6 386153745 CSURFER Study grazoprevir elbasvir in genotype 1 with chronic kidney disease N 111 GZR EBR Placebo GZR EBR Intensive PK N 113 N 11 GZREBR W 12 W16 ID: 621731
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Slide1
Roth D. Lancet 2015; Oct
6; 386:1537-45
C-SURFER Study:
grazoprevir
+ elbasvir in genotype 1 with chronic kidney disease
N = 111
GZR + EBR
Placebo
GZR + EBR (Intensive PK)
N = 113
N = 11
GZR/EBR
W
12
W16
W28
Objective
SVR12 (HCV RNA < 15 IU/ml) > 45% in immediate and PK groups :reference rate, with 2-sided significance level of 0.05
≥ 18 yearsHCV infection,Genotype 1CKD stage 4/5** ± hemodialysisTreatment naïve or pre-treated with IFN-based regimenCompensated cirrhosis allowedNo HBV or HIV co-infection
Open label
Results
n
ot
available
Design
Randomisation
*
1 : 1
Double blind
* Randomisation was stratified on diabetes (yes or no) and hemodialysis status (yes or no)** based on eGFR (MDRD equation) : 15-29 ml/min = CKD 4 ; < 15 ml/min = CKD 5GZR 100 mg qd, EBR 50 mg qd, GZR/EBR 100mg/50 mg fixed dose combination 1 pill qd
C-SURFERSlide2
C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease
GZR + EBR
(Immediate + PK groups)
N = 122
Placebo
N = 113
Mean age, years
57
55
Female
25%
29%
White / African-American
50% / 45%
43% / 47%
Genotype, n (%)
1a
1b
1 other
63 (52)
59 (48)
0
59 (52)
53 (47)
1 (<1)
IL28B CC
26.2%
26.5%
HCV RNA > 800,000 IU/ml
56.6%
58.4%
Prior treatment history, n (%)
NaïveExperienced101 (83)21 (17)88 (78)25 (22)Cirrhosis, n (%)7 (6)7 (6)Diabetes, n (%)44 (36)36 (32)Dialysis, n (%)92 (75)87 (77)CKD stage, n (%)Stage 4Stage 522 (18)100 (82)22 (19)91 (81)
C-SURFER
Baseline characteristics
Roth D. Lancet 2015; Oct
6; 386:1537-45Slide3
C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease
0
25
50
75
100
99.1
(95.3-100)
94.3
(88.5-97.7)
116
1
22ModifiedFull analysis Set
Full analysis Set
SVR12 (HCV RNA < 15 IU/ml), % (95% CI), mITT
%Primary analysis
100(94.1-100)
6198.2(90.3-100)55
97.6(87.1-99.9)41100(95.2-100)751a1b
No
Yes
Diabetes
Genotype
* Genotype 1b, non cirrhotic, CKD stage 5, NS5A RAV at baseline : L31M, at failure : L31M + Y93HModified full analysis set excluded patients who died or discontinued for reasons unrelated to treatment
C-SURFER
Relapse
1*
1
Discontinuation unrelated
to treatment
0
6
Roth D. Lancet 2015; Oct 6; 386:1537-45Slide4
C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease
Virologic outcomeSVR12 (99%) > to historical control (45%), p < 0.001 SVR rates similar in patients with unfavourable baseline characteristics
(African American, IL28B non-CC, cirrhosis), and in in all subgroups including haemodialysis and non-haemodialysisResistance associated variants at baselineNS3 : 36/112 (32.1%) patients : SVR
12 in 36/36NS5A : 17/115 (14.8%) of patients : SVR12 in 16/17
C-SURFER
Roth D. Lancet 2015; Oct 6; 386:1537-45Slide5
C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease
GZR + EBR
N = 111
Placebo
N = 113
p
Discontinuation due to an adverse event
0
5 (4.4%)
0.026
Serious adverse event
14,4%
16,8%
-
Drug-related serious adverse event
0
1
-
Death
1 (0.9%)
3 (2.7%)
-
Adverse events in ≥ 10% in either group
Headache
Nausea
Fatigue
Insomnia
Dizziness
Diarrhea
17.1%
15.3%
9.9%
6.3%5.4%5.4%16.8%15.9%15.0%10.6%15.9%13.3%-----0.0110.044Hemoglobin < 10 g/dl*28.8%21.2%-ALT > 2.5 x baseline0.8%6.2%-ALT > 2.5 x baseline04.6%
0.045
Total bilirubin > 2.5 -5 x baseline
0.9%
2.7%
-
Adverse events and laboratory abnormalities, N (%)
*
Erythropoietin
use : 23% of GZR + EBR group vs 35% of placebo
C-SURFER
Roth D. Lancet 2015; Oct
6; 386:1537-45Slide6
C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease
C-SURFER
GZR + EBR
N = 111
Placebo
N = 113
Initiation of maintenance dialysis, n/N
2/25
0/26
Increase in CKD stage, not on dialysis, n/N
4/25
2/26
Worsening of proteinuria, n
4
8
Mean change from baseline in
eGR
(mL/min/1.73m
2
)
in patients not on dialysis
At W12
At follow-up W4
- 0.32 ± 4.79
- 0.13 ± 4.79
- 1.08 ± 3.83
- 1.13 ± 4.85
Renal function monitored events
Roth D. Lancet 2015; Oct
6; 386:1537-45Slide7
C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease
SummaryOnce daily GZR + EBR for 12 weeks achieved SVR12 of 99% for treatment of HCV genotype 1 infection among patients with chronic kidney disease stage 4-5SVR12
of 100% in naïve patientsSVR12 of 95% in experienced patientsEfficacy was consistent across different subpopulationGenotypes 1a and 1b
DiabetesHemodialysisFailure to achieve SVR12 was rareOne patient with genotype 1b relapsedOnce daily GZR + EBR for 12 weeks was well-tolerated
C-SURFER
Roth D. Lancet 2015; Oct
6; 386:1537-45