1-
6) the sustained virological response rate 12 weeks following treatment 
with glecaprevir (300mg)/pibrentasvir (120mg) among those receiving a 


 
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simplified monitoring schedule will be non-inferior to that in those 
receiving a standard monitoring schedule based on the intention-to-treat 
(ITT) population. 
Study objectives 
Primary Objective: 
To compare the proportion of participants with undetectable HCV RNA 
(HCV RNA <LLOQ) at 12 weeks post-treatment (SVR12) following 8 weeks 
treatment with glecaprevir (300mg)/pibrentasvir (120mg) in HCV 
treatment naïve non-cirrhosis chronic HCV patients who have received a 
standard versus simplified schedule of safety and virological monitoring 
(ITT analysis). 
Secondary Objectives: 
• To compare the proportion of participants achieving SVR12 between 
those who received a standard versus simplified schedule of safety 
and virological monitoring based on mITT population; 
• To evaluate the proportion adherent to treatment and study visits 
(both on-treatment adherence and early treatment discontinuation); 
• To evaluate patient reported outcomes following treatment; 
• To evaluate safety and tolerability by monitoring adverse events 
during treatment; 
• To measure patient satisfaction on both arms; 
• To evaluate the prevalence and impact of baseline Resistance 
Associated Substitutions (RAS) on SVR12; 
• To evaluate cost-effectiveness of simplified monitoring; 
• To evaluate immunovirological factors associated with treatment 
clearance. 
Exploratory Objective: 
• To measure the provider acceptability of the simplified monitoring 
strategy. 
Participant population  
A total of 375 participants with chronic HCV will be enrolled.  
Inclusion criteria 
Participants must meet all of the following inclusion criteria to be eligible 
to participate in this study.  
1) Have voluntarily signed the informed consent form. 


 
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2) 18 years of age or older. 
3) Chronic HCV infection as defined by anti-HCV antibody or HCV RNA 
detection for greater than 6 months. 
4) HCV RNA plasma ≥ 10,000 IU/ml at screening. 
5) HCV genotype 1-6. 
6) HCV treatment naïve (no prior treatment with an approved or 
investigation anti-HCV medication). 
7) Stage F0-3, based on: hepatic elastography <12.5 kPa on Fibroscan® 
or APRI <1.0. 
8) If co-infection with HIV is documented, the subject must meet the 
following criteria: 
- 
ART naïve with CD4 T cell count >500 cells/mm3; 
OR 
- 
On a stable ART regimen (containing only permissible ART – see 
section 3.2) for >8 weeks prior to screening visit, with CD4 T cell 
count >200 cells/mm3 and a plasma HIV RNA level below the limit 
of detection. 
9) Negative pregnancy test at screening and baseline (females of 
childbearing potential only). 
10) All fertile females must be using effective contraception during 
treatment and during the 30 days after treatment end. 
Exclusion criteria 
Participants who meet any of the exclusion criteria are not to be enrolled 
in this study. 
1) History of any of the following: 
a. Clinically significant illness (other than HCV) or any other 
major medical disorder that may interfere with the 
participant treatment, assessment or compliance with the 
protocol; participants currently under evaluation for a 
potentially clinically significant illness (other than HCV) are 
also excluded.  
b. Clinical hepatic decompensation (i.e. ascites, encephalopathy 
or variceal haemorrhage). 


 
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c. Solid organ transplant. 
d. History of severe, life-threatening or other significant 
sensitivity to any excipients of the study drugs. 
2) Any of the following lab parameters at screening: 
a. ALT > 10 x ULN 
b. AST > 10 x ULN 
c. Direct bilirubin > ULN 
d. Platelets < 90,000/μL (cells/mm3) if Fibroscan® <12.5 kPa  OR 
< 150,000/μL (cells/mm3) if Fibroscan® is unavailable and 
patient is included with APRI <1 
e. Creatinine clearance (CLcr) < 50 mL/min  
f. Haemoglobin < 12g/dL for males; <11g/dL for females 
g. Albumin < LLN 
h. INR > 1.5 ULN unless subject has known haemophilia or is 
stable on an anticoagulant regimen affecting INR 
3) Pregnant or breastfeeding female. 
4) HBV infection (HBsAg positive). 
5) Use of prohibited concomitant medications as described in section 
5.3. 
6) Chronic use of systemically administered immunosuppressive agents 
(e.g. prednisone equivalent > 10 mg/day for >2 weeks). 
7) Therapy with any anti-neoplastic or immunomodulatory treatment 
(including supraphysiologic doses of steroids and radiation) ≤6 
months prior to the first dose of study drug. 
8) Any investigational drug ≤6 weeks prior to the first dose of study 
drug. 
9) Ongoing severe psychiatric disease as judged by the treating 
physician.  
10) Positive result of a urine drug screen at the Screening Visit for 
opiates, barbiturates, amphetamines, cocaine, benzodiazepines, 
phencyclidine, propoxyphene, or alcohol, with the exception of a 
positive result (including methadone) associated with documented 
short-term use or chronic stable use of a prescribed medication in 
that class. 
11) Injecting drug use within the previous six months. 
12) Inability or unwillingness to provide informed consent or abide by the 


 
SMART-C 1701 Protocol Version 2.0 dated 14-Jun-17 
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requirements of the study. 
Study design 
This study will be conducted as a Phase IIIb, randomised, controlled, 
multicentre, international trial. 
There will be a maximum screening period of 6 weeks prior to Baseline. 
Eligible patients will be randomised into one of two on-treatment 
monitoring strategies; standard clinical trial monitoring (4-weekly on-
treatment visits) vs simplified monitoring (no on-treatment visits). 
Randomisation will be 1:2 (standard vs simplified) and all participants 
will receive treatment with glecaprevir (300mg)/pibrentasvir (120mg) for 
8 weeks. 
All participants will attend the clinic for screening and baseline visit. 
Randomisation will occur at the baseline visit.  
The two on-treatment monitoring strategies will differ as follows: 
• 
Standard monitoring arm participants will have on-treatment 
clinic visits at weeks 4 and 8 (EoT). 
• 
Simplified monitoring arm participants will have no on-
treatment clinic visits. 
Study nurse phone contact will also be made to participants in BOTH 
arms 1-2 days prior Week 4 and EoT (Week 8) visits to provide 
standardized reporting of adverse events, concomitant medication and 
adherence. One post treatment clinic visit will be conducted at SVR12 
(week 20) for all participants. 
Treatment of participants 
Participants will receive 8 weeks of glecaprevir (300mg)/pibrentasvir 
(120mg) as a co-formulated three tablets daily regimen. Dose 
modifications are prohibited. 
Study procedures 
Refer to the Study Schedule of Assessments. 
Statistics 
Sample Size 
Assuming an SVR12 of 96% in both arms a sample size of 375 provides 
>80% power to detect non-inferiority at a 6% level. 
Assessments of efficacy  
Primary endpoints:  
1. SVR12 defined as the proportion of patients with undetectable 
HCV RNA at 12 weeks post end of treatment (week 20) based on 
ITT population. 
 


 
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Secondary endpoints:  
2. SVR12 defined as the proportion of patients with undetectable 
HCV RNA at 12 weeks post end of treatment (week 20) based on 
mITT population. 
3. Proportion adherent to treatment and study visits (on-treatment 
adherence and early treatment discontinuation); 
4. Change in health-related quality of life during treatment 
(measured by EQ-5D-3L); 
5. Resistance associated substitutions (RAS): SVR12 in participants 
with and without baseline RAS, and RAS distribution in 
participants with virological failures; 
6. Patient treatment satisfaction measured by a questionnaire 
applied to all participants;   
Assessments of safety  
Safety endpoints: 
7. Proportion of patients with common adverse events (reported in 
greater than 5%). 
8. Proportion of patients with at least one severe or potentially life 
threatening (grade 3 or 4) adverse event. 
9. Proportion of patients with un-scheduled clinic visits. 
Exploratory endpoint 
10. Provider acceptability of simplified monitoring strategy. 
 


 
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Schedule of Assessments (Standard monitoring arm) 
 
Assessment / Procedure 
Screening 
Baseline 
On-treatment 
Phase 
Follow-Up 
Phase 
Study weeks 
-6 to 0 
0 
4 
8 
(EoT) 
20 
(SVR12) 
Study Days 
-42 to 0 
0 
28 
56 
140 
Visit Window (Days) 
+/- 3 
+/- 3 
+/- 14 
Informed consent 
x 
 
Medical history / Patient demographics 
x 
 
 
 
 
Randomisation 
 
x 
 
 
 
Dispense study drug 
 
x 
x 
 
 
Return study drug 
 
 
 
 
x 
Vital signs & physical measurements 
x 
x 
x 
x 
x 
HCV-RNA testing (Local Laboratory) 
x 
x 
x 
HCV genotyping (Local Laboratory) 
xa 
 
Study Drug Adherence Survey 
xb 
xb 
 
Health outcomes survey (EQ-5D-3L) 
x 
x 
Participant Satisfaction Survey 
x 
 
 
 
x 
Fibroscan® / APRI 
xc 
 
 
 
 
Liver function tests/ Full blood count/ Biochemistry 
x 
x 
x 
x 
x 
Clotting (INR) 
x 
 
 
 
 
Urinary Drug Screen 
x 
 
HIV & HBV serology 
x 
 
Pregnancy Testd 
x 
x 
x 
x 
x 
Adverse events 
x 
xb 
xb 
x 
Concomitant medication 
x 
x 
xb 
xb 
x 
Research Specimen Collection 
 
EDTA Whole Blood (4mL) 
x 
 
 
 
 
EDTA plasma (10mL) 
xe 
xe 
x 
x 
x 
PBMCsf (60mL) 
x 
 
x 
 
x 
aWithin 5 years prior to screening; bCompleted by study nurses during phone contact; cFibroscan within 6 months prior to 
screening; dWomen of child bearing potential only; e20mL at Screening and Baseline; fAt selected sub-study sites only 
 
 


 
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Schedule of Assessments (Simplified monitoring arm) 
 
Assessment / Procedure 
Screening 
Baseline 
On-treatment 
Phase 
Follow-Up 
Phase 
Study weeks 
-6 to 0 
0 
4 
8 
(EoT) 
20 
(SVR12) 
Study Days 
-42 to 0 
0 
28 
56 
140 
Visit Window (Days) 
+/- 3 
+/- 3 
+/- 14 
Informed consent 
x 
 
 
 
 
Medical history / Patient demographics 
x 
 
 
 
 
Randomisation 
 
x 
 
 
 
Dispense study drug (8 weeks) 
 
x 
 
 
 
Return study drug 
 
 
 
 
x 
Vital signs & physical measurements 
x 
x 
 
 
x 
HCV-RNA testing (Local Laboratory) 
x 
 
 
 
x 
HCV genotyping (Local Laboratory) 
xa 
 
 
 
 
Study Drug Adherence Survey 
 
 
xb 
xb 
 
Health outcomes survey (EQ-5D-3L) 
x 
 
 
 
x 
Participant Satisfaction Survey 
x 
 
 
 
x 
Fibroscan® / APRI 
xc 
 
 
 
 
Liver function tests/ Full blood count/ Biochemistry 
x 
x 
 
 
x 
Clotting (INR) 
x 
 
 
 
 
Urinary Drug Screen 
x 
 
 
 
 
HIV & HBV serology 
x 
 
 
 
 
Pregnancy Teste 
x 
x 
xd 
xd 
x 
Adverse events 
 
x 
xb 
xb 
x 
Concomitant medication 
x 
x 
xb 
xb 
x 
Research Specimen Collection 
 
 
 
 
 
EDTA Whole Blood (4mL) 
x 
 
 
 
 
EDTA plasma (10mL) 
xf 
xf 
 
 
x 
PBMCsg (60mL) 
x 
 
 
 
x 
aWithin 12 months prior to screening; bCompleted by study nurse during phone contact; cFibroscan within 6 months prior to 
screening; dSelf-completed by participants at home; eWomen of child bearing potential only;  f20mL at Screening and Baseline; gAt 
selected sub-study sites only 
 
 


 
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1.0 
Background and rationale 
Chronic hepatitis C virus (HCV) treatment was interferon-based for two decades, with the addition of 
ribavirin (RBV),3 Pegylated interferon (PEG-IFN),4 and initial protease inhibitor direct acting antiviral (DAA) 
therapies (telaprevir, boceprevir)5,6 providing stepwise improvements in the rate of sustained virological 
response (SVR). Despite these improvements in interferon-containing regimens, treatment uptake 
remained low in most countries, ranging from <1% to a maximum of 5% of people with chronic HCV 
initiating therapy each year.7 
Fortunately, recent years have seen a revolution in HCV therapeutic development, in particular the 
interferon-free direct acting antiviral (DAA) regimens.8 Short, simple (once daily dosing oral regimens), 
highly tolerable, short-duration (8-12 weeks) therapy with pangenotypic potency and extremely high 
efficacy (cure rates above 95%) will soon be the norm. The broad implementation of such therapeutic 
regimens has the potential to produce one of the major turnarounds in disease burden seen in public 
health and clinical medicine. 
The capacity to scale-up interferon-free DAA therapy would be enhanced by simplified treatment 
monitoring strategies. The “next generation” DAA regimen of glecaprevir (300mg)/pibrentasvir (120mg), a 
protease inhibitor and NS5A inhibitor, provides key features for HCV treatment simplification, including 
on-treatment monitoring: 1) pangenotypic activity with extremely high efficacy (SVR>95%); 2) no 
relationship between time to undetectable HCV RNA and SVR; 3) minimal drug-related toxicity; 4) ease of 
dosing (three pills once daily); and short duration (8 weeks in non-cirrhosis and 12 weeks in cirrhosis for 
treatment naïve patients).1,2 In phase II and III clinical trials in patients without cirrhosis, 8 weeks of 
glecaprevir (300mg)/pibrentasvir (120mg) has provided intention-to treat SVR rates of 99.1%, 98%, 97%, 
and 93.1%  in genotype 1, 2, 3, and 4-6 populations, respectively with extremely low rates of drug-related 
toxicity.9,10,11 
Current standard on-treatment monitoring in clinical trials involves clinic-based visits every 4 weeks. In 
the DAA era where treatments are highly tolerable, effective and short duration, this intensive monitoring 
strategy may no longer be required.  A simplified on-treatment monitoring strategy is hypothesised to be 
non-inferior to the standard clinical trial on treatment monitoring strategy. If successful, a simplified on-
treatment monitoring strategy is likely to be highly attractive to patients, clinicians and health care 
payers. It has the potential to improve the rapid scale up of treatment providing population level benefits 
in the reduction of global hepatitis C disease burden. 
 
 


 
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2.0 
Study objectives 
2.1 Hypothesis 
In treatment naïve non-cirrhosis patients with chronic HCV (genotypes 1-6) the sustained virological 
response rate 12 weeks following treatment with glecaprevir (300mg)/pibrentasvir (120mg) among those 
receiving a simplified monitoring schedule will be non-inferior to that in those receiving a standard 
monitoring schedule based on the intention-to-treat (ITT) population. 
 
2.2 Primary objective 
To compare the proportion of patients with undetectable HCV RNA (HCV RNA <LLOQ) at 12 weeks post-
treatment (SVR12) following 8 weeks treatment with glecaprevir (300mg)/pibrentasvir (120mg) in HCV 
treatment naïve non-cirrhosis chronic HCV patients who have received a standard versus simplified 
schedule of safety and virological monitoring. 
 
2.3 Secondary objective(s) 
• To compare the proportion of participants achieving SVR12 between those who received a standard 
versus simplified schedule of safety and virological monitoring based on mITT population; 
• To evaluate the proportion adherent to treatment and study visits (both on-treatment adherence and 
early treatment discontinuation); 
• To evaluate patient reported outcomes following treatment; 
• To evaluate safety and tolerability by monitoring adverse events during treatment; 
• Patient treatment satisfaction measured by a questionnaire applied to all participants;   
• To evaluate the prevalence and impact of baseline Resistance Associated Substitutions (RAS) on 
SVR12; 
• To evaluate cost-effectiveness of simplified monitoring; 
• To evaluate immunovirological factors associated with treatment clearance. 
 
2.4 Exploratory objective 
• To measure the provider acceptability of the simplified monitoring strategy. 
 
3.0 
Participant population 
3.1 Number of Participants and Participant Selection 
375 participants will be enrolled through INPACT-C network sites in Australia, New Zealand, North 


 
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America (United States and Canada) and Europe. The Kirby Institute may close or suspend screening at 
specific sites prior at to reaching 375 participants in order to manage the total study enrolment numbers. 
 
3.2 Inclusion criteria 
Participants must meet all of the following inclusion criteria to be eligible to participate in this study.  
1) Have voluntarily signed the informed consent form. 
2) 18 years of age or older. 
3) Chronic HCV infection as defined by anti-HCV antibody or HCV RNA detection for greater than 6 
months. 
4) HCV RNA plasma ≥ 10,000 IU/ml at screening. 
5) HCV genotype 1-6. 
6) HCV treatment naïve (no prior treatment with an approved or investigation anti-HCV medication). 
7) Stage F0-3, based on hepatic elastography <12.5 kPa on Fibroscan® or APRI <1.0. 
8) If co-infection with HIV is documented, the subject must meet the following criteria: 
- 
ART naïve with CD4 T cell count >500 cells/mm3; 
OR 
- 
On a stable ART regimen for >8 weeks prior to screening visit, with CD4 T cell count >200 
cells/mm3 and a plasma HIV RNA level below the limit of detection. 
Permissible ARTs include: 
• 
Raltegravir 
• 
Dolutegravir 
• 
Rilpivirine 
• 
Elvitegravir/cobicistat 
• 
Tenofovir disoproxil fumarate 
• 
Tenofovir alafenamide 
• 
Emtricitabine 
• 
Lamivudine 
• 
Abacavir 
9) Negative pregnancy test at screening and baseline (females of childbearing potential only). 


 
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10) All fertile females must be using effective contraception during treatment and during the 30 days 
after treatment end. 
 
3.3 Exclusion criteria 
Participants who meet any of the exclusion criteria are not to be enrolled in this study. 
1) History of any of the following: 
a. Clinically significant illness (other than HCV) or any other major medical disorder that may 
interfere with the participant treatment, assessment or compliance with the protocol; 
participants currently under evaluation for a potentially clinically significant illness (other than 
HCV) are also excluded.  
b. Clinical hepatic decompensation (i.e. ascites, encephalopathy or variceal haemorrhage). 
c. Solid organ transplant. 
d. History of severe, life-threatening or other significant sensitivity to any excipients of the study 
drugs. 
2) Any of the following lab parameters at screening: 
a. ALT > 10 x ULN 
b. AST > 10 x ULN 
c. Direct bilirubin > ULN 
d. Platelets < 90,000/μL (cells/mm3) if Fibroscan® <12.5 kPa  OR < 150,000/μL (cells/mm3) if 
Fibroscan® is unavailable and patient is included with APRI <1 
e. Creatinine clearance (CLcr) < 50 mL/min  
f. Haemoglobin < 12g/dL for males; <11g/dL for females 
g. Albumin < LLN 
h. INR > 1.5 ULN unless subject has known haemophilia or is stable on an anticoagulant regimen 
affecting INR 
3) Pregnant or breastfeeding female. 
4) HBV infection (HBsAg positive). 
5) Use of prohibited concomitant medications as described in section 5.3. 
6) Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent > 10 
mg/day for >2 weeks). 
7) Therapy with any anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses 
of steroids and radiation) ≤6 months prior to the first dose of study drug. 
8) Any investigational drug ≤6 weeks prior to the first dose of study drug. 
9) Ongoing severe psychiatric disease as judged by the treating physician. 


 
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10) Positive result of a urine drug screen at the Screening Visit for opiates, barbiturates, amphetamines, 
cocaine, benzodiazepines, phencyclidine, propoxyphene, or alcohol, with the exception of a positive 
result (including methadone) associated with documented short-term use or chronic stable use of a 
prescribed medication in that class. 
11) Injecting drug use within the previous six months. 
12) Inability or unwillingness to provide informed consent or abide by the requirements of the study. 
 
4.0 
Study design 
4.1 Summary of study design 
This study will be conducted as a Phase IIIb, randomised, controlled, multicentre, international trial. 
There will be a maximum screening period of 6 weeks prior to Baseline. Eligible patients will be 
randomised into one of two on-treatment monitoring strategies; standard clinical trial monitoring (4-
weekly on-treatment visits) vs simplified monitoring (no on-treatment visits) (see Figure 1). 
Randomisation will be 1:2 (standard vs simplified) and all participants will receive treatment with 
glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks. 
All participants will attend the clinic for screening and baseline visit. Randomisation will occur at the 
baseline visit.  
The two on-treatment monitoring strategies will differ as follows: 
• 
Standard monitoring arm participants will have on-treatment clinic visits at weeks 4 and 8 (EoT). 
• 
Simplified monitoring arm participants will have no on-treatment clinic visits. 
 
Study nurse phone contact will also be made to participants in BOTH arms 1-2 days prior Week 4 and EoT 
(Week 8) visits to provide standardized reporting of adverse events, concomitant medication and 
adherence.  
One post treatment clinic visit will be conducted at SVR12 (week 20) for all participants.  


 
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Figure 1: Study schema  
 
4.2 Visit Schedule 
All participants will complete screening, on-treatment and post-treatment assessments as outlined in the 
Schedule of Assessments and described in Section 6.0. 
Screening assessments must be completed within 6 weeks prior to Baseline. 
Following Screening and Baseline: 
• 
Standard monitoring arm participants will have on-treatment clinic visits at weeks 4 and EoT 
(week 8). Post treatment visit will be conducted at SVR12 (week 20). 
• 
Simplified monitoring arm participants will have no on-treatment clinic visits. One post 
treatment visit will be conducted at SVR12 (week 20). 
All participants will have study nurse phone contact-based visits at week 4 and EoT (week 8). During 
phone contact visits the following will be completed: adherence survey, adverse events and concomitant 


 
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medications. The phone contact visits for participants in both arms will be undertaken 1-2 days prior to 
their scheduled visits. 
 
4.3 Treatment Discontinuation Criteria 
Study drug may be discontinued for reasons including, but not limited to, the following: 
• 
AEs or laboratory abnormalities for which study drug discontinuation is deemed necessary by 
the Investigator and/or the Medical Monitor 
• 
Significant protocol violation. 
• 
Participant request to discontinue study drug or withdraw from the study for any reason. 
• 
Discontinuation of the study by the Kirby Institute, regulatory agencies or a Human Research 
Ethics Committee / Research Ethics Committee /  Institutional Review Board. 
In the event that a positive pregnancy test result is obtained in a female participant during treatment with 
glecaprevir/pibrentasvir, the administration of study drug may be continued at the Principal Investigator's 
discretion after discussion with the participant, if the benefit of continuing study drug is felt to outweigh 
the potential risk. 
Participants who cease study medication will, wherever possible, continue to be followed up according to 
the protocol study plan by completing the EoT visit at the time of treatment termination and SVR12 visit 
at week 20. Participants may revoke consent for follow-up without jeopardizing their relationship with 
either their doctor or the UNSW. If a participant wishes to withdraw from the study then, if possible, all 
assessments scheduled for the SVR12 (week 20) visit should be completed. 
 
5.0 
Treatment of participants 
Participants will receive eight week of open-label glecaprevir (300mg)/pibrentasvir (120mg) in an oral 
once-daily fixed dose. Dose modifications are prohibited. 
 
5.1 Method of Assigning Participants to Treatment Groups (Randomisation) 
At the Screening Visit, all participants will be assigned a screening ID.   
For participants who meet the study selection criteria and are enrolled in the study, the site personnel will 
assign a Participant ID number which will then be retained by the participant for the duration of the 
study.  The site personnel will randomise the participant to one of the two treatment groups at baseline 
via the study randomisation system.  


 
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Randomisation will be 1:2 (standard:simplified).  Randomisation will be using blocks and will be stratified 
by country and genotype (1 vs non-1). 
 
5.2 Study Drug and Study Visit Adherence 
Treatment will be administered in four-weekly supply for standard arm participants and eight-weekly 
supply for simplified arm participants. 
All participants will be required to return the study drug to the site at the SVR12 visit. Participants in the 
standard arm will be instructed to only return all study medication at SVR12 to provide standardised drug 
accountability assessments across the two arms. 
Treatment adherence will be also recorded through an adherence questionnaire completed at Week 4 
and EoT via the phone-contact visits as described in section 6.2. Study visit adherence will be recorded in 
the eCRF.  
 
5.3 Prior and Concomitant Medications 
Concomitant medication must be recorded in the source documents and eCRF from screening until the 
SVR12 visit. 
Subjects must be able to safely discontinue any prohibited medications or supplements listed in 1 at least 
14 days or 10 half-lives (whichever is longer) prior to the first dose of glecaprevir/pibrentasvir  and not 
use these during the entire Treatment Period and for 14 days following discontinuation of study drugs. 
 
 


 
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Table 1. Contraindicated and non-recommended concomitant medications with glecaprevir/pibrentasvir 
Drug Class 
Drug(s) within Class that are 
contraindicated/not recommended 
Clinical Comments 
Antiarrhythmics 
Digoxin 
Digoxin dose should be reduced by 
50% when coadministered with 
glecaprevir/pibrentasvir. 
Anticoagulants 
Dabigatran etexilate 
Use of glecaprevir/pibrentasvir may 
increase dabigatran exposure, 
therefore concomitant use is not 
recommended. 
Anticonvulsants  
Carbamazepine, phenytoin, 
phenobarbital  
May decrease DAA exposure 
leading to a potential loss of 
therapeutic activity, therefore not 
recommended. 
Antihistamine 
Astemizole 
Terfenadine 
Exposures to Astemizole and 
Terfenadine may be increased, 
therefore not recommended. 
Antimycobacterial  
Rifampin  
Rifabutin 
May decrease DAA exposure 
leading to a potential loss of 
therapeutic activity, therefore not 
recommended. 
Ethinyl estradiol-containing 
products  
Ethinyl estradiol-containing 
medications (such as combined oral 
contraceptives and hormone 
replacement therapy) 
Potential for ALT elevations, 
therefore not recommended. 
Gastrointestinal pro-kinetic agent 
Cisapride 
It is a CY3PA4 substrate. 
Concomitant use is not 
recommended. 
Herbal Product  
All herbal supplements (including 
milk thistle) 
St. John’s Wort (Hypericum 
perforatum)  
Red yeast rice (monacolin K) 
May decrease DAA exposure 
leading to a potential loss of 
therapeutic activity, therefore not 
recommended. 
HIV non-nucleoside reverse 
transcriptase inhibitor  
Efavirenz  
Etravirine 
Nevirapine 
May decrease DAA exposure 
leading to a potential loss of 
therapeutic activity, therefore not 
recommended. 
HIV protease inhibitor  
Tipranavir/ritonavir 
Atazanavir 
Colbicistat Boosted PIs 
Darunavir 
Fosamprenavir 
Indinavir 
Lopinavir  
Ritonavir 
Saquinavir 
May increase DAA exposure, 
therefore not recommended. 
HMG-CoA Reductase  
Inhibitors * 
Atorvastatin 
Lovastatin  
Simvastatin 
Pivastatin 
Potential for myopathy including  
rhabdomyolysis., therefore not 
recommended. 
Chronic systemic 
immunosuppressants 
Corticosteroids (prednisolone 
equivalent of >10mg/day for >2 
weeks) 
Azathioprine 
Monoclonal antibodies 
 
Strong CYP3A inducers 
Carbamazepine 
 
* Some HMG-CoA reductase inhibitors (including atorvastatin, lovastatin, or simvastatin) should not be taken with 
glecaprevir/pibrentasvir. Participants receiving these statins should either switch to pravastatin or rosuvastatin prior to the first 


 
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dose of study drug or interrupt statin therapy throughout the treatment period and until 30 days after the last dose. If switching 
to or continuing pravastatin or rosuvastatin, it is recommended to reduce the pravastatin dose by 50% or limit the rosuvastatin 
dose to 10 mg daily while on treatment.  
 
Post-menopausal hormone replacement therapy i.e., estradiol, esterified or conjugated estrogens, as long 
as they do not contain ethinyl estradiol, may be used with glecaprevir /pibrentasvir at the discretion of 
the Investigator. 
Glecaprevir /pibrentasvir is not recommended for use in patients requiring stable cyclosporine doses 
> 100 mg per day. 
Use of investigational agents or devices for any indication within 2 weeks or 10 half-lives, whichever is 
longer, prior to study drug administration is contra-indicated. 
Should any participant need to initiate treatment with any contra-indicated medication during the study, 
the Medical Monitor must be consulted prior to the initiation of any contra-indicated medication. In the 
event that a contra-indicated medication is initiated prior to discussion, the Medical Monitor must be 
made aware of the use of the contra-indicated medication as soon as possible. Medical Monitor’s contact 
details are listed on the cover of this protocol. 
 
5.4 Methods of contraception: 
Women of Childbearing Potential must practice at least one of the following methods of birth control 
from baseline (or earlier) through at least 30 days after the last dose of study drug (postmenopausal or 
permanently surgically sterile women are excluded). 
● Progestogen-only hormonal contraception (oral, injectable, implantable), initiated at least 1 
month prior to Study Day 1. 
● Bilateral tubal occlusion/ligation (if via hysteroscopy [i.e., Essure], provided that a 
hysterosalpingogram confirms success of the procedure) 
● Vasectomized partner(s), provided the vasectomized partner verbally confirms receipt of 
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). 
● Male or female condom with or without spermicide. 
● Cap, diaphragm or sponge with spermicide. 


 
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● A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier method). 
● 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]. 
There are no specific contraception requirements for male participants.  
 
6.0 
Study procedures 
6.1 Visits and Procedures 
The following assessments must be conducted at study visits as per the schedule of assessments: 
Vital signs & physical 
measurements 
Sitting systolic and diastolic blood pressure, heart rate, body weighta, 
heighta 
FibroScan® 
Transient elastography; within 6 months prior to screening. Use APRI in the 
absence of FibroScan® 
Biochemistry 
 
Creatinine, sodium, chloride, potassium and BUN  
Liver Function Tests 
ALT, AST, GGT, total bilirubin, albumin, alkaline phosphatase, total protein 
Full Blood Count 
Haemoglobin, haematocrit , White Blood Cells, platelets, neutrophils 
Clotting 
INR 
Urinary Drug Screen 
Screen for Opiates (other than methadone and buprenorphrine), 
Amphetamines and Cocaine 
HCV RNA 
Must be quantitative at Screening 
HCV Genotype 
Within 5 years prior to screening 
HIV Serology 
Anti-HIV Ab 
HBV Serology 
HBsAg 
HCG Pregnancy Test 
For women of childbearing potential, a negative urine (or serum) HCG test 
at screening and baseline 
Questionnaires 
Adherence survey, EQ-5D-3L, Practitioner Acceptability Questionnaire, 
Participant Satisfaction Survey  
a at screening only 
 
The following assessments and procedures must be performed at each visit as specified below: 
Screening visit (Week -6 to Week 0) - All participants 
• 
Informed consent 
• 
Medical history and patient demographics 
• 
Concomitant medication 


 
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• 
Vital signs and physical measurements 
• 
Health outcome survey (EQ-5D-3L) 
• 
Participant Satisfaction survey 
• 
Fibroscan® 
• 
HCV RNA and genotype (Local Lab.) 
• 
LFTs, FBC and biochemistry (Local Lab.) 
• 
HIV antibody & HBV serology (Local Lab.) 
• 
Clotting (INR) 
• 
UDS 
• 
Pregnancy test (females of child bearing potential only)  
• 
Research specimen collection (Central Lab.):  
o EDTA plasma & whole blood (at all sites)  
o PBMCs (at selected sub-study sites only) 
 
Baseline visit (Week 0) - All participants 
• 
Vital signs and physical measurements 
• 
LFTs, FBC and biochemistry (Local Lab.) 
• 
Pregnancy test (females of child bearing potential only) 
• 
Adverse Events 
• 
Concomitant medication 
• 
Research specimen collection (Central Lab.): EDTA plasma 
• 
Randomisation 
• 
Study drug dispensed (4-weekly supply for standard arm participants and 8-weekly supply for 
simplified arm participants) 
 
Week 4 – All participants 
Via phone contact 1-2 days prior to week 4. A maximum of three attempts should be made by the site 
personnel to contact the participant over the phone. Phone contact attempts must be within the visit 
window allowed per protocol. All attempts must be recorded in the source documents. 


 
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• 
Adverse Events 
• 
Concomitant medication  
• 
Adherence survey 
In addition to the above the following assessments will be completed at week 4: 
 
Standard treatment monitoring group 
Simplified treatment monitoring group 
HOME 
Completed at HOME by the participant: 
NIL 
Completed at HOME by the participant: 
• 
Pregnancy test (females of child bearing 
potential only) 
CLINIC 
Completed at the CLINIC: 
• 
Vital signs and physical measurements 
• 
LFTs, FBC and biochemistry (Local Lab.) 
• 
Pregnancy test (females of child bearing 
potential only) 
• 
Research specimen collection (Central Lab.): 
• 
EDTA plasma (at all sites)  
• 
PBMCs (at sub-study sites only) 
• 
Study drug dispensed (4-weekly supply) 
Completed at the CLINIC: 
NIL – participant is not required to attend the 
clinic 
 
 
 
End of Treatment (Week 8) – All participants 
Via phone contact 1-2 days prior to week 8. A maximum of three attempts should be made by the site 
personnel to contact the participant over the phone. Phone contact attempts must be within the visit 
window allowed per protocol. All attempts must be recorded in the source documents. 
• 
Adverse Events 
• 
Concomitant medication  
• 
Adherence survey 
 
 
 
 
 
 
 
 


 
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In addition to the above the following assessments will be completed at week 8: 
 
Standard treatment monitoring group 
Simplified treatment monitoring group 
HOME 
Completed at HOME by the participant: 
NIL 
 
Completed at HOME by the participant: 
• 
Pregnancy test (females of child bearing 
potential only) 
CLINIC 
Completed at the CLINIC: 
• 
Vital signs and physical measurements 
• 
HCV RNA (Local Lab.) 
• 
LFTs, FBC and biochemistry (Local Lab.) 
• 
Pregnancy test (females of child bearing 
potential only) 
• 
Research specimen collection (Central Lab.): 
• 
EDTA plasma (at all sites)  
Completed at the CLINIC: 
NIL – participant is not required to attend the 
clinic 
 
 
 
 
SVR12 (week 20) - All participants 
• 
Vital signs and physical measurements 
• 
Return study drug 
• 
Health outcome survey (EQ-5D-3L)  
• 
Participant Satisfaction survey 
• 
HCV RNA (Local Lab.) 
• 
LFTs, FBC and biochemistry (Local Lab.) 
• 
Pregnancy test (females of child bearing potential only) 
• 
Adverse Events 
• 
Concomitant medication 
• 
Research specimen collection (Central Lab.):  
o EDTA plasma (at all sites)  
o PBMCs (at selected sub-study sites only) 
 
Unscheduled visits 
Unscheduled visits may occur for a number of reasons including, but not limited to, adverse events, early 
treatment discontinuation or study termination. In the event of treatment or study termination an 


 
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unscheduled visit should be performed where possible.  In the event of an unscheduled visit the following 
data may be collected if applicable: 
• 
Adverse Events 
• 
Concomitant medication 
• 
Vital signs and physical measurements 
• 
HCV RNA and genotype (Local Lab.) 
• 
LFTs, FBC and biochemistry (Local Lab.) 
• 
HIV antibody & HBV serology (Local Lab.) 
• 
Pregnancy test (females of child bearing potential only) 
 
6.2 Study Questionnaires 
All participants will undertake a number of study questionnaires at selected study visits as described 
below. 
Adherence Survey 
Adherence to study drug will be assessed by a structured self-report adherence questionnaire completed 
at week 4 and EoT (week 8) by the participants with the nurse during the telephone contact visits. 
Health Outcomes Survey (EQ-5D-3L) 
The EQ-5D-3L health questionnaire provides a simple descriptive profile and a single index value for 
health status. This information can then be translated into a health utility, which can be used for cost-
effectiveness analyses. The EQ-5D-3L will be completed by all participants in the clinic at screening and 
SVR12 (week 20). 
Participant Satisfaction Survey 
Participant satisfaction will be assessed via questionnaire completed by all participants at the screening 
visit and again following the completion to treatment at the SVR12 visit. 
Practitioner Acceptability Questionnaire 
Acceptability of simplified HCV treatment monitoring will be assessed via study specific questionnaire 
completed by each site Principal Investigator and the primary Research Nurse prior to the 
commencement of screening and again following the completion of the SVR12 visit of the last patient at 
each site. 
Practitioner Acceptability Questionnaire will not be completed on a per participant basis. It will only be 
completed by the practitioners twice during the study: before FPFV and after LPLV. 


 
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7.0 
Recording and reporting Adverse Events (AEs) and Product Complaints 
7.1 Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events 
7.1.1 
Adverse Event definition 
Adverse events and adverse drug reactions may occur in the course of this study and within the specified 
follow-up period. These events may also occur in screened participants during the screening period prior 
to enrolment as a result of protocol-specified interventions. Adverse events will be collected for all 
participants in the clinic at baseline and SVR (week 20) visits and via phone contact at the week 4 and EoT 
(week 8) visits. 
The definition of an adverse event is any untoward medical occurrence in a participant administered with 
a pharmaceutical product which does not necessarily have a causal relationship with the product.  
Pre-existing conditions or diseases that occur during the study (e.g. seasonal allergies, asthma or 
recurrent headaches) should not be considered as adverse events unless they change in frequency or 
severity 
All adverse events encountered during treatment and for 12 weeks after drug discontinuation must be 
reported on the Adverse Event Page of the electronic case report form (eCRF). 
Laboratory test abnormalities (results outside the normal range) as such should not be reported as 
adverse events unless they result in a clinically relevant condition including but not limited to 
modification or discontinuation of study drug. Overdoses of study drug without clinical sequelae should 
not be reported as an adverse event. 
 
7.1.2 
Serious Adverse Event (SAE) (including Serious Adverse Drug Reactions) 
The Investigator shall report serious adverse events to the Kirby Institute and AbbVie within twenty-four 
(24) hours of learning of the event. In addition, the Investigator shall report to the Kirby Institute and 
AbbVie all pregnancies experienced by a Study subject within 24 hours of learning of the event. 
A serious adverse event is defined as any event that results in any of the following: 
(i) death; 
(ii) a life threatening adverse event experience (i.e., participant was at immediate risk of death from 
the event as it occurred); 
(iii) a persistent or significant disability/incapacity; 
(iv) inpatient hospitalisation 


 
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(v) prolongation of existing hospitalisation; 
(vi) a congenital anomaly/birth defect; or 
(vii) an important medical event that jeopardizes the participant and requires medical/surgical 
intervention to prevent one of the outcomes listed in (i) through (vii) of this definition. 
 
7.2 Assessment of Adverse Events and Serious Adverse Events 
7.2.1 
Assessment of Causality for Study Drugs and Procedures  
The investigator or designee must assess each adverse event for the following: 
Relationship 
Unlikely: 
An adverse event that is unlikely to be related to the use of the drug or 
procedures. 
Possibly: 
 An adverse event that might be related to the use of the drug or procedures. 
Probably: 
 An adverse event that is likely to be related to the use of the drug or procedures. 
 
7.2.2 
Assessment of Severity 
The investigator or designee must assess each adverse event for the following: 
Severity 
Mild: 
 
 
Discomfort noticed but no disruption of normal daily activity. 
Moderate: 
 
Discomfort sufficient to reduce or affect normal daily activity. 
Severe:  
 
Incapacitating with inability to work or perform normal daily activity. 
Life threatening: 
Represents an immediate threat to life. 
 
7.3 Reporting Requirements 
7.3.1 
Adverse Events  
All adverse events from the date of signing the consent form until twelve weeks after the last dose of 
study drug administration should be reported on the case report form. All clinically significant adverse 
events should be followed and recorded until its resolution (or stabilization in case it cannot resolve).  
Coding 
Adverse events will be assigned preferred terms and categorised into system organ classes according to 
the Medical Dictionary for Drug Regulatory Affairs (MedDRA) classification of the WHO terminology. 


 
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7.3.2 
Serious Adverse Events  
All serious adverse events (SAEs) should be reported within 24 HOURS of becoming aware of the event to 
the Kirby Institute and AbbVie by email or fax on the Serious Adverse Event Reporting Form. The 
appropriate Serious Adverse Event form should be used. Reports should be followed promptly by 
detailed, written follow-up reports when all information is not included in the initial report. Follow-up 
reports should be reported within 24 HOURS also. The immediate and follow up reports should identify 
participants by unique code numbers assigned to study participants rather than personal identification. 
The investigator must also comply with all applicable ethical and regulatory requirement/s relating to the 
reporting of serious adverse events.  
Any serious adverse event that is ongoing at the post-study follow-up visit must be followed until 
resolution or until the event stabilizes (for those events that will not resolve). 
For deaths, the Principal Investigator will supply the sponsor and the IRB/IEC with any additional 
requested information (e.g. death certificate, autopsy reports and medical reports). 
The Investigator shall make available to both the Kirby Institute and AbbVie promptly such records as may 
be necessary and pertinent to investigate any adverse event, if specifically requested by AbbVie.  
SAE reports must be submitted to BOTH the Kirby Institute AND AbbVie: 
Kirby Institute: Email: smartc@kirby.unsw.edu.au 
Fax: 
+61 2 9385 9214 
AbbVie:  
Email: PPDINDPharmacovigilance@abbvie.com 
 
 
 
7.4 Suspected Unexpected Serious Adverse Reaction (SUSAR)  
The Project Team in collaboration with the Medical Officer will review and identify all serious events 
which fit the criteria of a SUSAR and requiring expedited reporting to relevant parties.  
The definition of a SUSAR is a serious adverse event which is both suspected as being related to the drug 
(i.e. has a reasonable suspected causal relationship and is unexpected) and where the nature and severity 
is not consistent with known information (e.g. the Investigator’s Brochure).  
The sponsor must expedite the reporting of all SUSARs to all concerned investigators/institutions, 
IRB/IEC/s, and regulatory authorities within the reporting timeframe. Reports must comply with the 
applicable regulatory requirements and ICH Guideline for Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting.  


 
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Researchers must inform the IRB/IEC and regulatory authorities of all SUSARs that occur during the study 
that may affect the conduct of the study or the safety of the participants or their willingness to continue 
participation in the study. Researchers must inform the IRB/IEC as soon as possible of any new 
information from other published or unpublished studies which may have an impact on the continued 
ethical acceptability of the study or which may indicate the need for amendments to the study protocol. 
 
7.5 Product Complaints 
All Product Complaints at any Study Site must be reported to both the Kirby Institute and AbbVie within 
twenty-four (24) hours. 
Kirby Institute: Email: smartc@kirby.unsw.edu.au 
Fax: 
+61 2 9385 9214 
AbbVie:  
Email: RD_PQC_QA@abbvie.com 
Product Complaint means any suspected quality defect in the study drug or its package or 
labelling. Product Complaints may include, but are not limited to: 
(i) 
damaged or broken product or packaging issues; 
(ii) product appearance whose color/markings do not match the labeling; 
(iii) labeling discrepancies/inadequacies in the labeling/instructions; 
(iv) missing components/product. 
 
8.0 
Packaging, labelling, storage and accountability of clinical trial supplies 
Glecaprevir/pibrentasvir will be provided by AbbVie and should be dispensed under the supervision of the 
investigator or a qualified member of the investigational staff, or by a hospital/clinic pharmacist.  
All participants will be required to return the study drug to the site at the SVR12 visit. Returned study 
drug must not be dispensed again. Study drug may not be relabeled or reassigned for use by other 
participants.  
A designated person at the study site must receive the study drug shipment. That person must check that 
the supplies are in good condition and are complete as per the shipping records. Study drugs must be 
stored in a secure location with limited access. The study drug must only be dispensed according to the 
protocol and records must be kept detailing supplies received, dispensed to the participant, returned 
from the participant and returned to the sponsor or destroyed at site, as applicable. 
Study staff must not open and count clinical trial supplies prior to dispensing. 
 


 
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8.1 Formulation 
Glecaprevir and pibrentasvir are presented as a co-formulated, film-coated, immediate release tablet. The 
tablet strength is 100 mg glecaprevir and 40 mg pibrentasvir. The tablets are pink-colored, oblong 
biconvex shaped and debossed with “2nd” on one side. 
The tablets do not contain gluten. The tablets contain lactose. 
 
8.2 Packaging and labelling 
Glecaprevir/pibrentasvir 100mg/40mg tablets are packaged in bottles of 30 tablets. 3 bottles are required 
for 4 weeks of treatment, which includes an extra 2 days of treatment. 6 bottles are required for 8 weeks 
of treatment, which includes an extra 4 days of treatment. 
 
8.3 Storage and handling 
Study drug should be stored in a securely locked area, accessible only to authorized site personnel. To 
ensure the stability of the study drug and to ensure proper product identification, the drug product 
should not be stored in a container other than the container in which they are supplied. 
Glecaprevir/pibrentasvir should be stored between 15°C (59°F) and 25°C (77°F). 
Care should be taken to ensure that the study drug is stored securely away from children and in dry 
conditions. The study drug should be kept in the original packaging. 
 
8.4 Dosage and administration 
The study drug is to be administered orally once a day (three tablets per day) with food. Each participant 
must be given instructions to maintain approximately the same daily dosing interval between study drug 
doses.  Participants should be instructed to swallow the study drug tablets whole. Participants should be 
instructed to only remove the tablets from the bottle immediately prior to dosing.  
For a missed dose of study drug, participants should be instructed to take the missed dose of study drug 
as soon as possible during the same day. However, no more than the daily dose of 
glecaprevir/pibrentasvir should be taken on any calendar day. Participants should be cautioned never to 
double the next dose with a missed dose of study drug under any circumstances. 
Participants in the standard arm will be dispensed with four-week supply (three bottles) at the Baseline 
and Week 4 visits.  
Participants in the simplified arm will be dispensed with eight-week supply (6 bottles) at the Baseline visit.  
 


 
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9.0 
Biological samples 
9.1 Laboratory supplies and sample processing 
Laboratory supplies for collection of research specimens (plasma, whole blood and PBMCs) will be 
supplied by the Kirby Institute. 
The following blood samples will be collected as time point specified in the schedule of assessments: 
• 
10 mL EDTA plasma (20 mL at screening and baseline) for HCV RNA testing, virological factors 
associated with treatment clearance and future HCV related research; 
• 
4 mL EDTA whole blood for human genomic DNA analysis; 
• 
60 mL ACD plasma for PBMCs (sub-study sites only) for immunological factors associated with 
treatment clearance and future HCV related research; 
Samples will be collected by sites and then processed and stored at -80°C (-200°C for PBMCs) at the site 
local laboratory for bulk shipment to the Kirby Institute laboratory. Detailed sample processing 
instructions will be provided in the Laboratory Manual. 
EDTA plasma samples will be used for study endpoint analysis. HCV viral load will be measured using in-
house and commercial assays. Sequencing of the viral genome will also be performed as a more accurate 
means of genotyping. Data generated from the sequencing may also be used to distinguish relapse from 
reinfection, to examine the prevalence of mixed infection and to look at factors associated with relapse 
including RASs.  
PBMCs and whole blood samples may be used to examine host factors associated with viral clearance, 
including but not limited to HLA Type, IL28-B, ISG expression, IP-10 and other biomarkers. 
 
9.2 Shipping of biological samples 
Samples must only be shipped to the Kirby Institute laboratory on the instruction from the SMART-C 
Project Coordinator. 
It is the responsibility of each site Principal Investigator to ensure that all site staff handling, packaging, 
and/or shipping biological samples understand and comply with International Air Transport Association 
(IATA) regulations relating to the handling and shipping of hazardous goods and/or diagnostic specimens. 
 
9.3 Future use of biological samples 
After the samples have been analyzed for the study endpoints as specified in the protocol, remaining 
samples will be stored for use in future Human Research Ethics Committee approved hepatitis C related 
research. Additional consent will not be sought for this storage and future use. It is not optional. 


 
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Participants not wishing to have their samples stored or used in future hepatitis C related research will 
not be eligible to participate in this study. 
 
10.0 
Statistics 
10.1 
Sample Size 
The study is designed to enrol a total of 375 patients: 125 in the standard arm and 250 in the simplified 
arm. The primary efficacy endpoint of SVR12 will be assessed within each arm, and the primary 
comparison of SVR12 rates will be for non-inferiority of standard to simplified arms. With these patient 
numbers, the study has approximately 80% power to show non-inferiority to standard treatment 
monitoring with a lower confidence bound for the difference (standard – simplified) in SVR12 rates 
greater than –6% (assuming an SVR12 rate of 96% in both arms). 
 
10.2 
Assessments of efficacy 
A final full statistical analysis plan will be written and signed off by the Protocol Steering Committee prior 
to final study data lock. 
Primary endpoints:  
1. SVR12 defined as the proportion of patients with undetectable HCV RNA at 12 weeks post end of 
treatment (week 20) based on ITT population. 
Secondary endpoints:  
2. SVR12 defined as the proportion of patients with undetectable HCV RNA at 12 weeks post end of 
treatment (week 20) based on mITT population. 
3. Proportion adherent to treatment and study visits (on-treatment adherence and early treatment 
discontinuation); 
4. Change in health-related quality of life during treatment (measured by EG-5D-3L); 
5. Resistance associated substitutions (RAS): SVR12 in participants with and without baseline RAS, 
and RAS distribution in participants with virological failures; 
6. Patient treatment satisfaction measured by a questionnaire applied to all participants; 
Exploratory endpoint: 
7. Provider acceptability of simplified monitoring strategy. 
 


 
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10.3 
Efficacy analysis 
The primary analysis will compare the randomised treatment arms on an ITT basis (see section 10.4). The 
primary efficacy endpoint is the proportion of patients with undetectable HCV RNA at 12 weeks post end 
of treatment. The treatment arms will be considered non-inferior if the lower limit 95% CI of the 
difference between the two arms does not exceed -6%. There will be no extrapolation of data for the 
primary endpoint. Patients with missing data will be analysed as missing equals failure. Secondary 
analyses will compare randomised treatment groups based on available data (mITT Population). 
For all secondary endpoints simple pairwise comparisons of the randomised treatment arms will be 
undertaken for both the ITT and mITT populations. 
 
10.4 
Assessments of safety  
Safety endpoint: 
8. Proportion of patients with common adverse events (reported in greater than 5%). 
9. Proportion of patients with at least one severe or potentially life threatening (grade 3 or 4) 
adverse event. 
10. Proportion of patients with un-scheduled clinic visits. 
Safety analyses will also be undertaken with the proportion of patients with Grade 3 or 4 adverse events, 
and grade adverse events will be summarised by randomised treatment group, by severity and relation to 
study drug. Serious adverse events will be summarised for all enrolled patients. 
 
10.5 
Definition of Intent-to-treat Population  
Intent-to-treat (ITT) and modified intent-to-treat (mITT) populations will be used for efficacy analyses. All 
patients who receive at least one dose of study drug will be included in the ITT population (and safety 
population). The mITT population will exclude patients who have completed treatment (>95% adherence) 
(according to phone contact at week 8), but have not returned for their SVR12 assessment. The data from 
the ITT and mITT will be presented by the treatment arm assigned at the time of randomisation. For the 
primary analyses of non-inferiority tests, the percentage of patients achieving SVR12 in each arm will be 
calculated with confidence intervals (CI) using the normal approximation to the binomial distribution. 
 
10.6 
Definition and evaluation of HCV resistance 
Regions encoding NS3 and NS5A will be sequenced from available baseline samples from all patients, and 
from the first available post-baseline sample with HCV RNA ≥1000 IU/mL from patients with virologic 
failure. Baseline polymorphisms relative to a subtype-specific reference sequence for all patients, and 


 
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treatment-emergent substitutions relative to the patient’s baseline sequence for patients with virologic 
failure will be identified using the following set of amino acid positions:  36, 43, 54, 55, 56, 80, 155, 156, 
166, 168 in NS3; 24, 28, 29, 30, 31, 32, 58, 92, 93 in NS5A.  These are positions at which substitutions have 
been observed in vitro or clinically in NS3 or NS5A in any genotype with drugs for the respective inhibitor 
class. 
 
11.0 
Data Safety and Monitoring Board (DSMB) 
A data safety and monitoring board (DSMB) will consist of at least 1 statistician and 2 practicing 
gastroenterologist/infectious diseases specialists. The meeting will include the interim safety and 
adherence analysis which will be performed when the first 75 participants have either completed SVR12 
or dropped out of the study. Additional DSMB meetings will be scheduled at a frequency commensurate 
with the risk as determined by the DSMB. 
 
12.0 
Data collection, source documents and record retention 
The Principal Investigator and the institution where the study will be conducted will permit study-related 
monitoring, audits, ethics committee review and regulatory inspection providing direct access to source 
documents. 
Data will be collected on study specific electronic or paper copy case record forms. The Principal 
Investigator is responsible for ensuring the data collected are complete, accurate and recorded in a timely 
manner.  
 
12.1 
Submission of data 
Electronic CRFs: following each participant visit the designated site staff will complete the visit specific 
eCRF. Once all required information is received the eCRF shall be considered complete. Project Team staff 
will then monitor the data for completeness and accuracy. Any eCRF discrepancies, either manual or 
automatic, will be addressed with the site staff for clarification. 
The site Principal Investigator is responsible for ensuring the completion of accurate source 
documentation to support data collected on case report forms. Source documents include all recordings 
of observations or notations of clinical activities and all reports and records necessary for the evaluation 
and reconstruction of the trial. Source documents include, but are not limited to; participant medical 
records, laboratory reports, ECG tracings, X-rays, radiologist reports, participant diaries, biopsy reports, 
ultrasound images, participant progress notes, pharmacy records and any other reports or records of 
procedures performed in accordance with the protocol.  


 
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It is not acceptable for the CRF to be the only record of study participation and progress must also be 
recorded in the each person’s medical record. This is to ensure that anyone accessing the medical record 
has adequate knowledge that the person is a clinical trial participant. 
Any document that acts as a source document (the point of the initial recording of a piece of data) should 
be signed and dated by the person recording or reviewing the data for issues of medical significance (for 
example the review of laboratory reports). Persons signing the source documents must be listed as a site 
staff member. 
The sponsor’s monitor will visit sites to conduct source document verification. The number of visits will 
depend upon study complexity and recruitment rate; however, the monitor will conduct a minimum of 
three source data verification visits during the study. Ideally the first will occur shortly after 
randomisation of the first participant(s), the second during study conduct and the final following 
completion of all study visits. Additional monitoring visits may be scheduled if required.  
The Principal Investigator is responsible for retaining all essential documents listed in ICH Good Clinical 
Practice guidelines. These must be organised in a comprehensive filing system that is accessible to study 
monitors and other relevant personnel. 
 
12.2 
Archiving  
The Principal Investigator is responsible for ensuring all study documents are retained for a minimum of 
15 years following completion and publication of the study or for the duration required by the local 
regulatory authority.  
 
13.0 
Ethics committee/regulatory approval and informed consent 
The sponsor is responsible for ensuring regulatory approval for the study is obtained. 
The site Principal Investigator is responsible for obtaining IRB/EC approval for the protocol and participant 
information and informed consent form in compliance with local regulatory requirements prior to 
entering any participant into the study. The approval letter/document must clearly identify the protocol 
and all documents approved by the IRB/EC including version number & date of the protocol and 
participant information and consent form. A copy of the approval document must be sent to the study 
sponsor.  
The site Principal Investigator must also obtain approval for any amendments to the protocol or 
participant information and informed consent form. The Principal Investigator must comply with all 
IRB/EC reporting requirements for all adverse events, annual updates and end of study reports and must 
agree to abide by any IRB/EC conditions of approval. 


 
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The site Principal Investigator (or designee) is responsible for ensuring freely-given consent is obtained 
from each potential participant prior to the conduct of any protocol-specific procedures. The Principal 
Investigator may delegate the task of obtaining consent to appropriately qualified Sub-investigator(s). 
Consent must be documented by the participant’s dated signature on the participant information and 
consent form together with the dated signature of the person conducting the consent discussion.  
A copy of the signed and dated participant information and consent form must be given to the person 
prior to study participation. The participant or their legally authorised representative must be informed in 
a timely manner of any new information that becomes available during the course of the study that may 
affect his/her willingness to continue study participation. 
This study shall be conducted in accordance with the ethical principles laid out in the Declaration of 
Helsinki (most current issued version) and the National Statement on Ethical Conduct in Research 
Involving Humans (most current issued version). 
 
14.0 
Confidentiality of data 
14.1 
Confidentiality of participant records 
By signing the Clinical Trial Agreement, the site Principal Investigator agrees that the sponsor, IRB/EC or 
regulatory authorities may consult and/or copy study documents to verify information in the case report 
form. By signing the consent form the participant agrees to these processes. 
Participant confidentiality will be maintained at all times and no documents containing the participant’s 
name or other identifying information will be collected by the sponsor. It may be necessary for the 
sponsor’s representatives, the IRB/EC and regulatory authority representatives to have direct access to 
the participant’s medical records. If study documents need to be photocopied during the process of 
verifying case report form data, the participant will be identified by a unique code only; full names and 
other identifying information will be masked. 
 
14.2 
Confidentiality of study data 
By signing the Clinical Trial Agreement, the site Principal Investigator affirms to the sponsor that 
information provided to them by the sponsor will be maintained in confidence and divulged only as 
necessary to the ethics committee and institution employees directly involved in the study. Both ethics 
committee members and employees must also understand the confidentiality requirements for any 
information divulged to them. The data generated by this study will be considered confidential, except 
where it is included in a publication as agreed in the publication policy of this protocol. 


 
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At sites where regulations restrict the collection of full date of birth and/or initials, the following 
conventions will be used: 
• 
Date of birth will be entered as 01/01/YYYY 
• 
Initials will be entered as AA-AA, BB-BB, CC-CC etc. 
 
15.0 
Governance 
This research protocol is sponsored by UNSW Sydney with funding and provision of study drug by AbbVie 
Pty LTD. The study is coordinated through the Kirby Institute for Infection and Immunity in Society, UNSW 
Australia. The Kirby Institute has established governance and implementation structures which use 
resources efficiently to deliver program objectives on schedule. 
 
16.0 
Quality Control (QC) and Quality Assurance (QA) 
The sponsor agrees to be responsible for implementing and maintaining quality control and quality 
assurance systems with written standard operating procedures to ensure the study is conducted and data 
are generated, documented and reported in compliance with the protocol, Good Clinical Practice 
standards and all applicable local laws and regulations relating to the conduct of a clinical trial. 
 
17.0 
Publication Policy 
The results of this study may be published and presented at scientific meetings. Publication of data 
derived from this protocol will be governed by the Protocol Steering Committee. All published data will be 
non-identifiable grouped data and will follow the guidelines set forth by the International Committee of 
Medical Journal Editors (ICMJE).  
 
 
 
 


 
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18.0 
List of References 
1. 
Gane E, Poordad F, Wang S, et al. High Efficacy of ABT-493 and ABT-530 Treatment in Patients 
With HCV Genotype 1 or 3 Infection and Compensated Cirrhosis. Gastroenterology 2016; 151(4): 651-9 
e1. 
2. 
Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and Pibrentasvir for 12 Weeks for HCV 
Genotype 1 Infection and Prior Direct-acting Antiviral Treatment. Hepatology 2017. 
3. 
McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with 
ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.[comment]. 
New England Journal of Medicine 1998; 339(21): 1485-92. 
4. 
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with 
interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.[comment]. 
Lancet 2001; 358(9286): 958-65. 
5. 
Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic 
hepatitis C virus infection. The New England journal of medicine 2011; 364(25): 2405-16. 
6. 
Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 
infection. The New England journal of medicine 2011; 364(13): 1195-206. 
7. 
Dore GJ, Ward J, Thursz M. Hepatitis C disease burden and strategies to manage the burden 
(Guest Editors Mark Thursz, Gregory Dore and John Ward). Journal of viral hepatitis 2014; 21 Suppl 1: 1-4. 
8. 
Asselah T, Marcellin P. New direct-acting antivirals' combination for the treatment of chronic 
hepatitis C. Liver international : official journal of the International Association for the Study of the Liver 
2011; 31 Suppl 1: 68-77. 
9. 
Zeuzem S, Feld J, Wang S et al.  ENDURANCE-1: A Phase 3 Evaluation of the Efficacy and Safety of 
8- versus 12-week Treatment with Glecaprevir/Pibrentasvir (formerly ABT-493/ABT-530) in HCV Genotype 
1 Infected Patients with or without HIV-1 Co-infection and without Cirrhosis. HEPATOLOGY 2016; 64  
Suppl 1: 132A. 
10. 
Hassanein T, Wyles D, Wang S et al. G/P Demonstrates High SVR Rates in Patients with HCV GT2, 
4, 5, or 6 Infection without Cirrhosis Following an 8-Week Treatment Duration (SURVEYOR-II, Part 4). 
HEPATOLOGY 2016; 64  Suppl 1: 132A. 
11. 
Muir A, Strasser S, Wand S et al. High SVR Rates With ABT-493 + ABT-530 Co-Administered For 8 
Weeks in Non-Cirrhoti c Pati ents With HCV Genotype 3. J Hepatol 2016; 64 (Suppl 2):S186 (oral 
presentation). 
 
 
 


 
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19.0 
Abbreviations List 
 
ACD 
Acid Citrate Dextrose 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APRI 
AST to Platelet Ratio Index 
ART 
Antiretroviral Therapy 
AST 
Aspartate Aminotransferase 
CI 
Confidence interval 
DAA 
Direct Acting Antiviral 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediamine Tetraacetic Acid 
EOT 
End of Treatment 
FBC 
Full Blood Count 
FPFV 
First Patient First Visit 
GGT 
Gamma Glutamic Transpeptidase 
HBC 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
Hgb 
Haemoglobin 
HIV 
Human Immunodeficiency Virus 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LFTs 
Liver Function Tests 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit Of Quantification 
LPLV 
Last Patient Last Visit 
mITT 
Modified intent-to treat 
PEG-IFN 
Pegylated interferon alfa 2a/b 
PBMC 
Peripheral Blood Mononuclear Cell 
RAS 
Resistance Associated Substitutions 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVR12 
Sustained Virological Response (HCV RNA undetectable 12 weeks post-
treatment) 
UDS 
Urinary Drug Screen 
ULN 
Upper Limit of Normal 
UNSW 
University of New South Wales 
WCC 
White Cell Count 
WOCBP 
Women of Childbearing Potential 
 

SAP_001.pdf: 
SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
 
 
 
 
 
 
Simplified Monitoring - A Randomised Trial in hepatitis C 
 
A phase IIIb, open-label, multicentre, international randomised controlled trial of simplified treatment 
monitoring for 8 weeks glecaprevir (300mg)/pibrentasvir (120mg) in chronic HCV treatment naïve 
patients without cirrhosis 
 
EUDRACT:  2017-00694-37 / ClinicalTrials.gov Identifier: NCT03117569 
 
Statistical Analysis Plan 
 
 
 
Study Title: 
Simplified Monitoring – A Randomised Trial in hepatitis C 
Name of Study Drug: 
Glecaprevir/Pibrentasvir (300mg/120mg) 
Protocol Number: 
VHCRP1701 
Protocol Version: 
2.0 
Protocol Date: 
14 June 2017 
Co-ordinating Principal Investigators: 
Professor Gregory Dore 
Name/s of Sponsor: 
UNSW Sydney 
Analysis Type: 
Primary analysis 
Analysis Plan Version: 
1.0 
Analysis Plan Date: 
9 July 2018 
Analysis Plan Author: 
Dr Marianne Martinello 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Contents 
LIST OF ABBREVIATIONS ............................................................................................................................... 3 
INTRODUCTION ............................................................................................................................................. 4 
STUDY DEFINITIONS ...................................................................................................................................... 5 
STUDY OBJECTIVES AND DESIGN .................................................................................................................. 6 
Study objectives ................................................................................................................................... 6 
Study design ......................................................................................................................................... 6 
Sample size and power ........................................................................................................................ 7 
TYPE OF ANALYSIS ......................................................................................................................................... 8 
Data Safety and Monitoring Board (DSMB) Analysis ........................................................................... 8 
Primary analysis: Post-treatment week 12 .......................................................................................... 8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................................................................... 8 
Statistical Methods .............................................................................................................................. 8 
Analysis Sets ......................................................................................................................................... 8 
Data Handling Conventions ................................................................................................................. 9 
Missing Data .......................................................................................................................................... 9 
Outliers .................................................................................................................................................. 9 
Visit Windows ...................................................................................................................................... 9 
Definition of Study Day ......................................................................................................................... 9 
Analysis Windows ............................................................................................................................... 10 
PARTICIPANT DISPOSITION ......................................................................................................................... 11 
Recruitment ....................................................................................................................................... 11 
Participant Enrolment and Disposition .............................................................................................. 11 
Protocol violations/exemptions ......................................................................................................... 11 
BASELINE DATA ........................................................................................................................................... 15 
Demographic Data and Baseline Characteristics ............................................................................... 15 
STUDY ENDPOINTS ...................................................................................................................................... 19 
Primary efficacy endpoint .................................................................................................................. 19 
Secondary efficacy endpoints ............................................................................................................ 20 
Primary safety endpoint .................................................................................................................... 20 
Adherence  ........................................................................................................................................ 20 
Exploratory Analysis ........................................................................................................................... 20 
SAFETY ANALYSES ....................................................................................................................................... 24 
Extent of Exposure ............................................................................................................................. 24 
Adverse Events ................................................................................................................................... 24 
Adverse Event Severity ....................................................................................................................... 24 
Relationship of Adverse Events to Study Drug ................................................................................... 24 
Summaries of Adverse Events and Deaths ........................................................................................ 24 
Serious adverse events (SAE) .............................................................................................................. 25 
Laboratory Evaluation ........................................................................................................................ 25 
Reference List .............................................................................................................................................. 32 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
LIST OF ABBREVIATIONS 
AE 
 
adverse event 
ALT 
 
alanine aminotransferase 
APRI 
 
AST:platelet ratio index 
APTT 
 
activated partial thromboplastin time 
ARV 
 
antiretroviral 
AST 
 
aspartate aminotransferase 
BLoQ 
 
below the lower limit of quantitation 
cART 
 
combination antiretroviral therapy 
CI 
 
confidence interval 
CPT 
 
Child-Pugh-Turcotte 
DAA 
 
direct acting antiviral 
ECG 
 
electrocardiogram 
eCRF 
 
electronic case report form 
EOT 
 
end of treatment 
FDC 
 
fixed-dose combination 
FU 
 
follow-up 
GT 
 
genotype 
HCV 
 
hepatitis C virus 
HLGT 
 
high level group term 
HLT 
 
high level term 
ITT 
 
intention-to-treat 
INR 
 
international normalized ratio of prothrombin time 
LLOQ 
 
lower limit of quantitation 
LLT 
 
lower level term  
LSM 
 
liver stiffness measurement 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD  
Model for End-Stage Liver Disease 
mITT 
 
modified intention-to-treat 
mITT-VF 
modified intention-to-treat, virological failure 
PP 
 
per-protocol 
PT 
 
preferred term 
Q1 
 
first quartile 
Q3 
 
third quartile 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SD 
 
standard deviation 
SOC 
 
system organ class 
SVR 
 
sustained virologic response 
SVRx 
 
sustained virologic response x weeks after stopping study drug 
TD 
 
target detected 
TND 
 
target not detected 
ULN 
 
upper limit of normal 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
INTRODUCTION 
The capacity to scale-up interferon-free DAA therapy would be enhanced by simplified treatment 
monitoring strategies.  The “next generation” DAA regimen of glecaprevir/pibrentasvir, an NS3/4a 
protease inhibitor and an NS5A inhibitor, provide key features for HCV treatment simplification, 
including on-treatment monitoring: 1) pan-genotypic activity with very high efficacy (SVR>95%); 2) no 
relationship between time to undetectable HCV RNA and SVR; 3) minimal drug-related toxicity; 4) ease 
of dosing (three pills once daily); and 5) short duration (8 weeks for HCV treatment naïve individuals 
without cirrhosis; 12 weeks for HCV treatment naïve individuals with cirrhosis).   
 
Current standard on-treatment monitoring in clinical trials involves clinic-based visits every 4 weeks.  In 
the interferon-free DAA era with highly tolerable, effective and short duration therapy, this intensive 
monitoring strategy may no longer be required.  A simplified on-treatment monitoring strategy is 
hypothesised to be non-inferior to the standard clinical trial on-treatment monitoring strategy.  If 
successful, a simplified on-treatment monitoring strategy is likely to be highly attractive to patients, 
clinicians and health care payers.  It has the potential to improve HCV treatment scale up, providing 
population level benefits in the reduction of global hepatitis C disease burden. 
 
In people with chronic HCV (genotypes 1-6) who are treatment naïve and do not have cirrhosis, we 
hypothesise that the proportion achieving SVR following glecaprevir/pibrentasvir for 8 weeks with a 
simplified monitoring schedule will be non-inferior to glecaprevir/pibrentasvir for 8 weeks with a 
standard monitoring schedule. 
 
This document describes the statistical analysis to be performed for the primary analysis of the SMART-C 
study, protocol version 2.0.  
 
The analysis for the primary endpoint will be conducted after all participants complete the post-
treatment Week 12 visit or prematurely discontinue from study. All the safety and efficacy data through 
to the post-treatment Week 12 visit will be cleaned, finalised, and included for the analysis.  Prior to 
analyses, the study database will be locked in accordance with VHCRP Standard Operating Procedures 
and will have completed required quality assurance. 
 
The primary analysis will focus on the non-inferiority of eight weeks of glecaprevir/pibrentasvir for 
treatment naïve patients without cirrhosis administered with simplified on-treatment monitoring 
strategy compared with a standard on-treatment monitoring strategy. 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
STUDY DEFINITIONS 
Chronic HCV infection is defined by detection of anti-HCV antibody and/or HCV RNA for greater than six 
months prior to screening. 
 
HCV virological suppression is defined as HCV RNA below the lower limit of quantitation (LLoQ) (target 
not detected [TND] or target detected, not quantifiable [TDnq]).   
 
An end-of-treatment response (ETR) is defined as HCV RNA below the LLoQ (TND or TDnq) at the end of 
treatment (date of treatment cessation). 
 
HCV treatment outcome will be classified as: 
• 
Sustained virological response at 12 weeks post-treatment (SVR12): Defined as HCV RNA 
below the LLoQ (TND or TDnq) at 12 weeks post cessation of treatment.   
• 
Virologic failure: Defined as HCV RNA above the LLoQ at 12 weeks post cessation of 
treatment (excluding reinfection).  
o In the standard monitoring arm, HCV virologic failure will be further defined as one of 
the following: 
 
Non-response (failure of virological suppression on-treatment with quantifiable 
HCV RNA at all time points measured between baseline and end of treatment).  
 
Breakthrough (an increase from non-quantifiable to quantifiable HCV RNA or to 
at least 1 log10 above nadir while on treatment).  
 
Post-treatment relapse (the presence of quantifiable HCV RNA after end of 
treatment with detection of infection with an HCV strain consistent with the 
primary infecting strain, confirmed as homologous virus on sequencing).   
• 
Non-virologic failure: Defined as death, premature treatment discontinuation, loss to follow 
up or missing plasma HCV RNA at post treatment week 12.   
• 
Reinfection: Defined as HCV RNA above the LLoQ after end of treatment with detection of 
infection with an HCV strain that was distinct from the primary infecting strain, confirmed as 
heterologous virus on sequencing.   
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
STUDY OBJECTIVES AND DESIGN 
Study objectives 
The primary objective of this study is: 
• 
To compare the proportion of patients with undetectable HCV RNA (HCV RNA <LLOQ) at 12 
weeks post-treatment (SVR12) following 8 weeks treatment with glecaprevir/pibrentasvir 
(300/120mg) in HCV treatment naïve non-cirrhosis chronic HCV patients who have received a 
standard versus simplified schedule of safety and virological monitoring (intention-to-treat 
population). 
 
The secondary objectives of this study are: 
• 
To compare the proportion of patients achieving SVR12 between those who received a standard 
versus simplified schedule of safety and virological monitoring, in the modified intention-to-
treat population; 
• 
To compare the proportion of patients achieving SVR12 between those who received a standard 
versus simplified schedule of safety and virological monitoring, in the per-protocol population; 
• 
To evaluate the proportion adherent to treatment and study visits (on-treatment adherence and 
early treatment discontinuation); 
• 
To evaluate patient reported outcomes following treatment; 
• 
To evaluate safety and tolerability by monitoring adverse events during treatment; 
• 
To evaluate patient treatment satisfaction;   
• 
To evaluate the prevalence and impact of baseline resistance associated substitutions (RAS) on 
efficacy (SVR12); 
• 
To evaluate cost-effectiveness of simplified monitoring; 
• 
To evaluate immune-virological factors associated with SVR12. 
 
The exploratory objective of this study is: 
• 
To examine the provider acceptability of the simplified monitoring strategy. 
 
Last dose of study drug refers to the last dose of glecaprevir/pibrentasvir and will be used in the 
definition of treatment-emergent adverse events and laboratory abnormalities, as well as the primary 
efficacy endpoint (SVR12). 
 
Study design  
SMART-C is a Phase IIIb multicentre international randomised controlled trial.  All participants will 
attend the study site for screening and baseline visits.  Randomisation to study arm will occur at the 
baseline visit (Figure 1).   
 
The two on-treatment monitoring strategies will differ as follows: 
• 
Participants in the standard monitoring arm will have on-treatment study visits conducted at the 
site at weeks 4 and 8 (End of Treatment [EoT]). 
• 
Participants in the simplified monitoring arm will have no on-treatment study visits conducted 
at the site. 
 
Phone contact between the participant and site study nurse will occur in both arms 1-2 days prior to week 
4 and week 8 (EoT) to provide standardized reporting of adverse events, concomitant medication and 
adherence.   
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
One post treatment clinic visit will be conducted at post-treatment week 12 for all participants.  
 
Figure 1 Study Schema 
Sample size and power 
The study was designed to enrol a total of 375 participants with genotype 1-6 HCV infection who had 
not received previous HCV treatment and did not have cirrhosis, randomised 2:1 - 250 participants in 
the simplified monitoring arm and 125 participants in the standard monitoring arm.  
 
With these participant numbers and under the assumption that the proportion achieving SVR12 would 
be 96% in both arms, the study would have approximately 80% power to show non-inferiority of the 
simplified monitoring strategy to the standard monitoring strategy, with a lower confidence bound for 
SVR12 in the standard monitoring arm greater than 90% or with a lower confidence bound for the 
difference (simplified arm minus standard arm) in SVR12 greater than –6%.  The 90% threshold for non-
inferiority of the eight weeks glecaprevir/pibrenatasvir with standard monitoring was based on the 
clinical trial data available at the time of study design (SVR12 96%), minus a 6% non-inferiority margin.1,2  
The non-inferiority margin of 6 percentage points was selected in accordance with the principles 
outlined in guidance on conducting non-inferiority trials3,4; the choice of margin ensured minimal to no 
loss of efficacy. 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
TYPE OF ANALYSIS 
This document describes the primary statistical analysis for SMART-C study in accordance with protocol 
version 2.0. 
 
Data Safety and Monitoring Board (DSMB) Analysis  
This study has a DSMB to review the progress and safety of the study.  The DSMB will conduct an interim 
safety and adherence analysis when the first 75 participants have either reached post-treatment week 
12 or dropped out of the study.  Additional meetings may be considered by the DSMB at a frequency 
commensurate with the risk as determined by the DSMB. 
 
Primary analysis: Post-treatment week 12 
The analysis for the primary endpoint, SVR12, will be conducted after all participants have completed 
the post-treatment week 12 visit or prematurely discontinue from study.  All the safety and efficacy data 
through to the post-treatment week 12 visit will be cleaned, finalised, and included for the analysis. 
 
 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Statistical Methods 
Analysis results will be presented using descriptive statistics.  For categorical variables, the number (n) 
and percentage of participants in each category will be presented.  For continuous variables, the number 
of participants (n), mean and standard deviation (SD), median, interquartile range (IQR, Q1-Q3), range 
(minimum, maximum) will be reported; for inclusion in the manuscript, an appropriate determination 
will be made depending on the variable, size and distribution of the population studied.  Statistical tests 
will be 2-sided and performed at the 5% significance level, unless specified.  For the analysis of 
categorical outcomes, Chi-squared tests or exact equivalents (for small numbers) will be used. For 
comparison of continuous measures, t tests or non-parametric equivalents will be used as appropriate 
for the observed data distribution. 
 
For the primary analysis of non-inferiority, the percentage of participants achieving SVR12 in each arm 
and the difference in percentages of participants achieving SVR12 between study arms will be calculated 
with confidence intervals using the normal approximation to the binomial distribution.  
 
Non-inferiority of the 8-week regimen of glecaprevir/pibrentasvir with a simplified monitoring strategy 
to the 8-week regimen of glecaprevir/pibrentasvir with a standard monitoring strategy with regard to 
the proportion achieving SVR12 will be shown if the lower bound of the confidence interval for the 
differences is above the non-inferiority margin of −6 percentage points.  
 
Analysis Sets 
Intention-To-Treat (ITT) Population  
The ITT population includes all participants who received at least one dose of study drug and will be 
analysed and presented by the on-treatment monitoring arm assigned at randomisation.    
 
Modified Intention-To-Treat (mITT) Population 
The mITT population excludes participants who have completed treatment (>95% adherence) (according 
to phone contact at week 8), but have not attended follow up at post-treatment week 12.    
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Modified Intention-To-Treat Virologic Failure (mITT-VF) Population 
The mITT population includes participants in the ITT population with SVR12 or virologic failure, but 
excludes participants with non-virologic failure or reinfection.    
 
Per-Protocol Population 
The per-protocol population includes all participants who completed the 8-week regimen of 
glecaprevir/pibrentasvir (with >95% adherence, according to phone contact at week 8) and attended 
follow up at post-treatment week 12.   
 
Safety Population 
The Safety population includes all participants who received at least one dose of study drug and will be 
analysed and presented according to the actual on-treatment monitoring arm received during the study.  
 
The ITT population will be used for primary efficacy analyses, and the safety population will be used for 
all safety analyses.   
 
Data Handling Conventions 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are specified.  For 
the primary efficacy endpoint, participants with missing data will be analysed as missing equals failure.   
 
Where appropriate, safety data for participants who did not complete the study will be included in 
summary statistics.  
For example:  
• 
If a participant took at least 1 dose of study drug, the participant will be included in a summary 
of adverse events according to the treatment received; otherwise, if the participant is not 
dosed, then they will be excluded from the summary. 
• 
If safety laboratory results for a participant are missing for any reason at a time point, the 
participant will be excluded from the calculation of the summary statistics for that time point.  
 
Values for missing safety laboratory data will not be imputed; however, a missing baseline (day 0) result 
will be replaced with a screening result, if available.  
 
Outliers  
Outliers will be identified during data management and data analysis process, but no sensitivity analyses 
will be conducted. All data will be included in the data analysis. 
 
Visit Windows  
Definition of Study Day 
Study day will be calculated from the date of first dose of study drug administration and derived as 
follows:  
• 
For post-dose study days: Assessment Date minus First Dose Date + 1  
• 
For days prior to the first dose: Assessment Date minus First Dose Date  
 
The last dose date of the study drug will be the end date entered in the Treatment Termination or Drug 
Administration eCRF.  
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
If there are participants for whom the date of last study drug is unknown (lost to follow-up and not able 
to be contacted), the date of last dose will be estimated using the maximum of non-missing study drug 
start or stop dates, visit dates, and laboratory collection dates (post-treatment visits and unscheduled 
visits are not included).  
 
Analysis Windows 
Participant visits might not occur on protocol-specified days. Therefore, for the purposes of analysis, 
observations will be assigned to analysis windows.  In general, the baseline value will be the last non-
missing value on or prior to the first dose date of study drug.  HCV RNA and safety laboratory data 
collected up to the last dose date + ≤3 days are considered on-treatment data.  HCV RNA and safety 
laboratory data collected after the last dose date + >3 days are considered post-treatment data.  
 
The following days are based on treatment start date and stop date for the on and post treatment 
period, respectively. 
 
On-treatment 
Nominal 
visit 
Standard monitoring arm 
Simplified monitoring arm 
Nominal 
day 
Lower Limit 
Upper Limit 
Nominal 
day 
Lower Limit 
Upper Limit 
Baseline 
1 
NA 
1 
1 
NA 
1 
Week 4 
28 
21 
42 
NA 
NA 
NA 
Week 8 
56 
43 
59 
NA 
NA 
NA 
*The protocol specifies that the visit window for Week 4 and Week 8 is plus or minus 3 days. 
 
Post-treatment 
Nominal 
visit 
Standard monitoring arm 
Simplified monitoring arm 
Nominal 
day 
Lower Limit 
Upper Limit 
Nominal 
day 
Lower Limit 
Upper Limit 
PT week 12 
84 
70 
NA 
84 
70 
NA 
*The protocol specifies that the visit window for Post Treatment Week 12 is plus or minus 14 days. 
As the post treatment week 12 visit is the final scheduled study visit, the upper limit for the post-
treatment week 12 visit will not be specified, and instead will be set at study close.  
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
PARTICIPANT DISPOSITION 
Recruitment 
The following dates will be presented to define the period of recruitment and follow-up: 
I. 
first and last participant screened 
II. 
first and last participant baselined 
III. 
first and last participant to complete post treatment week 12 
 
Participant Enrolment and Disposition  
A summary of participant disposition will be provided overall and by study arm (Table 1).  The total 
number of participants who were screened, enrolled (randomised) and treated will be depicted by a 
flowchart (Figure 2). Reasons for participant exclusion, including screen failure and loss to follow up, will 
be summarised (Table 2, Table 3, Table 4).  
 
Protocol violations/exemptions 
Number, proportion, type and reason for any protocol violations will be described (Table 5).  For this 
purpose, a protocol violation/exemption will be defined as any person who was enrolled in the study 
despite failing an inclusion criterion and/or meeting an exclusion criterion. 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 1.  Recruitment and follow-up 
Participant disposition 
Total 
N (%) 
Standard 
N (%) 
Simplified 
N (%) 
Total participants screened, n 
 
NA 
NA 
Participants screened and excluded, n 
 
NA 
NA 
Participants allocated to treatment (randomised), N  
 
 
 
Commenced allocated treatment, n/N (%)  
 
 
 
Did not commence allocated treatment, n/N (%) 
 
 
 
Treated Participants  
 
 
 
Completed allocated treatment course, n (%) 
 
 
 
Discontinued treatment, n (%) 
 
 
 
Lost to study follow-up, n (%) 
 
 
 
Study follow up 
 
 
 
Completed study follow up, n (%) 
 
 
 
Did not complete study follow up, n (%) 
 
 
 
Population for analysis 
 
 
 
Intention-to-treat, n 
 
 
 
Modified intention-to-treat, n 
 
 
 
Modified intention-to-treat virological-failure, n 
 
 
 
Per protocol, n 
 
 
 
 
Table 2.  Reasons for screen failure 
Participant disposition 
Total 
N (%) 
Total participants screened, n 
 
Participants screened and excluded, n 
 
Screen fail participants who did not meet eligibility criteria 
  List reasons (inclusion and exclusion criteria) 
 
Participants who met eligibility criteria but were not enrolled 
  List reasons for not being enrolled 
    Lost to follow up 
    Withdrew consent 
    Other 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 3. Proportion lost to follow-up 
Study arm 
Number 
randomised 
Proportion lost to follow-up (n/N, %) 
Standard Monitoring 
 
 
Simplified Monitoring 
 
 
 
Table 4. Reasons for loss to study follow-up 
Study 
Number 
Arm 
Date of treatment 
commencement 
Date last 
follow-up 
Reason lost to follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5. Protocol violations or deviations 
Protocol violations or deviations 
Reason 
N (%) 
Total number with protocol violations or deviations 
 
 
Violation of study inclusion or exclusion criteria 
 
 
Enrolment errors 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
 
Figure 2.  Participant disposition  
 
Screened
Assessed for eligibility  (n)
Randomised (n)
Randomised to standard monitoring (n)
Received allocated intervention (n)
Did not receive allocated intervention (reasons, n)
Lost to follow up (reasons, n)
Discontinued (reasons, n)
Analysed (n)
Excluded from analysis (reasons, n)
ITT (n)
mITT (n)
mITT-VF (n)
PP (n)
Randomised to simplified monitoring (n)
Received allocated intervention (n)
Did not receive allocated intervention (reasons, n)
Lost to follow up (reasons, n)
Discontinued (reasons, n)
Analysed (n)
Excluded from analysis (reasons, n)
ITT (n)
mITT (n)
mITT-VF (n)
PP (n)
Excluded (n)
Reasons for excusion
Not meeting inclusion criteria (n), consent 
withdrawn (n), lost to follow up (n), other (n, list)
Enrolment 
Allocation 
Follow-Up 
Analysis 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
BASELINE DATA 
Demographic Data and Baseline Characteristics 
 
Demographic and baseline measurements will be summarized using standard descriptive methods 
(Table 6, Table 7).  
 
Baseline data will be summarised for the ITT population and by study arm as: number (n) and proportion 
for categorical parameters; or n, mean and standard deviation (SD), median, Q1, Q3, minimum and 
maximum for continuous parameters. 
 
Age will be calculated in years at the date of initial study drug administration (baseline).  
 
P values will not be reported for differences between the two groups at baseline, since appropriate 
randomisation methods will have accounted for this.  Any differences identified would be due to chance 
such that a significant p value would in reality be representative of a type 1 error.  Large differences at 
baseline (more than half a SD for continuous variables or 10% for categorical variables) will be 
investigated in a sensitivity analysis.  
 
Prevalence of baseline polymorphisms in NS3 and NS5A will be summarised (Table 8).  
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 6.  Baseline characteristics (ITT population) 
Variable 
Total study 
population 
(N=XXX) 
Standard arm 
(N=XXX) 
Simplified arm 
(N=XXX) 
Age, median (range) 
 
 
 
Gender, n (%) 
 
 
 
  Male 
 
 
 
  Female 
 
 
 
  Transgender 
 
 
 
Ethnicity, n (%) 
 
 
 
  White 
 
 
 
  Asian  
 
 
 
  Black  
 
 
 
  Other 
 
 
 
BMI, median (range) 
 
 
 
HCV genotype/subtype, n (%) 
 
 
 
  Genotype 1 
 
 
 
    1a 
 
 
 
    1b 
 
 
 
    1, not specified 
 
 
 
  Genotype 2 
 
 
 
    2a 
 
 
 
    2b 
 
 
 
  Genotype 3 
 
 
 
    3a 
 
 
 
  Genotype 4 
 
 
 
  Genotype 5 
 
 
 
  Genotype 6 
 
 
 
  Genotype mixed 
 
 
 
    Specify 
 
 
 
  Genotype indeterminate 
 
 
 
HCV RNA, IU/mL 
 
 
 
  Quantitative, median (range) 
 
 
 
  Log10, median (range) 
 
 
 
HIV infection, n (%) 
 
 
 
Opioid substitution therapy, n (%) 
 
 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 7. Baseline viral characteristics 
Baseline characteristics 
Total study 
population 
(N=XXX) 
Standard arm 
N=XXX 
Simplified arm 
N=XXX 
HCV 
 
 
 
Fibrosis stage determination, n (%) 
  Transient elastography (Fibroscan) 
  APRI 
 
 
 
Median liver stiffness measurement (Fibroscan®), kPa (range) 
 
 
 
Median APRI (range) 
 
 
 
APRI (by category), n (%) 
  <0.5 (significant fibrosis unlikely) 
 
 
 
  0.5-1.5 (significant fibrosis likely) 
 
 
 
Fibrosis stage, n (%) 
  No or mild fibrosis (F0/F1; LSM <7.1 kPa or APRI <0.5) 
  Moderate fibrosis (F2; LSM 7.1-9.4 kPa or APRI 0.5 – 1.5) 
  Severe fibrosis (F3; LSM 9.5-12.4 kPa) 
 
 
 
HIV 
 
 
 
HIV infection, n (%) 
  CD4 count (106/L), median (IQR) 
  HIV VL ≤50 at screening, n (%) 
  On cART, n (%) 
    Specify regimen - list 
 
 
 
Abbreviations: Combination antiretroviral therapy (cART) 
 
Evaluation of fibrosis stage 
If more than one measure was used, the hierarchy is as follows:  
1. Transient elastrography (FibroScan) 5 
2. APRI 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 8. Prevalence of polymorphisms in NS3 and NS5A at baseline 
Polymorphism, n (%) 
Total study 
population 
N=XXX 
Standard arm 
N=XXX 
Simplified arm 
N=XXX 
Any NS3 
N 
N 
N 
Q80K/R 
R155T 
A156G/T/V 
A166T 
D/Q168A/K/L/R 
 
 
 
Any NS5A 
N 
N 
N 
K/Q/S24R/F 
M/L/F28A/G/K/T/V 
Q/R/K/A30D/E/R 
L/M/V31M 
P/H58D/T 
Y/T93H/N 
 
 
 
 
Baseline polymorphisms detected by Sanger sequencing at the following amino acid positions:  
NS3: 36, 56, 155, 156, 166, 168 
NS5A: 24, 28, 30, 31, 58, 93 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
STUDY ENDPOINTS  
 
Table 9. Study endpoints and outcomes 
Primary endpoint 
Non-inferiority of simplified on-
treatment monitoring to standard on-
treatment monitoring (ITT population) 
Included in primary analysis 
Secondary endpoints 
Non-inferiority of simplified on-
treatment monitoring to standard on-
treatment monitoring (mITT population) 
Included in primary analysis 
Non-inferiority of simplified on-
treatment monitoring to standard on-
treatment monitoring (per-protocol 
population) 
Included in primary analysis 
Virologic failure 
Included in primary analysis 
On-treatment adherence 
Included in primary analysis 
Early treatment discontinuation 
Included in primary analysis 
SVR12, by genotype 
Included in primary analysis 
SVR12, by HIV serostatus 
Included in primary analysis 
Adverse events 
Included in primary analysis 
Laboratory abnormalities 
Included in primary analysis 
Unscheduled clinic visits 
Included in primary analysis 
Change from baseline in patient 
reported outcome summary measures 
Included in primary analysis 
Presence of baseline polymorphisms 
Included in primary analysis 
Presence of treatment-emergent 
substitutions in patients with virologic 
failure 
Included in primary analysis 
Additional pre-
specified outcomes 
Cost-effectiveness 
Not included in primary analysis 
Health practitioner acceptability 
Included in primary analysis 
 
Primary efficacy endpoint 
The primary efficacy endpoint is sustained virologic response at week 12 post treatment (SVR12), 
defined as plasma HCV RNA below the lower limit of quantitation (<10 IU/mL; target not detected [TND] 
or target detected, not quantifiable [TDnq]) at 12 weeks after the last dose of study drug in the ITT 
population.  
 
The Aptima HCV Quant Dx assay, version 2.15.5 will be used to measure HCV RNA (Hologic, Inc., 
Marlborough, MA, USA). The LLOQ for this assay is 10 IU/mL. 
 
The primary efficacy endpoint of SVR12 will be assessed within each arm, and the primary comparison 
of SVR12 will be for non-inferiority of the simplified monitoring arm compared to the standard 
monitoring arm (simplified arm minus standard arm).   
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Secondary efficacy endpoints 
Secondary efficacy endpoints include: 
• 
Proportion of participants achieving SVR12 in each arm (in the mITT, mITT-VF and per-protocol 
populations); 
• 
Proportion of participants with virological failure; 
• 
Proportion of participants who are adherent to treatment and study visits (on-treatment 
adherence and early treatment discontinuation); 
For virological endpoints, the point estimates and 95% exact confidence intervals will be reported by 
study arm, by HCV genotype and by HIV serostatus.   
 
Primary safety endpoint 
The primary safety endpoints are: 
• 
Proportion of participants with common adverse events (reported by greater than 5% of the 
study population); 
• 
Proportion of participants with at least one severe or potentially life threatening (grade 3 or 4) 
adverse event; 
• 
Proportion of participants with unscheduled clinic visits. 
 
Adherence 
On-treatment adherence is recorded through self-reported adherence questionnaire at week 4 and 
week 8 (EoT) via phone contact visits, and by pill count at post-treatment week 12. 
Study drug exposure and compliance will be summarised for all treated participants.  
 
On-treatment adherence will be calculated by subtracting the number of missed doses from the total 
number of doses prescribed for therapy duration and dividing by the total number of doses prescribed 
for therapy duration.  By pill count and self-reported questionnaire, compliance with 
glecaprevir/pibrentasvir will be individually calculated at the 90/90, 95/95 and 100/100 adherence 
levels, defined as receipt of ≥90, ≥95 or 100% of scheduled doses for ≥90, ≥95 or 100% of the scheduled 
treatment period, respectively.   
 
A participant will be considered compliant if the individual receives ≥95% of scheduled doses for ≥95% 
of the scheduled treatment period.  The percentage of compliant participants will be summarised for 
each arm and overall.   
 
Exploratory Analysis 
Changes in quality of life data (EQ-5D-5L) and participant satisfaction will be compared at screening and 
post-treatment week 12 using the McNemar test (exact binomial probability).   
 
Practitioner acceptability data will be compared at the time points of before FPFV and after LPLV at each 
site.  
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 10. HCV RNA response during and post treatment, ITT population 
Response 
Standard 
monitoring 
(N=XXX) 
Simplified 
monitoring 
(N=XXX) 
Difference 
between 
arms 
(95% CI) 
P 
HCV RNA <LLOQ, n (%) 
  On treatment week 8 (end of treatment) 
  Post treatment week 12 
 
 
 
 
NA 
 
 
NA 
 
 
*Analysis tables will also be presented for the mITT, mITT-VF and PP populations 
Table 11. Treatment outcome, ITT population 
Outcome 
Standard 
monitoring 
(N=XXX) 
Simplified 
monitoring 
(N=XXX) 
Difference 
between 
arms 
(95% CI) 
P 
SVR12, n (%) 
 
 
 
 
Virologic failure, n (%) 
  On-treatment failure (non-response, breakthrough) 
  Post-treatment relapse 
 
 
 
 
NA 
NA 
 
NA 
NA 
 
Failure for other reasons, n (%) 
  Discontinuation 
  Loss to follow up or missing SVR12 data 
 
 
 
 
*Analysis tables will also be presented for the mITT, mITT-VF and PP populations 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 12. SVR12 in participant subgroups, ITT population 
Subgroup 
Standard monitoring arm 
n/N (%; 95% CI) 
Simplified monitoring arm 
n/N (%; 95% CI) 
Male 
 
 
Female 
 
 
<65 years old 
 
 
≥65 years old 
 
 
BMI <30 
 
 
BMI ≥30 
 
 
HCV mono-infection 
 
 
HIV/HCV co-infection 
 
 
Genotype 1 
 
 
Genotype 1a 
 
 
Genotype 1b 
 
 
Genotype 2 
 
 
Genotype 3 
 
 
Genotype 4 
 
 
Genotype 5 
 
 
Genotype 6 
 
 
F0/F1 fibrosis 
 
 
F2 fibrosis 
 
 
F3 fibrosis 
 
 
Baseline HCV RNA ≥1,000,000 
 
 
Baseline HCV RNA ≥6,000,000 
 
 
Baseline HCV RNA ≥10,000,000 
 
 
On OST 
 
 
 
Table 13. Primary reason for premature discontinuation of study drug 
Reason for premature discontinuation, n 
(%) 
Standard monitoring arm 
(n=XXX) 
Simplified monitoring arm 
(n=XXX) 
Adverse event 
 
 
Non-compliance 
 
 
Withdrawal of consent 
 
 
Loss to follow up 
 
 
Other 
Specify - list 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 14. NS3 and NS4A polymorphisms at baseline and virologic failure 
Subject ID 
Genotype/subtype 
Virologic 
failure 
NS3 Variants 
NS5A variants 
Baseline 
Failure 
Baseline 
Failure 
Standard monitoring arm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Simplified monitoring arm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
SAFETY ANALYSES 
All participants who receive at least one dose of study drug will be included in the safety analyses. Safety 
analyses will be performed overall and by treatment arm.  Safety will be evaluated by assessment of 
clinical laboratory tests at various time points during the study, and by the documentation of AEs.   
 
All safety data collected on or after the first dose of study drug administration up to 30 days after the 
last dose of study drug will be summarised. 
 
Extent of Exposure 
A participant’s extent of exposure to study drug will be generated from the study drug administration 
page of the eCRF. 
 
Adverse Events 
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, insert version).  System organ class (SOC), high level group term (HLGT), high level term (HLT), 
preferred term (PT), and lower level term (LLT) will be provided. 
 
Events will be summarised on the basis of the date of onset for the event.  
 
A treatment-emergent AE (TEAE) will be defined as: 
• 
Any AEs with an onset date on or after the study drug start date and no later than 30 days after 
permanent discontinuation of study drug 
• 
Any AEs leading to premature discontinuation of study drug 
 
Adverse Event Severity 
Adverse events are graded by the investigator as mild (Grade 1), moderate (Grade 2), severe (Grade 3),  
or life-threatening (Grade 4) according to toxicity criteria specified in the protocol. The severity grade of 
events for which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings, and the most severe will be considered (for sorting purpose only) in data 
presented.  For example, if an adverse event of the same type (PT) is listed more than once for an 
individual, the highest grade will be used to summarise severity.  
 
Relationship of Adverse Events to Study Drug 
Related AEs are those for which the investigator selected “Related” (“Possibly related” or “Probably 
related”) on the AE CRF to the question of “Related to Study Treatment.” Events for which the 
investigator did not record the relationship to study drug will be considered to be related to study drug 
for summary purposes.  
 
Summaries of Adverse Events and Deaths 
The number and percentage of participants overall and in each arm with treatment-emergent adverse 
events will be tabulated by primary MedDRA System Organ Class (SOC) and preferred term (PT). The 
tabulation of the number of participants with treatment-emergent adverse events by severity grade and 
relationship to study drug also will be provided.  
 
Participants reporting more than one adverse event for a given MedDRA PT will be counted only once 
for that term using the most severe grade for the severity grade table and the most related for the 
relationship to study drug tables.  Participants reporting more than one type of event within a SOC will 
be counted only once for that SOC, but both PTs will be listed.  


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
 
Summaries of treatment-emergent AEs (by SOC and PT) will be provided for the following: 
• 
All TEAEs 
• 
TAAEs of Grade 3 or above 
• 
All treatment-related TEAEs 
• 
Treatment-related TEAEs of Grade 3 or above 
• 
All SAEs (including death) 
• 
All treatment-related SAEs 
• 
All TEAEs leading to premature discontinuation of the study drug  
• 
TEAEs that occurred in at least 5% of subjects within any treatment group 
 
Adverse event summaries will provide the number and percentage of subjects with treatment-emergent 
AEs by SOC and PT, divided by treatment group. 
 
Adverse events will be summarised and listed first in alphabetic order of SOC and then by PT in order of 
descending incidence of the pooled treatment groups within each SOC.  
 
In summaries by severity grade, the most severe grade will be used for those AEs that occurred more 
than once in a participant during the study.  
 
Serious adverse events (SAE) 
The proportion of participants with at least one SAE will be reported overall. Serious adverse events will 
be summarized and relationship between the SAE and study drug will be detailed (Table 15, Table 16). 
 
Laboratory Evaluation 
Selected laboratory data will be summarised (n, mean, SD, median, IQR, range) by study visit along with 
the corresponding change from Baseline/Day 1 to Post Treatment Week 12 (Table 17, Table 18, Table 
19). 
Depending on sample distribution, parametric or non-parametric tests can be used to compare the 
change in biochemical and haematological indicators over time.  
 
The NIH DAIDS AE Grading Table Version 2.0- November 2014 will be used to grade severity.   
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 15. Safety parameters – adverse events and treatment discontinuation 
Adverse events 
Standard 
monitoring arm 
(N=XX) 
Simplified 
monitoring arm 
(N = XX) 
Participants reporting any TEAE up to 30 days after last dose, n (%) 
  Grades 1-2, n (%) 
  Grade 3, n (%) 
  Grade 4, n (%) 
 
 
Participants reporting treatment-related TEAE up to 30 days after 
last dose, n (%) 
  Grades 1-2, n (%) 
  Grade 3, n (%) 
  Grade 4, n (%) 
 
 
Serious TEAE, n (%) 
 
 
Treatment-related serious TEAE, n (%) 
 
 
Treatment discontinuation due to adverse event, n (%) 
 
 
Death, n (%) 
 
 
Adverse events 
Common (>5% of study population), n (%) 
  Specify (list) 
 
 
Unscheduled clinic visits or phone contact, n (%) 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 16. Safety parameters – adverse events and treatment discontinuation, by visit type 
Adverse events 
Standard 
monitoring 
arm 
Phone contact 
(N=XXX) 
Standard 
monitoring 
arm 
Clinic contact 
(N=XXX) 
Simplified 
monitoring 
arm 
Phone contact 
(N = XXX) 
Participants reporting any TEAE up to 30 days after last dose, n 
(%) 
  Grades 1-2, n (%) 
  Grade 3, n (%) 
  Grade 4, n (%) 
 
 
 
Participants reporting treatment-related TEAE up to 30 days after 
last dose, n (%) 
  Grades 1-2, n (%) 
  Grade 3, n (%) 
  Grade 4, n (%) 
 
 
 
Serious TEAE, n (%) 
 
 
 
Treatment-related serious TEAE, n (%) 
 
 
 
Treatment discontinuation due to adverse event, n (%) 
 
 
 
Death, n (%) 
 
 
 
Adverse events 
Common (>5% of study population), n (%) 
  Specify (list) 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 17.  Listing of serious adverse events  
Study Arm 
Date 
Onset 
Date 
resolved 
Diagnosis or event 
description 
SAE criteria‡ 
Outcome§ 
Relationship to 
study drug 
Standard 
monitoring  
 
 
 
 
 
 
 
 
 
 
 
 
Simplified 
monitoring  
 
 
 
 
 
 
 
 
 
 
 
 
 
‡ Death, hospitalised, life threatening, medically important, congenital anomaly, disability 
§ Recovered, Improved, Unchanged, Worsened, Unknown, Died 
 
Table 18.  Serious adverse events summary 
SAE – event summary 
Standard 
monitoring 
N=XXX 
Simplified 
monitoring 
N=XXX 
N of participants experiencing any treatment-emergent SAE by MedDRA SOC 
and Preferred Term, n (%) 
  SOC (alphabetical order) 
    List PT 
 
 
 
 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 19.  Summary table for key laboratory evaluations – Standard monitoring arm 
Lab parameter 
N 
Mean 
SD 
Min 
Q1 
Median 
Q3 
Max 
 
 
 
 
 
 
 
 
 
Hb 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in Hb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WBC 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in WBC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plt 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in plt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in ALT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in AST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin, total 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in bilirubin 
 
 
 
 
 
 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 20.  Summary table for key laboratory evaluations – Simplified monitoring arm 
Lab parameter 
N 
Mean 
SD 
Min 
Q1 
Median 
Q3 
Max 
 
 
 
 
 
 
 
 
 
Hb 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in Hb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WBC 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in WBC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plt 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in plt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in ALT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in AST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin, total 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Post treatment week 12 
 
 
 
 
 
 
 
 
Change in bilirubin 
 
 
 
 
 
 
 
 
 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
Table 21.  Laboratory evaluation  
Laboratory evaluation 
Standard monitoring 
(N=XX) 
Simplified monitoring 
(N=XX) 
Haematological parameters 
Baseline Hb, g/L (mean, SD) 
 
 
Change in Hb at post-treatment week 12, g/L (mean, SD) 
 
 
Haemoglobin #, n (%) 
  Grade 2 
  Grade 3 
  Grade 4 
 
 
Biochemical parameters 
Baseline ALT, U/L (mean, SD) 
 
 
ALT, n (%) 
  Grade 2 (3-5x ULN) 
  Grade ≥3 (>5x ULN) 
 
 
Change in ALT at post-treatment week 12, g/L (mean, SD) 
 
 
Baseline AST, U/L (mean, SD) 
 
 
AST, n (%) 
  Grade 2 (3-5x ULN) 
  Grade ≥3 (>5x ULN) 
 
 
Change in AST at post-treatment week 12, g/L (mean, SD) 
 
 
Baseline total bilirubin, mg/dl or mmol/L (mean, SD) 
 
 
Total bilirubin *, n (%) 
  >2.5-3.0 mg/dl (43 – 51 mmol/L) 
  >3.0 mg/dl (>51 mmol/L) 
 
 
Change in bilirubin at post-treatment week 12, g/L 
(mean, SD) 
 
 
# At any time during treatment and up to 30 days post; each participant should only be included once - 
record most severe grade of anaemia for each participant  
*At any time during treatment and up to 30 days post; add footnote, if bilirubin elevated at 
screening/baseline 
 
 


SMART-C Statistical Analysis Plan_V1.0_9 July 2018 
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