Sofosbuvir and Velpatasvir (Page 8 of 11)

14.2 Clinical Trials in Subjects without Cirrhosis and Subjects with Compensated Cirrhosis

Genotype 1, 2, 4, 5, and 6 HCV Infected Adults (ASTRAL-1)

ASTRAL-1 was a randomized, double-blind, placebo-controlled trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) compared with 12 weeks of placebo in subjects with genotype 1, 2, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis. Subjects with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to treatment with sofosbuvir and velpatasvir or placebo for 12 weeks. Subjects with genotype 5 HCV infection were enrolled to the sofosbuvir and velpatasvir group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of compensated cirrhosis.

Demographics and baseline characteristics were balanced between the sofosbuvir and velpatasvir and placebo group. Of the 740 treated subjects, the median age was 56 years (range: 18 to 82); 60% of the subjects were male; 79% were White, 9% were Black; 21% had a baseline body mass index at least 30 kg/m² ; the proportions of subjects with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5%, and 7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced.

Table 13 presents SVR12 and other virologic outcomes in sofosbuvir and velpatasvir-treated subjects in the ASTRAL-1 trial by HCV genotype. No subjects in the placebo group achieved SVR12.

Table 13 Study ASTRAL-1: Virologic Outcomes by HCV Genotype in Sofosbuvir and Velpatasvir-Treated Subjects without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment)

	Sofosbuvir and Velpatasvir 12 Weeks(N=624)
	Total(all GTs)(N=624)	GT-1			GT-2(N=104)	GT-4(N=116)	GT-5(N=35)	GT-6(N=41)
		GT-1a(N=210)	GT-1b(N=118)	Total(N=328)
GT = genotype; no subjects in the placebo group achieved SVR12.
* The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. † Other includes subjects who did not achieve SVR and did not meet virologic failure criteria.
SVR12	99% (618/624)	98% (206/210)	99% (117/118)	98% (323/328)	100% (104/104)	100% (116/116)	97% (34/35)	100% (41/41)
Outcome for Subjects without SVR
On-Treatment Virologic Failure	0/624	0/210	0/118	0/328	0/104	0/116	0/35	0/41
Relapse *	<1%(2/623)	<1%(1/209)	1%(1/118)	1%(2/327)	0/104	0/116	0/35	0/41
Other †	1%(4/624)	1%(3/210)	0/118	1%(3/328)	0/104	0/116	3%(1/35)	0/41

Genotype 2 HCV Infected Adults (ASTRAL-2)

ASTRAL-2 was a randomized, open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) compared with 12 weeks of treatment with SOF with ribavirin in subjects with genotype 2 HCV infection. Subjects were randomized in a 1:1 ratio to the treatment groups. Randomization was stratified by the presence or absence of compensated cirrhosis and prior treatment experience (treatment-naïve vs treatment-experienced).

Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266 treated subjects, the median age was 58 years (range: 23 to 81); 59% of the subjects were male; 88% were White; 7% were Black; 33% had a baseline body mass index at least 30 kg/m² ; 62% had non-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels at least 800,000 IU/mL; 14% had compensated cirrhosis; and 15% were treatment-experienced.

Table 14 presents SVR12 and other virologic outcomes from the ASTRAL-2 trial.

Table 14 Study ASTRAL-2: Virologic Outcomes in Subjects with Genotype 2 HCV without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment)

	Sofosbuvir and Velpatasvir 12 Weeks(N=134)	SOF + RBV 12 Weeks(N=132)
SOF = sofosbuvir; RBV = ribavirin.
* The denominator for relapse is the number of subjects with HCV RNA <LLOQ at the last on-treatment assessment. † Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria.
SVR12	99% (133/134)	94% (124/132)
	Treatment difference +5.2%;95% confidence interval (+0.2% to +10.3%)
Outcome for subjects without SVR
On-Treatment Virologic Failure	0/134	0/132
Relapse *	0/133	5% (6/132)
Other †	1% (1/134)	2% (2/132)

Genotype 3 HCV Infected Adults (ASTRAL-3)

ASTRAL-3 was a randomized, open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) compared with 24 weeks of treatment with SOF with ribavirin in subjects with genotype 3 HCV infection. Subjects were randomized in a 1:1 ratio to the treatment groups. Randomization was stratified by the presence or absence of compensated cirrhosis and prior treatment experience (treatment-naïve vs treatment-experienced).

Demographics and baseline characteristics were balanced across the treatment groups. Of the 552 treated subjects, the median age was 52 years (range: 19 to 76); 62% of the subjects were male; 89% were White; 9% were Asian; 20% had a baseline body mass index at least 30 kg/m² ; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels at least 800,000 IU/mL; 30% had compensated cirrhosis; and 26% were treatment-experienced.

Table 15 presents SVR12 and other virologic outcomes from the ASTRAL-3 trial.

Table 15 Study ASTRAL-3: Virologic Outcomes in Subjects with Genotype 3 HCV without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment)

	Sofosbuvir and Velpatasvir 12 Weeks(N=277)	SOF + RBV 24 Weeks(N=275)
SOF = sofosbuvir; RBV = ribavirin.
* The denominator for relapse is the number of subjects with HCV RNA <LLOQ at the last on-treatment assessment. † Other includes subjects who did not achieve SVR and did not meet virologic failure criteria.
SVR12	95% (264/277)	80% (221/275)
	Treatment difference +14.8%;95% confidence interval (+9.6% to +20.0%)
Outcome for subjects without SVR
On-Treatment Virologic Failure	0/277	<1% (1/275)
Relapse *	4% (11/276)	14% (38/272)
Other †	1% (2/277)	5% (15/275)

SVR12 for selected subgroups are presented in Table 16.

Table 16 Study ASTRAL-3: SVR12 by Prior Treatment and Presence/Absence of Compensated Cirrhosis in Subjects with Genotype 3 HCV

	Sofosbuvir and Velpatasvir 12 Weeks		SOF + RBV 24 Weeks *
	Treatment-Naïve(N=206)	Treatment-Experienced(N=71)	Treatment-Naïve(N=201)	Treatment-Experienced(N=69)
SOF = sofosbuvir; RBV = ribavirin.
* Five subjects with missing cirrhosis status in the SOF + RBV 24-week group were excluded from this subgroup analysis. † One treatment-experienced subject without cirrhosis treated with sofosbuvir and velpatasvir had genotype 1a HCV infection at failure, indicating HCV re-infection, and is therefore excluded from this analysis.
Without cirrhosis	98% (160/163)	94% (31/33)†	90% (141/156)	71% (22/31)
With compensated cirrhosis	93% (40/43)	89% (33/37)	73% (33/45)	58% (22/38)