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Efficacy and Safety of Maraviroc (MVC) Plus Optimized Background Therapy (OBT) In Viraemic, Antiretroviral Treatment-Experienced Patients Infected with CCR5-Tropic (R5) HIV-1 in Europe, Australia and North America (MOTIVATE 2): 48-Week Results
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Reported by Jules Levin
11th European AIDS Conference, Oct 24-27, 2007, Madrid
G Fatkenheuer1, I Konourina2, M Nelson3, N Clumeck4, A Lazzarin5, IM Hoepelman6,
H Mayer7, J Sullivan2, F Raffi8, D Cooper9, M Tawadrous7, B Clotet10, A Karlsson11,
J Buscemi Montana12, B Hirschel13, A Horban14, E van der Ryst2, on behalf of the MOTIVATE 2 Study Team
1University of Cologne, Köln, Germany
2Pfizer Global Research and Development, Sandwich, UK
3Chelsea & Westminster Hospital, London, UK
4CHU St-Pierre, Brussels, Belgium
5IRCCS San Raffaele, Milan, Italy
6University Medical Center, Utrecht, The Netherlands
7Pfizer Global Research and Development, New London, USA
8University of Nantes, Nantes, France
9University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
10Hospital Universitari Germans Trias i Pujol, Fundacio irsiCaixa, Barcelona, Spain
11Venhalsan, Karolinska University Hospital, Stockholm, Sweden
12St Vincent's Hospital, New York, USA
13Geneva University Hospital, Geneva, Switzerland
14Szpital Zakazny Centrum Diagnostyki i Terapii AIDS, Warsaw, Poland
AUTHOR SUMMARY
Maraviroc (BID or QD) + OBT provided significantly greater virological suppression rates and increases in CD4+ count compared with
PBO + OBT at 48 weeks in this treatment-experienced population
No new or unique safety findings emerged
--Adverse events, serious adverse events and lab abnormalities (including grade 3/4 transaminase elevations) occurred with similar frequency between treatment groups
No patient died whilst receiving PBO + OBT; none of the deaths in patients receiving maraviroc (BID or QD) + OBT were related to study drug according to investigators
--Category C (AIDS-defining) events were balanced across treatment groups
These results demonstrate that treatment with maraviroc + OBT provides sustained antiretroviral efficacy and tolerability in treatment-experienced patients
BACKGROUND
MOTIVATE 2 is one of two randomized, double-blind, placebo-controlled Phase 3 studies assessing the safety and efficacy of maraviroc in treatment-experienced patients with R5 HIV-1
The study is being conducted in Europe, Australia and North America
In a planned interim analysis at 24 weeks1, maraviroc (QD and BID) + OBT vs Placebo (PBO) + OBT demonstrated
--significantly greater virological suppression rates
--significantly greater increases in CD4+ count
--no clinically relevant differences in safety profile
Primary endpoint: change from baseline in HIV-1 RNA at 48 weeks
Trial design
474 patients were randomized 1:2:2 to placebo or maraviroc 150 mg once daily (qd) or maraviroc (mvc) twice daily (bid), all 3 groups along with OBT, optimized therapy background.
Patient eligibility criteria:
--R5 HIV-1 infection
--HIV-1 RNA ≥5,000 copies/ml
--Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks
--Resistance to and/or ≥ 6 months' experience with ≥ one ARV from three classes (≥ two for PIs)
Patients stratified by:
-- Enfuvirtide use in OBT
-- HIV-1 RNA < and ≥100,000 copies/ml at screening
OBT = optimized background therapy of 3-6 ARVs (PK boosting doses of RTV not counted as an ARV)
Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients received 300 mg dose of MVC
Demographics and Baseline Characteristics
Includes all patients who received at least one dose of study medication (full analysis set).
84-89% of patients are men; 82-87% are white. Median cd4 count is 174-182; mean viral load is 4.88 log. 45% in placebo and 38% in MVC arms had fuzeon in background therapy; 66% in placebo and 63% in MVC QD and 62% in MVC bid had 2 or less active drugs in OBT. Of note, Darunavir use was not permitted for this study.
Calculated for each patient as the mean of up to three pre-dose assessments (screening, randomization, and baseline)
According to overall susceptibility score
Mean Change from Baseline in HIV-1 RNA
After 48 weeks, placebo group had mean viral load log reduction of -0.76, MVC qd group -1.72, and MVC bid -1.87. this compared with reductions at week 24 of -0.93 for placebo, -1.95 for MVC qd, and -1.97 for MVC bid.
Percentage of Patients with Undetectable HIV-1 RNA
At week 48, 45% in both the qd and bid groups had <50 copies/ml and 18% in the placebo group had <50 c/ml. After 24 weeks of study the authors report in this slide, 55% in bid MVC and 53% in MVC qd groups had <400 c/ml.
--Includes all patients who received at least one dose of study medication.
--Number of patients remaining on study treatment at Week 48:
PBO + OBT, 39 (33%); MVC QD + OBT, 143 (62%); MVC BID + OBT, 151 (64%)
Mean Change from Baseline in CD4+ Count
Includes all patients who received at least one dose of study medication.
Cd4 increas was a mean of 112 cells for qd MVC and 102 for MVC bid at week 24, and a 64 cell increase for placebo. After 48 weeks, mean cd4 increase was 69 for placebo, 121 for MVC qd, and 128 for MVC bid.
Percentage of Patients With HIV-1 RNA <50 copies/ml at Week 48 According to Screening HIV-1 RNA
51% using MVC qd and 48% using MVC bid had <50 c/ml in this analysis. For patients with >100,000 c/ml at baseline, 38% taking MVC bid and 34% taking MVC qd achieved <50 c/ml after 48 weeks, and 13% on placebo. For patients with <100,000 c/ml at baseline, 64% taking qd, 56% taking bid, and 25% taking placebo achieved <50 c/ml.
--Includes all patients who received at least one dose of study medication and had a post-baseline observation.
MOTIVATE 1 and 2: Proportion of Patients Receiving ENF with Undetectable HIV-1 RNA at Week 48 According to ENF First Use (clearly, use of Fuzeon for patients who had not previously taken Fuzeon made a big difference in response)
For patients who never before used Fuzeon, 64% taking MVC qd, 61% taking MVC bid, and 27% taking placebo achieved <50 c/ml after 48 weeks. For patients with Fuzeon experience/resistance, 25% taking MVC qd, 32% taking MVC bid, and 7% taking placebo achieved <50 c/ml. 71% taking MVC qd or bid achieved <400 c/ml if taking first use of Fuzeon, and 36% of patients in placebo group taking first use of Fuzeon achieved <400 c/ml. This compared with 35% taking MVC qd, 43% taking MVc bid and 3% taking placebo who had Fuzeon experience/resistance who achieved <400 c/ml.
--Includes all patients who received at least one dose of study medication and who received ENF in their OBT.
Safety Analyses Unadjusted for Duration of Exposure
Patients discontinuing due to AEs: 4% placebo, 6% MVC qd, 5% MVC bid.
Patients with grade 3 AEs: 18% placebo, 25% MVC qd, 26% MVC bid.
Patients with serious AEs: 18% placebo, 17% MVC qd, 16% MVC bid.
Patients with category C events: 115 placebo, 105 MVC qd, 6% MVC bid,
Patients with category C malignancies: 1% placebo, 1% MVC qd, 2% MVC bid.
Includes all patients who received at least one dose of study medication.
AEs = adverse events; SAEs = serious adverse events
Deaths reported up to 28 days after stopping study drug
Patient received open-label MVC prior to death
No deaths were related to study drug according to investigators
Incidence of Adverse Events Occurring in ≥10% of Patients in Any Group, Unadjusted for Exposure
Diarrhea, nausea, headache, fatigue appear to be the most common listed in the table but there does not appear to be difference between placebo and MVC. Nasopharyngitis appears to occur more often in MVC arms compared to placebo as well as upper respiratory infections and cough.
Includes all patients who received at least one dose of study medication
Total exposure in patient-years: PBO + OBT 46, MVC QD 132, MVC BID 140
Maximum Liver Function Test Values Over 48 Weeks Without Regard to Baseline
Rate of grade 3 ALT elevations (5-10 x ULN) is 4.4% in placebo group, 2.8% in MVC qd, and 1.1% for MVC bid. Grade 4 ALT elevations (>10 x ULN). AST elevations-- grade 3: 2.2% placebo, 2.85 MVC qd, 3.7% MVC bid; grade 4: 0 placebo, 0.6% (n=1) MVC qd, 1.1% (n=2) MVC bid. Total bilirubin: grade 3: 4.4% placebo, 6,1% MVC qd, 5.9% MVC bid. Grade 4: 1.1% placebo, 1.7% MVC qd, 0 MVC bid.
ALT = alanine transaminase; AST = aspartate transaminase
Total patients evaluated for each laboratory parameter
Upper limit of normal
Data missing for one patient
MOTIVATE 1 and 2: Mean change in CD4+ Cell Count from Baseline by Tropism Result at Time of Failure.
For patients who failed with X4 or DM tropism, mean CD4 change was +47 for MVC qd and +57 for MVC bid. Mean Cd4 change for patients on placebo was +24. For patients with R5 at failure: +77 cd4s for MVC qd and +133 for MVC bid.
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