Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Co-administered with Ribavirin (RBV) in Treatment-Experienced Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection (SAPPHIRE-II)
Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
Summary
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EudraCT number |
2012-002035-29 |
Trial protocol |
DE GB CZ PT IE NL IT DK ES |
Global end of trial date |
23 Oct 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
22 May 2016
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First version publication date |
22 May 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
M13-098
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01715415 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Abbvie Deutschland GmbH & Co.KG
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Sponsor organisation address |
Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4XE
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Public contact |
Global Medical Information, AbbVie, 001 800-633-9110,
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Scientific contact |
Jeff Enejosa, MD, AbbVie, jeff.enejosa@abbvie.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Oct 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Oct 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives of this study were to compare the percentage of subjects achieving sustained virologic response 12 weeks postdosing (SVR12; HCV ribonucleic acid [RNA] < lower limit of quantitation [LLOQ] 12 weeks following treatment) after 12 weeks of treatment with ABT-450/r/ABT-267 and ABT-333 coadministered with RBV (the direct-acting antiviral agent [DAA] combination regimen) to the historical SVR rate of telaprevir plus pegylated interferon (pegIFN) and RBV therapy and to assess the safety of the DAA combination regimen versus placebo for 12 weeks in pegIFN/RBV treatment-experienced HCV genotype 1-infected adults without cirrhosis.
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Protection of trial subjects |
All subjects entering the study had to sign an informed consent that was explained to them and questions encouraged.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Nov 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 7
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Country: Number of subjects enrolled |
Portugal: 20
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Country: Number of subjects enrolled |
Spain: 30
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Country: Number of subjects enrolled |
United Kingdom: 21
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Country: Number of subjects enrolled |
Czech Republic: 7
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Country: Number of subjects enrolled |
Denmark: 8
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Country: Number of subjects enrolled |
France: 37
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Country: Number of subjects enrolled |
Germany: 22
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Country: Number of subjects enrolled |
Ireland: 12
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Country: Number of subjects enrolled |
Italy: 24
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Country: Number of subjects enrolled |
Australia: 14
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Country: Number of subjects enrolled |
Canada: 20
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Country: Number of subjects enrolled |
Russian Federation: 24
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Country: Number of subjects enrolled |
United States: 149
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Worldwide total number of subjects |
395
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EEA total number of subjects |
188
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
362
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From 65 to 84 years |
33
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||
Pre-assignment
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Screening details |
One subject in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm was randomized but did not received treatment; this subject was not included in the Safety Population and is accounted for in the Pre-assignment Milestones below. | |||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
395 | |||||||||||||||||||||
Number of subjects completed |
394 | |||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Randomized but not treated: 1 | |||||||||||||||||||||
Period 1
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Period 1 title |
Double-blind Treatment
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||
Blinding implementation details |
AbbVie, investigators, and subjects were blinded to drug assignment and virologic results for the duration of the Double-blind Treatment Period.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ABT-450/r/ABT-267 and ABT-333, Plus RBV | |||||||||||||||||||||
Arm description |
Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
ABT-450/r/ABT-267
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Investigational medicinal product code |
ABT-450/r/ABT-267
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Other name |
ABT-267 also known as ombitasvir, ABT-450 also known as paritaprevir, (with ABT-333) Viekira PAK
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
At the double-blind (DB) Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.
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Investigational medicinal product name |
Ribavirin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
At the DB Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.
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Investigational medicinal product name |
ABT-333
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Investigational medicinal product code |
ABT-333
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Other name |
dasabuvir, (with ABT-450/r/ABT-267) Viekira PAK
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
At the DB Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.
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Arm title
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Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV | |||||||||||||||||||||
Arm description |
Double-blind placebo for 12 weeks | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
At the DB Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: One subject in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm were randomized but did not received treatment; these subjects were not included in the Safety Population. The Pre-assignment Milestones, above, accounts for the worldwide number enrolled. |
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Period 2
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Period 2 title |
Open-label Treatment
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||
Arms
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Arm title
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Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV | |||||||||||||||||||||
Arm description |
Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
ABT-450/r/ABT-267
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Investigational medicinal product code |
ABT-450/r/ABT-267
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Other name |
ABT-267 also known as ombitasvir, ABT-450 also known as paritaprevir, (with ABT-333) Viekira PAK
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects entering the open-label (OL) Treatment Period were given drugs at the DB Week 12 Visit, along with instructions to begin dosing the next day.
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Investigational medicinal product name |
Ribavirin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects entering the OL Treatment Period were given drugs at the DB Week 12 Visit, along with instructions to begin dosing the next day.
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Investigational medicinal product name |
ABT-333
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Investigational medicinal product code |
ABT-333
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Other name |
dasabuvir, (with ABT-450/r/ABT-267) Viekira PAK
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects entering the OL Treatment Period were given drugs at the DB Week 12 Visit, along with instructions to begin dosing the next day.
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Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Only subjects in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm (n=96) were continued on to Period 2, per protocol. |
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Baseline characteristics reporting groups
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Reporting group title |
ABT-450/r/ABT-267 and ABT-333, Plus RBV
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Reporting group description |
Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
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Reporting group description |
Double-blind placebo for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ABT-450/r/ABT-267 and ABT-333, Plus RBV
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Reporting group description |
Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks | ||
Reporting group title |
Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
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Reporting group description |
Double-blind placebo for 12 weeks | ||
Reporting group title |
Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
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Reporting group description |
Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks | ||
Subject analysis set title |
ABT-450/r/ABT-267 and ABT-333, Plus RBV
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Intent-to-treat (ITT) Population: All randomized subjects in the ABT-450/r/ABT-267 and ABT-333, Plus RBV arm who received at least 1 dose of blinded study drug.
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Subject analysis set title |
Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Intent-to-treat (ITT) Population: All randomized subjects in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm who received at least 1 dose of blinded study drug.
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End point title |
Percentage of Subjects With Sustained Virologic Response 12 Weeks After Treatment [1] | ||||||||
End point description |
The percentage of subjects with sustained virologic response (plasma HCV RNA level < LLOQ) 12 weeks after the last dose of study drug.
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End point type |
Primary
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End point timeframe |
12 weeks after the last actual dose of active study drug
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: See attached zip file (M-13-098 Statistical Analysis for Primary Endpoint.pdf) for the statistical analysis data, which could not be entered directly due to EudraCT system limitations. |
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Attachments |
Untitled (Filename: M13-098 Statistical Analysis for Primary Endpoint.pdf) |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Normalization of Alanine Aminotransferase (ALT) at Final Treatment Visit During the Double-Blind Treatment Period | ||||||||||||
End point description |
Normalization is defined as alanine aminotransferase less than or equal to the upper limit of normal (ULN) at final treatment visit for subjects with alanine aminotransferase greater than ULN at baseline.
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End point type |
Secondary
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End point timeframe |
At 12 weeks
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Notes [2] - Subjects in the ITT population who had ALT ≥ ULN of the reference range at baseline [3] - Subjects in the ITT population who had ALT ≥ ULN of the reference range at baseline |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
In order to control the Type I error rate at 0.05, a fixed-sequence testing procedure was used to proceed through the primary and the first 3 secondary endpoints.
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Comparison groups |
Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV v ABT-450/r/ABT-267 and ABT-333, Plus RBV
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Number of subjects included in analysis |
302
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Confidence interval |
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End point title |
Percentage of HCV Genotype 1a-infected Subjects With Sustained Virologic Response 12 Weeks After Treatment | ||||||||
End point description |
The percentage of subjects with sustained virologic response (plasma HCV RNA level < LLOQ) 12 weeks after the last dose of study drug. One subject, who had genotype 1 HCV with an indeterminate subgenotype, is not included in this analysis.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last actual dose of active study drug
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Attachments |
Untitled (Filename: M13-098 Statistical Analysis for Secondary Endpoint 3.docx) |
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Notes [4] - Subjects in ITT population with HCV genotype 1a who received at least 1 dose of blinded study drug. |
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No statistical analyses for this end point |
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End point title |
Percentage of HCV Genotype 1b-infected Subjects With Sustained Virologic Response 12 Weeks After Treatment | ||||||||
End point description |
The percentage of subjects with sustained virologic response (HCV RNA level < LLOQ) 12 weeks after the last dose of study drug. One subject, who had genotype 1 HCV with an indeterminate subgenotype, is not included in this analysis.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last actual dose of active study drug
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Attachments |
Untitled (Filename: M13-098 Statistical Analysis for Secondary Endpoint 4.docx.pdf) |
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Notes [5] - Subjects in ITT population with HCV genotype 1b who received at least 1 dose of blinded study drug. |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With On-treatment Virologic Failure During the Double-blind Treatment Period: ABT-450/r/ ABT-267 and ABT-333, Plus RBV Arm | ||||||||
End point description |
Virologic failure was defined as rebound (HCV RNA ≥ LLOQ after HCV RNA < LLOQ or increase in HCV RNA of at least 1 log10 IU/mL) or failure to suppress (all on-treatment values of plasma HCV RNA ≥ LLOQ with at least 36 days of treatment) during treatment.
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End point type |
Secondary
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End point timeframe |
12 weeks after the last actual dose of active study drug
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Virologic Relapse After Treatment: ABT-450/r/ABT-267 and ABT-333, Plus RBV Arm | ||||||||
End point description |
Subjects were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma HCV RNA ≥ LLOQ between the end of treatment and 12 weeks after the last dose of study drug among subjects who completed treatment with HCV RNA < LLOQ at the end of treatment.
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End point type |
Secondary
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End point timeframe |
Within 12 weeks post-treatment
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Notes [6] - Subjects with HCV RNA < LLOQ at the final treatment visit who completed treatment in the DB period. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events (AEs) were collected from the start of active study drug administration (DB or OL active) to 30 days after the last dose of active study drug (total 16 weeks).
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Adverse event reporting additional description |
DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AEs collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
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Reporting groups
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Reporting group title |
Double Blind ABT-450/r/ABT-267 and ABT-333, Plus RBV
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Reporting group description |
Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Double Blind Placebo
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Reporting group description |
Double-blind placebo for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Open Label ABT-450/r/ABT-267 and ABT-333, Plus RBV
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Reporting group description |
Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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19 Oct 2012 |
The purpose of this amendment was to:
● update secondary endpoints to remove rapid virological response and end-of-treatment response, which are irrelevant in the absence of SVR, and to include rebound and relapse rates which are relevant in clinical practice when using DAAs;
● clarify inclusion/exclusion criteria to ensure the appropriate subject population was enrolled;
● clarify the timing of efficacy analyses based on the availability of post-treatment virologic data;
● update plan for resistance analysis throughout the protocol in order to clarify and more accurately reflect plans for assessing resistance development;
● update RBV toxicity management in a manner that aligns with the RBV label;
● address inconsistencies throughout the protocol. |
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01 Mar 2013 |
The purpose of this amendment was to:
● include SVR12 rates within HCV subgenotypes (1a, 1b) as secondary endpoints.
● update the thresholds for success of the primary and secondary efficacy endpoints to be based on historical SVR rates from telaprevir plus pegIFN and RBV therapy.
● clarify inclusion/exclusion criteria to ensure the appropriate subject population was enrolled.
● update the definition of relapse to prior pegIFN and RBV treatment to allow the measurement of a detectable HCV RNA to be within 52 weeks post treatment due to clinical practice standards of assessment of HCV RNA in some regions.
● clarify the timing of primary and follow-up efficacy analyses based on the availability of post-treatment virologic data.
● address inconsistencies throughout the protocol. |
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08 Apr 2013 |
● prohibit the use of hormonal contraceptives during study drug administration. Rationale: Hormonal contraceptives are not expected to be effective when dosed with the DAA regimen and may be associated with an increased risk for ALT elevation.
● correct typographical error for sponsor/emergency contact mobile number. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |