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Published on October 29, 2007

Author: Jolene

Source: authorstream.com

Efficacy and Safety of Maraviroc in Antiretroviral-Experienced Patients Infected With CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE 1:  Efficacy and Safety of Maraviroc in Antiretroviral-Experienced Patients Infected With CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE 1 J Lalezari1, J Goodrich2 , E DeJesus3, R Gulick4, H Lampiris5, M Saag6, N Bellos7, J Nadler8, P Tebas9, B Trottier10, M Wohlfeiler11, C Ridgeway12, M McHale12, E van der Ryst12, H Mayer2, on behalf of the MOTIVATE 1 Study Team 47th ICAAC Chicago, USA, September 17–20, 2007 1Quest Clinical Research, UCSF, San Francisco, CA, USA 2Pfizer Global Research and Development, New London, CT, USA 3Orlando Immunology Center, Orlando, FL, USA 4Weill Medical College of Cornell University, New York, NY, USA 5San Francisco Veterans Affairs Medical Center, UCSF, San Francisco, CA, US 6University of Alabama at Birmingham, Birmingham, AL, USA 7Southwest Infectious Disease Associates, Dallas, TX, USA 8University of South Florida, Tampa, FL, USA 9University of Pennsylvania, Philadelphia, PA, USA 10Clinique Medicale L'Actuel, Montreal, QC, CANADA 11Wohlfeiler, Piperato & Associates, North Miami Beach, FL, USA 12Pfizer Global Research and Development, Sandwich, UK Background :  Background MOTIVATE 1 is one of two randomized, double-blind, placebo-controlled, Phase 3 studies investigating the safety and efficacy of the CCR5 antagonist maraviroc, in treatment-experienced patients with R5 HIV-1 In a planned interim analysis at 24 weeks1, maraviroc (QD and BID) + OBT vs OBT alone demonstrated significantly greater virologic suppression rates significantly greater increases in CD4+ count no clinically relevant differences in safety profile The MOTIVATE 1 primary efficacy endpoint is the change from baseline in HIV-1 RNA at 48 weeks 1. Lalezari J et al. 14th CROI 2007; Presentation 104bLB J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a MOTIVATE 1 Trial Design:  Randomization 1:2:2 N=601 MOTIVATE 1 Trial Design OBT* + maraviroc (150 mg† BID) OBT* + maraviroc (150 mg† QD) OBT* + placebo 0 24w * 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 Screening (6 weeks) 48w Patients stratified by: Enfuvirtide use in OBT HIV-1 RNA < and ≥100,000 copies/mL at screening 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) J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Demographics and Baseline Characteristics:  Demographics and Baseline Characteristics MOTIVATE 1-Week 48 Includes all patients who received at least one dose of study medication (full analysis set) § Two patients (1 MVC QD, 1 OBT alone) were assigned to the wrong treatment group due to a transcription error * Calculated for each patient as the mean of up to three pre-dose assessments (screening, randomization, and baseline) † According to overall susceptibility score J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Mean Change from Baseline in HIV-1 RNA:  Mean Change from Baseline in HIV-1 RNA Includes all patients who received at least one dose of study medication HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks *Treatment difference vs OBT alone MOTIVATE 1-Week 48 Mean change in HIV-1 RNA from baseline (log10 copies/mL) Difference: -0.85* (97.5% CI: -1.22, -0.49) Difference: -1.02* (97.5% CI: -1.39, -0.66) Study week Difference: -0.79* (97.5% CI: -1.14, -0.44) Difference: -0.92* (97.5% CI: -1.28, -0.57) 24 48 J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Percentage of Patients with Undetectable HIV-1 RNA :  Percentage of Patients with Undetectable HIV-1 RNA Time (weeks) Time (weeks) Patients (%) MOTIVATE 1-Week 48 HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks *P<0.0001 vs OBT alone #P<0.0006 vs OBT alone Includes all patients who received at least one dose of study medication Number of patients remaining on study treatment at Week 48: OBT alone, 27 (30%); MVC QD + OBT, 109 (60%); MVC BID + OBT, 127 (66%) J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Mean Change from Baseline in CD4+ Count:  MOTIVATE 1-Week 48 Last observation carried forward * P<0.0001 vs OBT alone Mean Change from Baseline in CD4+ Count Includes all patients who received at least one dose of study medication Mean change from baseline in CD4+ count (cells/mm3) 24 48 Difference: +59 * (95% CI: +34, +84) Difference: +69 * (95% CI: +44, +93) Difference: +55 * (95% CI: +30, +79) Difference: +59 * (95% CI: +35, +83) Study week J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Percentage of Patients With HIV-1 RNA <50 copies/mL at Week 48 According to Screening HIV-1 RNA*:  Percentage of Patients With HIV-1 RNA <50 copies/mL at Week 48 According to Screening HIV-1 RNA* Includes all patients who received at least one dose of study medication and had a post-baseline observation Patients (%) MOTIVATE 1-Week 48 <100,000 copies/mL ≥100,000 copies/mL Total population N = 70 135 139 46 93 95 116 228 234 Last observation carried forward * Protocol-defined randomization stratum J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With Undetectable HIV-1 RNA at Week 48 According to ENF First Use:  Patients (%) N= <400 copies/mL <50 copies/mL MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With Undetectable HIV-1 RNA at Week 48 According to ENF First Use MOTIVATE 1 & 2-Week 48 Last observation carried forward J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a 3 27 36 3 25 64 71 35 32 61 71 43 0 10 20 30 40 50 60 70 80 90 100 Safety Analyses Unadjusted for Duration of Exposure:  Safety Analyses Unadjusted for Duration of Exposure AEs = adverse events; SAEs = serious adverse events *Includes deaths reported up to 28 days after stopping study drug No deaths were related to study drug according to the investigator MOTIVATE 1-Week 48 Includes all patients who received at least one dose of study medication J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Incidence of Adverse Events Occurring in ≥10% of Patients in Any Group, Unadjusted for Exposure:  Incidence of Adverse Events Occurring in ≥10% of Patients in Any Group, Unadjusted for Exposure Includes all patients who received at least one dose of study medication Total exposure in patient-years: OBT alone 64, MVC QD + OBT 168, MVC BID + OBT 169 MOTIVATE 1-Week 48 MVC QD + OBT (N=232) MVC BID + OBT (N=235) OBT alone (N=118) Patients (%) RTI = respiratory tract infection; ISR = injection site reaction J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Number of Category C Events:  Number of Category C Events * Includes T-cell and diffuse large B-cell lymphomas MOTIVATE 1-Week 48 Includes all patients who received at least one dose of study medication J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Maximum Liver Function Test Values Over 48 Weeks Without Regard to Baseline :  Maximum Liver Function Test Values Over 48 Weeks Without Regard to Baseline * Total patients evaluated for each laboratory parameter † Upper limit of normal MOTIVATE 1-Week 48 J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a MOTIVATE 1 and 2: Change in CD4+ Cell Count from Baseline by Tropism Result at Time of Failure:  MOTIVATE 1 and 2: Change in CD4+ Cell Count from Baseline by Tropism Result at Time of Failure MOTIVATE 1 & 2-Week 48 * Includes patients with non-reportable/non-phenotypable tropism result at baseline and patients with non-reportable/non-phenotypable/missing tropism result at time of failure J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a MOTIVATE 1: Summary of 48-Week Primary Analysis:  MOTIVATE 1: Summary of 48-Week Primary Analysis Maraviroc (BID or QD) + OBT provided significantly greater virologic suppression rates and increases in CD4+ count compared to OBT alone 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 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 J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a Acknowledgments:  Acknowledgments Investigators and study site staff Patients who participated in the study Colleagues from Monogram Biosciences: J Whitcomb, E Coakley, C Petropoulos R Harrigan, BC Centre for Excellence in HIV Colleagues from Quintiles Colleagues from Pfizer: S Felstead, A Bullivant, I Oborska, K George, M Westby, K Turner, D Lindell, D Paige, S Nuttall, J Merson, L Kapili, M Dunne J Lalezari et al, 47th ICAAC, 17-20 September 2007, presentation number H-718a

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