1 / 24

A-HeFT ― Design and Study Population

A-HeFT ― Design and Study Population. Anne Taylor, MD Professor of Medicine University of Minnesota Medical School. 6. A-HeFT Objective. DV A-HeFT CSR P 15.

duc
Download Presentation

A-HeFT ― Design and Study Population

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. A-HeFT―Design and Study Population Anne Taylor, MD Professor of MedicineUniversity of Minnesota Medical School

  2. 6 A-HeFT Objective DV A-HeFT CSR P 15 • Demonstrate the safety and efficacy of BiDil® compared with placebo in black patients with moderate to severe HF concurrently receiving standard HF treatment

  3. 6 A-HeFT Study Design DV A-HeFT CSR P. 15 CSR • Double-blind, randomized, parallel-group, placebo-controlled study of black patients with stable symptomatic HF while on standard HF therapy

  4. 6 A-HeFT Dosing DV A-HeFT CSR P 37, 40 • BiDil® is an oral fixed-dose combination tablet • 20 mg ISDN • 37.5 mg HYD • Patients were randomized to BiDil or placebo • 1 tablet tid, with forced titration to a target of 2 tablets tid • Target dose • 120 mg/day ISDN • 225 mg/day HYD

  5. 6 CD-5 A-HeFT Study Design DV A-HeFT CSR F 1 RandomizeQoLEcho QoL Echo QoL QoL QoL QoL QoL BiDil® Placebo Screening Titration Baseline 1 tab tid 2 tabs tid 4 Visit no. 1 2 3 5 6 7 8 (final) 6mo Day/wk/mo –2 wk 0 3-5days 3mo 9mo 12mo 15mo 18mo Randomization stratified by β-blocker usage.

  6. Inclusion Criteria DV A-HeFT CSR pp 37-38 • Self-identified African American (black) patients • Symptomatically stable NYHA Class III-IV • On standard HF treatment • If on β-blockers, treated for at least 3 mo prior to study entry • Ejection fraction • LVEF ≤ 35% or • LVEF < 45% with resting LVIDD > 2.9 cm/m2(or > 6.5 cm)

  7. Exclusion Criteria (1) DV A-HeFT CSR § 4.3.2 • Unstable angina, myocardiaI infarction, acute coronary syndrome, cerebrovascular accident, cardiac surgery, percutaneous cardiac intervention within 3 mo • Valvular disease, hypertrophic obstructive cardiomyopathy, or myocarditis • Sustained VT unless implantable cardiac defibrillator • Requirement for inotropes • Women of childbearing age who were pregnant, nursing, or not using contraception • Rapidly deteriorating or uncompensated HF such that cardiac transplantation would be likely over the ensuing 1 year

  8. Exclusion Criteria (2) DV A-HeFT CSR § 4.3.2 • Symptomatic hypotension • Significant hepatic, renal, or other disease limiting survival over 1 year trial duration • Any condition that would jeopardize the evaluation of efficacy or safety • Any contraindications to the use of isosorbide dinitrate or hydralazine • Receipt of another investigational drug or device within 3 mo • Requirement for hydralazine, long-acting nitrates, or phosphodiesterase type 5 inhibitors

  9. DV A-HeFT CSR § 4.5.2 Primary Endpoint • Composite score • All-cause mortality • First HF hospitalization • Change in QoL at 6 mo relative to baseline

  10. Primary Endpoint Composite Score DV A-HeFT CSR 66, 67, T26, T24 Score Death (at any time during the trial) –3 Alive at end of trial 0 First HF hospitalization (adjudicated) –1 No HF hospitalization 0 Change in QoL at 6 mo(or last measurement, if earlier than 6 mo) Improvement ≥ 10 units +2 Improvement ≥ 5 and < 10 units +1 Change < 5 units 0 Worsening ≥ 5 and < 10 units –1 Worsening ≥ 10 units –2 Possible score = –6 to +2

  11. A-HeFT―Quality-of-Life Assessment • The Minnesota Living With Heart Failure questionnaire (MLHFQ) is a self-administered, 21-question tool measuring physical and emotional effects of HF • Scores range from 0 to 5 for each question(0 to 105 total possible score) • Lower scores indicate better QoL • QoL was measured at baseline and every 3 mo during the trial

  12. A-HeFT Design—Statistical Analysis for Primary Endpoint Composite Score DV A-HeFT CSR pp 36, 76 • Intention-to-treat analysis • Worst-case score for missing data • 3 components • Mortality (score 0 or –3) • Hospitalization for HF (score 0 or –1) • Change in QoL at 6 mo (score –2 to 2) • Cui, Hung, and Wang (1999) group sequential method

  13. Secondary Endpoints DV A-HeFT CSR § 4.5.2 • Death from any cause • Time to death • Cause-specific mortality • HF hospitalizations • Time to first hospitalization • Number of hospitalizations • Total days in hospital • Change from baseline in overall QoL MLHFQ score at each timepoint

  14. A-HeFT Design—Statistical Analysis for Secondary Endpoints DV A-HeFT CSR, NitroMed BB • Analysis of death: Kaplan-Meier, log-rank test • Analysis of first hospitalization for HF: Kaplan-Meier, log-rank test • Comparison of event rates of death and hospitalization for HF: 2-sample t test or Wilcoxon test • Comparison of change in QoL: 2-sample t tests for the difference between groups in MLHFQ scores at each timepoint

  15. Sample Size Calculation and Interim Analyses DV NitroMed BB pp 68-70 • Protocol specified 2 interim analyses plus a final analysis • Sample size re-estimation at the second interim analysis when 300 patients completed 6 mo • 313 patients who reached 6 mo were included in this interim analysis (528 patients were randomized) • Cui, Hung, and Wang method for analysis • For an α= 0.05 • 900 patients were required for 80% power • Per advice of FDA used an α = 0.02 for sample size re-estimation but not for hypothesis testing • 1100 patients were required for 80% power

  16. Trial Termination (1) DV NitroMed BB p 69-70 • No boundaries to terminate trial for mortality had been formulated at start of study (May 2001) • DSMB noted a disparity between treatment groups in deaths (March 2004) • O’Brien-Fleming type group sequential alpha spending function as described by Lan and DeMets to guide further decision making established at that time • Treatment difference in mortality in March 2004 fell just below the value specified by newly formulated boundaries • DSMB recommended 1 additional safety review to take place 3 mo to 5 mo later

  17. Trial Termination (2) DV NitroMed BB pp 69-71 • DSMB recommendation to stop trial at added safety review (July 2004) • Due to positive effect in mortality in BiDil group relative to placebo • Results discussed with Steering Committee, who also recommended study be stopped • NitroMed followed recommendations and stopped study on July 19, 2004

  18. Trial Overview DV A-HeFT CSR< NitroMed BB • 180 sites (169 sites randomized at least 1 patient) • 1050 randomized patients (518 BiDil®, 532 placebo) • Up to 18 mo of follow-up • No patient lost to follow-up for vital status • First patient enrolled 5/29/01 • Study terminated 7/19/04 for significant survival benefit in the BiDil group

  19. Baseline Characteristics (1) DV A-HeFT CSR T 14, 15 *P < 0.05

  20. Baseline Characteristics (2) DV A-HeFT CSR T 14, 15, 16, PTT16.1 *P < 0.05

  21. DV A-HeFT CSR T22 Baseline Cardiovascular Medications

  22. 6 Patient Disposition DV A-HeFT CSR P. 83

  23. 17-DV Study Drug Prescribed as Assessed by Total Tablets/Day at Various Time PointsA-HeFT CSR T20

  24. Mean Daily Prescribed Dose of BiDil® DV A-HeFT CSR T 20 Dose, mg/day (SD)

More Related