Upload
penha
View
42
Download
0
Embed Size (px)
DESCRIPTION
Phase 3, Treatment Naïve. Treatment Naïve. Simeprevir in Treatment-Naïve Genotype 1 QUEST-1 Trial. Jacobson I , et al. 48 th Annual Meeting of EASL. Abstract 1425. Simeprevir + PEG + Ribavirin for Treatment-Naïve HCV GT1 QUEST-1 Trial. - PowerPoint PPT Presentation
Citation preview
Hepatitisweb study
Hepatitisweb study
Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1QUEST-1 Trial
Phase 3
Treatment Naïve
Jacobson IM, et al. Lancet. 2014;384:403-13.
Hepatitisweb studySource: Jacobson IM, et al. Lancet. 2014;384:403-13.
Simeprevir + PEG + Ribavirin for Treatment-Naïve HCV GT1 QUEST-1 Trial
QUEST-1 Trial: Features Design: Randomized, double-blind, placebo-controlled, phase 3 trial with
simeprevir + PEG + RBV versus PEG + RBV in treatment-naïve GT 1
Setting: Multicenter at 71 sites in 13 countries
Entry Criteria - Treatment-naïve, chronic HCV monoinfection- HCV Genotype 1 (1a or 1b)
Patient Characteristics- N = 394- HCV Genotype: 1a (56%); 1b (44%) - IL28B Genotype: 71% non-CC - Age: median age 48- Sex: 56% male- Race: 89% white, 8% black - Liver disease: F3 = 18%; F4 = 12%
Primary end-points: Efficacy (SVR12) and safety
Hepatitisweb studySource: Jacobson IM, et al. Lancet. 2014;384:403-13.
N =130 Placebo+ PEG + RBV
Simeprevir + PEG + RBV
N = 264
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Design
PEG + RBVPEG + RBV
PEG + RBV
Response-Guided TherapyPatients with HCV RNA <25 IU/ml at week 4 and <15 IU/ml at week 12 completed treatment after 24 weeks.
Randomized 2:1; stratified on IL28B and HCV1 subtype
Drug DosingSimeprevir: 150 mg once dailyPeginterferon alfa-2a (PEG): 180 mcg/weekRibavirin (RBV) weight-based (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75kg
Week 0 12 4824 36
Hepatitisweb study
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
QUEST-1: Proportion of Patients with SVR12
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Simeprevir + PEG + RBV PEG + RBV0
20
40
60
80
100
80
50
Patie
nts
(%) w
ith S
VR 1
2
Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin
P < 0.0001
65/130210/264
Hepatitisweb studySource: Jacobson IM, et al. Lancet. 2014;384:403-13.
1a 1b0
20
40
60
80
100
71
90
49 52
Simeprevir + PEG + RBV PEG + RBV
HCV Genotype
Patie
nts
(%) w
ith S
VR 1
2
SVR12 by HCV Genotype 1 Subtype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
Abbreviations: PEG = Peginterferon; RBV = Ribavirin
105/147 36/74 105/117 29/56
Hepatitisweb studySource: Jacobson IM, et al. Lancet. 2014;384:403-13.
1a (with baseline Q80K) 1a (without baseline Q80K)0
20
40
60
80
100
52
85
5344
Simeprevir + PEG + RBV PEG + RBV
HCV Genotype
Patie
nts
(%) w
ith S
VR 1
2
QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
Abbreviations: PEG = Peginterferon; RBV = Ribavirin
31/60 16/30 73/86 19/43
Hepatitisweb study
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
SVR12 Response in Simeprevir Arm Based on Achievement of RGT Criteria
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Met RGT Did Not Meet RGT
0
20
40
60
80
10091
21Pa
tient
s (%
) with
SR
V 12
RGT= response-guided therapy: in simeprevir study arm, patients with HCV RNA<25 IU/ml at week 4 (undetectable or detectable) and <25 IU/ml at week 12 (undetectable) stopped treatment after 24 weeks
85%
11%
4%
Chart TitleMet RGT CriteriaDid Not Meet RGT CriteriaUnclassified
SVR12 Based on Meeting RGTPatients (%) who Met RGT Criteria
203/224 6/28N = 264
Hepatitisweb studySource: Jacobson IM, et al. Lancet. 2014;384:403-13.
CC CT TT0
20
40
60
80
100
94
76
65
78
42
24
Simeprevir + PEG + RBV PEG + RBV
Patie
nts
(%) w
ith S
VR 1
2
Abbreviations: PEG = Peginterferon; RBV = Ribavirin
QUEST 1: SVR12 by Host IL28B Genotype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
72/77 29/37 114/50 32/76 24/37 4/17
Hepatitisweb studySource: Jacobson IM, et al. Lancet. 2014;384:403-13.
F0-F2 F3 F4 (Cirrhosis)0
20
40
60
80
100
8378
5860
26 29
Simeprevir + PEG + RBV PEG + RBV
Metavir Fibrosis Score
Patie
nts
(%) w
ith S
VR 1
2
QUEST 1: SVR12 by Liver Fibrosis (Metavir Score)
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
Abbreviations: PEG = Peginterferon ; RBV = Ribavirin
152/183 54/90 36/46 6/23 18/31 5/17
Hepatitisweb study
On-Treatment Failure Relapse0
10
20
30
40
50
60
9 9
34
21
Simeprevir + PEG + RBV PEG + RBV
Patie
nts
(%)
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Stopping rules: (1) Stop simeprevir or placebo if HCV RNA>1000 at week 4; (2) Stop all therapy if HCV RNA < 2 log 10 IU/mL reduction at week 12; (3) Stop all therapy if HCV RNA ≥25 IU/mL at week 24 or 36.On-treatment failure: Detectable HCV RNA at end of treatment.
On-Treatment Failure or Relapse
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
24/264 44/130 21/234 18/84
Hepatitisweb study
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Results
Emergent Protease Resistance in Patients who Failed to Achieve SVR12
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Among simeprevir-treated patients who failed to achieve SVR12, emergent mutations in NS3 protease domain detected in 35 (92%) of 38
Genotype 1A: Most common mutation = R155K alone or in combination with mutations at codons 80 and/or 168
Genotype 1B: Most common mutation = D168V
Hepatitisweb study
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Adverse Effects
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
QUEST 1: Event Simeprevir + PEG + RBV(n=264)
Placebo + PEG + RBV (n=130)
Discontinuation (due to adverse event) 3% 2%
Grade 3 adverse event 25% 33%
Grade 4 adverse event 3% 5%
Fatigue 42% 41%
Headache 33% 39%
Pruritus 30% 20%
Rash (any type) 34% 32%
Anemia 20% 21%
Photosensitivity condition 3% <1%
Neutropenia 24% 18%
Bilirubin increase 9% 5%
Hepatitisweb studySource: Jacobson IM, et al. Lancet. 2014;384:403-13.
Interpretation: “Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin.”
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1QUEST-1 Trial: Conclusions
Hepatitisweb study
Hepatitisweb study
This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects.
Hepatitis C Onlinewww.hepatitisc.uw.edu
Hepatitis Web Studyhttp://depts.washington.edu/hepstudy/
Funded by a grant from the Centers for Disease Control and Prevention.