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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 l.jpg

A-HeFT―Design and Study Population

Anne Taylor, MD

Professor of MedicineUniversity of Minnesota Medical School


A heft objective l.jpg

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


A heft study design l.jpg

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


A heft dosing l.jpg

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


A heft study design5 l.jpg

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.


Inclusion criteria l.jpg
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)


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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


Exclusion criteria 2 l.jpg
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


Primary endpoint l.jpg

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


Primary endpoint composite score l.jpg
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


A heft quality of life assessment l.jpg
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


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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


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Secondary Endpoints Composite Score

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


A heft design statistical analysis for secondary endpoints l.jpg
A-HeFT Design—Statistical Analysis for Secondary Endpoints Composite Score

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


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Sample Size Calculation and Composite ScoreInterim 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


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Trial Termination (1) Composite Score

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


Trial termination 2 l.jpg
Trial Termination (2) Composite Score

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


Trial overview l.jpg
Trial Overview Composite Score

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


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Baseline Characteristics (1) Composite Score

DV A-HeFT CSR T 14, 15

*P < 0.05


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Baseline Characteristics (2) Composite Score

DV A-HeFT CSR T 14, 15, 16, PTT16.1

*P < 0.05


Baseline cardiovascular medications l.jpg

DV A-HeFT CSR T22 Composite Score

Baseline Cardiovascular Medications


Patient disposition l.jpg

6 Composite Score

Patient Disposition

DV A-HeFT CSR P. 83


Study drug prescribed as assessed by total tablets day at various time points a heft l.jpg

17-DV Composite Score

Study Drug Prescribed as Assessed by Total Tablets/Day at Various Time PointsA-HeFT

CSR T20


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Mean Daily Prescribed Dose of BiDil Composite Score®

DV A-HeFT CSR T 20

Dose, mg/day (SD)


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