obv/ptv/r + dsv + rbv obv/ptv/r + dsv + placebo randomisation* partial blind 18-70 years chronic hcv...

OBV/PTV/r + DSV + RBV

OBV/PTV/r + DSV + placebo

Randomisation*Partial blind

18-70 yearsChronic HCV infection

Genotype 1 Treatment-naïve

HCV RNA > 10,000 IU/mlNo cirrhosis

No HBV or HIV co-infection

* Randomisation 1:2 if genotype 1a (PEARL-IV) ; 1:1 if genotype 1b (PEARL-III), stratified on IL-28B (CC or non-CC)

W12 W24 W60

SVR12

PEARL III & IV Ferenci P. NEJM 2014;370:1983-92

Design

Treatment regimens– Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg qd = 2 tablets– Dasabuvir (DSV) : 250 mg bid– RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)

PEARL-III and IV Studies: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1

Efficacy endpoints– Sustained virologic response (HCV RNA < 25 IU/mL) 12 weeks after end of

treatment, with two-sided 95% CI, modified ITT analysis– Non-inferiority of SVR assessed vs estimated rate of SVR24 with a telaprevir-

based regimen – for genotype 1a : 72%, 95% CI: 68 to 75 – for genotype 1b : 80%, 95% CI: 75 to 84 – Non-inferiority (primary end-point) established if lower bound of the 95%

CI for the SVR greater than the upper bound of the 95% CI for SVR of telaprevir-based therapy minus 10.5%, i.e. 65% in PEARL-IV and 73% in PEARL-III ; power 95%

– Superiority in PEARL-IV (genotype 1a) if lower margin of the 95% CI for the SVR12 > 75% ; in PEARL-III (genotype 1b) if lower margin of the 95% CI for the SVR12 > 84% ; power 90%

– Non inferiority of RBV vs placebo in both studies : SVR12 rate, with lower

margin of the 95% CI for the difference = -10.5% ; power 95% Trial conduct

– Hemoglobin and hematocrit results blinded to investigators, unless criteria for virologic failure or relevant predefined toxicity were met



HCV RNA : COBAS TaqMan real-time RT–PCR assay, v 2.0 (Roche)

Virologic failure : – 2 consecutive HCV RNA > 1 log10 IU/ml above the nadir at any time during

treatment,

– HCV RNA ≥ 25 UI/ml at all assessments during treatment among patients who received at least 6 weeks of treatment,

– confirmed HCV RNA ≥ 25 IU/ml after a level < 25 IU/ml during treatment

Virologic relapse : confirmed HCV RNA ≥ 25 IU/ml between the end of treatment and 12 weeks after the last dose of study drug among patients who completed treatment and had an HCV RNA < 25 IU/ml at the final visit during the treatment period

Exploratory analysis : stepwise logistic-regression model to assess the association between the rate of SVR12 and continuous and categorical subgroup variables



3D + RBVN = 100

3D + placeboN = 205

Mean age, years 51.6 51.4

Female 30% 37.1%

Race : white/black 86.0% / 10.0% 83.4% / 12.7%

Body mass index, mean (SD) 26.9 ± 4.0 26.7 ± 4.3

Metavir fibrosis score : F0-F1 / F2 / F3 63% / 21% / 16% 64% / 17% / 19%

IL28B CC genotype 31.0% 30.7%

HCV RNA log10 IU/ml, mean (SD) 6.64 ± 0.50 6.53 ± 0.68

Discontinued treatment, N 0 11

For adverse event / for virologic failure - 2 / 6


Baseline characteristics and patient disposition

PEARL-IV Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1a

3D + RBVN = 210

3D + placeboN = 209

Mean age, years 48.4 49.2

Female 49.5% 58.9%

Race : white/black 94.3% / 4.8% 94.2% / 4.8%

Body mass index, mean (SD) 25.8 ± 3.8 26.1 ± 4.2

Metavir fibrosis score : F0-F1 / F2 / F3 71% / 18% / 11% 68% / 23% / 10%

IL28B CC genotype 21.0% 21.1%

HCV RNA log10 IU/ml, mean (SD) 6.29 ± 0.77 6.33 ± 0.67

Discontinued treatment, N 1 1

Withdrew consent 1 1


Baseline characteristics and patient disposition

PEARL-III Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1b

SVR12 (HCV RNA < 25 IU/ml)

3D + RBV3D + placebo

PEARL-IV (GT 1a)

3D + RBV3D + placebo

PEARL-III (GT 1b)

3D + RBV

3D + placebo

PEARL-IV, N 3 20

On-treatment virologic failure

1 6

Relapse 1/98 10/194

Early discontinuation 0 3

Missing data 1 1

3D + RBV

3D + placebo

PEARL-III, N 1 2

On-treatment virologic failure

1 0

Relapse 0 0

Early discontinuation 0 0

Missing data 0 2

Outcomes for patients without SVR12

25

50

100

75

9790.2

% 99.5 99.0

N 100 205 210 209

SV

R12

≠ - 6.8%(95% CI: -12.0 to -1.5)

≠ - 0.5%(95% CI: -2.1 to 1.1)

superiority, and non-inferiority thresholds (vs TVR)


0



Multivariate analysis of factors associated with increased SVR– IL28B CC genotype (p = 0.03)

Resistance testing (population sequencing) – 18 virologic failures (on-treatment or relapse)– Resistance, N = 18/18

• Most frequent variants : – D168V (NS3), – M28T and Q30R (NS5A), – S556G (NS5B)


3D + RBV 3D + placebo pAny adverse event 92.0% 82.4% 0.03

AE leading to treatment discontinuation 0 2

Serious AE 3 (3.0%) 1 (0.5%

AE occurring in > 10% in either group

Headache 25.0% 28.3%

Fatigue 46.0% 35.1%

Pruritus 10.0% 5.9%

Nausea 21.0% 13.7%

Insomnia 17.0% 7.8% 0.02

Diarrhea 14.0% 16.1%

Laboratory abnormalities

Hemoglobin < LLN 42.0% 3.9% < 0.001

Hemoglobin ≤ 10 g/dl 4.0% 0 0.01

Total biliubin > 3 x ULN 3.0% 0.5%

ALT > 5 x ULN 1.0% 0.5%

AST > 5 x ULN 0 0

Adverse events and laboratory abnormalities, n (%)



3D + RBV 3D + placebo pAny adverse event 80.0% 67.0% 0.003

AE leading to treatment discontinuation 0 0

Serious AE 4 (1.9%) 4 (1.9%)

AE occurring in > 10% in either group

Headache 24.3% 23.4%

Fatigue 21.4% 23.0%

Pruritus 11.9% 5.3% 0.02

Nausea 11.0% 4.3% 0.02

Insomnia 9.0% 3.3% 0.02

Diarrhea 4.3% 6.2%

Laboratory abnormalities 12.8%

Hemoglobin < LLN 51.2% 3.4% < 0.001

Hemoglobin ≤ 10 g/dl 9.0% 0 < 0.001

Total biliubin > 3 x ULN 5.7% 0.5% 0.003

ALT > 5 x ULN 1.0% 0

AST > 5 x ULN 0 0


Adverse events and laboratory abnormalities, n (%)

PEARL-III Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1b

Summary– After 12 weeks of treatment with ombitasvir/paritaprevir/ritonavir

and dasabuvir with or without RBV, 90.2% to 99.5% of previously untreated patients with HCV genotype 1 infection and no cirrhosis had a SVR12

– Response rates in all treatment groups were superior to the historical response rate with a PEG-IFN-containing telaprevir-based regimen

• In genotype 1b, SVR12 was > 99% with or without RBV• A total of 18 patients with genotype 1a had virologic failure, and only

2/18 received RBV. The use of RBV in genotype 1a confers an additional benefit

– Regardless of whether the antiviral regimen included RBV, the rate of discontinuation of the study drugs owing to adverse events was low (<1%)



obv/ptv/r + dsv + rbv obv/ptv/r + dsv + placebo randomisation* partial blind 18-70 years chronic hcv...

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