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Clinical Trial Results:
A Phase 3, Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 12 Weeks in Direct-Acting Antiviral-Experienced Subjects with Chronic HCV Infection

Summary
EudraCT number	2015-003455-21
Trial protocol	DE GB FR
Global end of trial date	21 Jun 2017

Results information
Results version number	v2(current)
This version publication date	08 Aug 2018
First version publication date	01 Jul 2018
Other versions	v1
Version creation reason	New data added to full data set Correction of full data set Removed data for placebo arm and update analysis population

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GS-US-367-1171

ISRCTN number

US NCT number

NCT02607735

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

21 Jun 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Oct 2016

Global end of trial reached?

Yes

Global end of trial date

21 Jun 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this study are to evaluate the safety and efficacy of treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in adults with chronic Hepatitis C Virus (HCV) infection who have previously received treatment with direct-acting antiviral therapy.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Nov 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

France: 72

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

United States: 237

Country: Number of subjects enrolled

Canada: 42

Country: Number of subjects enrolled

Australia: 26

Country: Number of subjects enrolled

New Zealand: 7

Worldwide total number of subjects

416

EEA total number of subjects

104

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

344

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled at study sites in North America, Europe, and Asia Pacific. The first participant was screened on 11 November 2015. The last study visit occurred on 21 June 2017.

Screening details

520 participants were screened.

Period 1 title

Primary Study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

SOF/VEL/VOX (Primary Study)

Arm description

SOF/VEL/VOX for 12 weeks

Arm type

Experimental

Investigational medicinal product name

Sofosbuvir/velpatasvir/voxilaprevir

Investigational medicinal product code

Other name

Vosevi®, GS-7977/GS-5816/GS-9857, SOF/VEL/VOX

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

400/100/100 mg fixed-dose combination (FDC) tablet administered orally once daily with food

Placebo (Primary Study)

Arm description

Placebo 12 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet administered orally once daily with food

Number of subjects in period 1 ^[1]	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)
Started	263	152
Completed	257	152
Not completed	6	0
Withdrew Consent	2	-
Lost to follow-up	4	-

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: 1 participant in the SOF/VEL/VOX (Primary Study) group who was randomized but never treated is not included in the subject disposition table.

Period 2 title

Deferred Treatment Substudy

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

SOF/VEL/VOX (Deferred Treatment Substudy)

Arm description

Participants who completed placebo treatment were eligible to enroll in to the open-label Deferred Treatment Substudy to receive SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

Sofosbuvir/velpatasvir/voxilaprevir

Investigational medicinal product code

Other name

Vosevi®, GS-7977/GS-5816/GS-9857, SOF/VEL/VOX

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

400/100/100 mg fixed-dose combination (FDC) tablet administered orally once daily with food

Number of subjects in period 2 ^[2]	SOF/VEL/VOX (Deferred Treatment Substudy)
Started	147
Completed	142
Not completed	5
Withdrew Consent	1
Lost to follow-up	4

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 participants who completed placebo treatment and continued to meet the treatment criteria were eligible to enroll in to the open-label Deferred Treatment Substudy.

Baseline characteristics

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Reporting group title

SOF/VEL/VOX (Primary Study)

Reporting group description

SOF/VEL/VOX for 12 weeks

Reporting group title

Placebo (Primary Study)

Reporting group description

Placebo 12 weeks

Reporting group values	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)	Total
Number of subjects	263	152	415
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	58 ± 8.5	59 ± 8.0	-
Gender categorical
Units: Subjects
Female	63	31	94
Male	200	121	321
Race
Units: Subjects
White	211	124	335
Black or African American	38	22	60
Asian	8	6	14
Native Hawaiian or Pacific Islander	3	0	3
Not Disclosed	1	0	1
American Indian or Alaska Native	1	0	1
Other	1	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	15	10	25
Not Hispanic or Latino	247	142	389
Not Disclosed	1	0	1
IL28b Status
The CC, CT, and TT alleles are different forms of the IL28b gene
Units: Subjects
CC	47	27	74
CT	165	93	258
TT	51	32	83
HCV RNA Category
Units: Subjects
< 800,000 IU/mL	73	36	109
≥ 800,000 IU/mL	190	116	306
HCV RNA
Units: log10 IU/mL
arithmetic mean (standard deviation)	6.3 ± 0.68	6.3 ± 0.63	-

End points

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Reporting group title

SOF/VEL/VOX (Primary Study)

Reporting group description

SOF/VEL/VOX for 12 weeks

Reporting group title

Placebo (Primary Study)

Reporting group description

Placebo 12 weeks

Reporting group title

SOF/VEL/VOX (Deferred Treatment Substudy)

Reporting group description

Primary: Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) (Primary Study)

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End point title

Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) (Primary Study) ^[1] ^[2]

End point description

SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ) at 12 weeks after stopping study treatment. Participants in the Full Analysis Set (all randomized/enrolled participants who took at least 1 dose of study drug) were analyzed.

End point type

Primary

End point timeframe

Posttreatment Week 12

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: The statistical analysis of this primary endpoint is provided in the attachment.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was not assessed for participants in the Placebo group because they did not have a Posttreatment Week 12 visit.

End point values	SOF/VEL/VOX (Primary Study)
Number of subjects analysed	263
Units: percentage of participants
number (confidence interval 95%)	96.2 (93.1 to 98.8)

Attachments

Untitled (Filename: 367-1171_PrimaryEndpoint_StatsAnalysis.pdf)

No statistical analyses for this end point

Primary: Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (Primary Study)

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End point title

Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (Primary Study) ^[3]

End point description

Participants in the Full Analysis Set (all randomized/enrolled participants who took at least 1 dose of study drug) were analyzed.

End point type

Primary

End point timeframe

Up to 12 weeks

Notes
[3] - 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: No statistical comparison was planned or performed.

End point values	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)
Number of subjects analysed	263	152
Units: percentage of participants
number (not applicable)	0.4	2.0

No statistical analyses for this end point

Secondary: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) (Primary Study)

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End point title

Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) (Primary Study)

End point description

SVR4 was defined as HCV RNA < LLOQ at 4 weeks after stopping study treatment, respectively. Participants in the Full Analysis Set (all randomized/enrolled participants who took at least 1 dose of study drug) were analyzed.

End point type

Secondary

End point timeframe

Posttreatment Week 4

End point values	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)
Number of subjects analysed	263	152
Units: percentage of participants
number (confidence interval 95%)	97.7 (95.1 to 99.2)	0 (0.0 to 2.4)

No statistical analyses for this end point

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Primary Study)

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End point title

Percentage of Participants With HCV RNA < LLOQ On Treatment (Primary Study)

End point description

Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Weeks 1, 2, 4, 8 and 12

End point values	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)
Number of subjects analysed	263	152
Units: percentage of participants
number (confidence interval 95%)
Week 1 (SOF/VEL/VOX: N = 263; Placebo: N = 152)	15.6 (11.4 to 20.5)	0 (0.0 to 2.4)
Week 2 (SOF/VEL/VOX: N = 263; Placebo: N = 150)	56.7 (50.4 to 62.7)	0 (0.0 to 2.4)
Week 4 (SOF/VEL/VOX: N = 262; Placebo: N = 150)	92.7 (88.9 to 95.6)	0 (0.0 to 2.4)
Week 8 (SOF/VEL/VOX: N = 262; Placebo: N = 150)	100.0 (98.6 to 100.0)	0 (0.0 to 2.4)
Week 12 (SOF/VEL/VOX: N = 261; Placebo: N = 149)	99.6 (97.9 to 100.0)	0 (0.0 to 2.4)

No statistical analyses for this end point

Secondary: Change From Baseline in HCV RNA (Primary Study)

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End point title

Change From Baseline in HCV RNA (Primary Study)

End point description

Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Weeks 1, 2, 4, 8 and 12

End point values	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)
Number of subjects analysed	262	150
Units: log10 IU/mL
arithmetic mean (standard deviation)
Week 1 (SOF/VEL/VOX: N = 258; Placebo: N = 150)	-4.20 ± 0.733	0.02 ± 0.300
Week 2 (SOF/VEL/VOX: N = 261; Placebo: N = 148)	-4.81 ± 0.704	0.02 ± 0.322
Week 4 (SOF/VEL/VOX: N = 261; Placebo: N = 150)	-5.07 ± 0.677	-0.01 ± 0.441
Week 8 (SOF/VEL/VOX: N = 262; Placebo: N = 149)	-5.11 ± 0.678	0.05 ± 0.434
Week 12 (SOF/VEL/VOX: N = 261; Placebo: N = 138)	-5.10 ± 0.690	0.03 ± 0.430

No statistical analyses for this end point

Secondary: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) (Primary Study)

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End point title

Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) (Primary Study) ^[4]

End point description

SVR24 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment. Participants in the Full Analysis Set in the SOF/VEL/VOX group were analyzed. This outcome measure was not assessed for participants in the Placebo group because they did not have a Posttreatment Week 24 visit.

End point type

Secondary

End point timeframe

Posttreatment Week 24

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was not assessed for participants in the Placebo group because they did not have a Posttreatment Week 24 visit.

End point values	SOF/VEL/VOX (Primary Study)
Number of subjects analysed	263
Units: percentage of participants
number (confidence interval 95%)	96.2 (93.1 to 98.2)

No statistical analyses for this end point

Secondary: Percentage of Participants With Virologic Failure (Primary Study)

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End point title

Percentage of Participants With Virologic Failure (Primary Study) ^[5]

End point description

Virologic failure is defined as: • On-treatment virologic failure: • Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA LLOQ while on treatment), or • Rebound (confirmed 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or • Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) • Virologic relapse: • Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA LLOQ at last ontreatment visit. Participants in the Full Analysis Set in the SOF/VEL/VOX group were analyzed. This outcome measure was not assessed for participants in the Placebo group because they did not have a Posttreatment Week 24 visit.

End point type

Secondary

End point timeframe

Up to Posttreatment Week 24

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was not assessed for participants in the Placebo group because they did not have a Posttreatment Week 24 visit.

End point values	SOF/VEL/VOX (Primary Study)
Number of subjects analysed	263
Units: percentage of participants
number (not applicable)	2.7

No statistical analyses for this end point

Secondary: Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (Deferred Treatment Substudy)

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End point title

Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (Deferred Treatment Substudy)

End point description

SVR4, SVR12 and SVR24 was defined as HCV RNA < LLOQ at 4, 12 and 24 weeks after stopping study treatment respectively. Participants in the Full Analysis Set (all enrolled participants who took at least 1 dose of study drug) from the Deferred Treatment Substudy were analyzed.

End point type

Secondary

End point timeframe

Posttreatment Weeks 4, 12, and 24 (Deferred Treatment Substudy)

End point values	SOF/VEL/VOX (Deferred Treatment Substudy)
Number of subjects analysed	147
Units: percentage of participants
number (confidence interval 95%)
SVR4	98.6 (95.2 to 99.8)
SVR12	97.3 (93.2 to 99.3)
SVR24	97.3 (93.2 to 99.3)

No statistical analyses for this end point

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Deferred Treatment Substudy)

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End point title

Percentage of Participants With HCV RNA < LLOQ On Treatment (Deferred Treatment Substudy)

End point description

Participants in the Full Analysis Set of the Deferred Treatment Substudy were analyzed.

End point type

Secondary

End point timeframe

Weeks 1, 2, 4, 8 and 12 (Deferred Treatment Substudy)

End point values	SOF/VEL/VOX (Deferred Treatment Substudy)
Number of subjects analysed	147
Units: percentage of participants
number (confidence interval 95%)
Week 1	14.3 (9.1 to 21.0)
Week 2	62.6 (54.2 to 70.4)
Week 4	93.2 (87.8 to 96.7)
Week 8	100.0 (97.5 to 100.0)
Week 12	100.0 (97.5 to 100.0)

No statistical analyses for this end point

Secondary: Change From Baseline in HCV RNA (Deferred Treatment Substudy)

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End point title

Change From Baseline in HCV RNA (Deferred Treatment Substudy)

End point description

Participants with available data in the Full Analysis Set of the Deferred Treatment Substudy were analyzed.

End point type

Secondary

End point timeframe

Baseline; Weeks 1, 2, 4, 8, and 12 (Deferred Treatment Substudy)

End point values	SOF/VEL/VOX (Deferred Treatment Substudy)
Number of subjects analysed	147
Units: log10 IU/mL
arithmetic mean (standard deviation)
Week 1 (N = 139)	-4.30 ± 0.626
Week 2 (N = 145)	-4.93 ± 0.602
Week 4 (N = 147)	-5.16 ± 0.512
Week 8 (N=147)	-5.20 ± 0.532
Week 12 (N= 147)	-5.20 ± 0.532

No statistical analyses for this end point

Secondary: Percentage of Participants With Virologic Failure (Deferred Treatment Substudy)

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End point title

Percentage of Participants With Virologic Failure (Deferred Treatment Substudy)

End point description

Participants in the Full Analysis Set of the Deferred Treatment Substudy were analyzed.

End point type

Secondary

End point timeframe

Up to Posttreatment Week 24 (Deferred Treatment Substudy)

End point values	SOF/VEL/VOX (Deferred Treatment Substudy)
Number of subjects analysed	147
Units: percentage of participants
number (not applicable)	2.7

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Primary Study: Up to 12 Weeks + 30 days; Deferred Treatment Substudy: Up to 12 Weeks + 30 days

Adverse event reporting additional description

Safety Analysis Set: all participants who received at least 1 dose of study drug

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

SOF/VEL/VOX (Primary Study)

Reporting group description

SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 12 weeks

Reporting group title

Placebo (Primary Study)

Reporting group description

Placebo tablet orally once daily with food for 12 weeks

Reporting group title

SOF/VEL/VOX (Deferred Treatment Substudy)

Reporting group description

Participants who completed placebo treatment were eligible for open-label Deferred Treatment Substudy. SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 12 weeks

Serious adverse events	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)	SOF/VEL/VOX (Deferred Treatment Substudy)
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 263 (1.90%)	7 / 152 (4.61%)	6 / 147 (4.08%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenal neoplasm
subjects affected / exposed	1 / 263 (0.38%)	0 / 152 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 263 (0.00%)	1 / 152 (0.66%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	1 / 263 (0.38%)	0 / 152 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Subdural haematoma
subjects affected / exposed	0 / 263 (0.00%)	1 / 152 (0.66%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 263 (0.00%)	0 / 152 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Arteritis
subjects affected / exposed	1 / 263 (0.38%)	0 / 152 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 263 (0.00%)	0 / 152 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 263 (0.00%)	1 / 152 (0.66%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 263 (0.00%)	1 / 152 (0.66%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	1 / 263 (0.38%)	0 / 152 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 263 (0.00%)	0 / 152 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 263 (0.38%)	0 / 152 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Mesenteric vein thrombosis
subjects affected / exposed	0 / 263 (0.00%)	0 / 152 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 263 (0.00%)	1 / 152 (0.66%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 263 (0.38%)	0 / 152 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Schizophrenia
subjects affected / exposed	0 / 263 (0.00%)	1 / 152 (0.66%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 263 (0.00%)	0 / 152 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 263 (0.38%)	0 / 152 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Scrotal infection
subjects affected / exposed	0 / 263 (0.00%)	1 / 152 (0.66%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 263 (0.00%)	0 / 152 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	SOF/VEL/VOX (Primary Study)	Placebo (Primary Study)	SOF/VEL/VOX (Deferred Treatment Substudy)
Total subjects affected by non serious adverse events
subjects affected / exposed	206 / 263 (78.33%)	107 / 152 (70.39%)	87 / 147 (59.18%)
Nervous system disorders
Headache
subjects affected / exposed	66 / 263 (25.10%)	26 / 152 (17.11%)	29 / 147 (19.73%)
occurrences all number	72	32	30
Dizziness
subjects affected / exposed	11 / 263 (4.18%)	14 / 152 (9.21%)	7 / 147 (4.76%)
occurrences all number	11	14	7
General disorders and administration site conditions
Fatigue
subjects affected / exposed	56 / 263 (21.29%)	30 / 152 (19.74%)	31 / 147 (21.09%)
occurrences all number	58	30	31
Asthenia
subjects affected / exposed	20 / 263 (7.60%)	9 / 152 (5.92%)	3 / 147 (2.04%)
occurrences all number	22	9	3
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	48 / 263 (18.25%)	19 / 152 (12.50%)	28 / 147 (19.05%)
occurrences all number	58	24	32
Nausea
subjects affected / exposed	37 / 263 (14.07%)	12 / 152 (7.89%)	21 / 147 (14.29%)
occurrences all number	41	13	24
Psychiatric disorders
Insomnia
subjects affected / exposed	19 / 263 (7.22%)	8 / 152 (5.26%)	5 / 147 (3.40%)
occurrences all number	19	8	5
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	11 / 263 (4.18%)	8 / 152 (5.26%)	7 / 147 (4.76%)
occurrences all number	11	8	7
Arthralgia
subjects affected / exposed	8 / 263 (3.04%)	8 / 152 (5.26%)	9 / 147 (6.12%)
occurrences all number	8	8	10

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Were there any global substantial amendments to the protocol? Yes

09 Oct 2015

• The definition of treatment experience for eligibility has been revised from DAA-experienced to NS5A inhibitor-experienced. • Participants with DAA experience that did not include an NS5A inhibitor will be eligible for screening in a separate protocol Study GS-US-367-1170. • The total number of study centers participating has been increased from 100 to 120. • Revisions have been made to the approximate number of participants by genotype to be randomized or enrolled into each group • The randomization ratio for Group 1 subjects with genotype 1 has been revised from 2:1 to 1:1 • Updates have been made to Section 1 including Rationale for This Study, Rationale for the Study Design, and Risk/Benefit Assessment for the Study to account for study changes and provide clarification. • Section 6 Procedures has been revised to now include procedures for breaking treatment code/unblinding of subjects for medical emergencies. • Additional formatting, minor grammatical corrections and updates were made throughout the document.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/28564569

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Clinical trials

Clinical Trial Results:
A Phase 3, Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 12 Weeks in Direct-Acting Antiviral-Experienced Subjects with Chronic HCV Infection

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) (Primary Study)

Primary: Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) (Primary Study)

Primary: Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (Primary Study)

Primary: Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (Primary Study)

Secondary: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) (Primary Study)

Secondary: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) (Primary Study)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Primary Study)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Primary Study)

Secondary: Change From Baseline in HCV RNA (Primary Study)

Secondary: Change From Baseline in HCV RNA (Primary Study)

Secondary: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) (Primary Study)

Secondary: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) (Primary Study)

Secondary: Percentage of Participants With Virologic Failure (Primary Study)

Secondary: Percentage of Participants With Virologic Failure (Primary Study)

Secondary: Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (Deferred Treatment Substudy)

Secondary: Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (Deferred Treatment Substudy)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Deferred Treatment Substudy)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Deferred Treatment Substudy)

Secondary: Change From Baseline in HCV RNA (Deferred Treatment Substudy)

Secondary: Change From Baseline in HCV RNA (Deferred Treatment Substudy)

Secondary: Percentage of Participants With Virologic Failure (Deferred Treatment Substudy)

Secondary: Percentage of Participants With Virologic Failure (Deferred Treatment Substudy)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: A Phase 3, Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 12 Weeks in Direct-Acting Antiviral-Experienced Subjects with Chronic HCV Infection

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) (Primary Study)

Primary: Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) (Primary Study)

Primary: Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (Primary Study)

Primary: Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (Primary Study)

Secondary: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) (Primary Study)

Secondary: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4) (Primary Study)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Primary Study)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Primary Study)

Secondary: Change From Baseline in HCV RNA (Primary Study)

Secondary: Change From Baseline in HCV RNA (Primary Study)

Secondary: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) (Primary Study)

Secondary: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24) (Primary Study)

Secondary: Percentage of Participants With Virologic Failure (Primary Study)

Secondary: Percentage of Participants With Virologic Failure (Primary Study)

Secondary: Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (Deferred Treatment Substudy)

Secondary: Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (Deferred Treatment Substudy)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Deferred Treatment Substudy)

Secondary: Percentage of Participants With HCV RNA < LLOQ On Treatment (Deferred Treatment Substudy)

Secondary: Change From Baseline in HCV RNA (Deferred Treatment Substudy)

Secondary: Change From Baseline in HCV RNA (Deferred Treatment Substudy)

Secondary: Percentage of Participants With Virologic Failure (Deferred Treatment Substudy)

Secondary: Percentage of Participants With Virologic Failure (Deferred Treatment Substudy)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Phase 3, Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 12 Weeks in Direct-Acting Antiviral-Experienced Subjects with Chronic HCV Infection