www.hivandmore.de comparison of 48 week efficacy and safety of 400mg qd nevirapine (nvp) extended...
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Comparison of 48 week efficacy and safety of 400mg QD nevirapine (NVP) extended release formulation (Viramune XR) versus 200mg BID nevirapine immediate release formulation (Viramune IR) in combination with emtricitabine/tenofovir in antiretroviral (ARV) naïve HIV-1 infected patients (VERxVE)
J. Gathe, JR. Bogner, S. Santiago, A. Horban, M. Nelson, P. Cahn, J. Andrade, D. Spencer, C. Yong, T. Nguyen, W. Zhang,
M. Drulak and A. Quinson*
*Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
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Viramune 200mg immediate release (IR) is a well established
component of effective antiretroviral therapy in HIV-1 infected
patients
Viramune 200mg IR plus emtricitabine/tenofovir (FTC/TDF) recently
demonstrated similar efficacy to atazanavir/ritonavir plus FTC/TDF,
with a more favourable lipid profile1
Viramune extended release formulation (Viramune XR) may
increase therapeutic benefit by improving compliance through once-
daily
(QD) dosing
1. Soriano V. et al. 2010 Manuscript submitted
VERX VE: Rationale for Viramune Extended Release (XR) Formulation
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Objective:
To evaluate the efficacy of Viramune XR 400 mg QD vs Viramune IR
200 mg BID, in ARV treatment-naïve, HIV–1-infected patients after
48 weeks of treatment
• Study design:
• Double-blind, double-dummy, non-inferiority study
• 1:1 randomization to Viramune XR or Viramune IR after 14-day
Viramune IR lead-in 200 mg QD dose (given to all patients)
• Emtricitabine/tenofovir (FTC/TDF) fixed-dose background
ARV treatment
• Baseline viral load (VL) stratification
(≤100,000 vs >100,000 copies/mL)
VERX VE: Objectives and Study Design
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Primary endpoint:
Sustained virologic response at 48 weeks defined as VL
<50 copies/mL prior to and at week 48, without virologic
rebound or change of ARV therapy
Secondary endpoints:
Time-to-loss of virologic response (TLOVR)
Time to new AIDS or AIDS-related progression event or
death
Genotypic resistance associated with virologic failure
AEs, SAEs, AEs leading to discontinuation; laboratory
parameters
VERX VE: Study Endpoints
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Parameter Viramune IR Viramune XR
Number of patients, N 508 505
Gender
Male, n 433 431
Female, n 75 74
Age, mean 38.0 38.3
Region
North America/Australia 150 141
Europe 252 257
Latin America 49 58
Africa 57 49
Baseline HIV-1 viral load, median log10 copies/mL
4.7 4.7
CD4+ cell count, mean cells/mm3 227 229
History of AIDS (%) 26 30
Note: Total randomised=1068, 1011=randomized & treated (full analysis set, FAS), 2 randomized not treated, 55 DC during lead-in
VERX VE: Demographic Data
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Parameter Viramune IR Viramune XR Total
Randomized, N 508 505 1013
Treated with blinded dose, n (%) 506 (100.0) 505 (100.0) 1011 (100)
Completed Week 48 visit, n (%) 409 (80.1) 421 (83.4) 830 (82.1)
Prematurely discont. prior to Week 48 visit, n (%)
97 (19.2) 84 (16.6) 181 (17.9)
Reasons for discont., n (%)
Death/events leading to death* 3 (0.6) 1 (0.2) 4 (0.4)
Adverse events 42 (8.3) 32 (6.3) 74 (7.3)
Lost to follow-up 7 (1.4) 8 (1.6) 15 (1.5)
Consent withdrawn 9 (1.8) 4 (0.8) 13 (1.3)
Non-adherence 9 (1.8) 6 (1.2) 15 (1.5)
Lack of efficacy 26 (5.1) 24 (4.8) 50 (4.9)
Pregnancy 0 (0.0) 6 (1.2) 6 (0.6)
Other 1 (0.2) 3 (0.6) 4 (0.4)
VERX VE: Disposition of Randomized Patients Through Week 48
*None of the deaths/events were related to study medication, as judged by the investigators
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Pro
port
ion
of
pati
en
ts w
ith
V
irolo
gic
Resp
on
se W
eek 4
8
Viramune IR: 75.89% (384/506)Viramune XR: 80.99% (409/505)
Adjusted difference
4.92% in favour of Viramune XR, with 95% CI of (−0.11, 9.96)
Viramune XR shows non-inferiority to Viramune IR within pre-specified margin of −10%
Virologic response was independent of age, gender, race or geographic region
75.8980.99
0
10
20
30
40
50
60
70
80
90
100
Viramune IR Viramune XR
VERX VE: Sustained Virologic Response at Week 48 (VL <50 copies/mL, FAS)
FAS = Full analysis set
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Viramune IRViramune XR
100.00
Weeks
Pro
port
ion o
f V
irolo
gic
Resp
on
ders
80.00
60.00
40.00
20.00
0.00
0 2 4 6 8 12 16
24
32 40 48
VERX VE: Proportion with Virologic Response by Visit (VL <50 copies/mL, FAS)
FAS = Full analysis set
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• Designated trial centres participated in a pharmacokinetic sub-study, involving ~30 patients from each treatment arm
• Blood samples collected intensively for 24 hr following morning NVP administration in week 4 (visit 4): day 28
• Plasma NVP levels measured by tandem mass spectrometry (LC-MS/MS)
• Arithmetic mean (±SD) plasma concentration of NVP following 400mg QD and 200mg BID dosing determined
VERX VE: PK Sub-study at Day 28
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200 mg NVP IR bid (n=25)700
0
Time [hours]
Vir
am
une P
lasm
a (
ng/m
L)
6000
5000
4000
3000
2000
200 mg NVP XR qd (n=24)
0 4 8 12 16 20 24
(N=25)
(N=24)200mg Viramune IR BID400mg Viramune XR QD
VERX VE: PK Sub-study at Day 28: Results
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Parameter Viramune IR Viramune XR
Total number of patients, n/N 372/464 (80.2) 406/486 (83.5)
Geometric mean, trough ss (ng/mL), No. Responders/Total within stratum (n/N)
<1000 3/5 (60.0) 3/9 (33.3)
1000–<2000 25/31 (80.6) 46/54 (85.2)
2000–<3000 50/66 (75.8) 124/144 (86.6)
3000–<4000 108/125 (86.4) 71/90 (86.4)
≥4000 186/237 (78.5) 43/57 (80.3)
LLOQ (lower limit of quantification) = 50 copies/mL
Virologic response rates stratified by geometric mean steady state (ss) trough plasma concentrations (ng/mL)
FAS = Full analysis set
VERX VE: PK-PD Response Week 48 (FAS): Viramune XR Equivalent to Viramune IR at ≥1000ng/mL
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Change in median value from baseline at Week 48 (%)
Substrate
[mg/dL]
Viramune IR
(N=406)
Viramune XR
(N=419)
Triglycerides -8 (–9%) -6 (–7%)
Cholesterol 22 (13%) 19 (11%)
LDL-c 8 (9%) 7 (7%)
HDL-c 12 (32%) 10 (27%)
Total cholesterol/HDL-c -14% -12%
VERX VE: Percentage Change in Lipid Profile Viramune IR vs Viramune XR at Week 48
Viramune XR demonstrated a similar lipid friendly profile to that of Viramune IR
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*Investigator defined. Please note: No drug-related fatalities. Atherosclerosis/hypertension; tuberculosis (meningitis); two sepsis, myocardial infarction; respiratory alkalosis.
Parameter Viramune IR Viramune XR
Number of patients (N) 506 505
Any AE, n (%) 452 (89.3) 443 (87.7)
AEs leading to discontinuation, n (%)
45 (8.9) 32 (6.3)
Serious AEs, n (%) 54 (10.7) 58 (11.5)
Deaths 5 (1.0) 1 (0.2)
Drug-related* AEs 123 (24.3) 100 (19.8)
DAIDS Grade 3 or 4 AEs 91 (18.0) 73 (14.5)
DAIDS Grade 4 AEs 23 (4.5) 16 (3.2)
VERX VE: AE Summary Randomized Phase, FAS
FAS = Full analysis set
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Pivotal Trial (VERXVE) demonstrated: non-inferior efficacy for Viramune XR to Viramune IR similar safety and tolerability for both formulations; no new AEs
identified the combination of Viramune IR or Viramune XR with FTC/TDF is an
effective ARV treatment
PK – PD: Similar efficacy noted across many PK strata indicating adequate
trough drug exposure for Viramune XR Consistent relative trough exposure of Viramune XR to IR across
gender, region, and baseline viral-load strata
Once-daily dosing with VIRAMUNE XR provides patients with a more convenient treatment regimen with comparable efficacy and safety to VIRAMUNE IR
VERX VE: Conclusions
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Comparison of 48 week efficacy and safety of 400mg QD nevirapine extended release formulation (Viramune XR)
versus 200mg BID nevirapine immediate release formulation (Viramune IR) in combination with Truvada® in antiretroviral
(ARV) naïve HIV-1 infected patients (VERxVE)
J. Gathe, JR. Bogner, S. Santiago, A. Horban, M. Nelson, P. Cahn, J. Andrade, D. Spencer, C. Yong, T. Nguyen, W. Zhang,
M. Drulak and A. Quinson*
*Boehringer-Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA