Placebo + PR W48 Placebo + PR Yes Hezode C. Gut 2015;64:948-56 COMMAND-1 COMMAND-1 Study:...

Placebo + PR

W48

Placebo + PR

Placebo + PR

Yes

Hezode C. Gut 2015;64:948-56COMMAND-1

COMMAND-1 Study: daclatasvir + PEG-IFN + RBV for genotype 1 or 4

DCV60 + PEG-IFN + RBVN = 158

No

Yes

No

Randomisation*2 : 2 : 1

Double blind

Design

18-70 yearsChronic HCV infection

Genotype 1 or 4Treatment naïve

HCV RNA ≥ 100,000 IU/mlCompensated cirrhosis

allowedNo HBV or HIV coinfection

Placebo + PEG-IFN + RBVN = 78


PDR (protocol-defined response) = HCV RNA < 25 IU/ml at W4 and undetectable at W10

W12

* Randomisation stratified on genotype (1 or 4)

W24Randomisation

if PDR

DCV20 + PR

Placebo + PR

DCV60 + PR

PDR


Dosage of drugs– DCV : 20 mg or 60 mg qd or matching placebo

– PEG-IFNa-2a : 180 mg SC once weekly

– RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)

Co-primary endpoints : % of genotype 1 with eRVR (undetectable HCV RNA at W4 and W12) and SVR24 (undetectable HCV RNA) by m-ITT analysis

Resistance analyses : all baseline samples and on-treatment or follow-up samples with HCV RNA ≥ 1000 IU/ml

Objectives – eRVR of one of DCV dose superior to placebo, in genotype 1 (lower bound of the

80% CI for the difference > 35%, power of 90%)

– SVR24 of one of DCV dose superior to placebo, in genotype 1 (lower bound of the 80% CI for the difference > 0%, power of 82%)


DCV20 + PEG-IFN + RBV

N = 159


N = 158


Median age, years 51 50 51

Female 33% 35% 30%

HCV RNA log10 IU/ml, mean 6.5 6.5 6.4

Genotype1a1b4

67%26%8%

72%20%8%

72%21%8%

Cirrhosis 8% 5% 10%

IL28B CC 33% 28% 30%

Discontinued treatment Adverse event Lost to follow-up / Other Lack of efficacy

In patients with PDR31

1 / 1-

In patients with PDR107

1 / 2-

418

1 / 725

Did not achieve PDR 47 (lack of efficacy: 15) 42 (lack of efficacy: 18) -

Baseline characteristics and patient disposition



SVR24 (HCV RNA < 25 IU/ml)

25

50

100

7562

%

60

Genotype 1

38

57

67

77

N 147 146 72 106 31 12113 56 12 6

55

100

4450

In genotype 1, both doses of DCV were not significantly superior to placebo (lower bound of the 80% CIs for the difference (DCV - placebo) : 33% for eRVR and 13% for SVR24, for both DCV groups

1641

Genotype 1a Genotype 1b Genotype 4

36

76



DCV60 PlaceboDCV20

0



25

50

100

75

80

%

6961

43

6770

N 41 36 18 53 20 661 26 4 2

27

75

40

0

1024

Genotype 1a Genotype 1b

49

67

36 36

22

100

11 14 9 11 7 4

75

100

CC CT TT CC CT TT

DCV60 PlaceboDCV20

0

SVR24 (HCV RNA < 25 IU/ml) by IL28B genotype



PDR (mITT)

Genotype 1a

Genotype 1b

72.1%

67.0%

82.9%

72.6%

67.3%

87.1%

RegimenDCV + PR 12W

+ PR 12W DCV + PR 24W

DCV + PR 12W

+ PR 12W DCV + PR 24W

SVR24 among patients achieving PDR

Genotype 1a

Genotype 1b

75.5%

71.8%85.7%

71.2%

71.9%

70.0%

79.2%

76.9%

85.7%

71.2%

70.3%

76.9%

Rates of protocol-defined response (PDR) in genotype 1 and effect on SVR24, N (%)





OverallVirologic breakthroughOther on-treatment failureRelapseOther

40.8%8.1%9.5%

15.0%8.2%

40.4%10.3%8.2%

15.1%6.8%

RegimenDCV + PR 12W

+ PR 12W N = 53

DCV + PR 24W

N = 52

DCV + PR 12W + PR 12W

N = 53

DCV + PR 24W

N = 50

Patients achieving PDROverall

Virologic breakthroughOther on-treatment failureRelapseOther

24.5%0

1.9%13.2%9.4%

28.8%0

7.7%19.2%1.9%

20.8%0

3.8%9.4%7.5%

30.0%00

20.0%10.5%

Treatment failures in genotype 1, N (%)

Virologic breakthrough was more frequent in genotype 1a




N = 159


N = 158


Serious adverse event 7.5% 8.2% 7.7%

Adverse event leading to discontinuation 4.4% 4.4% 10.3%

AE in ≥ 25% of patients

Fatigue 55% 54% 59%Headache 43% 43% 46%Pruritus 35% 40% 33%Insomnia 31% 34% 39%Rash 34% 25% 32%Nausea 35% 34% 26%Myalgia 28% 27% 32%Influenza-like illness 28% 31% 21%Dry skin 30% 26% 19%Irritability 22% 23% 28%Alopecia 25% 26% 17%Decreased appetite 17% 25% 22%

Grade 3-4 bilirubin increase 1 0 1Grade 3-4 ALT elevation 0 6 (3.8%) 1

Adverse events and hepatic liver laboratory abnormalities, N (%)




Resistance analysis

– Genotype 1• At baseline : NS5A polymorphisms associated with DCV resistance

(L31M/V and/or Y93H/N/S) detected in 12 genotype 1a patients and 10 genotype 1b patients

– 8/12 genotype 1a (L31M/V and Y93H/N/S) and 2/10 genotype 1b (Y93H) failed to achieve SVR24

• At virologic failure, DCV-associated resistant variants in all patients ; most frequent :

– Q30 in genotype 1a – L31I/M/V and Y93H in genotype 1b

– Genotype 4• 4 virologic failures, sequencing available in 3 patients ; emergence of

L28M + L30H in 1 patient, and L28M + L30S in 2 patients



Summary

– In this phase IIb study, the combination of daclatasvir + PEG-IFN + RBV was generally well tolerated and achieved higher SVR24 rates compared with placebo + PEG-IFN + RBV among patients infected with HCV genotype 1 or 4

• Genotype 1a patients had lower rates of SVR24 and higher rates of virologic failure compared with genotype 1b patients

• Although sample size was small, SVR24 was 100% with DCV 60 mg + PEG-IFN + RBV in genotype 4

• IL28B genotype predicted response, with higher rates of SVR24 observed among patients with a CC genotype

– Dose of 60 mg QD of DCV selected for Phase III studies


Placebo + PR W48 Placebo + PR Yes Hezode C. Gut 2015;64:948-56 COMMAND-1 COMMAND-1 Study:...

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