CWORTHYD GZR EBR RBV GZR EBR RBV N 21 N 20 Design W12 W18 SVR 12 gt 18 years HCV genotype 3 HCV RNA 10 000 IUmL Treatment naïve No cirrhosis No HBV or HIV coinfection ID: 933918
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Slide1
C-WORTHY Study Part D: grazoprevir + elbasvir + RBV in genotype 3
C-WORTHY/D
GZR + EBR + RBV
GZR + EBR + RBV
N = 21
N = 20
Design
W12
W18
SVR
12
>
18 years
HCV genotype
3
HCV RNA ≥ 10 000 IU/mL
Treatment naïve No cirrhosisNo HBV or HIV co-infection
Randomisation
1 : 1Open-label
Primary efficacy endpoint
SVR
12 (HCV RNA < 25 IU/mL), with 2-sided 95% CI, comparison between groups (intention to treat analysis)
Grazoprevir (GZR): 100 mg qdElbasvir (EBR): 50 mg qdRBV (bid dosing): 800 mg/day if 51-65 kg, 1000 mg/day if 66-80 kg, 1200 mg/day if 81-105 kg, 1400 mg/day if > 105 kg
Gane E. J Viral Hepat. 2017 ; 10 :895-9
Slide2GZR + EBR + RBV12 weeks (N = 20)
GZR + EBR + RBV
18 weeks (N
= 21)
Female
60%62%
Age, years
(mean)
49
42
IL28B CC
40%
38%
HCV
RNA
≤ 10M IU/ml
75%
76.2%
Metavir
F0-F2
/
F3
95% / 5%
95.2% / 4.8 %DiscontinuationOn-treatment failureAdverse eventLost to follow-up, Withdrew consent21012011
Baseline characteristics and patient disposition
C-WORTHY Study Part D: grazoprevir + elbasvir + RBV in genotype 3
Gane E. J Viral Hepat. 2017 ; 10 :895-9
C-WORTHY/D
Slide3Rebound3
2
Breakthrough
6
5
Non response
1 (quantifiable virus at TW8)
0
Relapse
0
0
SVR
12
(
HCV RNA < 25 IU/ml), % (95% CI), ITT
100
75
50
25
0
45.0
(23.1-68.5)
57.1
(34.0-78.2)
12 weeks18 weeks2021
%
C-WORTHY Study Part D: grazoprevir + elbasvir + RBV in genotype 3
Gane E. J Viral Hepat. 2017 ; 10 :895-9
C-WORTHY/D
Slide4NS3 RAVs
NS5A RAVs
12W arm
At baseline
At failure
At baseline
At failure
Breakthrough
V170I
V170I
A30L
A30S, Y93Y/H,
L31L/I
Breakthrough
V170I
Q80K
WT
A30G, Y93H
Rebound
V170I
na
WT
na
Breakthrough
V170IV170I, A156GWTY93HBreakthroughV170IQ80K, V170IWTY93HRebound
V170I
V170I, A156G, Q80KWT
Y93H
Breakthrough
V170I, L132I
Q80R, V170I, L132I
WT
Y93H
Non
response
V170I
Q80K, V170I
A30A/E/K/T, Y93H
Y93H
Rebound
V170I
Y56Y/H, Q168Q/K, V170I
Y93H
Y93H
Breakthrough
V170I
V170I, A156G
WT
Y93H
18W arm
Breakthrough
V170I, Q168R
V170I, Q168R
WT
L31F
Breakthrough
V170I
Q80K, V170I
WT
L31F
Breakthrough
V170IV170IWTY93HReboundV170IV170I, A156GWTY93HReboundV170IA156GA30KA30K, P58SBreakthroughV170IQ80K, V170IWTY93HBreakthroughV170IQ80KWTY93H
Resistance associated substitutions in subjects with virologic failure
C-WORTHY Study Part D: grazoprevir + elbasvir + RBV in genotype 3
Gane E. J Viral Hepat. 2017 ; 10 :895-9
C-WORTHY/D
Slide5SVR12 according to baseline RASs
Overall
Population
GZR + EBR + RBV
12 weeksGZR + EBR + RBV18 weeks
Overall efficacy,n/N (%)
21/38
(55%)
9/19
(47%)
12/19
(63%)
NS3 RASs not detected,
n/N (%)
3/3
(100%)
2/2(100%)
1/1
(100%)
NS3 RASs at baseline,
n /N (%)
18/35(51%)
7/17
(41%)
11/18(61%)NS5A RASs not detected, n/N (%)14/21(67%)5/9
(56%)
9/12(75%)
NS5A RASs at baseline, n/N (%)
7/17
(41%)
4/10
(40%)
3/7
(43%)
C-WORTHY Study Part D: grazoprevir + elbasvir + RBV in genotype 3
Gane E. J Viral Hepat. 2017 ; 10 :895-9
C-WORTHY/D
Slide6GZR + EBR + RBV12 weeks (N
= 20)
GZR + EBR + RBV
18 weeks (N = 21)
Adverse eventsHeadacheUpper respiratory tract infection
Accidental overdoseInsomniaRashNauseaAsthenia
17 (85.0)
5 (25.0)3 (15.0)
3 (15.0)3 (15.0)3 (15.0)
3 (15.0)2 (10.0)
19 (90.5)
5 (23.8)5 (23.8)2 (9.5)
3 (14.3)2 (9.5)
5 (23.8)3 (14.3)
Serious adverse
event
00
Serious drug-related adverse
event
0
0
Discontinuation due to adverse
event
0
1* (4.8)Adverse events, N (%)* dyspnea, fatigue and asthenia 2-3 days after starting treatmentC-WORTHY Study Part D: grazoprevir + elbasvir + RBV in genotype 3Gane E. J Viral Hepat. 2017 ; 10 :895-9C-WORTHY/D
Slide7Summary
Efficacy of 12 or 18 weeks of GZR + EBR + RBV in HCV genotype 3 infected patients
Was suboptimal due to on-treatment virologic failure in 17 of 41 patientsNo subject relapsed after the end of therapyNS5A RASs found in 16 of 17 failures, Y93H the most common NS5A RAS identified
GZR + EBR + RBV was generally safe and well toleratedAdverse events were slightly more common in the 18-week arm compared with the 12-week armNo differences in serious adverse events or laboratory abnormalitiesAdverse event considered to be severe in intensity reported in only 1 patient (non-drug related depression during follow-up)
C-WORTHY Study Part D: grazoprevir + elbasvir + RBV in genotype 3
Gane E. J Viral Hepat. 2017 ; 10 :895-9
C-WORTHY/D