ASTRAL-1: Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Adults With Chronic HCV Infection

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02201940
• Collaborator: (none)
• Enrollment: 741
• Locations: 80
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) fixed dose combination (FDC) for 12 weeks in adults with chronic genotype 1, 2, 4, 5, or 6 hepatitis C virus (HCV) infection.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C Virus Infection	Drug: SOF/VEL; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 741 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Sofosbuvir/GS-5816 Fixed Dose Combination for 12 Weeks in Subjects With Chronic HCV
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SOF/VEL SOF/VEL for 12 weeks	Drug: SOF/VEL; 400/100 mg FDC tablet administered orally once daily; Other Names: Epclusa® GS-7977/GS-5816
Placebo Comparator: Placebo SOF/VEL placebo for 12 weeks	Drug: Placebo; Tablet administered orally once daily

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; ie, 15 IU/mL) at 12 weeks after stopping study treatment.

2. Percentage of Participants Who Permanently Discontinued Any 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 at Weeks 1, 2, 4, 6, 8, 10, and 12 [Weeks 1, 2, 4, 6, 8, 10, and 12]

3. Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 [Baseline; Weeks 1, 2, 4, 6, 8, 10, 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

Inclusion Criteria:

• Willing and able to provide written informed consent

• HCV RNA ≥ 10^4 IU/mL at screening

• HCV genotype 1, 2, 4, 5, 6, or indeterminate assessed at screening by the central laboratory

• Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy

• Classification as treatment naive or treatment experienced

• Males and females of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception

Exclusion Criteria:

• Current or prior history of clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with treatment, assessment, or compliance with the protocol; individuals currently under evaluation for a potentially clinically-significant illness (other than HCV) are also excluded.

• Screening ECG with clinically significant abnormalities

• Laboratory results outside of acceptable ranges at Screening

• Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A inhibitor

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States
2		Long Beach	California	United States
3		Los Angeles	California	United States	90027
4		Los Angeles	California	United States	90036
5		Los Angeles	California	United States	90048
6		Palo Alto	California	United States
7		Sacramento	California	United States
8		San Diego	California	United States	92123
9		San Diego	California	United States	92154
10		Aurora	Colorado	United States	80045
11		Gainesville	Florida	United States	32610-0272
12		Jacksonville	Florida	United States
13		Miami	Florida	United States
14		Orlando	Florida	United States
15		Wellington	Florida	United States
16		Atlanta	Georgia	United States	30308
17		Marietta	Georgia	United States
18		Chicago	Illinois	United States	60611
19		Indianapolis	Indiana	United States	46237
20		Baltimore	Maryland	United States
21		Lutherville	Maryland	United States	21093
22		Boston	Massachusetts	United States	02215
23		Detroit	Michigan	United States	48188
24		Bronx	New York	United States	10468
25		New York	New York	United States	10021
26		Philadelphia	Pennsylvania	United States	19104
27		Pittsburgh	Pennsylvania	United States	15213
28		Pittsburgh	Pennsylvania	United States	15240
29		Providence	Rhode Island	United States	02905
30		Germantown	Tennessee	United States
31		Nashville	Tennessee	United States
32		San Antonio	Texas	United States	78215
33		Norfolk	Virginia	United States
34		Richmond	Virginia	United States
35		Antwerp		Belgium	2060
36		Brussels		Belgium	1070
37		Kortrijk		Belgium	8500
38		Calgary	Alberta	Canada	T2N 4Z6
39		Edmonton	Alberta	Canada	T6G 2B7
40		Vancouver	British Columbia	Canada	V5Z 1M9
41		Vancouver	British Columbia	Canada	V6Z2C7
42		Ottawa	Ontario	Canada	K1H 8L6
43		Montreal	Quebec	Canada	H2X 0A9
44		Toronto		Canada	M5T 2S8
45		Hong Kong		China
46		Clermont-Ferrand		France	63000
47		Clichy		France	92110
48		Creteil		France	94000
49		Lille		France	59037
50		Limoges		France	87042
51		Lyon		France	69004
52		Marseille		France	13008
53		Paris		France	75014
54		Pessac		France	33604
55		Toulouse		France	31059
56		Villejuif		France	94804
57		Frankfurt am Main	Hessin	Germany	60590
58		Duesseldorf	North Rhine-Westphalia	Germany	40237
59		Hufelandstr	NRW	Germany	45122
60		Koln	NRW	Germany	50932
61		Berlin		Germany	12157
62		Berlin		Germany	D-10969
63		Hamburg		Germany	20099
64		Hannover		Germany	30625
65		München		Germany	81377
66		San Giovanni Rotondo	Foggia	Italy	71013
67		San Giovanni Rotondo	Foggia	Italy
68		Firenze		Italy	50012
69		San Juan		Puerto Rico
70		Plymouth	Devon	United Kingdom	PL6 8DH
71		Portsmouth	Hampshire	United Kingdom	PO6 3LY
72		Glasgow		United Kingdom	G12 0YN
73		London		United Kingdom	E1 4AT
74		London		United Kingdom	NW3 2PF
75		London		United Kingdom	SE5 9RS
76		London		United Kingdom	SW170QT
77		London		United Kingdom	W2 1NY
78		Manchester		United Kingdom	M8 5RB
79		Nottingham		United Kingdom	NG7 2UH
80		Oxford		United Kingdom	OX3 9DU

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: John McNally, PhD, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02201940
• Other Study ID Numbers: GS-US-342-1138; 2014-001683-35
• First Posted: Jul 28, 2014
• Last Update Posted: Nov 15, 2018
• Last Verified: Jul 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Gilead Sciences: Sofosbuvir; SOF/VEL; Velpatasvir; Hepatitis C; HCV; cirrhosis
• Additional relevant MeSH terms: Infections; Hepatitis C; Hepatitis; Sofosbuvir; Sofosbuvir-velpatasvir drug combination; Velpatasvir

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at study sites in the United States, Canada, Europe, and Asia. The first participant was screened on 18 July 2014. The last study visit occurred on 23 September 2015.
Pre-assignment Detail	847 participants were screened.

Arm/Group Title	SOF/VEL	Placebo
Arm/Group Description	Sofosbuvir/velpatasvir (SOF/VEL) (400/100 mg) fixed-dose combination (FDC) tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks
Period Title: Overall Study
STARTED	625	116
COMPLETED	613	0
NOT COMPLETED	12	116

Baseline Characteristics

Arm/Group Title	SOF/VEL	Placebo	Total
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks	Total of all reporting groups
Overall Participants	624	116	740
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54 (10.9)	53 (10.4)	54 (10.8)
Sex: Female, Male (Count of Participants)
Female	250 40.1%	48 41.4%	298 40.3%
Male	374 59.9%	68 58.6%	442 59.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	31 5%	5 4.3%	36 4.9%
Not Hispanic or Latino	589 94.4%	111 95.7%	700 94.6%
Unknown or Not Reported	4 0.6%	0 0%	4 0.5%
Race/Ethnicity, Customized (participants) [Number]
Black or African American	52 8.3%	12 10.3%	64 8.6%
White	493 79%	89 76.7%	582 78.6%
Asian	62 9.9%	11 9.5%	73 9.9%
American Indian/ Alaska Native	7 1.1%	0 0%	7 0.9%
Hawaiian or Pacific Islander	1 0.2%	1 0.9%	2 0.3%
Other	6 1%	3 2.6%	9 1.2%
Not Disclosed	3 0.5%	0 0%	3 0.4%
Region of Enrollment (participants) [Number]
Canada	55 8.8%	7 6%	62 8.4%
Belgium	40 6.4%	5 4.3%	45 6.1%
United States	234 37.5%	45 38.8%	279 37.7%
China	19 3%	4 3.4%	23 3.1%
Italy	16 2.6%	2 1.7%	18 2.4%
United Kingdom	91 14.6%	13 11.2%	104 14.1%
France	126 20.2%	32 27.6%	158 21.4%
Germany	44 7.1%	8 6.9%	52 7%
Cirrhosis Status (participants) [Number]
Present	121 19.4%	21 18.1%	142 19.2%
Absent	501 80.3%	95 81.9%	596 80.5%
Missing	2 0.3%	0 0%	2 0.3%
HCV Genotype (participants) [Number]
Genotype 1	328 52.6%	65 56%	393 53.1%
Genotype 2	104 16.7%	21 18.1%	125 16.9%
Genotype 4	116 18.6%	22 19%	138 18.6%
Genotype 5	35 5.6%	0 0%	35 4.7%
Genotype 6	41 6.6%	8 6.9%	49 6.6%
IL28b Status (participants) [Number]
CC	186 29.8%	36 31%	222 30%
CT	339 54.3%	53 45.7%	392 53%
TT	94 15.1%	26 22.4%	120 16.2%
Missing	5 0.8%	1 0.9%	6 0.8%
HCV RNA (log10 IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log10 IU/mL]	6.3 (0.66)	6.3 (0.58)	6.3 (0.65)
HCV RNA Category (participants) [Number]
< 800,000 IU/mL	163 26.1%	29 25%	192 25.9%
≥ 800,000 IU/mL	461 73.9%	87 75%	548 74.1%

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; ie, 15 IU/mL) at 12 weeks after stopping study treatment.
Time Frame	Posttreatment Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: participants randomized or enrolled into the study and received at least 1 dose of study drug.

Arm/Group Title	SOF/VEL	Placebo
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks
Measure Participants	624	116
Number (95% Confidence Interval) [percentage of participants]	99.0 15.9%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SOF/VEL
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Participants in the SOF/VEL group were compared to the performance goal of 85% using a 2-sided exact 1-sample binomial test at the 0.05 significance level.
	Method	Binomial test
	Comments

2. Primary Outcome

Title	Percentage of Participants Who Permanently Discontinued Any 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	Placebo
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks
Measure Participants	624	116
Number [percentage of participants]	0.2 0%	1.7 1.5%

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	Placebo
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks
Measure Participants	624	116
SVR4	99.2 15.9%	0 0%
SVR24	99.0 15.9%	0 0%

4. Secondary Outcome

Title	Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12
Time Frame	Weeks 1, 2, 4, 6, 8, 10, and 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SOF/VEL	Placebo
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks
Measure Participants	624	116
Week 1 (SOF/VEL: N = 624; Placebo: N = 116)	18.8 3%	0 0%
Week 2 (SOF/VEL: N = 624; Placebo: N = 116)	56.9 9.1%	0 0%
Week 4 (SOF/VEL: N = 623; Placebo: N = 116)	90.5 14.5%	0 0%
Week 6 (SOF/VEL: N = 623; Placebo: N = 115)	98.9 15.8%	0 0%
Week 8 (SOF/VEL: N = 622; Placebo: N = 114)	99.7 16%	0 0%
Week 10 (SOF/VEL: N = 622; Placebo: N = 114)	100.0 16%	0 0%
Week 12 (SOF/VEL: N = 622; Placebo: N = 113)	100.0 16%	0 0%

5. Secondary Outcome

Title	Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12
Time Frame	Baseline; Weeks 1, 2, 4, 6, 8, 10, and 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	SOF/VEL	Placebo
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks
Measure Participants	624	116
Change at Wk 1 (SOF/VEL: N= 617; Placebo: N= 114)	-4.29 (0.647)	-0.05 (0.561)
Change at Wk 2 (SOF/VEL: N= 622; Placebo: N= 116)	-4.82 (0.685)	0.01 (0.280)
Change at Wk 4 (SOF/VEL: N= 617; Placebo: N= 114)	-5.08 (0.656)	-0.01 (0.297)
Change at Wk 6 (SOF/VEL: N= 623; Placebo: N= 115)	-5.11 (0.664)	0.07 (0.298)
Change at Wk 8 (SOF/VEL: N= 622; Placebo: N= 113)	-5.11 (0.664)	0.05 (0.281)
Change at Wk 10 (SOF/VEL: N= 622; Placebo: N= 112)	-5.12 (0.662)	0.05 (0.337)
Change at Wk 12 (SOF/VEL: N= 622; Placebo: N= 111)	-5.12 (0.662)	-0.06 (0.580)

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	Placebo
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks	SOF/VEL placebo tablet administered orally once daily for 12 weeks
Measure Participants	624	116
Number [percentage of participants]	0.3 0%	100 86.2%

Adverse Events

Time Frame	Up to 12 weeks plus 30 days
Adverse Event Reporting Description	Safety Analysis Set
Arm/Group Title	SOF/VEL		Placebo
Arm/Group Description	SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks		SOF/VEL placebo tablet administered orally once daily for 12 weeks
All Cause Mortality
	SOF/VEL		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	SOF/VEL		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/624 (2.4%)		0/116 (0%)
Cardiac disorders
Acute myocardial infarction	1/624 (0.2%)		0/116 (0%)
Palpitations	1/624 (0.2%)		0/116 (0%)
Gastrointestinal disorders
Small intestinal obstruction	1/624 (0.2%)		0/116 (0%)
General disorders
Sudden death	1/624 (0.2%)		0/116 (0%)
Infections and infestations
Abscess limb	1/624 (0.2%)		0/116 (0%)
Appendicitis	1/624 (0.2%)		0/116 (0%)
Bronchitis	1/624 (0.2%)		0/116 (0%)
Cellulitis	1/624 (0.2%)		0/116 (0%)
Gastroenteritis	1/624 (0.2%)		0/116 (0%)
Influenza	1/624 (0.2%)		0/116 (0%)
Vestibular neuronitis	1/624 (0.2%)		0/116 (0%)
Injury, poisoning and procedural complications
Ligament sprain	1/624 (0.2%)		0/116 (0%)
Upper limb fracture	1/624 (0.2%)		0/116 (0%)
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome	1/624 (0.2%)		0/116 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	1/624 (0.2%)		0/116 (0%)
Nervous system disorders
Epilepsy	1/624 (0.2%)		0/116 (0%)
Psychiatric disorders
Mania	1/624 (0.2%)		0/116 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/624 (0.2%)		0/116 (0%)
Vascular disorders
Extremity necrosis	1/624 (0.2%)		0/116 (0%)
Other (Not Including Serious) Adverse Events
	SOF/VEL		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	393/624 (63%)		77/116 (66.4%)
Gastrointestinal disorders
Diarrhoea	48/624 (7.7%)		8/116 (6.9%)
Nausea	75/624 (12%)		13/116 (11.2%)
General disorders
Asthenia	42/624 (6.7%)		9/116 (7.8%)
Fatigue	127/624 (20.4%)		24/116 (20.7%)
Infections and infestations
Nasopharyngitis	80/624 (12.8%)		12/116 (10.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	40/624 (6.4%)		9/116 (7.8%)
Back pain	29/624 (4.6%)		11/116 (9.5%)
Myalgia	25/624 (4%)		6/116 (5.2%)
Nervous system disorders
Headache	182/624 (29.2%)		33/116 (28.4%)
Psychiatric disorders
Insomnia	50/624 (8%)		11/116 (9.5%)
Respiratory, thoracic and mediastinal disorders
Cough	39/624 (6.3%)		4/116 (3.4%)

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