randomisation* 2 : 1 double blind *randomisation was stratified on genotype (1a or 1b or other) and...

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

W24 W48

Placebo + PEG-IFN

+ RBV

SMV + PEG-IFN

+ RBV

PEG-IFN + RBV PEG-IFN + RBV

PEG-IFN + RBV

W12

– SMV 150 mg : 1 pill QD ; PEG-IFNa-2a 180 mg SC once weekly – RBV : 1000 or 1200 mg/day (BID dosing) according to body weight (< or ≥ 75 kg)

Response-guided therapy : in SMV group, patients with HCV RNA < 25 IU/ml at W4 and < 15 IU/ml at W12 stopped treatment at W24, otherwise they continued until W48

Virological stopping rules : SMV or placebo discontinued if HCV RNA > 1000 IU/ml at W4, with continuation of PEG-IFN + RBV. PEG-IFN + RBV discontinued if RNA reduction < 2 log10 IU/ml at W12, or if HCV RNA confirmed ≥ 25 IU/ml at W24 or W36

open-label

PROMISE

> 18 yearsChronic HCV infection

Genotype 1IFN-experienced ≥ 24

weeks with relapseHCV RNA > 10,000 IU/mlCompensated cirrhosis

allowedNo HBV or HIV co-infection

Forns X. Gastroenterology 2014;146:1669-79

Design

PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy

Objectives– Primary endpoint : difference in SVR12 (HCV RNA < 25 IU/ml)

between the 2 groups : estimation of 20% in the placebo group, power of 90% to detect a significant difference with a 5% 2-sided significance level, by ITT

– Secondary endpoints• Virologic response in different patient subgroups (including METAVIR

score, HCV 1 subtype, and IL28B genotype)• Proportion of SMV-treated patients meeting RGT criteria to complete

treatment at W24• Incidence of viral breakthrough (HCV-RNA increase of >1 log10 IU/ml

from the lowest level observed or HCV RNA > 100 IU/ml when previously < 25 IU/ml), on-treatment failure (confirmed detectable HCV RNA at end of treatment), or viral relapse (detectable HCV RNA during follow-up or at the time of SVR assessments after achieving undetectable levels at end of treatment)

• Incidence of adverse events and laboratory abnormalities• Quality-of-life measures

PROMISE Forns X. Gastroenterology 2014;146:1669-79



SMVN = 260

PlaceboN = 133

Median age, years 52 52

Female 31% 41%

White / Black 94% / 3% 96% / 3%

HCV genotype : 1a / 1b 42% / 57% 41% / 59%

Metavir score : F3 / F4 18% / 16% 11% / 14%

HCV RNA log10 IU/ml, median 6.42 6.54

IL28B genotype CC 24% 26%

Time since end of prior (PEG)-IFN therapy, median months 31 (4-141) 31 (5-115)

Discontinued study, N (%)Adverse eventWithdrew consentLost to follow-upOther

10 (3.8%)1450

14 (10.5%)03

101


Baseline characteristics and patient disposition

Response guided therapy (RGT) : in SMV group, patients with HCV RNA < 25 IU/ml at W4 (undetectable or detectable) and < 15 IU/ml at W12 (undetectable) stopped treatment after W24– Of the 241 (93%) patients who met RGT, 83% had SVR12

– Of the 15 who did not, 40% had SVR12

SMV Placebo%

All 1a All 1a Q80K+ 1b

p < 0.001

1a Q80K-

p < 0.001p < 0.001

25

50

100

75

79.2

28

N 260 54

79

47

30

36.1

70

86

133 111 149 7914 79

43

020 34

2730



SVR12 (HCV RNA < 25 IU/ml)



SVR12 (HCV RNA < 25 IU/ml)SMV Placebo

%

CC CT TT F4F0-F2 F3

Metavir fibrosis scoreIL28B genotype

25

50

75

89

34

19

N 62 83

82

65

78

34 167 39 1916 167

41

198

26

31

73

44

20

15

74

53

100

0

all p < 0.01

Emergence of resistance among SMV-treated patients who failed to achieve SVR12 (sequencing data available in 52/59)

– Emergence of NS3 mutations in 47/52 (90%)

• Genotype 1a (N = 30/32) : most common = R155K alone (N =15) or in combination (N = 4), or D168V/A/E/H (N = 10) ; 14/32 with Q80K at baseline

• Genotype 1b (N = 17/20) : most common = D168V or D168A/E/T

SMV Placebo

Met W4 virologic stopping rule (continuation of PR)

5 (1.9%) 93 (69.9%)

On-treatment failure 8/260 (3.1%) 36/133 (27.1%)

Met stopping rule (W12 or W24 or W36) 5 (1.9%) 15 (11.3%)

Relapse46/249 (18.5%)

GT 1a : 28% ; GT 1b : 12%45/93(48.4%)



Virologic failure


SMV, N = 260 Placebo, N = 133

First 12W Entire phase First 12W Entire phaseDiscontinuation due to adverse event 1.2% 2.3%% 1.5% 5.3%

Grade 3 adverse event 18.1% 24.2% 18% 25.6%

Grade 4 adverse event 1.9% 3.5% 3% 4.5%

Serious adverse event 1.2% 5.4% 2.3% 7.5%

Most common adverse events

Fatigue 32% 32% 42% 44%

Headache 32% 33% 36% 36%

Influenza-like illness 30% 30% 20% 20%

Adverse events of clinical interest

Rash 19% 23% 14% 23%

Pruritus 24% 28% 17% 28%

Neutropenia 15% 18% 17% 22%

Photosensitivity (Grade 3, N) 4% (1) 4% 4% 0

Anemia 11% 17% 6% 20%


Adverse events


Summary– Oral, once-daily SMV150 mg for 12 weeks in combination with PEG-IFN + RBV

followed by 12–36 weeks of PEG-IFN + RBV led to a significant improvement in SVR12 compared with that seen in the placebo group, in patients with chronic HCV genotype 1 infection who had relapsed after previous IFN-based therapy

– Overall, 79.2% of SMV-treated patients achieved SVR12 compared with 36.1% of those who received PEG-IFN + RBV alone

• This superiority of SMV was seen across the different baseline characteristics (Gender, HCV RNA, Metavir score, IL28B genotype, HCV 1 subtype)

– Almost all SMV-treated patients (92.7%) met RGT criteria and were eligible to stop PEG-IFN + RBV at W24. The SVR12 rate in these patients was 83%

– The SVR12 rate with SMV was lower in HCV genotype 1a patients who had the Q80K polymorphism at baseline

– Relapse rate was higher in genotype 1a– Most patients treated with SMV who did not achieve SVR12 had emergent

mutations at the time of failure– The safety and tolerability profile of SMV + PEG-IFN + RBV was generally

similar to that of PEG-IFN + RBV alone, with no additional treatment-related adverse events. Discontinuation for adverse event was rare in both groups


randomisation* 2 : 1 double blind *randomisation was stratified on genotype (1a or 1b or other) and...

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