1. CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1
HCV-trial.com
CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1
Design
Randomisation *
1:1
Open-label
20-70 years, Japanese
Chronic HCV infection
Genotype 1
HCV RNA ≥ IU/ml
IFN-based pre-treated, non-responders
No prior DAA therapy
No cirrhosis
No HBV or HIV co-infection
N = 53
SMV 12W + PEG-IFN + RBV 24-48W **
SMV 24W + PEG-IFN + RBV 24-48W **
N = 53
* Randomisation was stratified on age (< 65 or ≥ 65 years old) and IL28B
** Response-guided therapy
SMV: 100 mg 1 capsule qd
PEG-IFNa-2a: 180 mg SC once weekly
RBV: 600 or 1000 mg/day according to body weight
Dosage adjustment of PEG-IFN and RBV permitted
Objective
Primary endpoint: SVR12 (HCV RNA < 1.2 log10 IU/ml), with 2-sided 95% CI, significant difference vs null hypothesis proportion ≤ 14% of success, 90% power
CONCERTO-2
Izumi N, J Gastroenterol 2014;49:941-53 1

2. CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1
Baseline characteristics, and disposition
SMV12
N = 53
SMV24
Median age, years 60
Female 49 51
Genotype : 1a / 1b, %
0 / 100
6 / 94
IL28B CC genotype, % 15 11
HCV RNA log10 IU/ml, median
6.4
Metavir stage in patients with biopsy : F0 / F1 / F2 / F3, %
0 / 55 / 15 / 30
18 /18 / 36 / 27
Prior therapy, %
IFN only
PEG-IFN only
IFN + RBV
PEG-IFN + RBV
7.5 0
7.5
84.9
3.8
1.9
86.8
Discontinuation during follow-up, %
Withdrawal of consent
4.7
Completion of all treatment, %
Discontinuation PR / SMV / both, N
77.8
3 / 9 / 10
CONCERTO-2
Izumi N, J Gastroenterol 2014;49:941-53 2

3. CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1
Virologic response, ITT (%)
SMV12
N = 53
SMV24
SVR12
95% CI, p *
52.8
, p <
35.8
, p =
Virologic breakthrough
13.2
11.3
Relapse
38.6
51.1
Met RGT criteria and completed 24W of PEG-IFN + RBV
81.1
60.5
73.6
48.7
Failure to achieve SVR12
HCV RNA detectable at end of treatment
HCV RNA detectable at SVR12 assessment
Missing at SVR12 timepoint
47.2
17.0
30.2
64.2
15.1
43.4
5.7
* One sample test for binomial distribution versus null hypothesis proportion ≤ 14 % for each treatment group
Of the 57 failures, 56 had NS3 sequence available: ≥ 1 emerging NS3 mutation in 46/56 (82.1% ; SMV12 = 80.0% , SMV24 = 83.9%)
CONCERTO-2
Izumi N, J Gastroenterol 2014;49:941-53 3

4. CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1
Adverse events (entire treatment period)
SMV12
N = 53
SMV24
Treatment discontinuation due to adverse event
SMV only, N
All study medication, N 2
Grade3-4 adverse events, N 11 17
Serious adverse event, N 3
Common adverse events, %
Pyrexia
White blood cell count decreased
Anemia
Neutrophil count decreased
Malaise
Platelet count decreased
Headache
Rash
Alopecia
Pruritus
Decreased appetite
Arthralgia
Hemoglobin decresaed
Myalgia
Hematocrit decreased
Nasopharyngitis
62 62 53 57 51 43 38 40 30 23 25 13 15 19 59 45 28
CONCERTO-2
Izumi N, J Gastroenterol 2014;49:941-53

5. CONCERTO-2 Study: SMV + PEG-IFNa-2a + RBV for genotype 1
Summary
In treatment-experienced patients with HCV genotype 1 infection who failed to respond to previous IFN-based therapy, re-treatment with 12 weeks of oral SMV QD in combination with PEG-IFN +RBV achieves high SVR rate
This study was not able to determine whether there is an additional efficacy benefit by prolonging SMV therapy beyond 12 weeks
Limitation:
prior partial response versus null-response status to previous IFN-based therapy was not clearly documented
SMV was generally well tolerated the incidences of serious adverse events or grade 3/4 rash or anemia were low, as were the rates of treatment discontinuations due to these adverse events
CONCERTO-2
Izumi N, J Gastroenterol 2014;49:941-53 5