POLARIS-2: Safety and Efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir and Sofosbuvir/Velpatasvir in Adults With Chronic HCV Infection Who Have Not Previously Received Treatment With Direct-Acting Antiviral Therapy

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02607800
• Collaborator: (none)
• Enrollment: 943
• Locations: 93
• Arms: 2
• Actual Duration (Months): 13.9
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The primary objectives of this study are to compare the efficacy, safety, and tolerability of treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) fixed dose combination (FDC) for 8 weeks with that of SOF/VEL FDC for 12 weeks in direct-acting antiviral-naive participants with chronic hepatitis C virus (HCV) infection.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C	Drug: SOF/VEL/VOX; Drug: SOF/VEL	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 943 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Global, Multicenter, Randomized, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 8 Weeks Compared to Sofosbuvir/Velpatasvir for 12 Weeks in Direct-Acting Antiviral-Naïve Subjects With Chronic HCV Infection
• Actual Study Start Date: Nov 16, 2015
• Actual Primary Completion Date: Oct 10, 2016
• Actual Study Completion Date: Jan 11, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SOF/VEL/VOX SOF/VEL/VOX tablet for 8 weeks	Drug: SOF/VEL/VOX; 400/100/100 mg tablet administered orally once daily with food; Other Names: GS-7977/GS-5816/GS-9857 Vosevi®
Active Comparator: SOF/VEL 12 weeks SOF/VEL tablet for 12 weeks	Drug: SOF/VEL; 400/100 mg tablet administered orally once daily with or without food; Other Names: GS-7977/GS-5816 Epclusa®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) [Posttreatment Week 12]

   SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ) at 12 weeks after stopping study treatment.

2. Percentage of Participants Who Permanently Discontinue Study Drug Due to an Adverse Event [Up to 12 weeks]

Secondary Outcome Measures

1. Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) [Posttreatment Weeks 4 and 24]

   SVR4 and SVR 24 were defined as HCV RNA < LLOQ at 4 and 24 weeks after stopping study treatment, respectively.

2. Percentage of Participants With HCV RNA < LLOQ On Treatment [Weeks 1, 2, 4, 8, and 12]

3. Change From Baseline in HCV RNA [Baseline; Weeks 1, 2, 4, 8, and 12]

4. Percentage of Participants With Virologic Failure [Up to Posttreatment Week 24]

   Virologic failure was 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 on-treatment visit

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Willing and able to provide written informed consent

• HCV RNA ≥ 10^4 IU/mL at screening

• Chronic HCV infection (≥ 6 months)

• HCV treatment naive or treatment experienced with an interferon (IFN)-based regimen

• Use of protocol specified methods of contraception

Key Exclusion Criteria:

• Current or prior history of clinically significant illness that may interfere with participation in the study

• Screening ECG with clinically significant abnormalities

• Laboratory parameters outside the acceptable range at screening

• Pregnant or nursing female

• Chronic liver disease not caused by HCV

• Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Long Beach	California	United States
2		Los Angeles	California	United States
3		Palo Alto	California	United States
4		Pasadena	California	United States
5		Rialto	California	United States
6		San Diego	California	United States
7		San Francisco	California	United States
8		Aurora	Colorado	United States
9		Englewood	Colorado	United States
10		Washington	District of Columbia	United States
11		Gainesville	Florida	United States
12		Miami	Florida	United States
13		Orlando	Florida	United States
14		Wellington	Florida	United States
15		Atlanta	Georgia	United States
16		Marietta	Georgia	United States
17		Chicago	Illinois	United States
18		Indianapolis	Indiana	United States
19		Bastrop	Louisiana	United States
20		Baltimore	Maryland	United States
21		Catonsville	Maryland	United States
22		Boston	Massachusetts	United States
23		Ann Arbor	Michigan	United States
24		Detroit	Michigan	United States
25		Kansas City	Missouri	United States
26		Saint Louis	Missouri	United States
27		Hillsborough	New Jersey	United States
28		Bronx	New York	United States
29		Manhasset	New York	United States
30		New York	New York	United States
31		Asheville	North Carolina	United States
32		Fayetteville	North Carolina	United States
33		Philadelphia	Pennsylvania	United States
34		Pittsburgh	Pennsylvania	United States
35		Providence	Rhode Island	United States
36		Germantown	Tennessee	United States
37		Knoxville	Tennessee	United States
38		Nashville	Tennessee	United States
39		Houston	Texas	United States
40		Live Oak	Texas	United States
41		San Antonio	Texas	United States
42		Murray	Utah	United States
43		Falls Church	Virginia	United States
44		Norfolk	Virginia	United States
45		Richmond	Virginia	United States
46		Seattle	Washington	United States
47		Madison	Wisconsin	United States
48		Darlinghurst	New South Wales	Australia
49		Herston	Queensland	Australia
50		Fitzroy	Victoria	Australia
51		Melbourne	Victoria	Australia
52		Perth	Western Australia	Australia
53		Calgary	Alberta	Canada
54		Edmonton	Alberta	Canada
55		Vancouver	British Columbia	Canada
56		Brampton	Ontario	Canada
57		Ottawa	Ontario	Canada
58		Toronto	Ontario	Canada
59		Montreal	Quebec	Canada
60		Bobigny		France
61		Clermont-Ferrand		France
62		Clichy		France
63		Creteil		France
64		Grenoble		France
65		Lille		France
66		Limoges		France
67		Lyon		France
68		Marseille		France
69		Montpellier		France
70		Nice		France
71		Orleans		France
72		Paris		France
73		Pessac		France
74		Rennes		France
75		Rouen		France
76		Strasbourg		France
77		Toulouse		France
78		Vandoeuvre-les-Nancy		France
79		Villejuif		France
80		Berlin		Germany
81		Bonn		Germany
82		Frankfurt am Main		Germany
83		Hamburg		Germany
84		Hannover		Germany
85		Köln		Germany
86		Christchurch		New Zealand
87		Grafton		New Zealand
88		San Juan		Puerto Rico
89		London		United Kingdom
90		Manchester		United Kingdom
91		Nottingham		United Kingdom
92		Oxford		United Kingdom
93		Portsmouth		United Kingdom

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: Gilead Study Director, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02607800
• Other Study ID Numbers: GS-US-367-1172; 2015-003460-36
• First Posted: Nov 18, 2015
• Last Update Posted: Mar 5, 2019
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Gilead Sciences: Chronic Hepatitis C Infection
• Additional relevant MeSH terms: Infections; Hepatitis C; Hepatitis; Sofosbuvir; Velpatasvir

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at study sites in North America, Europe, and, Asia Pacific. The first participant was screened on 16 November 2015. The last study visit occurred on 11 January 2017.
Pre-assignment Detail	1116 participants were screened.

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks
Arm/Group Description	Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi®; SOF/VEL/VOX) (400/100/100 mg) fixed dose combination (FDC) tablet orally once daily with food for 8 weeks	Sofosbuvir/Velpatasvir (Epclusa®; SOF/VEL) (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
Period Title: Overall Study
STARTED	502	441
COMPLETED	492	430
NOT COMPLETED	10	11

Baseline Characteristics

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks	Total
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 8 weeks	SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks	Total of all reporting groups
Overall Participants	501	440	941
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (11.1)	52 (11.9)	52 (11.5)
Sex: Female, Male (Count of Participants)
Female	246 49.1%	203 46.1%	449 47.7%
Male	255 50.9%	237 53.9%	492 52.3%
Race/Ethnicity, Customized (Count of Participants)
White	391 78%	365 83%	756 80.3%
Black or African American	48 9.6%	47 10.7%	95 10.1%
Asian	51 10.2%	22 5%	73 7.8%
Other	5 1%	2 0.5%	7 0.7%
American Indian or Alaska Native	3 0.6%	2 0.5%	5 0.5%
Native Hawaiian or Pacific Islander	3 0.6%	2 0.5%	5 0.5%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	32 6.4%	52 11.8%	84 8.9%
Not Hispanic or Latino	469 93.6%	388 88.2%	857 91.1%
Region of Enrollment (Count of Participants)
New Zealand	13 2.6%	13 3%	26 2.8%
Canada	36 7.2%	24 5.5%	60 6.4%
United States	283 56.5%	269 61.1%	552 58.7%
United Kingdom	24 4.8%	23 5.2%	47 5%
Australia	13 2.6%	11 2.5%	24 2.6%
France	105 21%	82 18.6%	187 19.9%
Germany	27 5.4%	18 4.1%	45 4.8%
IL28b Status (Count of Participants)
CC	166 33.1%	136 30.9%	302 32.1%
CT	253 50.5%	245 55.7%	498 52.9%
TT	82 16.4%	59 13.4%	141 15%
HCV RNA (log10 IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log10 IU/mL]	6.1 (0.75)	6.2 (0.66)	6.2 (0.71)
HCV RNA Category (Count of Participants)
< 800,000 IU/mL	155 30.9%	138 31.4%	293 31.1%
≥ 800,000 IU/mL	346 69.1%	302 68.6%	648 68.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)
Description	SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ) at 12 weeks after stopping study treatment.
Time Frame	Posttreatment Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized/enrolled participants who took at least 1 dose of the study drug

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 8 weeks	SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
Measure Participants	501	440
Number (95% Confidence Interval) [percentage of participants]	95.2 19%	98.2 22.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SOF/VEL/VOX 8 Weeks, SOF/VEL 12 Weeks
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Noninferiority was demonstrated if the lower bound of the 2-sided 95% confidence interval (CI) for the difference in SVR12 was greater than -5%. If the lower bound of the CI was greater than -5% (ie, the noninferiority null hypothesis was rejected), a 2-sided stratified Cochran-Mantel-Haenszel test was to be used to test for the superiority of SOF/VEL/VOX for 8 weeks over SOF/VEL for 12 weeks at a significance level of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportions
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) 95%; -6.0 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in proportions between treatment groups and associated 95% CI were calculated based on stratum-adjusted Mantel-Haenszel proportions.

2. Primary Outcome

Title	Percentage of Participants Who Permanently Discontinue Study Drug Due to an Adverse Event
Time Frame	Up to 12 weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 8 weeks	SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
Measure Participants	501	440
Number [percentage of participants]	0 0%	0.5 0.1%

3. Secondary Outcome

Title	Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
Description	SVR4 and SVR 24 were defined as HCV RNA < LLOQ at 4 and 24 weeks after stopping study treatment, respectively.
Time Frame	Posttreatment Weeks 4 and 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) tablet orally once daily with food for 8 weeks	SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
Measure Participants	501	440
SVR4	96.4 19.2%	98.9 22.5%
SVR 24	95.0 19%	98.0 22.3%

4. Secondary Outcome

Title	Percentage of Participants With HCV RNA < LLOQ On Treatment
Time Frame	Weeks 1, 2, 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Percentage of participants in Full Analysis Set with on-treatment data were analyzed.

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 8 weeks	SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
Measure Participants	501	440
Week 1	24.8 5%	22.7 5.2%
Week 2	65.9 13.2%	61.3 13.9%
Week 4	92.4 18.4%	92.0 20.9%
Week 8	99.2 19.8%	99.8 22.7%
Week 12	99.8 19.9%

5. Secondary Outcome

Title	Change From Baseline in HCV RNA
Time Frame	Baseline; Weeks 1, 2, 4, 8, and 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 8 weeks	SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
Measure Participants	501	440
Week 1	-4.23 (0.689)	-4.24 (0.679)
Week 2	-4.75 (0.747)	-4.77 (0.646)
Week 4	-4.95 (0.750)	-4.99 (0.656)
Week 8	-4.99 (0.754)	-5.03 (0.655)
Week 12	-5.03 (0.656)

6. Secondary Outcome

Title	Percentage of Participants With Virologic Failure
Description	Virologic failure was 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 on-treatment visit
Time Frame	Up to Posttreatment Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	SOF/VEL/VOX 8 Weeks	SOF/VEL 12 Weeks
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 8 weeks	SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
Measure Participants	501	440
Number [percentage of participants]	4.2 0.8%	0.7 0.2%

Adverse Events

Time Frame	Up to 12 weeks plus 30 days
Adverse Event Reporting Description	Safety Analysis Set
Arm/Group Title	SOF/VEL/VOX 8 Weeks		SOF/VEL 12 Weeks
Arm/Group Description	SOF/VEL/VOX (400/100/100 mg) FDC tablet orally once daily with food for 8 weeks		SOF/VEL (400/100 mg) FDC tablet orally once daily with or without food for 12 weeks
All Cause Mortality
	SOF/VEL/VOX 8 Weeks		SOF/VEL 12 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/501 (0%)		0/440 (0%)
Serious Adverse Events
	SOF/VEL/VOX 8 Weeks		SOF/VEL 12 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/501 (3%)		7/440 (1.6%)
Cardiac disorders
Acute myocardial infarction	1/501 (0.2%)		0/440 (0%)
Angina pectoris	0/501 (0%)		1/440 (0.2%)
Atrial fibrillation	1/501 (0.2%)		0/440 (0%)
Gastrointestinal disorders
Small intestinal obstruction	1/501 (0.2%)		0/440 (0%)
General disorders
Chest pain	1/501 (0.2%)		0/440 (0%)
Hepatobiliary disorders
Biliary colic	1/501 (0.2%)		0/440 (0%)
Cholelithiasis	1/501 (0.2%)		0/440 (0%)
Infections and infestations
Clostridium difficile colitis	0/501 (0%)		1/440 (0.2%)
Perineal abscess	1/501 (0.2%)		0/440 (0%)
Pneumonia	0/501 (0%)		1/440 (0.2%)
Pyelonephritis	1/501 (0.2%)		1/440 (0.2%)
Injury, poisoning and procedural complications
Multiple fractures	0/501 (0%)		1/440 (0.2%)
Road traffic accident	0/501 (0%)		1/440 (0.2%)
Musculoskeletal and connective tissue disorders
Back pain	1/501 (0.2%)		0/440 (0%)
Flank pain	0/501 (0%)		1/440 (0.2%)
Musculoskeletal chest pain	1/501 (0.2%)		0/440 (0%)
Myositis	0/501 (0%)		1/440 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/501 (0.2%)		0/440 (0%)
Lung adenocarcinoma metastatic	1/501 (0.2%)		0/440 (0%)
Nervous system disorders
Cerebral haemorrhage	1/501 (0.2%)		0/440 (0%)
Psychiatric disorders
Alcohol withdrawal syndrome	0/501 (0%)		1/440 (0.2%)
Depression	0/501 (0%)		1/440 (0.2%)
Suicide attempt	0/501 (0%)		1/440 (0.2%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/501 (0.2%)		0/440 (0%)
Vascular disorders
Peripheral artery occlusion	1/501 (0.2%)		0/440 (0%)
Other (Not Including Serious) Adverse Events
	SOF/VEL/VOX 8 Weeks		SOF/VEL 12 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	280/501 (55.9%)		213/440 (48.4%)
Gastrointestinal disorders
Diarrhoea	88/501 (17.6%)		32/440 (7.3%)
Nausea	80/501 (16%)		40/440 (9.1%)
General disorders
Asthenia	32/501 (6.4%)		27/440 (6.1%)
Fatigue	106/501 (21.2%)		91/440 (20.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	19/501 (3.8%)		24/440 (5.5%)
Nervous system disorders
Headache	134/501 (26.7%)		99/440 (22.5%)
Psychiatric disorders
Insomnia	26/501 (5.2%)		21/440 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years