BU 9202 UK STilDY 20 July 1999 Page 11 of 249

2 SYNOPSIS

COMPARATNE EFFECTS OF BUMETANIDE PLUS CAPTOPRIL AN D

FRUSEMIDE PLUS CAPTOPRIL IN PATIENTS WITH CONGESTIVE CARDIAC

FAILURE WITH LONG-TERM FOLLOW-UP FOR UP TO TWO YEARS

Objectives:

PHASE I: to compare the safety and efficacy of bumetanide given twice-daily and

frusemide given once-daily for 12 weeks in patients with congestive cardiac failure

receiving captopril concomitantly.

PHASE D: to monitor long-term safety and efficacy of maintenance treatment with

burnetanide and captopril, twice-daily for up to a further 96 weeks.

Study Design: This was a 12 week multicentre, prospective, randomised, single-

blind, parallel-group comparison of bumetanide O.Smg twice-daily and frusemide

40.0mg once-daily in patients with congestive cardiac failure receiving captopril

12.5mg twice-daily or 25.0mg twice-daily (phase I) followed by open-labeJ safety

assessment of bumetanide plus captopril for up to 2 years (phase ll). During Phase

I, the interval between visits was initially 2 weeks and then increased to 4 weeks.

During Phase IL there was an initial visit at four weeks, all subsequent visits being

12 weekly from commencement of phase IL The dose of loop diuretic remained

constant during Phase I at O.Smg twice-daily bumetanide or 40.0mg once-daily

frusemide. The dose of captopril was allowed to be adjusted to either 12.5mg

twice-daily or 25.0mg twice-daily. During phase J:!: patients were able to receive

one of the following doses to maintain optimum control.

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Page 12 of 249

each dose

bumetanide + captopril

O.Smg + 12.5mg O.Smg + 25.0mg l.Omg + 12.5mg l.Om,g + 25.0mg O.Smg + 50.0mg 1.0mg + SO.Omg

20 July 1999

total daily dose

bumetanide + captopril

l.Omg + 25.0mg l.Omg + SO.Omg 2.0mg + 25.0mg 2.0mg + 50.0mg 1.0mg + lOO.Omg 20mg + 100.0mg

Dwation of study phases: Phase 1: up to 12 weeks

BU 9202 UK STUDY

Phase ll: up to a further 96 weeks

SoUl"Ce of Patients: Primary care in the United Kingdom.

Eligibility Giteria: Patients of either sex, over 18 years of age receiving 40.0mg

frusemide or l.Omg bumetanide together with either 12.5mg twice-daily or 25.0mg

twice-daily captopril for the control of congestive cardiac failure. Patients should

have been treated for at least 8 weeks prior to inclusion and likely to require

maintenance therapy for 2 years. Excluded were pregnant or nursing females,

patients with significant hepatic or renal impairment, a histoty of urinary retentio~

adrenocortical insufficiency, aortic stenosis, serum potassium > 5.4mmol/l, serum

sodium

BU 9202 UK STilDY 20 fuly 1999 Page 13 of 249

Study medication: Burinex® tablets containing l.Omg bumetanide

Lasix® tablets containing 40.0mg frusemide

Capoten® tablets containing 12.5mg or 25.0mg captopril.

Giteria for efficacy and safety: The Primary Response Criterion was the

proportion of patients who "failed treatmenr' at the end of Phase I. "Failed

treatmenr' was defined as a patient with two or more defined features of

congestive cardiac failure or who required a dosage increase in diuretic or who

required more than 25.0mg twice-daily captopril daily. Defined features of cardiac

failure assessed were ankle oedema, dyspnoea and pulmonary crepitations.

Other response criteria included:

i) proportion of patients who responded satisfactorily, i.e. had no defined

features of congestive cardiac failure

ii) proportion of patients with changes in features of cardiac failure

iii) changes in weight, blood pressure and pulse

iv) changes in laboratory parameters

v) adverse events

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Study procedures:

PHASE I PHASE II

VISIT 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Weeks 0 2 4 8 12 16 24 36 48 60 72 84 96 108

±4 days ±3weeks

Patient hi~tory *

Clinical * * * * ... ... ... * ... ... ... * ...

assessment

Blood test * (*) * (*) * * * * ·* * * * *

Randomisation *

Adverse events * ... * * * * ... * * • " *

Dispense; collect * * * * * * * * * * * * trial medication

(*) If patient was withdrawn from study.

Adverse events: At each visit patients were asked if they had experienced any

problems. No specific symptoms were asked for. Any adverse events reported

were recorded in respect of nature, severity and relationship to therapy.

Patient numbers: The Primary Criterion of Efficacy was the proportion of patients

who had 'failed treatment'.

Based on previous experience with bumetanide, approximately 7% of patients

were expected to have such a response. To demonstrate that the difference in

failure rate between the two treatments is less than 10%, approximately 100

analysable patients were required in each treatment group. To achieve 200

analysable patients at visit 5, 240 (i.e. analysable + 20%) patients were to be

enrolled. Each study centre aimed to recruit 8 patients, although study medication

was available in blocks of four treatments.

*

*

*

*

I

BU 9202 UK STUDY 20 July 1999 Page 15 of 249

Efficacy results:

Phase I

Results in respect of the Primary Response Criterion, namely the proportion of

patients who failed treatment, are shown below for the intention-to-treat

population and the per-protocol population.

Number of patierzts who failed treahnent: intention-to-treat population.

Bumetanide frusemide Odds Rat i o11

(N~122 l IN.,126l (95% Cil

p-value

No . Ho. %

f ailed t r:eatment

Yes 34 28 .1 37 29.4 0 . 94 No 8'7 ., l. 9 8 9 '70 . 6 (0. 5 4 , 1 . 63} n 121 100.0 126 100 . 0 p - 0.83

11 Odds ratio for the comparison of bumetanide relative to frusemide .

Number of patients who foiled treatment: per-protocol population.

Burnetanide li'rusemide Odds ra t io11

IN=ll9l !N.,125l !95% Cl l

p-va l ue

No . % No. %

failed treatment

Yes 30 25.2 3'7 29.6 0 .80 No 89 74.8 88 10 . 4 ( 0 . 45, 1. 41) n 119 100.0 125 100 . 0 p" 0.44

11 Odds ratio for the comparison of bumetanide rel at-ive to frusemide.

There were no statistically significant differences between the two treatments. .

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The number of patients who achieved a satisfactory response to treatment, i.e. had

no features of congestive cardiac failure at the end of phase I, are shown below.

Number of patients with a satisfactory response to treatment: per-protocol population

Satisfactory response

t o treatme nt'

Yes No n

Bumetani de

{N=ll 9 )

No.

59 59

118

50 .0 50. 0

100. 0

E'rus emi de

(N= l 25l

No .

62 63

125

4 9 . 6 50 . 4

100 . 0

Odds rat i o 2

(95% CIJ

p -val ue

1. 02 (0 . 61, 1.66) p"' 0 . 95

A pa~ient had a sati sfacto ry response to treatment if t hey had no fea tures

of congest ive ca rdiac fail u re .

: Odds r atio f or the compa r ison of bumetanide relative to frusemide.

There was no statistically significant difference between the two treatments.

BU 9202 UK STUDY 20 July 1999 Page 17 o[249

Features of congestive cardiac failure at end of phase L are shown below.

Ankle oedema at end of phase I : per-protocol population

Bumetan ide .Fru semi de Odds ra t i o 1

(N•ll9) (N-125 ) (95% CII

p-val ue

. No . % No. %

ANK LE OEDEMA

Y f!'S 38 3 1.9 37 29.6 1.15 No 81 68.1 ea 7 0.4 ( 0. 641 2.09) n 1 1 9 100.0 125 100 . 0 p = 0. 64

I Odds l'a t io for the comparison of bumetanide rel at i ve t o fr:usemide.

Dyspnoea at end of phase 1 : per-protocol population

Burnet an i d e Frusemi de Odds ~:at iol

! N=l l 9l (N=l 25) (95 \ CI)

p-va lu~

No. ' No . % DYSPNOEA

Yes 38 31.9 42 33 . 6 0 . 84 No 81 69 . 1 83 66 .4 ( 0 . 48, 1. 47) n 119 100 . 0 125 100.0 p = 0 . 54

1 Odds ratio for: the comparison of bumetani de relative to frusemide .

Pulmonary crepitations at end of phase I : per-protocol papulation

Bumetani d e frusemide Odds r atio 1

(N,. l19) (N-125) (95\ CII

p-value

No. ' No. % E'U LHONARY CREPITATIONS

Yes 10 8 . 5 17 13.6 0.61 No 106 91.5 106 96 . 4 ( 0 . 2 5 , 1. 46) n 11 9 100.0 125 100.0 p - 0.27

Odds ra tio for the compa r ison of bumetanide relati ve to frus emide .

There was no statistically significant difference between treabnents.

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At the end of treabnent there were no statisticaUy significant differences between

treatments (bumetanide - frusemide) in sitting systolic blood pressure (0.4 mmHg,

95% CI, -3.4, 4.1, p=0.85) in sitting diastolic blood pressure (-0.2 mmHg, 95% CI, -

2.1, 1.8, p=0.87) in standing systolic blood pressure (2.4 mmHg, 95% Cl, -1.4, 6.3,

p=0.22) in standing diastolic blood pressure (-0.1 mmHg, 95% CI, -2.1, 2.0, p=0.95).

Similarly, at the end of treatment there were no statistically significant differences

between treatments (bumetanide- frusemide) in pulse (0.9 bpm, 95% a, -1.3, 3.1, p=0.42), or weight (-0.5 kg, 95% CL -1.0, 0.1, p""0.094).

Phase II

Change from frusemide to burnetanide.

The change in diuretic treatment from frusemide to bumetanide had no obvious

affect on patients' features of cardiac failure when assessed after 4 weeks. Features

of cardiac failure at this time were comparable to features of cardiac failure in

patients who continued to take bumetanide for. a further 4 weeks in Phase II.

Effect of dumging from frusemide to bumetanide : Jeahtres of cardiac failure after 4 weeks of phase II in relation to JeahJres at the end of phase I.

Continued Sumetan ide Frusemide pre-treated (N=ll9l (N,.. l25 )

Features of cardiac fa i l ure a fte r 4 weeks of Phase II

No Yes No Yes End o f Phase 1

No feat ur:es 41 lOl l 45 911

One fe a ture

Ankl e oedema 3 '1 8 l'l 10

Oysponea 42) 12 211 14

Pulmonary crepitat ions 1'1 0 111 3

Two features

Ankle oedema and dysponea 0 11 1 Z) 11

Ank l e oedema and pulmonary crepi t ations 0 2 0 5

Oysponea and pulmonary crepitations 0 2 J ZJ 2

All f eatures of cardiac fai 1 ure 12/ 2 1 11 2

n 50 47 52 56

NOTE : Al l patients received bumetanide between the end of phase I and visit 6 .

,, Re-appe arance of featu res in bold

21 Disappearance of fea1:ures in i calics

BU 9202 UK STUDY 20 July 1999 Page 19 of 249

Features of congestive cardiac failure (re)appeared in 9 (8.3%) of patients where

treatment was changed, this compares with 10 (10.3%) of patients who continued

to receive bumetanide. Symptoms disappeared in 7 (6.5%) patients where

treatment was changed and in 9 (9.3%) patients who continued to receive

bumetanide.

Long-term bumetanide treatment

During lone-term bumetanide treatment, the p;oportions of per-protocol patients

considered to have failed treatment at summary visits were week 12 : 18.5% (42 out

of '22.7), week 24 : 11.1% (20 out of 180), week 48 : 18.6% (29 out of 156), week 72 :

15.7% (14 out of 89) and week 108 : 13.6% (6 out of 44).

During long-term bumetanide and captopril treatment, the proportions of patients

whose treatment was not changed at each visit was greater than 80%. Dosage

changes, usually an increase in bumetanide or captopril, were made in less than

20% of patients at each assessment

Safety results: Phase I - Twenty-seven patients (21.3%) in the bumetanide group

and 22 patients (17.2%) in the frusemide group experienced adverse events that

were reported as either possibly or probably related to treatment The two

treatment groups were also similar with respect to the number of these adverse

events reported: 35 were reported in the bumetanide group compared with 31 in

the frusemide group.

·The adverse events most frequently reported as possibly or probably related to .

study treabnent were dizziness/postural hypotension and gastro-intestinal

disturbance in the bumetanide group and dizziness/postural hypotension in the

frusemide group.

Adverse events caused/ contributed to treatment withdrawal in 4.7% patients

given bumetanide and in 3.9% patients given frusemide in phase L

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Long-term bumetanide treatment

Overall, 66 (27.7%) of the 238 patients experienced an adverse event that was

reported as either possibly or probably related to treatment during the first 36

weeks treabnent with bumetanide.

Thirteen (9.8%) of the 132 patients who attended visits between weeks 36 and 60

experienced an adverse event that was either possibly or probably related to

treatment

Four (5.7%) of the 70 patients who attended visits between 60 and 84 weeks

experienced an adverse event that was either possibly or probably related to

treatment

One of the 26 p~tients who attended visits between 84 and 108 weeks experienced

an adverse event that was either possibly or probably related to treatment

Adverse events caused/contributed to treatment withdrawal in 14.3% patients

taking bumetanide and captopril long term.

Treatment did not appear to have any clinically important adverse effect on any of

the indices of haemopoietic, hepatic or renal fwtction monitored.

Conclusion: Bumetanide twice-daily plus captopril and frusemide once-daily

plus captopril are similarly effective in treating congestive cardiac failure. Long-

term bumetanide twice-daily plus captopril is effective, well tolerated and without

haemopoietic, hepatic or renal toxicity.