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.

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Hepatitis web study Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin in Genotype 1 COSMOS Trial Phase 2a, Treatment Naïve and Treatment Experienced.

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.

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.

LDV/SOF 90/400 mg qd Non-randomised Open-label N = 21 W12 SVR 12 NIAID SYNERGY GT4 Kohli A. Lancet Infect Dis 2015; Juky 15, ePub ahead of print ≥ 18 years.

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.

No prior therapy with PI

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:

OBV/PTV/r Open label years Chronic HCV infection Genotype 1b Treatment-naïve or failure to PEG-IFN + RBV HCV RNA > 10,000 IU/ml Without or with cirrhosis*

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 =

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.

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.

SMV 150 mg QD + SOF 400 mg QD Randomisation 1 : years HCV genotype 1 Naïve or pre-treated with IFN-based regimen No cirrhosis HCV RNA ≥

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

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.

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.

No randomization N = 59 W12W24 Arm B : compensated cirrhosis N = 31 N = 29 Arm C : compensated cirrhosis Arm A : No cirrhosis AGATE-II Study: OBV/PTV/r.

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.

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.

Asselah T. AASLD 2015, Abs. 714 Randomisation 1:1 Open-label years HCV genotype 4 HCV RNA ≥ 1,000 IU/ml Naïve or pre-treated with PEG-IFN + RBV (Part.

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.

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.

Asselah T. AASLD 2015, Abs OSIRIS  Design SMV + PEG-IFN + RBV Open label Chronic HCV infection Genotype 4 Treatment-naïve Mild to moderate fibrosis.

 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.

 Objective –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI, by ITT, descriptive analysis OBV/PTV/r + DSV + RBV No randomisation Open-label CORAL-I Study cohort.

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.

 Objective –SVR 12 (HCV RNA < 25 IU/ml), by ITT OBV/PTV/r + DSV + SOF +RBV Open-label W24 ≥ 18 years Chronic HCV Genotype 1 Prior failure on DAA-regimen.

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.

 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 +

SOF/VEL 400/100 mg qd N = 106 W12 > 18 years Chronic HCV infection Genotype 1-6 Naïve or pre-treatment with IFN-based regimen Compensated cirrhosis allowed*

 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.

Genotype 1 HCV infection Stable immunosuppressive therapy

TOPAZ-II Study: OBV/PTV/r + DSV + RBV for genotype 1

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

> 18 years Chronic HCV infection Compensated cirrhosis **

CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1

Retreatment study: SOF/VEL + RBV in prior NS5A failure - Phase II

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

SOF/VEL + GS-9857 in genotypes 1-6 Phase II

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

No HBV or HIV co-infection

GS-US Study: SOF/VEL + GS-9857 in genotype 1 - Phase II

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

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients

No HBV or HIV co-infection

CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1

Presentation transcript:

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 cohort 1 and treatment history (naïve or non-responder) in cohort 2 COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa  Design W12 W24 N = 24 ≥ 18 years Chronic HCV infection Genotype 1 HCV RNA ≥ 10,000 IU/ml Cohort 1 : prior non responders, Metavir F0-F2 Cohort 2 : treatment-naïve and prior non responders, Metavir F3-F4 –SOF : 400 mg (2 x 200 mg) qd in cohort 1, 400 mg qd in cohort 2 –SMV : 150 mg qd –RBV weight based (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Lawitz E. Lancet 2014;384: SOF + SMV + RBV SOF + SMV SOF + SMV + RBV SOF + SMV SOF + SMV + RBV SOF + SMV Cohort 1 Cohort 2 N = 16 N = 15 N = 27 N = 14 N = 30 N = 27 N = 14

COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa  Objective –Exploratory study –SVR 12 (HCV RNA < 25 IU/ml), with 95% CI –ITT analysis –No sample size calculation –Analyses within each cohort and on pooled cohort data COSMOS Lawitz E. Lancet 2014;384:

Drug regimenn Genotype 1a / 1b Treatment history No response / Naïve Metavir F0-F1 / F2 / F3 / F4 (%) HCV RNA, log 10 IU/ml, median IL28B CC Cohort 1 SOF + SMV + RBV 24W2483% / 17%100% / 046 / 54 / 0 / SOF + SMV 24W1573% / 27%100% / 020 / 80 / 0 / % SOF + SMV + RBV 12W2778% / 22%100% / 041 / 59 / 0 / % SOF + SMV 12W1471% / 29%100% / 057 / 43 / 0 / Cohort 2 SOF + SMV + RBV 24W3077% / 23%57% / 43%0 / 0 / 57 / % SOF + SMV 24W1675% / 25%50% / 50%0 / 0 / 38 / % SOF + SMV + RBV 12W2782% / 19%56% / 44%0 / 0 / 59 / % SOF + SMV 12W1479% / 21%50% / 50%0 / 0 / 50 / % Baseline characteristics Female : 36%, median age : 57 years ; white : 81%, black : 19% ; median BMI : 28.0 kg/m 2 NS3 Q80K polymorphism mutation present in 45% of genotype 1a COSMOS COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa Lawitz E. Lancet 2014;384:

SVR 12 (HCV RNA < 25 IU/ml) in Cohort 1 Prior non responders, Metavir F0-F2 % By subgenotype and G80K mutation (genotype 1a) COSMOS COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa Lawitz E. Lancet 2014;384: Overall 4N b1a Q80K 1a no Q80K 1b1a Q80K 1a no Q80K 1b1a Q80K 1a no Q80K 1b1a Q80K 1a no Q80K SOF + SMV + RBV 24WSOF + SMV 24WSOF + SMV + RBV 12WSOF + SMV 12W

SVR 12 (HCV RNA < 25 IU/ml) in Cohort 2 Treatment naïve and non responders, Metavir F3-F4 COSMOS COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa Lawitz E. Lancet 2014;384: By subgenotype and G80K mutation (genotype 1a) Overall 1b1a Q80K 1a no Q80K 1b1a Q80K 1a no Q80K 1b1a Q80K 1a no Q80K 1b1a Q80K 1a no Q80K % N SOF + SMV + RBV 24WSOF + SMV 24WSOF + SMV + RBV 12WSOF + SMV 12W

 SVR 12 similar in patients with IL28B CC and non-CC genotypes, irrespective of whether they received RBV, in treatment-naïve or previous non-responders, with 12 or 24 weeks of SMF + SOF, also high in F4 patients  Relapse in patients with HCV RNA < 25 IU/ml at end of completed treatment : 6 (all genotype 1a) Relapses Cohort 1Cohort Treatment groupSSR24SSR12SS12SSR12 SS12 Treatment historyNR Naïve MetavirF2 F0-F1F4F3F4 IL28B genotypeTT CTTTCC Baseline HCV RNA, log 10 IU/ml Time of relapse, week Baseline Q80KYes No Emergence of SMV resistance mutations N174S R155K NoD168E R155K D168E I170T SSR : SOF + SMV + RBV ; NR : null responder COSMOS COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa Lawitz E. Lancet 2014;384:

Adverse events, N (%) 24 weeks12 weeks SOF + SMV + RBV N = 54 SOF + SMV N = 31 SOF + SMV + RBV N = 54 SOF + SMV N = 28 Adverse event grade 3 / 49% / 2%3% / 10%9% / 2%7% / 0 Serious adverse event6%3%00 Death1* (2%)000 AE leading to discontinuation2 (4%)2 (7%)00 * Toxicity to alcohol and narcotics ; Aggression Raised CK ; Renal failure AE of clinical interest Rash19%16%20%11% Pruritus17%3%9%14% Neutropenia03%00 Anemia30%3%13%0 Photosensitivity4%7%6%7% AE of special interest Increased bilirubin11%3%9%0 COSMOS COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa Lawitz E. Lancet 2014;384:

COSMOS Study: SOF + SMV + RBV for genotype 1 – Phase IIa  Summary –High Rates of SVR 12 with SOF + SMV, even in difficult to treat groups, including patients with compensated cirrhosis and prior non response to therapy –Rapid virologic response did not predict SVR 12 –Addition of RBV did not improve SVR 12 rates –Extending treatment to 24 weeks did not improve SVR 12 rates, except possibly in patients with prior relapse and advanced fibrosis –Patients with baseline G80K mutation had high SVR 12 rates, including those with compensated cirrhosis, with no impact of RBV –Regimen well tolerated: fatigue, headache, and nausea were the most common side effects –Overall, SOF + SMV shows high efficacy and tolerability in patients with chronic HCV genotype 1 infection, either naïve or non-responders to previous IFN-based therapy COSMOS Lawitz E. Lancet 2014;384: