CD-1 A-HeFT― Design and Study Population Anne Taylor, MD Professor of Medicine University of...
-
Upload
stanley-johnston -
Category
Documents
-
view
213 -
download
0
Transcript of CD-1 A-HeFT― Design and Study Population Anne Taylor, MD Professor of Medicine University of...
CD-1
A-HeFT―Design and Study Population
Anne Taylor, MD
Professor of MedicineUniversity of Minnesota Medical School
CD-2
A-HeFT Objective
Demonstrate the safety and efficacy of BiDil® compared with placebo in black patients with moderate to severe HF concurrently receiving standard HF treatment
DV
A-H
eF
T C
SR
P 1
56
CD-3
A-HeFT Study Design
Double-blind, randomized, parallel-group, placebo-controlled study of black patients with stable symptomatic HF while on standard HF therapy
DV
A-H
eF
T C
SR
P.
15 C
SR
6
CD-4
A-HeFT Dosing
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
6D
V A
-He
FT
CS
R P
37,
40
A-HeFT Study Design
6D
V A
-He
FT
CS
R F
1
QoLEcho QoL QoL QoL QoL
Screening
RandomizeQoLEcho
BiDil®
Placebo
Visit no.
Day/wk/mo –2 wk 0
1
Baseline
Titration3-5
days
2
1 tab tid 2 tabs tid
3mo
3
QoL
6mo
4
9mo
5
12mo
6
15mo
7
18mo
8 (final)
Randomization stratified by β-blocker usage.
CD-5
CD-6
Inclusion Criteria
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)
DV
A-H
eFT
CS
R p
p 37
-38
CD-7
Exclusion Criteria (1)
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
DV
A-H
eFT
CS
R §
4.3
.2
CD-8
Exclusion Criteria (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
DV
A-H
eFT
CS
R §
4.3
.2
CD-9
Primary Endpoint
Composite score
– All-cause mortality
– First HF hospitalization
– Change in QoL at 6 mo relative to baseline
DV
A-H
eFT
CS
R §
4.5
.2
CD-10
Primary Endpoint Composite Score Score
Death (at any time during the trial) –3 Alive at end of trial 0
First HF hospitalization (adjudicated) –1No HF hospitalization 0
Change in QoL at 6 mo(or last measurement, if earlier than 6 mo)
Improvement ≥ 10 units +2Improvement ≥ 5 and < 10 units +1Change < 5 units 0Worsening ≥ 5 and < 10 units –1Worsening ≥ 10 units –2
Possible score = –6 to +2
DV
A-H
eFT
CS
R 6
6, 6
7, T
26,
T24
CD-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
CD-12
A-HeFT Design—Statistical Analysis for Primary Endpoint Composite Score
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
DV
A-H
eFT
CS
R p
p 36
, 76
CD-13
Secondary Endpoints
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
DV
A-H
eFT
CS
R §
4.5
.2
CD-14
A-HeFT Design—Statistical Analysis for Secondary Endpoints
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
DV
A-H
eFT
CS
R,
Nitr
oMed
BB
CD-15
Sample Size Calculation and Interim Analyses
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
DV
Nitr
oMed
BB
pp
68-7
0
CD-16
Trial Termination (1)
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
DV
Nitr
oMed
BB
p 6
9-70
CD-17
Trial Termination (2)
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
DV
Nitr
oMed
BB
pp
69-7
1
CD-18
Trial Overview
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
DV
A-H
eFT
CS
R<
Nitr
oMed
BB
CD-19
Baseline Characteristics (1)
* P < 0.05
BiDil®
n = 518Placebon = 532
Age (mean), yr 57 57
Male sex* 56% 64%
NYHA class
III 95% 95%IV 3% 5%
Primary cause of heart failure
Ischemic heart disease 23% 23%Hypertension 40% 37%Idiopathic 25% 28%Valvular heart disease 3% 3%Other 10% 9%
DV
A-H
eF
T C
SR
T 1
4, 1
5
CD-20
Baseline Characteristics (2)
BiDil®
n = 518Placebon = 532
Systolic BP, mm Hg (mean ± SD) 127 ± 18 125 ± 18
Diastolic BP,* mm Hg (mean ± SD) 78 ± 10 76 ± 11
QoL score (mean ± SD) 51 ± 25 51 ± 26
LVIDD, cm (mean ± SD) 6.5 ± 0.9 6.5 ± 1.0
Ejection fraction, % (mean ± SD) 24 ± 7 24 ± 8
Diabetes,* % 45 37
Renal insufficiency, % 16 18
Atrial fibrillation, % 15 18
Implantable cardiac defibrillator, % 17 17
DV
A-H
eF
T C
SR
T 1
4, 1
5,
16,
PT
T1
6.1
* P < 0.05
CD-21
Baseline Cardiovascular Medications
Patients, n (%)
BiDil®
(n = 518)Placebo(n = 532)
ACE inhibitor 386 (74.5) 400 (75.2)
ARB 124 (23.9) 112 (21.1)
ACE inhibitor or ARB 478 (92.3) 495 (93.0)
β-blocker 434 (83.8) 437 (82.1)
Aldosterone antagonist 208 (40.2) 201 (37.8)
Digitalis glycoside 304 (58.7) 324 (60.9)
Diuretic 473 (91.3) 494 (92.9)
Calcium channel blocker 109 (21.0) 104 (19.5)
DV
A-H
eFT
CS
R T
22
CD-22
Patient Disposition
Patients, n (%)
BiDil® Placebo
Total randomized patients 518 (100.0) 532 (100.0)
Completed study 469 (90.5) 457 (85.9)
Discontinued from study prematurely
49 (9.5) 75 (14.1)
Death 30 (5.8) 54 (10.2)
Investigator decision 9 (1.7) 13 (2.4)
Patient withdrew consent 5 (1.0) 3 (0.6)
Patients lost to follow-up (non-vital status follow-up)
2 (0.4) 0
Cardiac transplantation 3 (0.6) 3 (0.6)
Not reported 0 2 (0.4)
6D
V A
-HeF
T C
SR
P.
83
CD-23Study Drug Prescribed as Assessed by Total Tablets/Day at Various Time PointsA-HeFT
Mean ± SD
TimepointBiDil®
n = 517Placebon = 527
3 mo 4.4 ± 2.1 5.0 ± 1.96 mo 4.5 ± 2.0 5.1 ± 1.89 mo 4.8 ± 1.9 5.2 ± 1.712 mo 4.8 ± 1.9 5.3 ± 1.615 mo 4.9 ± 1.7 5.3 ± 1.7Endpoint 4.1 ± 2.0 5.2 ± 1.5
17-DV
CS
R T
20
CD-24
Mean Daily Prescribed Dose of BiDil®
ISDN HYD
3 mo (n = 368) 88 (42) 188 (71)
6 mo (n = 317) 90 (40) 191 (68)
9 mo (n = 260) 96 (38) 195 (64)
12 mo (n = 220) 96 (38) 199 (60)
15 mo (n = 169) 98 (34) 199 (64)
Dose, mg/day (SD)
DV
A-H
eFT
CS
R T
20