|clinicalStudies======Description of Clinical Trials=====
(Description)
*The efficacy and safety of HARVONI were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A), one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects, two trials in genotype 4, 5, or 6 HCV mono-infected subjects, two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH), and one trial in genotype 1 HCV pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 9.
=====Condition 2=====
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_1.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
(Description)
*HARVONI was administered once daily by mouth in these trials. For subjects without cirrhosis or with compensated cirrhosis who received ribavirin (RBV), the RBV dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status. RBV dose adjustments were performed according to the RBV labeling.
=====Condition 3=====
*Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in studies in adults and the key efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.
=====Clinical Trials in Subjects with Genotype 1 HCV=====
Treatment-Naïve Adults without Cirrhosis ─ ION-3 (Study 0108)
*ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 HCV. Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks, HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks.
*Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT).
*Table 10 presents the SVR12 for the HARVONI treatment groups in the ION-3 trial after 8 and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 10.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_2.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*The treatment difference between the 8-week treatment of HARVONI and 12-week treatment of HARVONI was –2.3% (97.5% confidence interval –7.2% to 2.5%). Among subjects with a baseline HCV RNA less than 6 million IU per mL, the SVR12 was 97% (119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week treatment of HARVONI.
*Relapse rates by baseline viral load are presented in Table 11.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_3.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
Treatment-Naïve Adults with or without Cirrhosis ─ ION-1 (Study 0102)
*ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1 HCV including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b).
*Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.
*Table 12 presents the SVR12 for the treatment group of HARVONI for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 12.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_4.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*SVR12 for selected subgroups are presented in Table 13.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_5.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
Previously-Treated Adults with or without Cirrhosis ─ ION-2 (Study 0109)
*ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse).
*Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis. Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were non-responder. Fifty-three percent (53%) of the subjects failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these subjects, 62% were relapse/breakthrough and 38% were non-responder.
*Table 14 presents the SVR12 for the HARVONI treatment groups in the ION-2 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arms are not presented in Table 14.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_6.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in the ION-2 study also achieved SVR24.
*SVR12 and relapse rates for selected subgroups are presented in Tables 15 and 16.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_7.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_8.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
Previously-Treated Adults with Cirrhosis ─ SIRIUS (Study 0121)
*SIRIUS was a randomized, double-blind and placebo-controlled trial that evaluated the efficacy of HARVONI + ribavirin for 12 weeks or HARVONI without ribavirin for 24 weeks in genotype 1 HCV-infected subjects with compensated cirrhosis who failed prior therapy with a Peg-IFN + RBV regimen followed by a subsequent Peg-IFN + RBV + an HCV protease inhibitor regimen. Subjects were randomized in a 1:1 ratio to receive placebo for 12 weeks followed by HARVONI + ribavirin for 12 weeks or HARVONI for 24 weeks. Randomization was stratified by HCV genotype (1a vs 1b) and response to prior HCV therapy (never achieved HCV RNA less than LLOQ vs achieved HCV RNA less than LLOQ).
*Demographics and baseline characteristics were balanced across the treatment groups. Of the 155 randomized subjects, the median age was 56 years (range: 23 to 77); 74% of the subjects were male; 97% were White; mean body mass index was 27 kg/m2 (range: 19 to 47 kg/m2); 63% had genotype 1a HCV infection; 94% had non-C/C IL28B alleles (CT or TT). One subject discontinued therapy while on placebo, and was not included in the efficacy analysis.
*The SVR12 was 96% (74/77) and 97% (75/77) in subjects treated with HARVONI + ribavirin for 12 weeks and HARVONI for 24 weeks without ribavirin, respectively. All 5 subjects who did not achieve SVR12 relapsed.
=====Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV=====
*Below are trial descriptions, SVR12 and relapse data in the genotype 4, 5, and 6 HCV populations. Trial results in the genotype 4, 5, and 6 HCV populations are based upon limited number of subjects in some subgroups, particularly in subjects who have been previously-treated and subjects with cirrhosis.
Genotype 4
*In two open-label studies (Study 1119 and ION-4), HARVONI was administered for 12 weeks to treatment-naïve and previously-treated adult subjects with genotype 4 HCV infection. Study 1119 enrolled 44 treatment-naïve or previously-treated subjects with genotype 4 HCV, with or without cirrhosis. ION-4 enrolled 4 treatment-naïve and 4 previously-treated subjects with genotype 4 HCV infection who were coinfected with HIV-1, none of whom had cirrhosis.
*In Study 1119, the overall SVR12 rate was 93% (41/44). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. In ION-4, all 8 subjects achieved SVR12.
Genotype 5
*In the open-label 1119 trial, HARVONI was administered for 12 weeks to 41 treatment-naïve or previously-treated adult subjects with genotype 5 HCV infection, with or without cirrhosis. The overall SVR12 was 93% (38/41). SVR12 was similar based upon prior HCV treatment history and cirrhosis status.
Genotype 6
*In the open-label ELECTRON-2 trial, HARVONI was administered for 12 weeks to 25 treatment-naïve or previously-treated adult subjects with genotype 6 HCV infection, with or without cirrhosis. The overall SVR12 was 96% (24/25). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. The single subject who relapsed discontinued study treatment early (at approximately Week 8).
=====Clinical Trials in Subjects Coinfected with HCV and HIV-1=====
*ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with HARVONI without ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV-1. Treatment-experienced subjects had failed prior treatment with Peg-IFN + RBV, Peg-IFN + RBV + an HCV protease inhibitor or sofosbuvir + RBV. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine, or raltegravir.
*Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the subjects were male; 61% were White; 34% were Black; mean body mass index was 27 kg/m2 (range: 18 to 66 kg/m2); 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the subjects were treatment-experienced.
*Table 17 presents the SVR12 in the ION-4 trial after 12 weeks of HARVONI treatment.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_9.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects who were previously-treated and had cirrhosis. The relapse rate in the ION-4 trial in Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none in non-Black subjects (0/220). In the ION-1, ION-2, and ION-3 HCV mono-infection studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-Black subjects.
*No subject had HIV-1 rebound during the study. The percentage of CD4+ cells did not change during treatment. Median CD4+ cell count increase of 29 cells/mm3 was observed at the end of treatment with HARVONI for 12 weeks.
=====Clinical Trials in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis=====
*SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of treatment with HARVONI in combination with ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease. The two trials were identical in study design. Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see TABLE 16). Subjects with a CPT score greater than 12 were excluded. Within each group, subjects were randomized in a 1:1 ratio to receive HARVONI + RBV for 12 weeks or HARVONI + RBV for 24 weeks. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status. RBV dose adjustments were performed according to the RBV labeling.
*Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the subjects were male; 91% were White; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the subjects failed a prior HCV therapy.
*Table 18 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype 1 HCV treated with HARVONI + RBV for 12 weeks. The SVR12 rates observed with 24 weeks of HARVONI + RBV were similar to the SVR12 rates observed with 12 weeks of treatment. Therefore, the results for the HARVONI + RBV 24 weeks arm are not presented in Table 18.
[[image:Ledipasvir-Sofosbuvir_Clinical_Studies_Table_10.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*There were 7 subjects with fibrosing cholestatic hepatitis in the 12 week treatment arm, and all subjects achieved SVR12.
*In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with HARVONI + RBV for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed. Available data in subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver transplantation) were insufficient for dosing recommendations; therefore, these results are not presented.
=====Clinical Trial in Pediatric Subjects=====
*The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) that evaluated 12 weeks of treatment with HARVONI once daily in genotype 1 HCV treatment-naïve (N=80) and treatment-experienced (N=20) pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis.
*Demographics and baseline characteristics were balanced across treatment-naïve and treatment-experienced subjects (patients had failed an interferon based regimen with or without ribavirin). Of the 100 treated subjects, the median age was 15 years (range: 12 to 17); 63% of the subjects were female; 90% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body mass index was 23 kg/m2 (range: 13.1 to 36.6 kg/m2); mean weight was 61 kg (range 33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; 76% had non-CC IL28B alleles (CT or TT). One subject had known compensated cirrhosis. The majority of subjects (84%) had been infected through vertical transmission.
*The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve subjects and 100% [20/20] in treatment-experienced subjects). No subject experienced on-treatment virologic failure or relapse. Two subjects were lost to follow-up.
(Description)
|howSupplied=*HARVONI tablets are orange, diamond-shaped, film-coated, debossed with "GSI" on one side and "7985" on the other side of the tablet. Each bottle contains 28 tablets (NDC 61958-1801-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.
|howSupplied=*HARVONI tablets are orange, diamond-shaped, film-coated, debossed with "GSI" on one side and "7985" on the other side of the tablet. Each bottle contains 28 tablets (NDC 61958-1801-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.
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Ledipasvir / sofosbuvir is a Acetylcholine release inhibitor, Adrenergic receptor agonist that is FDA approved for the (type of indication of drug) of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
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The efficacy and safety of HARVONI were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A), one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects, two trials in genotype 4, 5, or 6 HCV mono-infected subjects, two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH), and one trial in genotype 1 HCV pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 9.
This image is provided by the National Library of Medicine.
HARVONI was administered once daily by mouth in these trials. For subjects without cirrhosis or with compensated cirrhosis who received ribavirin (RBV), the RBV dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status. RBV dose adjustments were performed according to the RBV labeling.
Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in studies in adults and the key efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.
Clinical Trials in Subjects with Genotype 1 HCV
Treatment-Naïve Adults without Cirrhosis ─ ION-3 (Study 0108)
ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 HCV. Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks, HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT).
Table 10 presents the SVR12 for the HARVONI treatment groups in the ION-3 trial after 8 and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 10.
This image is provided by the National Library of Medicine.
The treatment difference between the 8-week treatment of HARVONI and 12-week treatment of HARVONI was –2.3% (97.5% confidence interval –7.2% to 2.5%). Among subjects with a baseline HCV RNA less than 6 million IU per mL, the SVR12 was 97% (119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week treatment of HARVONI.
Relapse rates by baseline viral load are presented in Table 11.
This image is provided by the National Library of Medicine.
Treatment-Naïve Adults with or without Cirrhosis ─ ION-1 (Study 0102)
ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1 HCV including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.
Table 12 presents the SVR12 for the treatment group of HARVONI for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not presented in Table 12.
This image is provided by the National Library of Medicine.
SVR12 for selected subgroups are presented in Table 13.
This image is provided by the National Library of Medicine.
Previously-Treated Adults with or without Cirrhosis ─ ION-2 (Study 0109)
ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis. Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were non-responder. Fifty-three percent (53%) of the subjects failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these subjects, 62% were relapse/breakthrough and 38% were non-responder.
Table 14 presents the SVR12 for the HARVONI treatment groups in the ION-2 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arms are not presented in Table 14.
This image is provided by the National Library of Medicine.
Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in the ION-2 study also achieved SVR24.
SVR12 and relapse rates for selected subgroups are presented in Tables 15 and 16.
This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.
Previously-Treated Adults with Cirrhosis ─ SIRIUS (Study 0121)
SIRIUS was a randomized, double-blind and placebo-controlled trial that evaluated the efficacy of HARVONI + ribavirin for 12 weeks or HARVONI without ribavirin for 24 weeks in genotype 1 HCV-infected subjects with compensated cirrhosis who failed prior therapy with a Peg-IFN + RBV regimen followed by a subsequent Peg-IFN + RBV + an HCV protease inhibitor regimen. Subjects were randomized in a 1:1 ratio to receive placebo for 12 weeks followed by HARVONI + ribavirin for 12 weeks or HARVONI for 24 weeks. Randomization was stratified by HCV genotype (1a vs 1b) and response to prior HCV therapy (never achieved HCV RNA less than LLOQ vs achieved HCV RNA less than LLOQ).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 155 randomized subjects, the median age was 56 years (range: 23 to 77); 74% of the subjects were male; 97% were White; mean body mass index was 27 kg/m2 (range: 19 to 47 kg/m2); 63% had genotype 1a HCV infection; 94% had non-C/C IL28B alleles (CT or TT). One subject discontinued therapy while on placebo, and was not included in the efficacy analysis.
The SVR12 was 96% (74/77) and 97% (75/77) in subjects treated with HARVONI + ribavirin for 12 weeks and HARVONI for 24 weeks without ribavirin, respectively. All 5 subjects who did not achieve SVR12 relapsed.
Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV
Below are trial descriptions, SVR12 and relapse data in the genotype 4, 5, and 6 HCV populations. Trial results in the genotype 4, 5, and 6 HCV populations are based upon limited number of subjects in some subgroups, particularly in subjects who have been previously-treated and subjects with cirrhosis.
Genotype 4
In two open-label studies (Study 1119 and ION-4), HARVONI was administered for 12 weeks to treatment-naïve and previously-treated adult subjects with genotype 4 HCV infection. Study 1119 enrolled 44 treatment-naïve or previously-treated subjects with genotype 4 HCV, with or without cirrhosis. ION-4 enrolled 4 treatment-naïve and 4 previously-treated subjects with genotype 4 HCV infection who were coinfected with HIV-1, none of whom had cirrhosis.
In Study 1119, the overall SVR12 rate was 93% (41/44). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. In ION-4, all 8 subjects achieved SVR12.
Genotype 5
In the open-label 1119 trial, HARVONI was administered for 12 weeks to 41 treatment-naïve or previously-treated adult subjects with genotype 5 HCV infection, with or without cirrhosis. The overall SVR12 was 93% (38/41). SVR12 was similar based upon prior HCV treatment history and cirrhosis status.
Genotype 6
In the open-label ELECTRON-2 trial, HARVONI was administered for 12 weeks to 25 treatment-naïve or previously-treated adult subjects with genotype 6 HCV infection, with or without cirrhosis. The overall SVR12 was 96% (24/25). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. The single subject who relapsed discontinued study treatment early (at approximately Week 8).
Clinical Trials in Subjects Coinfected with HCV and HIV-1
ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with HARVONI without ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV-1. Treatment-experienced subjects had failed prior treatment with Peg-IFN + RBV, Peg-IFN + RBV + an HCV protease inhibitor or sofosbuvir + RBV. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine, or raltegravir.
Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the subjects were male; 61% were White; 34% were Black; mean body mass index was 27 kg/m2 (range: 18 to 66 kg/m2); 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the subjects were treatment-experienced.
Table 17 presents the SVR12 in the ION-4 trial after 12 weeks of HARVONI treatment.
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SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects who were previously-treated and had cirrhosis. The relapse rate in the ION-4 trial in Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none in non-Black subjects (0/220). In the ION-1, ION-2, and ION-3 HCV mono-infection studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-Black subjects.
No subject had HIV-1 rebound during the study. The percentage of CD4+ cells did not change during treatment. Median CD4+ cell count increase of 29 cells/mm3 was observed at the end of treatment with HARVONI for 12 weeks.
Clinical Trials in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis
SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of treatment with HARVONI in combination with ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease. The two trials were identical in study design. Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see TABLE 16). Subjects with a CPT score greater than 12 were excluded. Within each group, subjects were randomized in a 1:1 ratio to receive HARVONI + RBV for 12 weeks or HARVONI + RBV for 24 weeks. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status. RBV dose adjustments were performed according to the RBV labeling.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the subjects were male; 91% were White; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the subjects failed a prior HCV therapy.
Table 18 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype 1 HCV treated with HARVONI + RBV for 12 weeks. The SVR12 rates observed with 24 weeks of HARVONI + RBV were similar to the SVR12 rates observed with 12 weeks of treatment. Therefore, the results for the HARVONI + RBV 24 weeks arm are not presented in Table 18.
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There were 7 subjects with fibrosing cholestatic hepatitis in the 12 week treatment arm, and all subjects achieved SVR12.
In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with HARVONI + RBV for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed. Available data in subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver transplantation) were insufficient for dosing recommendations; therefore, these results are not presented.
Clinical Trial in Pediatric Subjects
The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) that evaluated 12 weeks of treatment with HARVONI once daily in genotype 1 HCV treatment-naïve (N=80) and treatment-experienced (N=20) pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis.
Demographics and baseline characteristics were balanced across treatment-naïve and treatment-experienced subjects (patients had failed an interferon based regimen with or without ribavirin). Of the 100 treated subjects, the median age was 15 years (range: 12 to 17); 63% of the subjects were female; 90% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body mass index was 23 kg/m2 (range: 13.1 to 36.6 kg/m2); mean weight was 61 kg (range 33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; 76% had non-CC IL28B alleles (CT or TT). One subject had known compensated cirrhosis. The majority of subjects (84%) had been infected through vertical transmission.
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve subjects and 100% [20/20] in treatment-experienced subjects). No subject experienced on-treatment virologic failure or relapse. Two subjects were lost to follow-up.
How Supplied
HARVONI tablets are orange, diamond-shaped, film-coated, debossed with "GSI" on one side and "7985" on the other side of the tablet. Each bottle contains 28 tablets (NDC 61958-1801-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.
Storage
Store at room temperature below 30 °C (86 °F).
Dispense only in original container.
Do not use if seal over bottle opening is broken or missing.
Images
Drug Images
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Package and Label Display Panel
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Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of HBV infection.
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.
Drug Interactions
Inform patients that HARVONI may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St. John's wort.
Pregnancy
Advise patients to avoid pregnancy during combination treatment with HARVONI and ribavirin and for 6 months after completion of treatment. Inform patients to notify their healthcare provider immediately in the event of a pregnancy.
Administration
Advise patients to take HARVONI every day at the regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses and to take HARVONI for the duration that is recommended by the physician.
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Precautions with Alcohol
Alcohol-Ledipasvir / sofosbuvir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
Harvoni
Look-Alike Drug Names
There is limited information regarding Ledipasvir / sofosbuvir Look-Alike Drug Names in the drug label.
