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

• ClinicalTrials.gov Identifier: NCT02201940
• Recruitment Status: Completed
• First Posted: July 28, 2014
• Results First Posted: September 16, 2016
• Last Update Posted: November 15, 2018
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hepatitis C Virus Infection
• Interventions: Drug: SOF/VEL; Drug: Placebo
• Enrollment: 741

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 Details	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
Reason Not Completed
Randomized/Enrolled but Never Treated	1	0
Lack of Efficacy	2	113
Lost to Follow-up	5	0
Withdrew Consent	2	1
Investigator's Discretion	1	1
Death	1	0
Adverse Event	0	1

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 Number of Baseline Participants		624	116	740
Baseline Analysis Population Description		Safety Analysis Set: participants who received at least 1 dose of study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	624 participants	116 participants	740 participants
		54 (10.9)	53 (10.4)	54 (10.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	624 participants	116 participants	740 participants
	Female	250 40.1%	48 41.4%	298 40.3%
	Male	374 59.9%	68 58.6%	442 59.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	624 participants	116 participants	740 participants
	Hispanic or Latino	31 5.0%	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 0.0%	4 0.5%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	624 participants	116 participants	740 participants
Black or African American		52	12	64
White		493	89	582
Asian		62	11	73
American Indian/ Alaska Native		7	0	7
Hawaiian or Pacific Islander		1	1	2
Other		6	3	9
Not Disclosed		3	0	3
Region of Enrollment [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	624 participants	116 participants	740 participants
Canada		55	7	62
Belgium		40	5	45
United States		234	45	279
China		19	4	23
Italy		16	2	18
United Kingdom		91	13	104
France		126	32	158
Germany		44	8	52
		[1] Measure Description: All randomized participants were analyzed for Region of Enrollment (N = 741).
Cirrhosis Status; Measure Type: Number; Unit of measure: Participants	Number Analyzed	624 participants	116 participants	740 participants
Present		121	21	142
Absent		501	95	596
Missing		2	0	2
HCV Genotype; Measure Type: Number; Unit of measure: Participants	Number Analyzed	624 participants	116 participants	740 participants
Genotype 1		328	65	393
Genotype 2		104	21	125
Genotype 4		116	22	138
Genotype 5		35	0	35
Genotype 6		41	8	49
IL28b Status [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	624 participants	116 participants	740 participants
CC		186	36	222
CT		339	53	392
TT		94	26	120
Missing		5	1	6
		[1] Measure Description: CC, CT, and TT alleles are different forms of the IL28b gene.
HCV RNA; Mean (Standard Deviation); Unit of measure: Log10 IU/mL
	Number Analyzed	624 participants	116 participants	740 participants
		6.3 (0.66)	6.3 (0.58)	6.3 (0.65)
HCV RNA Category; Measure Type: Number; Unit of measure: Participants	Number Analyzed	624 participants	116 participants	740 participants
< 800,000 IU/mL		163	29	192
≥ 800,000 IU/mL		461	87	548

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
Overall Number of Participants Analyzed	624	116
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	99.0; (97.9 to 99.6)	0; (0.0 to 3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SOF/VEL
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

2. Primary Outcome

Title	Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
Description	[Not Specified]
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
Overall Number of Participants Analyzed	624	116
Measure Type: Number; Unit of Measure: percentage of participants
	0.2	1.7

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
Overall Number of Participants Analyzed	624	116
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
SVR4	99.2; (98.1 to 99.7)	0; (0.0 to 3.1)
SVR24	99.0; (97.9 to 99.6)	0; (0.0 to 3.1)

4. Secondary Outcome

Title	Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12
Description	[Not Specified]
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
Overall Number of Participants Analyzed	624	116
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Week 1 (SOF/VEL: N = 624; Placebo: N = 116)	18.8; (15.8 to 22.0)	0; (0.0 to 3.1)
Week 2 (SOF/VEL: N = 624; Placebo: N = 116)	56.9; (52.9 to 60.8)	0; (0.0 to 3.1)
Week 4 (SOF/VEL: N = 623; Placebo: N = 116)	90.5; (88.0 to 92.7)	0; (0.0 to 3.1)
Week 6 (SOF/VEL: N = 623; Placebo: N = 115)	98.9; (97.7 to 99.5)	0; (0.0 to 3.2)
Week 8 (SOF/VEL: N = 622; Placebo: N = 114)	99.7; (98.8 to 100.0)	0; (0.0 to 3.2)
Week 10 (SOF/VEL: N = 622; Placebo: N = 114)	100.0; (99.4 to 100.0)	0; (0.0 to 3.2)
Week 12 (SOF/VEL: N = 622; Placebo: N = 113)	100.0; (99.4 to 100.0)	0; (0.0 to 3.2)

5. Secondary Outcome

Title	Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12
Description	[Not Specified]
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
Overall Number of Participants Analyzed	624	116
Mean (Standard Deviation); Unit of Measure: log10 IU/mL
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
Overall Number of Participants Analyzed	624	116
Measure Type: Number; Unit of Measure: percentage of participants
	0.3	100

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 (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	SOF/VEL	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/624 (2.40%)	0/116 (0.00%)
Cardiac disorders
Acute myocardial infarction † 1	1/624 (0.16%)	0/116 (0.00%)
Palpitations † 1	1/624 (0.16%)	0/116 (0.00%)
Gastrointestinal disorders
Small intestinal obstruction † 1	1/624 (0.16%)	0/116 (0.00%)
General disorders
Sudden death † 1	1/624 (0.16%)	0/116 (0.00%)
Infections and infestations
Abscess limb † 1	1/624 (0.16%)	0/116 (0.00%)
Appendicitis † 1	1/624 (0.16%)	0/116 (0.00%)
Bronchitis † 1	1/624 (0.16%)	0/116 (0.00%)
Cellulitis † 1	1/624 (0.16%)	0/116 (0.00%)
Gastroenteritis † 1	1/624 (0.16%)	0/116 (0.00%)
Influenza † 1	1/624 (0.16%)	0/116 (0.00%)
Vestibular neuronitis † 1	1/624 (0.16%)	0/116 (0.00%)
Injury, poisoning and procedural complications
Ligament sprain † 1	1/624 (0.16%)	0/116 (0.00%)
Upper limb fracture † 1	1/624 (0.16%)	0/116 (0.00%)
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome † 1	1/624 (0.16%)	0/116 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant † 1	1/624 (0.16%)	0/116 (0.00%)
Nervous system disorders
Epilepsy † 1	1/624 (0.16%)	0/116 (0.00%)
Psychiatric disorders
Mania † 1	1/624 (0.16%)	0/116 (0.00%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	1/624 (0.16%)	0/116 (0.00%)
Vascular disorders
Extremity necrosis † 1	1/624 (0.16%)	0/116 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA Version 18
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	SOF/VEL	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	393/624 (62.98%)	77/116 (66.38%)
Gastrointestinal disorders
Diarrhoea † 1	48/624 (7.69%)	8/116 (6.90%)
Nausea † 1	75/624 (12.02%)	13/116 (11.21%)
General disorders
Asthenia † 1	42/624 (6.73%)	9/116 (7.76%)
Fatigue † 1	127/624 (20.35%)	24/116 (20.69%)
Infections and infestations
Nasopharyngitis † 1	80/624 (12.82%)	12/116 (10.34%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	40/624 (6.41%)	9/116 (7.76%)
Back pain † 1	29/624 (4.65%)	11/116 (9.48%)
Myalgia † 1	25/624 (4.01%)	6/116 (5.17%)
Nervous system disorders
Headache † 1	182/624 (29.17%)	33/116 (28.45%)
Psychiatric disorders
Insomnia † 1	50/624 (8.01%)	11/116 (9.48%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	39/624 (6.25%)	4/116 (3.45%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA Version 18

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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

Results Point of Contact

• Name/Title: Clinical Trial Disclosures
• Organization: Gilead Sciences
• EMail: ClinicalTrialDisclosures@gilead.com

Publications of Results:

Asselah T, Charlton M, Feld J, Foster GR, Mcnally J, Brainard DM, et al. The ASTRAL Studies: Evaluation of SOF/GS-5816 Single Tablet Regimen for the Treatment of Genotype 1-6 HCV Infection [Poster P1332]. J Hepatol 2015;62:S855-S6.

Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, Abergel A, Mangia A, Lai CL, Chan HL, Mazzotta F, Moreno C, Yoshida E, Shafran SD, Towner WJ, Tran TT, McNally J, Osinusi A, Svarovskaia E, Zhu Y, Brainard DM, McHutchison JG, Agarwal K, Zeuzem S; ASTRAL-1 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015 Dec 31;373(27):2599-607. doi: 10.1056/NEJMoa1512610. Epub 2015 Nov 16.

Feld JJ, Agarwal K, Hezode C, Asselah T, Ruane PJ, Gruener N, et al. A Phase 3 Double-Blind Placebo-Controlled Evaluation of Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Naive and Experienced Genotype 1, 2, 4, 5, 6 HCV Infected Patients with and without Cirrhosis: Results of the ASTRAL-1 Study. J Hepatol 2015;62(6) Suppl:1379A-1380A.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Younossi ZM, Stepanova M, Feld J, Zeuzem S, Sulkowski M, Foster GR, Mangia A, Charlton M, O'Leary JG, Curry MP, Nader F, Henry L, Hunt S. Sofosbuvir and Velpatasvir Combination Improves Patient-reported Outcomes for Patients With HCV Infection, Without or With Compensated or Decompensated Cirrhosis. Clin Gastroenterol Hepatol. 2017 Mar;15(3):421-430.e6. doi: 10.1016/j.cgh.2016.10.037. Epub 2016 Nov 12.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02201940
• Other Study ID Numbers: GS-US-342-1138; 2014-001683-35 ( EudraCT Number )
• First Submitted: July 24, 2014
• First Posted: July 28, 2014
• Results First Submitted: July 27, 2016
• Results First Posted: September 16, 2016
• Last Update Posted: November 15, 2018