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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.

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A-HeFT ― Design and Study Population

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  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)

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