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FISSION
Design
Objective– Non inferiority of SOF + RBV : SVR12 (2-sided significance level of 5%, lower
margin of the 95% CI for the difference = -15%, 95% power)
SOF + RBV (weight based)
PEG-IFNa-2a + RBV (fixed-dose)
Randomisation1 : 1*
Open-label, active-control
* Randomisation was stratified on cirrhosis (presence or absence), genotype (2 or 3) and HCV RNA (< or ≥ 6 log10 IU/ml)
FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3
W12
SVR12
W24
SVR12
W36
N = 243
N = 256
≥ 18 yearsChronic HCV infection
Genotype 2, 3Treatment-naïve
HCV RNA ≥ 10,000 IU/ml
Compensated cirrhosisallowed
– SOF : 400 mg qd– PEG-IFNa-2a : 180 mg SC once weekly– RBV weight based (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg– RBV fixed-dose : 400 mg bid
Lawitz E. NEJM 2013;368:1878-87
SOF + RBV 12 WN = 256
PEG-IFN + RBV 24WN = 243
Mean age, years 48 48
Female 33% 36%
Race : white/black 87% / 5% 87% / 2%
Body mass index, mean 28 28
HCV genotype 1 / 2 / 3 1%* / 27% / 71% 28% / 72%
IL28B CC genotype 42% 44%
HCV RNA log10 IU/ml, mean (SD) 6.0 ± 0.8 6.0 ± 0.8
HCV RNA ≥ 800,000 IU/ml 57% 65%
Cirrhosis 20% 21%
Discontinued treatment, NFor AE / for virologic failure / lost to follow-up
113 / 1 / 2
5426 / 17 / 5
Returned for post-treatment W4 visit 246 233
Returned for post-treatment W12 visit 239 225
Baseline characteristics and patient disposition
* Excluded from efficacy analysis
FISSION
FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3
Lawitz E. NEJM 2013;368:1878-87
HCV RNA < 25 IU/ml
SOF + RBVPEG-IFN + RBV
FISSION
FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3
Lawitz E. NEJM 2013;368:1878-87
250 236 253 243 253 243 253 243 70 67 183 176 204 193 49 500
25
50
75
10099
67
9889
74 7467 67
97
78
5663
72 74
4738
W4 W12 W4 W12 Genotype 2 Genotype 3 No cirrhosis Cirrhosis
During treatment Post treatment (SVR)
SVR12 by genotype and cirrhosis
Virologic breakthrough during treatment – 1 in SOF + RBV group vs 18 (7%) in PEG-IFN + RBV group
Relapse in patients with HCV RNA < 25 IU/ml at end of completed treatment– 74/249 (30%) in SOF + RBV group vs 46/217 (21%) in PEG-IFN + RBV
group
Resistance testing (sequencing) in SOF + RBV group – 74 relapses :
– No SOF-associated mutation (S282T)– No change in susceptibility to SOF in patients with NS5B substitutions
Multivariate analysis of factors associatedwith SVR12 in SOF + RBV group
OR (95% CI) p
Genotype 2 (vs 3) 42.49 (9.54 – 189.2) < 0.0001
Cirrhosis (no vs yes) 2.94 (1.38 – 6.26) 0.005
Baseline HCV RNA < vs ≥ 6 log10 IU/ml 2.33 (1.24 – 4.37) 0.009
RBV exposure, mg/kg/day 1.26 (1.09 – 1.46) 0.002
FISSION
FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3
Lawitz E. NEJM 2013;368:1878-87
Adverse events, n (%)SOF + RBV 12W
N = 256PEG-IFNa-2a + RBV 24W
N = 243
AE leading to treatment discontinuation 3 (1%) 26 (11%)
Serious adverse event 7 (3%) 3 (1%)
AE occurring in > 15% in either groupFatigueHeadacheNauseaInsomniaDecreased appetiteInfluenza-like illnessChillsRashDiarrheaPruritus MyalgiaIrritability
36%25%18%12%7%3%3%9%9%7%8%
10%
55%44%29%29%18%18%18%18%17%17%16%16%
FISSION
FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3
Lawitz E. NEJM 2013;368:1878-87
Summary– In this open-label, randomised trial of previously untreated patients
with genotype 2 or 3 infection, the rate SVR12 was the same among patients who were assigned 12 weeks of SOF + RBV or 24 weeks of PEG-IFN + RBV (67% in each group)
• In genotype 2, SVR12 was higher with SOF + RBV (97% vs 78%)
• In genotype 2, SVR12 was similarly low in both groups (56% vs 63%)
– SOF + RBV was associated with fewer adverse events than PEG-IFN
+ RBV• Influenza-like constitutional symptoms and neuropsychiatric events were less
common among patients receiving SOF + RBV than among those receiving PEG-IFN + RBV.
• Although the rates of anemia was similar in both groups, neutropenia and thrombocytopenia were not observed in the SOF + RBV group
– No virologic resistance was detected in patients who did not have a sustained virologic response
FISSION
FISSION Study: SOF + RBV vs PEG-IFNa-2a + RBVfor HCV genotype 2 and 3
Lawitz E. NEJM 2013;368:1878-87