AI444040 Study  Design SOF 1W then DCV + SOF 23W DVC + SOF Randomisation* 1 : 1 : 1 Open-label AI444040 Study: DCV + SOF + RBV for genotypes 1, 2 and.

Slides:

Advertisements

Similar presentations

VALENCE SOF + RBV Not randomised Open label* ≥ 18 years Chronic HCV infection Genotype 2 or 3 HCV RNA ≥ 10,000 IU/ml Treatment naïve or prior IFN-based.

Advertisements

ATOMIC  Design  Objective –SVR 24 by ITT-analysis, detection of a 30% or 25% difference between two treatment groups, 2-sided significance level of 5%,

ALLY-1  Design  Objective –SVR 12 (HCV RNA < 25 IU/ml) in genotype 1 DCV 60 mg qd + SOF 400 mg qd + RBV DCV 60 mg qd + SOF 400 mg qd + RBV Not randomised.

ELECTRON  Design SOF + RBV Randomisation* 1 : 1 : 1 : 1 Open-label ELECTRON Study: SOF-based therapy for genotypes 1, 2 and 3 W8W4W12 ≥ 19 years Chronic.

OBV/PTV/r + DSV + RBV Placebo Randomisation** 3 : 1 Double blind years Chronic HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Failure to pre-treatment with.

OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV Randomisation* 1 : 1 Open label years Chronic HCV infection Genotype 1b Prior failure to PEG-IFN + RBV HCV.

CURRY  Design Open-label CURRY Study: SOF + RBV for HCV with liver cancer before transplantation ≥ 18 years Chronic HCV infection Any genotype HCV RNA.

Egyptian Ancestry  Design  Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI SOF 400 mg qd + RBV Randomised 1 : 1 Open-label Egyptian Ancestry Study:

COSMOS SOF + SMV + RBV SOF + SMV Randomisation 2 : 1 : 2 : 1* Open-label * Randomisation was stratified on genotype (1a or 1b) in both cohorts, IL28B in.

SMV + PEG-IFN + RBV Open-label W12 W24* or W48* N = years Chronic HCV infection Genotype 4 Treatment-naïve or experienced with relapse or partial.

Randomisation* 2 : 1 Double blind *Randomisation was stratified on genotype (1a or 1b or other) and IL28B genotype (CC, CT or TT) N = 133 N = 260 W24W48.

FUSION  Design  Objectives –SVR ≥ 20% compared with historical control of 25%, 97% power –Difference of SVR > 20% between the 2 groups, 82% power SOF.

FISSION  Design  Objective –Non inferiority of SOF + RBV : SVR 12 (2-sided significance level of 5%, lower margin of the 95% CI for the difference =

No HBV or HIV co-infection

SOF + PEG-IFN  -2a + RBV Open-label Single arm ≥ 18 years Chronic HCV infection Genotype 1, 4, 5 or 6 Treatment-naïve HCV RNA ≥ 10,000 IU/ml Compensated.

SMV SOF 400 Open-label OPTIMIST-2 Study: SMV + SOF for genotype 1 and cirrhosis W12  Objective –Superiority of SVR 12 (HCV RNA historical control.

UNITY-1 DCV/ASV/BCB No randomisation Open-label UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir in genotype 1 without cirrhosis  Design W12 ≥ 18 years.

OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV + placebo Randomisation* Partial blind years Chronic HCV infection Genotype 1 Treatment-naïve HCV RNA > 10,000.

Reddy KR. Lancet Infect Dis. 2015;15:27-35 ATTAIN SMV + TVR placebo + PEG-IFN + RBV TVR + SMV placebo + PEG-IFN + RBV Randomisation* 1 : 1 Double-blind.

Placebo + PR W48 Placebo + PR Yes Hezode C. Gut 2015;64: COMMAND-1 COMMAND-1 Study: daclatasvir + PEG-IFN + RBV for genotype 1 or 4 DCV60 + PEG-IFN.

SIRIUS Placebo LDV/SOF + placebo Randomisation* 1 : 1 Double-blind SIRIUS Study: LDV/SOF ± RBV for genotype 1 and cirrhosis with non response to prior.

ARV-trial.com C-SWIFT Study: grazoprevir/elbasvir + SOF in genotypes 1 or 3, with or without cirrhosis Randomisation 1 : 1 Open-label Design W4 W6 W8.

ION-1  Design LDV/SOF LDV/SOF + RBV Randomisation* 1 : 1 : 1 : 1 Open-label ION-1 Study: LDV/SOF + RBV for genotype 1 W24W12 ≥ 18 years Chronic HCV infection.

W24 ≥ 18 years Chronic HCV infection Genotype 1 Treatment naïve Early fibrosis to compensated cirrhosis No HBV or HIV co-infection N = 10 SOF + weight-based.

OBV/PTV/r Placebo Randomisation** 2 : years Chronic HCV Genotype 1b HCV RNA ≥ 10,000 IU/ml Naïve or pre-treated, no prior failure with DAA Without.

TURQUOISE-I OBV/PTV/r + DSV + RBV Randomisation* 1 : 1 Open-label years HCV genotype 1 HCV RNA ≥ 10,000 IU/ml Naïve or pre-treated with PEG-IFN +

SOF/VEL 400/100 mg qd N = 75 W24 SOF/VEL > 18 years Chronic HCV infection Genotype 1 to 6 Naïve or treatment-experienced No prior treatment with NS5A or.

 Treatment regimens –Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg QD = 2 tablets –Dasabuvir (DSV) : 250 mg BID –RBV.

ALLY-3  Design  Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI DCV 60 mg qd + SOF 400 mg qd Not randomised Open-label ALLY-3 Study: DCV + SOF for.

> 18 years Chronic HCV infection Genotype 1 Failure (relapse) to 4, 6 or 8 weeks of GZR/EBR + SOF in C-SWIFT Part A Compensated cirrhosis assessed by liver.

SOF/VEL 400/100 mg qd N = 500 N = 100 W12 Placebo > 18 years Chronic HCV infection Genotype 1, 2, 4, 5 or 6 Naïve or pre-treatment with IFN-based regimen.

Forns X. J Hepatology 2015; 63: C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen –NS3 and NS5A RAVs.

SOF/VEL 400/100 mg qd N = 250 W24 SOF + RBV W12 * Randomisation was stratified on prior treatment (naïve or experienced) and cirrhosis (yes or no) ** Metavir.

Sulkowski M. Lancet 2015;385: C-WORTHY  Design Randomisation* Open-label > 18 years HCV genotype 1, treatment naïve HCV RNA ≥ 10,000 IU/ml No cirrhosis.

OBV/PTV/r + DSV Open label Chronic HCV infection Genotype 1 Treatment-naïve HCV RNA > 1,000 IU/ml Chronic kidney disease with eGFR < 30 ml/min/1.73m 2.

No randomisation Open-label years HCV genotype 1 Naïve or null-response to PEG-IFN + RBV HCV RNA > 10,000 IU/ml No cirrhosis No HBV or HIV co-infection.

 Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI, next observation carried backward DCV + SOF + RBV Randomised* 1:1 Open-label ALLY-3+ study: DCV.

SOF + RBV Randomisation* 1 : 1 : 1 Open-label BOSON Study: SOF + RBV + PEG-IFN for genotypes 2 and 3 ≥ 18 years Chronic HCV infection Genotype 2, treatment-

 Design  Objective –Difference in SVR ≥ 40% between the 2 groups, 99% power SOF + RBV Placebo Randomisation 3 : 1* Double blind HCV infection Genotype.

SAPPHIRE-I Feld JJ. NEJM 2014;370: SAPPHIRE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for genotype 1  Treatment regimens.

Open-label W24 ≥ 18 years Chronic HCV infection All genotypes HCV RNA ≥ 10,000 IU/ml Liver transplantation months earlier Child Pugh ≤ 7 and MELD.

LDV/SOF Failure Open-label W24 Chronic HCV infection Genotype 1 Failure to achieve SVR on LDV/SOF-containing regimen Compensated cirrhosis (liver biopsy.

SOF/VEL 400/100 mg qd N = 120 W12 SOF + RBV > 18 years Chronic HCV infection Genotype 2 Naïve or pre-treatment with IFN-based regimen Compensated cirrhosis.

Placebo + PR W24 DCV + PR Placebo + PR Yes Dore GJ. Gastroenterology 2015;148: COMMAND GT2/3 COMMAND GT2/3 Study: daclatasvir + PEG-IFN + RBV for.

Dore G. J Hepatol 2016; 64:19-28 MALACHITE TVR + PEG-IFN + RBV Randomisation Open-label years HCV genotype 1 HCV RNA > 10,000 IU/ml Naïve (MALACHITE-I)

 Design Randomisation* 2 : 1 Double blind *Randomisation was stratified on genotype (1a vs 1b) and ILB28 genotype (CC or non-CC) N = 134 N = 257 W24W48.

Poordad F. NEJM 2014;368: D Phase IIa  Design  Treatment regimens – Paritaprevir/rironavir (PTV/r) : PTV 250 or 150 mg qd/ritonavir 100 mg qd (2.

LDV/SOF Open-label Chronic HCV infection Genotype 1 Failure to achieve SVR 12 on a short-course of 1 st line LDV/SOF-containing regimen No cirrhosis N.

 Design Open-label years Chronic HCV infection Genotype 1 HCV RNA > 10,000 IU/mL HIV co-infection Stable ART* with HIV RNA < 50 c/mL ≥ 24 weeks.

PHOTON-1  Design  Objective –SVR 12 with 2-sided 95% CI, descriptive analysis –Multivariate analyses of predictors of SVR 12 SOF + RBV, N= 114 SOF +

 Objective –SVR 12 (HCV RNA < 25 IU/ml), by ITT OBV/PTV/r + SOF + RBV OBV/PTV/r + SOF Not randomised Open-label QUARTZ-II Study: OBV/PTV/r + SOF for HCV.

No HBV or HIV co-infection

SOF + RBV GT2 Japanese SOF + RBV Open-label Japanese SOF + RBV Study: SOF + RBV in genotype 2  Design W12 Japanese patients ≥ 20 years Chronic HCV infection.

LDV/SOF Randomisation * 1:1 Open-label ≥ 20 years, Japanese Chronic HCV infection Genotype 1 HCV RNA ≥ IU/ml Treatment-naive, or pre-treated Compensated.

C-ISLE study: EBR/GZR + SOF + RBV in genotype 3 and cirrhosis

PHOTON-2 Study: SOF + RBV in HCV-HIV co-infection

ARV-trial.com C-CREST study, Part B: uprifosbuvir (MK-3682)/GZR/ruzasvir (MK-8408) fixed-dose combination + RBV for genotypes 1, 2 and 3 - Phase II Randomisation.

Design Randomisation 2 : 1 Double-blind W12 ≥ 18 years, HCV genotype 3

No cirrhosis or compensated cirrhosis** No HBV or HIV co-infection

Creatinine clearance ≥ 50 ml/min No HBV or HIV co-infection

Failure to achieve SVR on No HBV or HIV co-infection

QUARTZ II-III : OBV/PTV/r + SOF RBV in genotype 2 or 3

LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1

No HBV or HIV co-infection

ION-3 Study: LDV/SOF + RBV for naïve genotype 1

ARV-trial.com TURQUOISE-I Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV in HIV co-infected patients Randomisation 1 : 1 Open-label.

MAGELLAN-3 Study: GLE/PIB + SOF + RBV in patients who failed GLE/PIB

LDV/SOF ± RBV in genotype 3 or 6 – Phase 2

ARV-trial.com C-CREST study, Part B: uprifosbuvir (MK-3682)/GZR/ruzasvir (MK-8408) fixed-dose combination + RBV for genotypes 1, 2 and 3 - Phase II Randomisation.

No HBV or HIV co-infection

Presentation transcript:

AI Study  Design SOF 1W then DCV + SOF 23W DVC + SOF Randomisation* 1 : 1 : 1 Open-label AI Study: DCV + SOF + RBV for genotypes 1, 2 and 3 W12W years Chronic HCV infection Genotype 1, 2, 3 HCV RNA ≥ 100,000 IU/ml No cirrhosis (Fibrotest ≤ 0.72 and APRI ≤ 2) No HBV or HIV co-infection Sulkowski MS. NEJM 2014;370: DCV + SOF + RBV Protocol amendment 123 additional patients Genotype 1 Randomisation 1 : 1 Open-label N = 15 N = 14 N = 15 SOF 1W then DCV + SOF 23W DVC + SOF DCV + SOF + RBV N = 16 N = 14 Genotype 1 naïve Genotypes 2, 3 naïve DCV + SOF DCV + SOF + RBV DVC + SOF DCV + SOF + RBV Treatment naïve Treatment experienced Failure to prior PI-based therapy N = 41 N = 20 N = 21 N = 41

Drug regimenN Genotype N Female % Fibrosis score HCV RNA, log 10 IU/ml, mean IL28B CC SOF 1W + DCV + SOF 23W16 2, N = 9 3, N = 7 31% F0-F1 : 6 F4 : % DCV + SOF + RBV 24W14 2, N = 8 3, N = 6 57% F0-F1 : 6 F4 : % DCV + SOF 24W14 2, N = 9 3, N = 5 64% F0-F1 : 6 F4 : % SOF 1W + DCV + SOF 23W15 1a, N = 11 1b, N = 4 53% F0-F1 : 4 F4 : % DCV + SOF 24W14 1a, N = 10 1b, N = 4 36% F0-F1 : 6 F4 : % DCV + SOF + RBV 24W15 1a, N = 11 1b, N = 4 53% F0-F1 : 6 F4 : % Baseline characteristics and dosing of medication  DCV : 60 mg qd  SOF : 400 mg qd  RBV (bid dosing) : weight based in genotype 1 : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg ; 800 mg/day in genotype 2 or 3 ; dose reduction to 600 mg/day if hemoglobin decreased < 10g/dL AI Study Sulkowski MS. NEJM 2014;370: AI Study: DCV + SOF + RBV for genotypes 1, 2 and 3

Drug regimenN Genotype N Female % Fibrosis score HCV RNA, log 10 IU/ml, mean IL28B CC DCV + SOF 12W41 1a, N = 34 1b, N = 7 51% F0-F1 : 15 F4 : % DCV + SOF + RBV 12W41 1a, N = 33 1b, N = 8 49% F0-F1 : 13 F4 : % DCV + SOF 24W21 1a, N = 16 1b, N = 5 38% F0-F1 : 2 F4 : % DCV + SOF + RBV 24W20 1a, N = 17 1b, N = 3 40% F0-F1 : 3 F4 : Baseline characteristics (second cohort) and Objective  Primary efficacy endpoint : SVR 12 (HCV RNA < 25 IU/ml) by mITT analysis  Secondary endpoints : SVR 4 SVR 24 Safety : adverse events, discontinuation for adverse events, grade 3-4 laboratory abnormalities AI Study Sulkowski MS. NEJM 2014;370: AI Study: DCV + SOF + RBV for genotypes 1, 2 and 3

HCV RNA < 25 IU/ml Drug regimenGenotypeNSVR 12 SVR 24 SOF 1W + DCV + SOF 23W2 + 3Naïve1688% DCV + SOF 24W2 + 3Naïve1493%100% DCV + SOF + RBV 24W2 + 3Naïve1486%93% SOF 1W + DCV + SOF 23W1a + 1bNaïve15100%93% DCV + SOF 24W1a + 1bNaïve14100% DCV + SOF + RBV 24W1a + 1bNaïve15100% DCV + SOF 12W1a + 1bNaïve41100%95% DCV + SOF + RBV 12W1a + 1bNaïve4195%93% DCV + SOF 24W1a + 1b Failure on prior PI therapy 21100%- DCV + SOF + RBV 24W1a + 1b Failure on prior PI therapy 2095%- HCV RNA < 25 IU/ml  All patients had HCV RNA < 25 IU/ml at end of treatment, except 1 in group B (DCV + SOF 24W) AI Study Sulkowski MS. NEJM 2014;370: AI Study: DCV + SOF + RBV for genotypes 1, 2 and 3

 Virologic relapse post-treatment : 1 patient with genotype 3 who did not received RBV –NS5A A30K polymorphism (DCV resistance) at baseline and failure  Resistance testing (sequencing) –NS5A polymorphisms associated with loss of susceptibility to DCV in vitro detected at baseline in 32 patients : 8% in genotype 1, 61% in genotype 2, 28% in genotype 3 –Most frequent mutations : Q30H (genotype 1a), L31M (genotype 1b and 2), Y93H (genotype 3) –Except the patient with relapse, all other patients with preexisting DCV resistant variants had a SVR –No mutation (S282T) to SOF at baseline or in the patient with breakthrough AI Study Sulkowski MS. NEJM 2014;370: AI Study: DCV + SOF + RBV for genotypes 1, 2 and 3

 Adverse events –Most common : fatigue, headache, nausea (≥ 25% in any group) –Grade 3-4 adverse events : 7 (3.3%) –Discontinuation of treatment for adverse events : 2 (both achieved SVR) DCV-SOF 24W : 1 cerebrovascular accident DCV-SOF + RBV 24W : 1 fibromyalgia exacerbation –Serious adverse events : 10 (4.7%) –Most common grade 3-4 laboratory abnormalities : low phosphorus and elevation of glucose levels –Hemoglobin level more reduced in groups with RBV Reduction of RBV dose in 5 patients because of anemia AI Study Sulkowski MS. NEJM 2014;370: AI Study: DCV + SOF + RBV for genotypes 1, 2 and 3

 Summary –DCV + SOF was assessed in untreated patients and patients in whom previous treatment with telaprevir or boceprevir had failed – Most patients had a SVR, including 98% of patients with genotype 1 infection, regardless of viral subtype or failure of prior treatment with PI, and 91% of naïve patients infected with genotype 2 or 3 – The most common adverse event was fatigue, which was reported in approximately one third of patients –Virologic breakthrough and relapse were rare and were not observed in any of the patients infected with HCV genotype 1 or 2, despite preexisting DCV-resistant variants in 14% –In genotype 3, 1 relapse in a patient with baseline DCV-resistant variant –No additional benefit of RBV addition but greater decrease in hemoglobin AI Study Sulkowski MS. NEJM 2014;370: AI Study: DCV + SOF + RBV for genotypes 1, 2 and 3