comparison of 48 week efficacy and safety of 400mg qd nevirapine (nvp) extended release formulation...
TRANSCRIPT
VERX VE
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
· 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
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
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
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 randomized=1068, 1011=randomized & treated (full analysis set, FAS), 2 randomized not treated, 55 DC during lead-in
VERX VE: Demographic Data
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
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
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
• Designated trial centres participated in a pharmacokinetic sub-study, involving ~25 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
7000
Time [hours]
Vir
am
une P
lasm
a (
ng/m
L)
6000
5000
4000
3000
20000 4 8 12 16 20 24
(N=25)(N=24)
200mg Viramune IR BID 400mg Viramune XR QD
VERX VE: PK Sub-study at Day 28: Results
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) 116/144 (86.6)
3000–<4000 108/125 (86.4) 127/147 (86.4)
≥4000 186/237 (78.5) 114/142 (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
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 profile to that of Viramune IR
*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
· Pivotal Trial (VERXVE) demonstrated:
· Non-inferior efficacy for Viramune XR to Viramune IR
· Similar safety and tolerability profiles for both formulations
· 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
We would like to thank all the patients and investigators for their involvement and
dedicated support in this trial
VERX VE: Acknowledgments