MEDICAL REVIEW OF EFFICACY
NDA#21,290
Drug Name: Bosentan (TracleerTM)
Sponsor: Acetlion
Date: June 29, 2001
Medical Reviewer: Maryann Gordon, M.D.
Summary of efficacy
Bosentan
has been evaluated for efficacy in pulmonary arterial hypertension (PAH) in 3
studies, 2 with the oral formulation evaluating walking distance and 1 with the
iv formulation evaluating acute hemodynamics. The latter trial was stopped
prematurely for safety reasons and is included in the efficacy review only for
completeness.
|
Study no. |
Design/duration |
Primary efficacy parameter |
No. planned/ completed |
doses |
comments |
|
AC 052-352 |
Double blind, randomized, placebo controlled for 16 weeks |
6 min walk test |
150/214 |
Oral 62.5 mg bid up titrated to 125 mg bid; 62.5 mg bid up titrated to 250 mg bid |
Significant increase in walking distance compared to placebo. |
|
AC 052-351 |
Double blind, randomized, placebo controlled for 12 weeks |
6 min walk test |
30/32 |
Oral 62.5 mg bid up titrated to 125 mg bid at week 4 |
Significant increase in walking distance compared to placebo. |
|
BD14884 |
Open label iv dosing 1 day followed by oral dosing |
Acute cardiac hemo-dynamics |
30/7 |
iv: 50 mg, 150 mg, 300 mg. Oral: 1000 mg bid |
Stopped for safety reasons |
Demonstration of efficacy of bosentan
The
walking distance was significantly increased in the bosentan groups compared to
placebo in both study AC 052 352 (352) and study AC 052 351 (351). Compared to
placebo, bosentan also delayed time clinical worsening, improved Borg dyspnea
index, improved WHO functional class, and lessened the increase in therapy for
PAH.
There
was no evidence of loss of efficacy of bosentan up to 16 weeks of placebo
controlled evaluation.
Study details
The studies were double blind, multicenter, parallel
groups, placebo controlled. Bosentan doses used were 125 mg bid (both studies),
250 mg bid (352 only). Both studies included a starting dose of 62.5 mg bid for
4 weeks. Minimum duration on study drug was 12 weeks. Treatment could continue
beyond the fixed efficacy timepoint[1].
Patient type
Patients
were those:
-
with
PAH resulting from primary pulmonary hypertension (PPH) or connective tissue or
autoimmune disease such as scleroderma or systemic lupus erythematosus;
-
WHO
functional class III-IV despite optimal therapy with vasodilators, cardiac glycosides,
diuretics, and /or supplemental oxygen.
-
receiving
anticoagulants but not receiving prostacyclin therapy or scheduled to receive
Flolan.
-
walk
between 150 m and 500 m, inclusive, on a 6-minute walk test. 352 reduced the
maximum walk distance to 450 m.
-
did
not have ALT/AST greater than 3 times upper limit of normal or
hemoglobin/hematocrit <30% below normal range.
Primary efficacy
endpoint
The
primary efficacy endpoint for both studies was change from baseline at endpoint
in total walk distance (meters). The studies predefined how data would be
handled for those patients who died or did not complete the study for other
reasons.
Secondary
endpoints
The
secondary efficacy endpoints included time to clinical worsening, changes in
Borg dyspnea index, changes in WHO functional class, and increase in therapy
for PAH, number of days patient was known to be alive and out of hospital during first 28 weeks (study 352), and
number of drop outs in the first 28 weeks.
Patient
disposition
No.
of patients
|
|
Study 352 |
Study 351 |
|||
|
|
Bos 125 mg bid |
Bos 250 mg bid |
Placebo bid |
Bos 125 mg bid |
Placebo bid |
|
No. randomized |
76 |
70 |
69 |
21 |
11 |
|
No. prematurely withdrawn |
3 |
3 |
6 |
0 |
3 |
Reasons
for premature withdrawal
No.
of patients
|
|
Study 352 |
Study 351
|
|||
|
|
Bos 125 mg bid |
Bos 250 mg bid |
Placebo bid |
Bos 125 mg bid |
Placebo bid |
|
No. prematurely withdrawn |
3 |
3 |
6 |
0 |
3 |
|
Worsening of condition |
2 |
1 |
3 |
0 |
1 |
|
Death |
1 |
0 |
2 |
0 |
0 |
|
AE/ intercurrent illness |
0 |
1 |
0 |
0 |
2 |
|
Increased LFTs |
0 |
1 |
0 |
0 |
0 |
|
Lack of clinical/walk test improvement |
0 |
0 |
1 |
0 |
0 |
Demographics
|
|
Study 352 |
Study 351 |
|||
|
|
Bos 125 mg bid |
Bos 250 mg bid |
Placebo bid |
Bos 125 mg bid |
Placebo bid |
|
No. randomized |
76 |
70 |
69 |
21 |
11 |
|
No. female |
57 |
57 |
54 |
17 |
11 |
|
No. male |
17 |
13 |
15 |
4 |
0 |
|
Mean age (yrs) |
50.4 |
47.0 |
47.2 |
52.2 |
47.4 |
|
No. white |
57 |
54 |
59 |
16 |
9 |
|
Mean time from diagnosis to randomization |
898 |
893 |
843 |
634 |
1091 |
The
most common concomitant medications in both studies were antithrombotic agents,
diuretics, ca channel blocker, and cardiac glycosides.
6
minute walk test
Mean
distances (m)
|
|
Study 352 |
Study 351 |
|||
|
|
Bos 125 mg bid N=74 |
Bos 250 mg bid N=70 |
Placebo bid N=69 |
Bos 125 mg bid N=21 |
Placebo bid N=11 |
|
Baseline |
326.3 |
333.0 |
344.3 |
360.5 |
355.5 |
|
Endpoint^ |
353.1 |
379.5 |
336.5 |
430.5 |
349.6 |
|
Change from baseline |
26.8 |
46.5 |
-7.8 |
70.1 |
-5.0 |
|
Placebo subtracted effect |
34.6 |
54.3 |
- |
75.9* |
- |
^
week 16 for study 352, week 12 for study 351
*p=0.0205
using t-test
***p=0.0002
using Mann-Whitney U test
Dose effect
Only
study 352 used more than 1 dose of bosentan. The walking distance by dose is
shown in the figure below
Walk
distance:
Change from baseline over time during Period 1 by dose,
ITT population
Note:
All bosentan patients received 62.5 m bid during the first
4 weeks of the study and then were up-titrated to the target dose
(125 mg bid or 250 mg bid).
The
250 mg bosentan group was numerically superior to the 125 mg group at weeks 8
and 16 but the confidence limits overlapped at both time points.
Walk distance by visit
The changes from baseline at weeks 4, 8 and 16 for the combined bosentan group and placebo in walk distance in study 352 and weeks 4, 6 and 12 for in study 351 are shown in the figures below.
Walk distance: Change from baseline over
time during Period 1,
ITT population
There
is no evidence that the effect of bosentan on walk distance dissipates over
12-16 weeks of treatment.
Subgroups
Effect
of bosentan by subgroups was only examined in study 352.
Bosentan increase walk distance, compared to placebo, regardless of gender,
age, weight, location, race, time from diagnosis, etiology (PPH vs. scleroderma),
and baseline walk test. Patients who
entered the study with lower mean PAP (< 50 mmHg) and/or higher
cardiac index (ł 2.3 l/min/m2)
had a smaller improvement with bosentan than did those who entered with a
higher mean PAP and/or lower cardiac index.
Secondary endpoints
Time
to clinical worsening defined as the shortest time to death, lung
transplantation, hospitalization or discontinuation due to worsening pulmonary
arterial hypertension, start of prostacyclin therapy or septostomy
The
figure below shows the results for 352, by dose of bosentan and placebo.
Time from randomization to clinical worsening by dose, ITT population
There
was an earlier time to deterioration by patients on placebo compared to those
on either dose of bosentan.
There
were 3 placebo and 0 bosentan patients who experienced clinical worsening in
study 351.
Changes
in Borg dyspnea index
Borg scale measures the levels of perceived exertion and the scale ranges from 0 (nothing at all) to 10 (maximal).
Means
|
|
Study 352 |
Study 351 |
|||
|
|
Bos 125 mg bid N=74 |
Bos 250 mg bin=70 |
Placebo bid N=69 |
Bos 125 mg bid N=21 |
Placebo bid N=11 |
|
Baseline |
3.3 |
3.8 |
3.8 |
4.38 |
4.18 |
|
Endpoint^ |
3.3 |
3.3 |
4.2 |
4.19 |
5.55 |
|
Change from baseline |
-0.1 |
-0.6 |
+0.3 |
-0.19 |
+1.36 |
|
Placebo subtracted effect |
-0.4 |
-0.9 |
- |
-1.55 |
- |
^
week 16 for study 352, week 12 for study 351
At
baseline patients in study 351 had a worse perception of their exertion
compared to the patients in study 352. However, the bosentan patients in both
studies had an improvement as measured by the scale compared to the placebo
patients. The overall treatment effect was greater in the 351 study, which may
mean that sicker patients have a greater perception of improvement with
bosentan. This would have to be confirmed by additional studies.
Changes in WHO functional class
Only
patients WHO functional classes III or IV at baseline were enrolled into the
efficacy studies.
No.
and (percent) of patients who improved
|
|
Study 352 |
Study 351 |
|||
|
|
Bos 125 mg bid N=74 |
Bos 250 mg bin=70 |
Placebo bid N=69 |
Bos 125 mg bid N=21 |
Placebo bid N=11 |
|
Improved
from baseline |
32 (43.2) |
29 (41.1) |
21 (30.4) |
9 (42.9) |
1 (9.1) |
^
week 16 for study 352, week 12 for study 351
More bosentan patients improved in their functional class compared to
placebo patients.
Increased therapy for PAH
The evaluation of the incidence of increased therapy for PAH was only
evaluated in study 352. The results are shown below.
Table 1 Incidence of increased therapy for
pulmonary arterial hypertension,
ITT population
(Table T14 / 04MAY01)
---------------------------------------------------------------------------------------------------------------
Bosentan Bosentan All
Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144
N=69
---------------------------------------------------------------------------------------------------------------
Period 1 (weeks 0 to 16)
n 74 70 144
69
Patients with increase [n(%)] 18 (24.3%)
14 (20.0%) 32 (22.2%) 20 (29.0%)
95% confidence limits (%) 15.1 , 35.7 11.4 , 31.3 15.7 , 29.9 18.7
, 41.2
Treatment effect*
Difference -4.7% -9.0% -6.8%
95% confidence limits (%) -20.0 , 10.6 -24.3 , 5.9 -19.5 ,
7.1
Period 1+2 (weeks 0 to 28)†
n 19 16 35
13
Patients with increase [n(%)] 6 (31.6%)
5 (31.3%) 11 (31.4%) 5 (38.5%)
95% confidence limits (%) 12.6 , 56.6 11.0 , 58.7 16.9 , 49.3 13.9
, 68.4
Treatment effect
Difference -6.9% -7.2% -7.0%
95% confidence limits (%) -41.0 , 27.5
-43.1 , 27.7 -36.5 , 25.4
---------------------------------------------------------------------------------------------------------------
† Analyzed only in those patients who were
scheduled to continue to period 2.
Compared
to placebo, fewer bosentan patients had an increase in therapy for PAH and this
remained true for the few patients who had up to 28 weeks of treatment.
Protocol AC 052-352
Because this study was
submitted at end of the NDA review, its safety is discussed fully in this
section. The safety from this trial was only partially integrated with the
overall safety medical review.
1.0 Introduction
The protocol was dated March 28, 2000. The first patient’s first visit was July 2000 and the last patient’s last visit was October 2000.
1.1
Study Design
This
was a double blind, multicenter, parallel, placebo controlled, randomized study
in patients with pulmonary arterial hypertension (PAH). The study was conducted
in Europe, North America, Israel, and Australia. Eligible subjects were those with either symptomatic severe
primary pulmonary hypertension (PPH) or pulmonary hypertension secondary to
scleroderma (SSc/PH), who were ambulatory and in functional class III-IV ( 1998
WHO classification).
1.2
Study Objective
The
objective of this study was to evaluate the efficacy of 2 doses of bosentan
compared to placebo on peak exercise capacity (6 minute walk test).
1.3. Patient Type
1.3.1. Inclusion Criteria
Eligible
patients had to meet all of the following inclusion criteria at the initial
screening visit of the study (visit 1) and at baseline for the 6-minute walk
test (visit 1 and visit 2)
1. Male or female aged 12 years or more.
Amendment #2 UK only: patients had to be > 18 years of age.
2. Patients must have provided written
informed consent to participate in the study. For a patient under the age of
consent, written informed consent must be obtained from the patient’s legal
guardian.
3. PAH resulting from either:
• primary pulmonary hypertension (PPH)
or
• Connective tissue or
autoimmune diseases such as scleroderma (SSc/PH) or systemic lupus
erythematosus (SLE).
In
patients with SSc/PH and interstitial lung disease, total lung capacity (TLC)
was to be >70 %. However, if TLC was between 60-70%, a high resolution CT
scan should have been used to confirm the mild nature of disease with a total
CT score < 2. The diffusion lung capacity for carbon monoxide (DLCO)
could be used to aid in the diagnosis. The CT scan was repeated at the end of
the study.
4. PAH of WHO functional class III-IV
despite optimal therapy with oral vasodilators, cardiac glycosides, diuretics
and/or supplemental oxygen for at least one month. Patients had to be receiving
oral anticoagulants unless there was a contraindication.
5. Hemodynamic documentation of PAH
within 2 months prior to screening, i.e. a patient who has undergone invasive
hemodynamics in the month preceding screening with the following results:
• Mean pulmonary arterial pressure
(PAP) > 25 mmHg at rest
• Pulmonary capillary wedge pressure
(PCWP) < 15 mmHg
• Pulmonary vascular resistance (PVR)
> 3 mmHg/l/min.
If
the capillary wedge pressure was not measured, an echocardiogram was acceptable
to rule out left ventricular dysfunction.
6. Baseline 6-min walk test of >
150 m and < 500 m (Amendment #1 reduced this to < 450 m).
The difference between the screening and randomization walk tests had to be <
15%. If the two tests differed by more than 15%, the patient underwent an
additional walk test at least 1 day later, the results of which had to within
15% of the previous walk test. The definition of baseline as the average of the
last 2 test results was added later (but not as an amendment).
7. women who were not pregnant and women
who were postmenopausal, surgically sterile or using an acceptable method of
contraception.
Exclusion Criteria
Eligible
patients could not have any of the following exclusion criteria at the initial
screening visit (visit 1) or at baseline (visit 1 or visit 2):
1. PAH of WHO functional class I or II.
2. PAH due to conditions other than PPH or
connective tissue diseases, e.g.:
congenital heart diseases (Eisenmenger’s syndrome)
• pulmonary venous hypertension (e.g.
left sided heart diseases)
• associated with disorders of the
respiratory system (e.g. chronic obstructive pulmonary disease (COPD), sleep
apnea, and patients with moderate to severe interstitial disease even of SSc
origin)
• associated with chronic thrombotic or
embolic diseases
• condition of inflammatory origin
(HIV, schistosomiasis, sarcoidosis)
• portal pulmonary hypertension.
3. SSc/PH with moderate to severe
interstitial disease or with TLC <60% or a CT scan total score (CT.Tot
score) >2.
4. Patients who stopped treatment with
oxygen, diuretics, oral vasodilators, cardiac glycosides within one month of
screening.
5. Patients who started new treatment with
oxygen, diuretics, oral vasodilators, cardiac glycosides within one month of
screening.
6. Patients receiving prostacyclin therapy
within 3 months of study screening. However patients who received acute
prostacyclin at the time of a catheterization procedure to test pulmonary
vascular reactivity could be included.
7. Patients scheduled to receive
prostacyclin therapy.
8. Musculoskeletal or rheumatic disorders
or any other condition that could limit his/her ability to perform the 6-minute
walk tests.
9. Hypotension defined as systolic blood
pressure < 85 mmHg.
10. Hemoglobin or hematocrit of less than
30% below the normal range (patients with secondary polycythemia were allowed).
11. AST and/or ALT values greater than 3
times the upper limit of normal.
12. Patients receiving cyclosporin-A,
glibenclamide (glyburide), troglitazone, encainide, flecainide, disopyramide,
propafenone, moricizine, pinacidil, minoxidil or oral positive inotropic agents
other than digitalis at inclusion into the study or were expected to receive
any of these drugs during the study period.
13. Patients who received therapy with an
investigational drug in the month preceding screening.
14. Known drug or alcohol dependence or any
other factors which could have interfered with conduct of the study or
interpretation of the results.
15.
Any illness other than PAH which might reduce life expectancy to less than 6
months.
1.4
Sample Size
Sample
size, 80 patients for each of the 3 treatment arms, was based on an assumed
change from baseline in walking distance of 45 m with standard deviation of 75
m.
1.5 Dose and duration
The 3 treatment arms were 1.) placebo bid for 16 weeks,
2.) bosentan 125 mg bid for 4 weeks titrated to 250 mg bid for 12 weeks, and
3.) bosentan 62.5 mg bid for 4 weeks titrated to 125 mg bid for 12 weeks. Down
titrating to the starting dose was allowed if patient could not tolerate the
higher dose. Amendment#1: patients with body weight < 40 kg were given half
the randomized target dose. If patients had to be discontinued, they were
weaned for 3-7 days.
Patients were instructed to take study drug at the time
of or within 30 minutes after food intake.
Each subject received a minimum of 16 weeks of double
blind treatment[2] and this
period was used to determine efficacy. Patients recruited by 9-30-2000 took
part in period 2 as well which was an additional 12 week treatment with double
blind medication. This period was reviewed for efficacy but was not part of
primary efficacy endpoint.
1.7
Study Procedure
The
flow chart below outlines study procedures at each clinic visit.
1.8 Protocol define study hypotheses and efficacy
endpoints:
Primary endpoint of the study: the change from baseline
(defined as the average of screening and randomization walk tests[3])
in exercise capacity at 16 weeks (6-minute walk test).
• Patients
who died, underwent lung transplantation during the study, or discontinued
study medication because of worsening of their PAH condition were analyzed
using their last assessment if it was recorded at the time of premature
withdrawal. If no assessment of walk distance was obtained at the time of
premature withdrawal, these patients were assigned a walk distance of 0 meters at
the 16-week time point.
• All
other patients including those with serious adverse events not related
to PAH worsening or lost to follow up without a week 16 assessment of the
primary endpoint had their last assessment carried forward. If no assessment was
obtained during the treatment period, the patient was assigned “no change”
(zero change from baseline, equivalent to carrying forward the baseline value).
7.2 Secondary Endpoints[4]
1. Time
from randomization to clinical worsening, defined as death from all causes,
lung transplantation or discontinuation of therapy due to clinical
deterioration due to PAH or need for prostacyclin or septostomy. Patients
without documentation of any of the events listed above were included in the
analysis as censored observations from randomization to the last date the
patient was known to be free of any of these events.
2. Changes
from baseline in dyspnea index (Borg dyspnea index). Patients prematurely
withdrawn from therapy and having had a “premature withdrawal” assessment will
be included in the analysis using the last available assessment on treatment.
Patients without any assessment during the treatment period were assigned worst
rank (10) if the reason for premature withdrawal is death, lung transplantation
or worsening of the patient’s PAH condition. Patients without any assessment
during the treatment period for reasons other than these were excluded from the
analysis.
3. Changes
from baseline in WHO functional class. Patients prematurely withdrawn from
therapy and having had a “premature withdrawal” assessment were included in the
analysis using the last available assessment on treatment. Patients without any
assessment during the treatment period were assigned worst rank if the reason
for premature withdrawal is death, lung transplantation or worsening of the
patient’s PAH condition. Patients without any assessment during the treatment
period for reasons different than these were excluded from the analysis.
4. Increase
in any therapy for PAH. Patients with missing data were analyzed as in item 3
above.
5. Number
of days the patient is known to be alive and out of hospital in the first 28
weeks.
6. Number
of dropouts in the first 28 weeks.
1.9
Disallowed concomitant medications
Prostacyclin
and any investigational agent other than study drug intended for the treatment
of PAH, cyclosporin-A, glibenclamide (glyburide), troglitazone, encainide,
flecainide, disopyramide, propafenone, moricizine, pinacidil, minoxidil or oral
positive inotropic agents other than digitalis.
1.10
Abnormal laboratory values
a)
Liver function test (LFT)
Patients
found to have abnormal LFTs during the study were treated according to the
following outline.
Figure 1 Guidelines for treatment of asymptomatic increases in liver enzymes
b)
Hemoglobin
· If hemoglobin decreased by at least 15% from baseline and was < 10 g/dl, and/or if hematocrit decreased by at least 15% from baseline and was < 0.30, a repeat test was performed to confirm the abnormality.
· If the abnormality was confirmed, the investigator was required to perform the following assessments using the local laboratory:
· Complete blood count including reticulocytes, mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, red cell distribution width, and direct inspection of blood smears
· Bilirubin, direct and indirect
· Serum iron, transferrin, iron-binding capacity, and serum ferritin
1.11
Major protocol amendments
Amendment 1, May 30, 2000: the hypothesis and analyses were simplified by changing from comparisons between each bosentan arm and placebo to a single comparison between pooled bosentan arms and the placebo arm. The change in analysis allowed a reduction in the number of patients required from 240 to 150 (50 per group) without affecting the power calculation and a consequent reduction in the number of centers from 40 to 30. The Mann-Whitney U-test replaced the Student’s t-test as a more appropriate test with the non-normal data distribution due to zero introduced as a substitutive value. The dose-response relationship would only be analyzed descriptively. Primary and secondary parameters were to be analyzed descriptively in four groups: the bosentan 125-mg arm, the bosentan 250-mg arm, the pool of both bosentan arms, and the placebo arm.
The upper limit of the 6‑minute walk test that determined eligibility was changed from < 500 m to Ł 450 m. To avoid potential overdosing, patients with body weights of Ł 40 kg were to be given half of the randomized target dose (i.e., 62.5 mg bid or 125 mg bid).
Amendment 2, June 30, 2000. This amendment applied only to centers in the UK. Local Institutional Review Boards (IRBs) for centers in the UK requested that only patients ł 18 years of age be included in the trial.
Amendment 3, July 19, 2000. This amendment applied only to centers in Austria. Local IRBs in Austria requested that only patients > 19 years of age be included in the trial and that pregnancy tests be performed every 4 weeks in all women of childbearing potential.
Amendment 4, August 22, 2000. This amendment introduced an echo/Doppler substudy that was to be conducted at 12 of the study centers (world wide) in a subset of study patients (29 in each treatment group) who were recruited into the substudy. Echo/Doppler imaging techniques were to be used to evaluate hemodynamic changes and alterations in right heart structure and function during the trial.
Amendment 5, September 4, 2000. This amendment applied only to centers in the UK. Local IRBs for centers in the UK requested that only patients over the age of 50 years and amenorrheic for at least 1 year be considered naturally sterile with regard to inclusion criteria. In addition, medication labels had been made for patients with body weight > 40 kg and could not be changed before the end of recruitment in the UK. Therefore, an inclusion criterion was added requiring patients in the UK to have a body weight of > 40 kg.
Amendment 6, 6 October 2000. Due to the delay in recruitment and in order to complete the study within the planned timelines, a recruitment date of September 30, 2000 was set as the cut-off for patients scheduled to continue randomized treatment past the first 16 weeks (i.e., participate in Period 2). Patients enrolling after September 30, 2000 were to participate in 16 weeks of randomized treatment only (Period 1), and the trial was to end when the last entered patient completed Period 1.
Some clarifications of study procedures were added and some changes were instituted to enhance patient safety (an inclusion criterion was changed so that hormone-based contraceptives alone were not acceptable forms of contraception; this change addressed concerns that an induction of CYP3A4 by bosentan would lead to a higher rate of metabolism of these compounds and possibly result in a loss of contraceptive efficacy; a pregnancy test at the end-of-study/premature-discontinuation visit in women of childbearing potential was added as a precautionary measure; and the procedures for use of weaning treatment upon temporary or permanent discontinuation of study medication were clarified for patients not entering the extension study; and study treatment was to be re‑instituted within 15 days of a temporary discontinuation.
The management of patients with an increase in serum
transaminases was changed at the request of the Data Safety and Monitoring
Board The safety committee felt a reduction in the dose rather than temporary
discontinuation of study medication would be more appropriate for asymptomatic
patients with a confirmed transaminase concentration > 8 times the
upper limit of normal. Following dose
reduction or discontinuation, the patient could be re-challenged with study
medication at the target dose (rather than half the target dose) provided that
liver enzymes had returned to baseline values at two consecutive tests, and
there was clear evidence that the reason for the increase was not related to
study drug.
2.0 Results
A
total of 258 patients were screened and 214 were enrolled into double blind
treatment phase. There were 27 sites in Europe, North America, Israel, and
Australia.
2.1
Patient disposition
Table
below shows the outcome for all randomized subjects by treatment group.
|
|
Bosentan 125 mg bid |
Bosentan 250 mg bid |
Placebo |
|
No.
randomized |
76 |
70 |
69 |
|
No.
who received study medication |
75^ |
70 |
69 |
|
Included
in safety and efficacy evaluations |
74 |
70 |
69 |
|
No.
prematurely withdrawn |
3 |
3 |
6 |
^1
patient (206 20604) was randomized but did not receive study medication because
he had an exclusion criterion (Eisenmenger’s syndrome) and difficulty in
keeping appointments because he lived in a remote location)
Patients
who discontinued prematurely from the trial are shown below.
Appendix 1 Summary of premature discontinuations during Period 1, safety population
Produced by maddest on 04MAY01
Ro 47-0203, Protocol: AC-052-352
Table T02a: Summary of premature discontinuations in period 1
Population: Safety
---------------------------------------------------------------------------------------------------
Reason for premature Bosentan Bosentan All Placebo
discontinuation 125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
No. % No. % No. % No. %
---------------------------------------------------------------------------------------------------
Total pts with at least one reason 3 4.1% 3 4.3% 6 4.2% 6 8.7%
WORSENING OF PATIENT CONDITION 2 2.7% 1 1.4% 3 2.1% 3 4.3%
DEATH 1 1.4% - 1 0.7% 2 2.9%
AE/INTERCURRENT ILLNESS - 1 1.4% 1 0.7% -
INCREASED LIVER ENZYMES - 1 1.4% 1 0.7% -
LACK OF CLINICAL/WALK TEST IMPROVEMENT - - - 1 1.4%
---------------------------------------------------------------------------------------------------
Note: only the discontinuations in period 1 are considered
(Page 1/1)
There
were 12 premature discontinuations in the first 16 weeks of treatment: 3
bosentan 125 mg, 3 bosentan 250 mg, and 6 placebo. Of the 6 who discontinued
because of worsening condition, 3 were on bosentan and 3 were on placebo. There
were 3 deaths: 1 on bosentan 125 mg and 2 on placebo. There was 1 drop out
(bosentan 250 mg) for adverse event/intercurrent illness; 1 drop out (bosentan
250 mg) for increased liver enzymes, and 1 drop out (placebo) for lack of
clinical/walk test improvement.
2.2
Demographics and baseline characteristics
Demographics
for the study subjects, by treatment group, are shown below.
Table 2 Summary of patient demographics, ITT population
(Table T04 / 04MAY01)
--------------------------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
--------------------------------------------------------------------------------------------------------------------
SEX [n (%)]
n 74 70 144 69
Males 17 23.0% 13 18.6% 30 20.8% 15 21.7%
Females 57 77.0% 57 81.4% 114 79.2% 54 78.3%
AGE (years)
n 74 70 144 69
Mean 50.4 47.0 48.7 47.2
Standard deviation 15.9 15.6 15.8 16.2
Median 50.5 48.0 49.0 50.0
Min , Max 15.0 , 79.0 13.0 , 80.0 13.0 , 80.0 12.0 , 80.0
AGE [n (%)]
n 74 70 144 69
12 - 20 years 3 4.1% 4 5.7% 7 4.9% 6 8.7%
21 - 40 years 13 17.6% 18 25.7% 31 21.5% 15 21.7%
41 - 60 years 38 51.4% 33 47.1% 71 49.3% 33 47.8%
> 60 years 20 27.0% 15 21.4% 35 24.3% 15 21.7%
WEIGHT (kg)
n 74 70 144 69
Mean 71.6 70.5 71.0 73.7
Standard deviation 21.2 17.8 19.6 18.3
Median 67.0 69.7 68.0 73.0
Min , Max 35.8 , 137.4 41.8 , 137.4 35.8 , 137.4 33.0 , 123.4
HEIGHT (cm)
n 74 70 144 69
Mean 163.7 163.8 163.7 162.9
Standard deviation 10.2 8.3 9.3 9.0
Median 162.6 162.6 162.6 160.0
Min , Max 137.2 , 190.5 150.0 , 188.0 137.2 , 190.5 148.0 , 187.0
RACE [n (%)]
n 74 70 144 69
Caucasian/white 57 77.0% 54 77.1% 111 77.1% 59 85.5%
Black 5 6.8% 7 10.0% 12 8.3% 1 1.4%
Asian 2 2.7% 1 1.4% 3 2.1% -
Other 10 13.5% 8 11.4% 18 12.5% 9 13.0%
LOCATION [n (%)]
n 74 70 144 69
US 41 55.4% 38 54.3% 79 54.9% 39 56.5%
Non-US 33 44.6% 32 45.7% 65 45.1% 30 43.5%
--------------------------------------------------------------------------------------------------------------------
The
majority of patients were female, in their late forties, weighed about 72 kg,
and were white. More than half of the study patients resided in the U.S. The
treatment groups were fairly well balanced.
2.2.1 Disease history
Summary
of baseline disease characteristics is shown below.
Table 3 Summary of baseline disease characteristics, ITT population
(Table T05 / 04MAY01)
--------------------------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
--------------------------------------------------------------------------------------------------------------------
Time from diagnosis of PAH (days)*
n 73 70 143 69
Mean 898.4 892.5 895.5 843.4
Standard deviation 985.3 1144.2 1062.3 1442.4
Median 511.0 421.0 453.0 381.0
Min , Max 9.0 , 3907.0 5.0 , 5259.0 5.0 , 5259.0 7.0 , 9923.0
Etiology of PAH [n (%)]
n 74 70 144 69
PPH 57 77.0% 45 64.3% 102 70.8% 48 69.6%
SSc/PHT 13 17.6% 20 28.6% 33 22.9% 14 20.3%
Other 4 5.4% 5 7.1% 9 6.3% 7 10.1%
Presence of Raynaud's syndrome [n (%)]
n 74 70 144 69
Yes 20 27.0% 21 30.0% 41 28.5% 19 27.5%
No 54 73.0% 49 70.0% 103 71.5% 50 72.5%
Presence of antinuclear antibody [n (%)]
n 74 70 144 69
Yes 22 29.7% 18 25.7% 40 27.8% 24 34.8%
No 35 47.3% 28 40.0% 63 43.8% 29 42.0%
Unknown 17 23.0% 24 34.3% 41 28.5% 16 23.2%
Presence of rheumatoid factor [n (%)]
n 74 70 144 69
Yes 4 5.4% 6 8.6% 10 6.9% 7 10.1%
No 35 47.3% 31 44.3% 66 45.8% 28 40.6%
Unknown 35 47.3% 33 47.1% 68 47.2% 34 49.3%
WHO grade at Baseline [n (%)]
n 74 70 144 69
III 68 91.9% 62 88.6% 130 90.3% 65 94.2%
IV 6 8.1% 8 11.4% 14 9.7% 4 5.8%
Baseline oxygen saturation (%) †
n 74 68 142 68
Mean 94.3 93.7 94.0 94.6
Standard deviation 3.8 4.5 4.1 3.7
Median 95.0 95.0 95.0 96.0
Min , Max 77.0 , 99.9 81.0 , 99.9 77.0 , 99.9 85.0 , 100.0
--------------------------------------------------------------------------------------------------------------------
(*) Reported number of days from diagnosis of pulmonary hypertension to randomization
(†) Last valid value between the visits 1 (Screening) and 2 (Randomization)
PAH=pulmonary arterial hypertension, PPH=primary pulmonary hypertension,
SSc/PHT=pulmonary hypertension due to scleroderma
The
mean time to from time of diagnosis to randomization was about 2.5 years. The
etiology of PAH for the majority of patients was PPH and the WHO grade at
baseline was class II for 89%-94% of patients; somewhat more bosentan patients
than placebo patients were identified as class IV. Mean oxygen saturation at
baseline was about 94%. Again, the treatment groups were well balanced.
2.2.2 Baseline hemodynamics
Summary
of baseline hemodynamics is shown below.
Table 4 Summary of baseline hemodynamics, ITT population
(Table T06 / 04MAY01)
--------------------------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
--------------------------------------------------------------------------------------------------------------------
Mean PAP (mmHg)
n 74 70 144 69
Mean 52.8 56.7 54.7 53.4
Standard deviation 14.5 16.8 15.8 16.6
Median 51.8 53.5 52.0 51.0
Min , Max 28.0 , 92.0 27.0 , 114.5 27.0 , 114.5 25.5 , 108.5
PVR (dyn*sec/cm^5)
n 73 62 135 65
Mean 884 1167 1014 880
Standard deviation 412 875 678 540
Median 857 962 888 800
Min , Max 196 , 2067 248 , 6467 196 , 6467 133 , 3727
Cardiac index (l/min/m^2)
n 74 70 144 68
Mean 2.46 2.24 2.35 2.43
Standard deviation 0.82 0.81 0.82 0.69
Median 2.41 2.06 2.23 2.33
Min , Max 1.19 , 5.84 0.35 , 4.84 0.35 , 5.84 1.35 , 4.16
PCWP (mmHg)
n 73 62 135 66
Mean 9.7 8.7 9.2 9.2
Standard deviation 4.1 3.6 3.9 4.1
Median 10.0 8.0 9.0 9.0
Min , Max 1.0 , 21.0 1.0 , 20.0 1.0 , 21.0 1.0 , 25.0
Mean RAP (mmHg)
n 74 69 143 67
Mean 9.7 9.9 9.8 8.9
Standard deviation 5.4 6.5 5.9 5.1
Median 8.3 8.0 8.0 8.0
Min , Max 1.0 , 27.0 0.0 , 27.0 0.0 , 27.0 0.5 , 20.0
--------------------------------------------------------------------------------------------------------------------
PAP = pulmonary arterial pressure, PCWP = pulmonary capillary wedge pressure, PVR = pulmonary vascular resistance,
RAP = right atrial pressure.
Mean
pulmonary arterial pressure, pulmonary capillary wedge pressure, and pulmonary
venous resistance were approximately 53 mmHg, 9.2 mmHg, and 1000 dyn-sec/cm5,
respectively. The treatment groups were well balanced.
Summary of previous and
concomitant diseases is shown below.
Table 5 Summary of previous and concomitant diseases by class, safety population
(Table T07 / 04MAY01)
---------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
No. %
No. % No.
% No. %
---------------------------------------------------------------------------------------------------
ALL DISEASE CLASSES
Total pts with at least one
disease 63 85.1% 63 90.0% 126 87.5% 59 85.5%
Total number of diseases 324 290 614 297
GASTROINTESTINAL
DISORDERS 28 37.8% 30 42.9% 58 40.3% 22 31.9%
METABOLISM AND NUTRITION
DISORDERS 26 35.1% 25 35.7% 51
35.4% 30 43.5%
VASCULAR DISORDERS 27 36.5% 23 32.9% 50 34.7% 21 30.4%
MUSCULOSKELETAL, CONNECTIVE
TISSUE 23 31.1% 22 31.4% 45 31.3% 21 30.4%
AND BONE DISORDERS
RESPIRATORY, THORACIC AND MEDIASTINAL 22 29.7% 18
25.7% 40 27.8% 21 30.4%
DISORDERS
CARDIAC DISORDERS 17 23.0% 23 32.9% 40 27.8% 16 23.2%
ENDOCRINE DISORDERS 14 18.9% 19 27.1% 33 22.9% 10 14.5%
PSYCHIATRIC DISORDERS 20 27.0% 8 11.4% 28 19.4% 17 24.6%
IMMUNE SYSTEM DISORDERS 14 18.9% 13 18.6% 27 18.8% 5 7.2%
GENERAL DISORDERS AND
ADMINISTRATION 13 17.6% 10 14.3% 23 16.0% 12 17.4%
SITE CONDITIONS
REPRODUCTIVE SYSTEM AND
BREAST 12 16.2% 9 12.9% 21 14.6% 12 17.4%
DISORDERS
NERVOUS SYSTEM DISORDERS 10 13.5% 10 14.3% 20 13.9% 14 20.3%
BLOOD AND LYMPHATIC SYSTEM
DISORDERS 10 13.5% 5
7.1% 15 10.4% 9 13.0%
SKIN & SUBCUTANEOUS TISSUE
DISORDERS 5 6.8%
6 8.6% 11 7.6% 8 11.6%
HEPATO-BILIARY DISORDERS 4 5.4%
5 7.1% 9 6.3% 7 10.1%
RENAL AND URINARY
DISORDERS 7 9.5%
2 2.9% 9 6.3% 6
8.7%
EYE DISORDERS 2 2.7%
2 2.9% 4 2.8% 5
7.2%
SURGICAL & MEDICAL
PROCEDURES 1 1.4%
1 1.4% 2 1.4% 2
2.9%
EAR AND LABYRINTH
DISORDERS 2 2.7%
- 2 1.4%
1 1.4%
INFECTIONS AND
INFESTATIONS 1 1.4%
- 1 0.7%
1 1.4%
INVESTIGATIONS 1 1.4%
- 1 0.7%
1 1.4%
PREGNANCY, PUERPERIUM AND
PERINATAL - 1 1.4% 1 0.7%
1 1.4%
CONDITIONS
CONGENITAL AND
FAMILIAL/GENETIC - 1 1.4% 1 0.7%
-
DISORDERS
NEOPLASMS BENIGN AND
MALIGNANT - 1 1.4% 1 0.7%
-
(INCLUDING CYSTS AND POLYPS)
INJURY AND POISONING -
- - 1 1.4%
Most
patients (85%-90%) had at least 1 concomitant disease. The most frequently
reported diseases were GI disorders, followed by metabolism and nutritional
disorders, vascular disorders, musculoskeletal/connective tissue/and bone
disorders. The treatment groups were well balanced.
2.2.4 Concomitant medications
Summary
of previous and concomitant treatments for PAH is shown below.
Table 6 Summary
of previous and concomitant treatments for pulmonary arterial hypertension by
class, safety population
---------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
No. % No.
% No. %
No. %
---------------------------------------------------------------------------------------------------
ALL TREATMENT CLASSES
Total pts with at least one TRT 65 87.8% 64
91.4% 129 89.6% 64 92.8%
Total number of TRTs 167 167 334 163
ANTITHROMBOTIC AGENTS 51 68.9%
50 71.4% 101 70.1% 50 72.5%
HIGH-CEILING DIURETICS
34 45.9% 31 44.3% 65 45.1% 26 37.7%
CALCIUM CHANNEL BLOCKERS 33 44.6%
31 44.3% 64 44.4% 36 52.2%
POTASSIUM SPARING AGENTS 15 20.3%
16 22.9% 31 21.5% 17 24.6%
CARDIAC GLYCOSIDES 12 16.2% 16 22.9% 28
19.4% 13 18.8%
LOW CEILING DIURETICS, THIAZIDES 6 8.1% 6
8.6% 12 8.3%
5 7.2%
AGENTS ACTING ON THE RENIN-ANGIOTENSIN 5 6.8% 4
5.7% 9 6.3%
3 4.3%
SYSTEM
MINERAL SUPPLEMENTS 1
1.4% 4 5.7%
5 3.5% 1 1.4%
BETA BLOCKING AGENTS 4
5.4% - 4 2.8% 1 1.4%
HYDRAZINOPHTALAZINE DERIVATIVES 1 1.4% 1
1.4% 2 1.4%
2 2.9%
LOW-CEILING DIURETICS, EXCL. THIAZIDES - 2 2.9%
2 1.4% 1 1.4%
ANTIARRHYTHMICS, CLASS I AND III 1 1.4% 1
1.4% 2 1.4%
-
ANTI-ASTHMATICS 1
1.4% - 1 0.7% 1 1.4%
ORGANIC NITRATES - 1 1.4% 1
0.7% 1 1.4%
ANTIADRENERGIC AGENTS, PERIPHERALLY -
1 1.4% 1 0.7%
-
ACTING
CORTICOSTEROIDS FOR SYSTEMIC USE 1 1.4% -
1 0.7% -
OTHER VASODILATORS USED IN CARDIAC -
1 1.4% 1 0.7% -
DISEASES
ANTIADRENERGIC AGENTS, CENTRALLY -
- - 1 1.4%
ACTING
IMMUNOSUPPRESSIVE AGENTS -
- - 1 1.4%
---------------------------------------------------------------------------------------------------
Note: only the medications reported during
the visit 1 are included
Most
patients (88%-93%) were taking at least 1 concomitant medication. The most
common were antithrombotic agents followed by diuretics, calcium channel
blockers, and cardiac glycosides. The treatment groups were well balanced.
2.3
Efficacy
2.3.1.Study discontinuations
The
table below shows the number and percent of all premature study
discontinuations in periods 1 and 2 (extension of the double blind phase).
Table 7 Summary
of all premature discontinuations, safety population
(Table T02c / 04MAY01)
---------------------------------------------------------------------------------------------------
Reason for premature Bosentan Bosentan
All Placebo
discontinuation 125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
No. %
No. % No.
% No. %
---------------------------------------------------------------------------------------------------
Total pts with at least one
reason 10 13.5% 9 12.9% 19 13.2% 11 15.9%
ADMINISTRATIVE/OTHER 6 8.1%
3 4.3% 9 6.3% 3
4.3%
WORSENING OF PATIENT
CONDITION 3 4.1%
2 2.9% 5 3.5% 5
7.2%
INCREASED LIVER ENZYMES - 3 4.3% 3
2.1% -
DEATH 1 1.4%
- 1 0.7%
2 2.9%
AE/INTERCURRENT ILLNESS - 1 1.4% 1 0.7%
-
LACK OF CLINICAL/WALK TEST
IMPROVEMENT - - -
1 1.4%
---------------------------------------------------------------------------------------------------
Note: All the discontinuations in periods 1 and 2 are considered,
including 7 patients who should
not have had a period 2
and dropped for administrative reasons in period 2.
A
slightly higher percentage of placebo patients (15.9%) discontinued the study
compared to the all bosentan patients (13.2%). The most common reason was
administrative (6.3% bosentan and 4.3% placebo) followed by worsening of the
patient’s condition (3.5% bosentan and 7.2% placebo). There were 3 bosentan
patients (2.1%) who withdrew because of increased liver enzymes, 1 bosentan and
2 placebo patients who died, and 1 bosentan patient who withdrew because of an
adverse event.
2.3.2 Primary endpoint (6 minute walk test)
The
mean baseline (the average of the screening and randomization) walk test, the
mean walk test at week 16, and the mean change from baseline at endpoint for
the walk test for the intent to treat
population are shown in the table below by treatment groups.
Table 8 Walk test: Change from baseline to Week 16, ITT population
--------------------------------------------------------------------------------------------------------------------
Walk test (m)
Bosentan Bosentan All Placebo
125 mg 250 mg
Bosentan
N=74 N=70 N=144 N=69
--------------------------------------------------------------------------------------------------------------------
Use of supplemental oxygen during
screening/randomization walk tests
n
74 70 144 69
Yes
11 14.9% 12
17.1% 23 16.0%
16 23.2%
No
63 85.1% 58
82.9% 121 84.0% 53 76.8%
Baseline
n
74 70 144 69
Mean
326.3 333.0 329.6 344.3
Standard deviation
73.2 75.4 74.1 76.4
95% CL of mean 309.3 , 343.2 315.0 , 351.0
317.4 , 341.8 326.0 , 362.7
Median
333.0 338.8 337.3 359.0
95% CL of median
306.5 , 357.5 316.0 , 369.0 320.0 , 357.0
344.0 , 382.5
Min , Max
159.0 , 464.5 173.5 , 440.0 159.0 , 464.5
150.0 , 448.5
Week 16
n
74 70 144 69
Mean
353.1 379.5 365.9 336.5
Standard deviation
115.0 101.2 109.0 129.2
95% CL of mean
326.4 , 379.7 355.3 , 403.6 348.0 , 383.9
305.4 , 367.5
Median
376.5 384.5 379.5 355.0
95% CL of median
338.0 , 396.0 363.0 , 417.0 363.0 , 396.0
333.0 , 378.0
Min , Max
0.0 , 602.0 57.0 , 555.0 0.0 , 602.0 0.0 , 585.0
Change from baseline
n
74 70 144 69
Mean
26.8 46.5 36.4 -7.8
Standard deviation
75.3 61.7 69.5 96.1
95% CL of mean
9.3 , 44.2 31.7 , 61.2 24.9 , 47.8
-30.9 , 15.2
Median
32.8 49.8 34.5 9.0
95% CL of median 19.5 , 40.0
19.5 , 66.0 26.0 , 48.5 -18.0 , 26.0
Min , Max
-205.0 , 214.0 -131.0 , 257.5 -205.0 , 257.5
-383.0 , 227.5
--------------------------------------------------------------------------------------------------------------------
TREATMENT EFFECT
Mean
34.6 54.3 44.2
95% CL of mean
6.2 , 63.1 27.3 , 81.4 21.4 , 67.0
Median
28.2 45.0 36.7
95% CL of median
7.5 , 51.5 23.1 , 67.1 17.9 , 55.9
p-value Mann-Whitney U-test 0.0002
--------------------------------------------------------------------------------------------------------------------
CL=confidence limits.
The
mean baseline walk tests were between 326.3 m and 344.3 m. Compared to the
bosentan groups, the placebo group walked the longest at baseline by about 15
m.
Both
bosentan groups, but not placebo, had a longer mean walk test at week 16
compared to baseline. The mean absolute changes from baseline (95% confidence
limits) for the 125 mg and 250 mg bosentan groups were 26.8 m (9.3, 44.2) and
46.5 m (31.7, 61.2), respectively. The mean change[5]
for the placebo group was –7.8 m (–30.9, 15.2).
The
mean treatment effects (95% CL) for the 1.25 mg and 250 mg bosentan groups were
34.6 m (6.2, 63.1) and 54.3 (27.3, 81.4), respectively. The mean change in walk
distance was significantly greater (p=0.0002 using the Mann-Whitney U test) for
the all bosentan group (n=144) compared to the placebo group.
2.3.2.1
Mean walk distances by visit
The
changes from baseline for the walk distance at baseline, weeks 4, 8, and 16 for
the all bosentan group and the placebo group are shown in the figure below.
N.B. all bosentan patients were receiving 62.5 mg bid for the first 4 weeks of
treatment.
Figure 2 Walk distance: Change from baseline
over time during Period 1,
ITT population
Note: All bosentan patients received 62.5 mg bid during the first 4 weeks of the study and then were up-titrated to the target dose (125 mg bid or 250 mg bid).
The
change from baseline for the bosentan group was greater at weeks 8 and 16 than
at week 4 and there was no discernable difference between the change from
baseline at weeks 8 and 16.
Placebo,
on the other hand, showed a slight increase in the mean walking distance at
week 4 compared to baseline, but there was a dramatic loss of effect at week 8
in this treatment group and it fell below baseline by week 16.
2.3.2.2 Dose effect
The
change from baseline at weeks 4, 8, and 16 by dose for the 2 bosentan dose groups
as well as the placebo effect are shown in the figure below. At week 4, all
bosentan patients were taking 62.5 mg bid.
Figure 3 Walk distance: Change from baseline
over time during Period 1 by dose,
ITT population
Note: All bosentan patients received 62.5 m b.i.d. during the first 4 weeks of the study and then were up-titrated to the target dose (125 mg b.i.d. or 250 mg b.i.d.).
The
250 mg bosentan group was numerically superior to the 125 mg group at weeks 8
and 16, but the confidence limits overlapped at both time points.
2.3.2.3 Subgroups
The
placebo corrected change from baseline for the walk test by sub group are shown
below.
The
point estimates for all subgroups were all above 0 m with most being at least
20 m improvement over baseline.
2.3.3
Secondary endpoints
2.3.3.1
Time from randomization to clinical worsening (defined as death from all causes, lung transplantation or
discontinuation of therapy because of clinical deterioration)
The
table and figures below shows the Kaplan Meier estimate of the event free rate
(%), by treatment group.
Table 9 Time from randomization to clinical worsening up to study end, ITT population
(Table T12a / 04MAY01)
--------------------------------------------------------------------------------------------------------------------
K-M estimate of the event-free
Bosentan
Bosentan All Placebo
rate (%)
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
--------------------------------------------------------------------------------------------------------------------
At 8 weeks
Patients at risk 71 70 141 63
Patients censored - - - -
Patients with event 3 - 3 6
K-M estimate (%) 95.9 100 97.9 91.3
95% confidence interval
(%) 91.5 , 100 100.0 , 100
95.6 , 100 84.7 , 98.0
At 16 weeks
Patients at risk 52 44 96 41
Patients censored 18 23 41 18
Patients with event 4 3 7 10
K-M estimate (%) 94.6 95.3 95.0 85.2
95% confidence interval
(%) 89.4 , 99.7 90.2 , 100 91.4 , 98.6 76.7 , 93.7
At 28 weeks
Patients at risk 5 6 11 3
Patients censored 64 60 124 52
Patients with event 5 4 9 14
K-M estimate (%) 88.3 90.0 89.3 62.9
95% confidence interval
(%) 75.4 , 100 78.8 , 100 80.6 , 97.9 41.2 , 84.7
--------------------------------------------------------------------------------------------------------------------
Treatment difference
Logrank p-value vs.
placebo 0.0133 0.0122 0.0015
--------------------------------------------------------------------------------------------------------------------
Patients were censored at the date of trial treatment end plus 1 day.
K-M = Kaplan-Meier.
Figure 4 Time from randomization to clinical worsening, ITT population
The
placebo group was significantly worse at week 16 compared to the 2 bosentan
groups. There is little difference between dose groups.
The
incidence of clinical worsening by treatment group is shown below.
Table 10 Incidence of clinical worsening, ITT population
(Table T13 / 04MAY01 and T13b / 07MAY01)
-----------------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
No. % No. % No. % No. %
-----------------------------------------------------------------------------------------------------------
Patients with clinical worsening to week 28* 5 6.8% 4 5.7% 9 6.3% 14 20.3%
Death 1 1.4% - 1 0.7% 2 2.9%
Hospitalization for PHT 3 4.1% 3 4.3% 6 4.2% 9 13.0%
Lack of clinical/walk test improvement - - - 1 1.4%
Worsening of patient condition 3 4.1% 2 2.9% 5 3.5% 5 7.2%
Receipt of prostacyclin 2 2.7% 2 2.9% 4 2.8% 3 4.3%
-----------------------------------------------------------------------------------------------------------
Patients with clinical worsening in Period 1* 4 5.4% 3 4.3% 7 4.9% 12 17.4%
Death 1 1.4% - 1 0.7% 2 2.9%
Hospitalization for PHT 3 4.1% 3 4.3% 6 4.2% 9 13.0%
Lack of clinical/walk test improvement - - - 1 1.4%
Worsening of patient condition 2 2.7% 1 1.4% 3 2.1% 3 4.3%
Receipt of prostacyclin 2 2.7% 1 1.4% 3 2.1% 2 2.9%
-----------------------------------------------------------------------------------------------------------
* Patients may fall into more than one category.
The
overall incidence rate of worsening was much greater for the placebo group at
weeks 16 and 28 (17.4% and 20.3%, respectively) compared to the all bosentan
group (4.9% and 6.3%, respectively). The largest difference was the result of
the placebo patients having a greater tendency to be hospitalized for pulmonary
hypertension.
There
was no evidence of a waning of effect of bosentan over the relatively brief
time of the study (28 weeks).
2.3.3.2
Changes from
baseline dyspnea index (Borg dyspnea index).
Table 11 Borg dyspnea index: Change from baseline to Week 16, ITT population
(Table T10 / 04MAY01)
--------------------------------------------------------------------------------------------------------------------
Borg dyspnea index
Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
--------------------------------------------------------------------------------------------------------------------
Baseline
n 74 70 144 69
Mean 3.3 3.8 3.6 3.8
Standard deviation 2.2 1.9 2.0 2.0
95% CL of mean 2.8 , 3.8 3.4 , 4.3 3.2 , 3.9 3.4 , 4.3
Median 3.0 4.0 3.0 4.0
95% CL of median 3.0 , 4.0 3.0 , 4.0 3.0 , 4.0 3.0 , 4.0
Min , Max 0.0 , 10.0 0.0 , 9.0 0.0 , 10.0 0.0 , 10.0
Week 16
n 74 70 144 69
Mean 3.3 3.3 3.3 4.2
Standard deviation 2.7 2.3 2.5 2.4
95% CL of mean 2.6 , 3.9 2.7 , 3.8 2.9 , 3.7 3.6 , 4.8
Median 3.0 3.0 3.0 4.0
95% CL of median 2.0 , 3.0 3.0 , 3.0 3.0 , 3.0 3.0 , 4.0
Min , Max 0.0 , 10.0 0.0 , 9.0 0.0 , 10.0 0.0 , 10.0
Change from baseline
n 74 70 144 69
Mean -0.1 -0.6 -0.3 0.3
Standard deviation 2.1 1.9 2.0 2.0
95% CL of mean -0.5 , 0.4 -1.0 , -0.1 -0.6 , 0.0 -0.2 , 0.8
Median 0.0 -0.3 0.0 0.0
95% CL of median 0.0 , 0.0 -1.0 , 0.0 0.0 , 0.0 0.0 , 0.0
Min , Max -6.5 , 6.0 -6.0 , 4.0 -6.5 , 6.0 -3.0 , 7.0
--------------------------------------------------------------------------------------------------------------------
TREATMENT EFFECT
Mean -0.4 -0.9 -0.6
95% CL of mean -1.1 , 0.3 -1.6 , -0.2 -1.2 , -0.1
Median -0.2 -0.7 -0.3
95% CL of median -0.8 , 0.4 -1.4 , -0.0 -1.0 , 0.1
--------------------------------------------------------------------------------------------------------------------
CL=confidence limits.
Bosentan
patients had an improvement in their Borg scale by week 16 while placebo
patients deteriorated. The placebo subtracted improvement ranged from -0.4 for
the 125 mg bid group to -0.9 for the 250 mg bid group.
2.3.3.4.Changes
from baseline in WHO functional class
The
incidence of improvement in WHO functional class is shown below.
Table 12 Incidence of improvement in WHO functional class during Period 1, ITT population
(Table T11b / 04MAY01)
---------------------------------------------------------------------------------------------------------------
Change at week 16 Bosentan Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
---------------------------------------------------------------------------------------------------------------
n 74 70 144 69
Improved [n (%)] 32 (43.2%) 29 (41.4%) 61 (42.4%) 21 (30.4%)
95% confidence limits (%) 31.8 , 55.3 29.8 , 53.8 34.2 , 50.9 19.9 , 42.7
Treatment effect*
Difference 12.8% 11.0% 11.9%
95% confidence limits (%) -4.0 , 28.6 -5.9 , 27.0 -2.9 , 25.2
---------------------------------------------------------------------------------------------------------------
* Compared with placebo
A higher incidence of
improvement was seen in the bosentan group (42.2%) compared to the placebo
group (30.4%). There was no difference
between the 2 bosentan groups.
The percent of patients who changed WHO functional
class is shown below.
Table 13 WHO functional class: Change from baseline to Week 16, ITT population
(Table T11a / 04MAY01)
---------------------------------------------------------------------------------------------------
Week 16
---------------------------------------------------------
Treatment N n (%)
Baseline I II III
IV
WHO class No. %
No. % No.
% No. %
---------------------------------------------------------------------------------------------------
Bosentan 125 mg 74 68 (91.9%) III 2 2.7%
26 35.1% 38
51.4% 2 2.7%
6 (8.1%)
IV - 2 2.7% 2 2.7%
2 2.7%
Bosentan 250 mg 70 62 (88.6%) III 1 1.4%
23 32.9% 37
52.9% 1 1.4%
8
(11.4%) IV -
1 1.4% 4
5.7% 3 4.3%
All Bosentan 144 130 (90.3%) III 3 2.1%
49 34.0% 75
52.1% 3 2.1%
14 (9.7%)
IV - 3 2.1% 6 4.2%
5 3.5%
Placebo 69 65 (94.2%) III - 19 27.5% 42 60.9%
4 5.8%
4 (5.8%)
IV - - 2 2.9% 2
2.9%
---------------------------------------------------------------------------------------------------
At
week 16, the majority of patients remained in their functional class:
-All
bosentan: 75 (52.1%) were class III at baseline and remained class III; 5
(3.5%) were class IV at baseline and remained class IV;
-Placebo:
42 (60.9%) were class III at baseline and remained class III; 2 (2.9%) were
class IV at baseline and remained class IV.
However,
more bosentan patients than placebo patients improved:
-All
bosentan: 49 (34%) moved from class III at baseline to class II at week 16, 3
(2.1%) moved from class III at baseline to class I at week 16, and 6 (4.2%)
moved from class IV at baseline to class III at week 16;
-Placebo:
19 (27.5%) moved from class III at baseline to class II at week 16, 0 moved
from class III at baseline to class I at week 16, and 2 (2.9%) moved from class
IV at baseline to class III at week 16
And
fewer bosentan patients than placebo patients grew worse:
-All
bosentan: 3 (2.1%) moved from class III to class IV;
-Placebo:
4 (5.8%) moved from class III to class IV.
2.3.3.5 Increased therapy for PAH
The
number and percent of patients who had an increase in their therapy for PAH is
shown below.
Table 14 Incidence of increased therapy for
pulmonary arterial hypertension,
ITT population
(Table T14 / 04MAY01)
---------------------------------------------------------------------------------------------------------------
Bosentan Bosentan All
Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144
N=69
---------------------------------------------------------------------------------------------------------------
Period 1 (weeks 0 to 16)
n 74 70 144
69
Patients with increase [n(%)] 18 (24.3%)
14 (20.0%) 32 (22.2%) 20 (29.0%)
95% confidence limits (%) 15.1 , 35.7 11.4 , 31.3 15.7 , 29.9 18.7
, 41.2
Treatment effect*
Difference -4.7% -9.0% -6.8%
95% confidence limits (%) -20.0 , 10.6 -24.3 , 5.9 -19.5 , 7.1
Period 1+2 (weeks 0 to 28)†
n 19 16 35
13
Patients with increase [n(%)] 6 (31.6%)
5 (31.3%) 11 (31.4%) 5 (38.5%)
95% confidence limits (%) 12.6 , 56.6 11.0 , 58.7 16.9 , 49.3 13.9
, 68.4
Treatment effect
Difference -6.9% -7.2% -7.0%
95% confidence limits (%) -41.0 , 27.5 -43.1 , 27.7 -36.5 , 25.4
---------------------------------------------------------------------------------------------------------------
† Analyzed only in those patients who were scheduled to continue to
period 2.
For
the first 16 weeks, 22.2% of bosentan patients had an increase in PAH therapy
compared to 29% of placebo patients. For the prolonged study period (up to 28
weeks), 31.4% bosentan patients compared to 38.5% placebo patients had an
increase in PAH therapy.
2.4
Safety
2.4.1
Dose and duration of treatment
Summary
of treatment duration is shown below.
Table 15 Summary of extent of exposure to trial treatment, safety population
(Table T15 / 04MAY01)
--------------------------------------------------------------------------------------------------------------------
Bosentan
Bosentan All Placebo
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
--------------------------------------------------------------------------------------------------------------------
During Period 1 (up to Week 16)
Duration of treatment (days)
n 74 70 144 69
Mean 113.4 113.8 113.6 112.8
Standard deviation 16.8
10.6 14.1 17.7
95% CL of mean 109.5 , 117.3
111.3 , 116.4 111.3 , 115.9 108.6 , 117.1
Median 114.0 114.0 114.0 114.0
95% CL of median 113.0 , 118.0
112.0 , 118.0 113.0 , 117.0 112.0 , 119.0
Min , Max 24.0 , 133.0 64.0 , 131.0 24.0 , 133.0 18.0 ,
139.0
Number (%) of patient who
n 74 70 144 69
Remained at target dose 63 85.1% 59 84.3% 122 84.7% 57 82.6%
Had >=1 reduction in
dose 7 9.5% 7 10.0%
14 9.7% 6 8.7%
Were withdrawn/weaned 4 5.4% 4 5.7% 8 5.6% 6 8.7%
During the study (up to end of treatment)
Duration of treatment (days)
n 74 70 144 69
Mean 129.4 128.7
129.1 123.8
Standard deviation 35.8 32.4 34.1 33.8
95% CL of mean 121.1 , 137.7
121.0 , 136.5 123.5 , 134.7 115.7 , 131.9
Median 118.0 118.0 118.0 115.0
95% CL of median 114.0 , 123.0
113.0 , 121.0 115.0 , 121.0 113.0 , 119.0
Min , Max 24.0 ,
207.0 64.0 , 204.0 24.0 , 207.0 18.0 , 214.0
Number (%) of patient who
n 74 70 144 69
Remained at target dose 56 75.7% 55 78.6% 111 77.1% 52 75.4%
Had >=1 reduction in
dose 7 9.5% 5 7.1% 12 8.3% 6 8.7%
Were withdrawn/weaned 11 14.9% 10 14.3% 21 14.6% 11 15.9%
Patients on treatment [n (%)]
n 74 70 144 69
>= 1 and <
4 weeks 1
1.4% - 1 0.7% 1 1.4%
>= 4 and <
8 weeks
1 1.4% - 1
0.7% 1 1.4%
>= 8 and < 16 weeks 16 21.6% 20 28.6% 36
25.0% 16 23.2%
>= 16 and < 28
weeks 49 66.2% 44 62.9% 93 64.6% 47 68.1%
>= 28 weeks 7 9.5% 6 8.6% 13 9.0% 4 5.8%
--------------------------------------------------------------------------------------------------------------------
Mean
duration of treatment was about 113 days for all 3 treatment groups, and
similar percentage of patients in each group remained at the target dose (about
83%). Dose reduction occurred in 8.7% of the placebo group compared to 9.7% in
the all bosentan group. There was little difference between the 125 mg and 250
mg groups. The majority of patients(about 66%) in all 3 treatment groups
remained on drug for at least 16 weeks.
2.4.2 Serious safety
2.4.2.1.Deaths
The
deaths reported during treatment and up to 28 days after stop of treatment are
shown below.
Table 19 Summary
of deaths during study treatment or within 28 days of treatment end,
safety population
(Table T17 /
04MAY01)
---------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
Cause of death 125 mg 250 mg
Bosentan
N=74 N=70 N=144 N=69
No. % No.
% No. %
No. %
---------------------------------------------------------------------------------------------------
Total patients who died 1 1.4%
3 4.3% 4 2.8% 2
2.9%
CARDIAC FAILURE NOS 1
1.4% 1 1.4%
2 1.4% -
PNEUMONIA NOS - 1 1.4% 1
0.7% -
PULMONARY HAEMORRHAGE - 1 1.4% 1 0.7%
-
SEPSIS NOS
- 1 1.4% 1
0.7% -
PULMONARY HYPERTENSION NOS AGGRAVATED - - - 2 2.9%
---------------------------------------------------------------------------------------------------
Note: All the
deaths reported up to 28 days after end of randomized treatment are included.
Patients may have had more than one
cause of death.
The
incidence rates for death during the first 16 weeks of the study (and up to 28
days after the stop of study drug treatment) were similar for the placebo
(2.9%) and the all bosentan group (2.8%). The incidence rate for the bosentan
125 mg group (4.3%) was twice the rate in the bosentan 125 mg group (1.4%).
The
6 deaths (4 bosentan and 2 placebo) are discussed below.
|
Patient # |
Dose/day of study |
comments |
|
115 10117 |
Bos 250 mg bid/84 |
69 year old female patient with systemic sclerosis and connective tissue disease, Raynaud's phenomenon, Sjogren's syndrome, atrial septal defect, anemia, duodenal and gastric ulcer hemorrhage, hiatus hernia, gastro-esophageal reflux disease, drug hypersensitivity, hypertension, tobacco abuse and cataract extraction. Concomitant medication included lansoprazole, furosemide, mecamylamine, and spironolactone. The patient was hospitalized on day 70 with bilateral pneumonia, hypotension and renal insufficiency. Study medication was withdrawn. She became hypoxemic and required intubation and mechanical ventilation. She was treated with antibiotics, dobutamine, dopamine and levophed, she remained hypotensive and required mechanical ventilation. Bilateral pleural effusion consistent with legionella pneumonia and pulmonary edema were reported. Cholelithiasis was seen on ultrasound. She developed hypotension and bradycardia within the context of septic shock and died on day 84. The cause of death was given as pneumonia and sepsis. |
|
301 30007 |
Bos 250 mg bid/68 |
49-year-old white male patient with systemic sclerosis, allergic rhinitis, gastrointestinal hemorrhage and esophagitis, thrombophlebitis and epilepsy and concomitant medication including digoxin, furosemide, spironolactone, warfarin, xylometazoline, omeprazole, phenobarbitone, carbamazepine, prednisolone eye drops, hypermellose eye drops, paracetamol, penicillin, clarithromycin, flucloxacillin, nystatin and vitamin K was prematurely withdrawn from the study on day 64 because of worsening of his condition. Patient reported dyspnea, dizziness, esophagitis and oral candidiasis during the early part of the trial. He was hospitalized with increased shortness of breath, pitting edema, cyanosis and abdominal ascites on day 63. Bosentan was stopped and the patient was treated with iv furosemide and epoprostenol. The patient died on day 68 of renal failure, hepatic failure and right ventricular failure. |
|
117 10105 |
Bos 250 mgbid/128 (open label phase) |
26 year old white male with a history of hemoptysis and thromboembolic pulmonary hypertension received bosentan 250 mg bid. Concomitant medication included warfarin.. he sustained an iatrogenic urethral tear as part of catheterization during a workup for lung transplantation on day 70. He required suprapubic catheter placement and treatment with antibiotic through day 93 until he had corrective cystoscopic surgery. Patient reported severe headache, nausea and vomiting on day 78. He was admitted to hospital and treated with compazine for the nausea and vomiting. A lumbar puncture revealed positive sero-sanguinous fluid. CT scan ruled out SAH. He was discharged the same day with the headache resolved. Patient was re-hospitalized on day 111 because of hemoptysis and lower extremity edema following a day of shortness of breath. Chest x-ray showed pneumonia. He was treated with antibiotics and antitussives and study medication was discontinued on day 113. He was enrolled into open label study AC 052-354 and after an intensive in-hospital workup revealed both pulmonary thromboses and hemorrhage, bosentan was discontinued after 7 days. The patient died on day 128. |
|
208 2001 |
Bos 125 mg bid/78 |
77 year old female patient with systemic sclerosis and Raynaud's syndrome and concomitant medications at time of event included furosemide, nadroparin, allopurinol and dopamine. The patient was hospitalized on day 44 of the study with worsening peripheral ischemia in both inferior limbs. Stenosis of the left popliteal artery was found and percutaneous dilation was performed on Day 59. Subsequently, her renal function deteriorated and she required increased furosemide, dopamine infusion, and oxygen. Chest X-ray showed bilateral pleural effusions, an abdominal echo revealed ascites, and an ECG showed asystole on day 78. The patient went on to develop hypotension; study medication was reduced but there was no improvement. She died the same day; the cause of death was irreversible right heart failure induced by further deterioration in renal function. Died of cardiac failure |
|
112 10070 |
Placebo/18 |
Died of aggravated PAH |
|
201 20614 |
Placebo/76 |
Died of aggravated PAH |
|
105 10014^ |
Bos 250 mg bid/115 |
48-year-old white female with pulmonary hypertension secondary to systemic sclerosis had a medical history of cardiac failure, anemia, thrombocytopenia, lupus erythematosus, Raynaud's syndrome, rectal bleeding, urinary tract infection, cholelithiasis, hip arthroplasty due to aseptic necrosis, and constipation. Concomitant medication included prednisone, mometasone, acetylsalicylic acid, omeprazole, fluorazepam, paracetamol, docusate, and calcium. She was randomized to bosentan She reported nausea treated with promethazine on day 1, dyspepsia on day 6, tinnitus on day 31, and arthralgia day 87. Hepatic function test abnormalities: elevated AST, ALT, alk phos levels at 659, 554 and 275 U/l, respectively. Bilirubin (direct and total) were also increased at 22 and 36 mm/l, respectively) on day 99. Study drug was permanently discontinued on day 116. Hepatic function tests returned to normal on day 141. The patient reported to her local pneumologist with symptoms of worsening pulmonary hypertension on day 145. Epoprostenol therapy was initiated. Inotropic drugs and mechanical ventilation were started. She died 3 days later; cause of death was given as right heart failure secondary due to worsening pulmonary hypertension. The investigator assessed the study drug-event relationship as unrelated. No autopsy was performed. |
^The
sponsor did not report this death in the BREATHE-1 table of Deaths because the
clinical worsening for PAH occurred 29 days after the study medication was
discontinued.
With
the understanding that this is a small sample size, there is no real indication
that bosentan has an impact on survival. However, the larger number of deaths
in the bosentan 250 mg is not reassuring.
2.4.2.2
Discontinuations for adverse events
The
premature discontinuations of study drug because of an adverse event are shown
below.
Table 16 Summary of discontinuations of study treatment due to adverse events, safety population
(Table T21c / 04MAY01)
---------------------------------------------------------------------------------------------------
Body system / Bosentan Bosentan
All Placebo
Adverse event 125 mg 250 mg Bosentan
N=74
N=70 N=144 N=69
No. %
No. % No.
% No. %
---------------------------------------------------------------------------------------------------
ALL BODY SYSTEMS
Total pts with at least one
AE 3 4.1%
6 8.6% 9 6.3% 5
7.2%
Total number of AEs 3 9 12 7
HEPATIC FUNCTION ABNORMAL
NOS - 3 4.3% 3
2.1% -
PULMONARY HYPERTENSION NOS
AGGRAVATED 2 2.7%
- 2 1.4%
4 5.8%
CARDIAC FAILURE NOS 1 1.4%
1 1.4% 2 1.4% 1
1.4%
CHOLELITHIASIS -
1 1.4% 1 0.7% -
JAUNDICE NOS - 1 1.4% 1 0.7%
-
PNEUMONIA NOS - 1 1.4% 1 0.7%
-
RENAL FAILURE NOS - 1 1.4% 1 0.7%
-
SEPSIS NOS - 1 1.4% 1 0.7%
-
SYNCOPE - - -
2 2.9%
---------------------------------------------------------------------------------------------------
Note: All the discontinuations in periods 1 and 2 are considered,
including 7 patients who should
not have had a period 2
and dropped for administrative reasons in period 2.
The
incidence rate of dropouts for adverse events was slightly higher in placebo
(7.2%) compared to all bosentan (6.3%). However, the incidence rate for the
higher dose of bosentan (8.6%) was more than twice the rate for either placebo
or low dose bosentan (4.1%).
The
most common adverse event given as a reason for placebo patients dropping out
was aggravated pulmonary hypertension, another way of indicating lack of
effect. On the other hand, there were 3 bosentan patients who dropped out for
abnormal hepatic function and 1 for jaundice (all were receiving 250 mg dose).
These patients are discussed below.
Jaundice
Patient # 110 10037. 43 year old white female with systemic sclerosis gastro-esophageal reflux disease, calcinosis, Raynaud's syndrome, sclerodactyly and telangiectasis and concomitant medication including digoxin, furosemide, omeprazole, metolazone, spironolactone, thyroid, hydrocodone, phenyltoloxamine, guaifenesin, metoclopramide, triamcinolone, warfarin, and azithromycin. During the course of the study, the patient experienced vomiting, dehydration, edema, respiratory tract infection, alopecia, drying of mucus membranes, and jaundice. On day 127, the patient's pulmonary hypertension worsened (indicated by a decrease in walking performance) and the patient was treated with i.v. epoprostenol. The study medication was
permanently discontinued on day 147 due to worsening of the condition. The LFTs are shown below. The patient had elevated levels at baseline.
Elevated LFT
Patient#
113 10050 59-year-old white male
patient with primary pulmonary hypertension and systemic hypertension.
Concomitant medication included potassium, felodipine, furosemide, metolazone,
spironolactone, and warfarin. He was found to have elevated liver enzymes (ALT
108 U/L, AST 135 U/L, alk phos 79 U/L, total bilirubin 12.2 mmol/L) and urine
discoloration on day 57. The study medication was reduced to half on day 64.
Liver enzymes continued to rise (ALT 628 U/L, AST 414 U/L, alk phos 108 U/L,
total bilirubin 26.1 mm/L day 92). Study drug was stopped on day 95. LFTs
gradually returned to baseline and the urine color normalized by day 127. The
patient was rolled over to the open label extension study.
2.4.2.3
Serious adverse events
The
sponsor stated that a number of adverse events considered by regulatory
definition as serious were censored in this study because these events were
expected in this patient population. Additionally, aggravated PAH that was
reported for one or more of these events was also not counted as serious in
this study.
A
list of serious adverse events that were reported during the study or within 2
days of treatment discontinuation followed by a list of serious adverse events
that were reported from 3 to 28 days after treatment discontinuations are
displayed below.
The most commonly
reported serious events (adding events from appendices 22 and 23 together) in
the bosentan group were anemia (4/144, 2.8% bosentan and 0 placebo) and
abdominal complaints[6] (6/144, 4.2% bosentan and 3/69, 4.8%
placebo).
The
4 anemia reports are discussed below.
Bosentan 125 mg bid. Patient# 104 10030: 67-year-old male with pulmonary hypertension due to systemic sclerosis was randomized to bosentan 125 mg bid. He had a history of systemic hypertension, hiatal hernia, ischemic heart disease with CABG, prostate cancer, GERD, CREST syndrome and borderline anemia and was receiving furosemide, spironolactone, aspirin, lisinopril, and omeprazole. On Day 28 of the study, the patient went to see his local doctor and was diagnosed with low hemoglobin. His hemoglobin and hematocrit values were as follows:
Visit Day Hemoglobin (g/dl)
Hematocrit (%)
Screening (0) 11.6 36
Day 28
8.6 27
Day 36
6.9 23
Day 42 10.9 36
On each of Days 37 and 39 he was transfused with 2 units of red blood cells. The study medication was not discontinued during the event.
Bosentan
125 mg bid. Patient #104 10139: 63 year old white female with pulmonary
hypertension due to systemic sclerosis was randomized to bosentan 125 mg bid.
She had a medical history of scleroderma and GERD and was receiving treatments
with omeprazole, estrogen, levothyroxine, warfarin, furosemide, lorazepam,
diphenhydramine, etidronate, and potassium.
On day 47 of the study, the patient's hemoglobin (Hb) and hematocrit
(Hct) were found to be lower than at screening. Her laboratory values were as
follows:
Hgb Hct
Screening: 10.5 g/dL 33 %
Day
35 9.5 g/dL 30 %
Day
47 8.3 g/dL 25.7%
She
was transfused with two units of RBCs. The study medication was not
discontinued during the event. The patient had experienced a similar drop in
Hct levels (from 28 % to 25%) one month prior to study start. At that time she
had been transfused with two units of RBC.
Bosentan
125 mg bid. Patient #117 10107: 64 year old female patient with pulmonary
hypertension was randomized to 125 mg bosentan bid and on day 111 was rolled
over to Open Label study AC-052-354, taking 62.5 mg bosentan bid. No relevant
medical history was reported. Concomitant medications included warfarin,
furosemide, and omeprazole. The patient was hospitalized on day 10 of the open
label study complaining of worsening dyspnea. The previous day at home she had
felt dizzy and had a syncopal episode that resulted in a fall during which she
had sustained trauma to her left arm.
On admission clinical laboratory investigations showed Hgb 8.9. She was
diagnosed with normocytic anemia, and study medication was discontinued. The
patient received two units of packed red blood cells. Of note: two hemoglobin
values done at screening and Day 28 of the blinded study were 16.1 and 15.0.
Bosentan
250 mg bid. Patient# 207 20713: 40 year
old female patient with primary pulmonary hypertension was randomized to
bosentan 250 mg bid and was rolled over to Open Label study AC-352-054 on day
107, receiving bosentan 62.5 mg bid. No additional medical history was given.
Concomitant medication included digoxin, furosemide and spironolactone. The patient was hospitalized on day 8 of the
open label study with progressive edema, dyspnea and increasing ascites,
considered to be exacerbation of right heart failure, and anemia with no evidence
of blood loss. Hgb 9.2, Hct 29 and INR 1.5. She was treated with increased
furosemide, dopamine, oxygen and blood
transfusion. On Day 27 the patient stopped taking bosentan. Of note: Hemoglobin at randomization: 12.0;
day 34: 10.8; day 107: 10. 3. WBC
decreased from the initial 5.7x10e9/L to 3.6; eosinophils remained
unchanged and WNL.
2.4.3.All
adverse events[7]
Adverse
events by body systems are shown below.
No. and (percent)
of patients with at least 1 event per body system
|
|
Bosentan |
|
|
||
|
Body
system Disorder |
125 mg n=74 |
250 mg n=70 |
All n=144 |
Placebo n=69 |
Placebo subtracted ^ (%) |
|
Vascular |
18 (24.3) |
17 (24.3) |
35 (24.3) |
9 (13.0) |
11.3 |
|
Hepatobiliary |
4 (5.4) |
12 (17.1) |
16 (11.1) |
3 (4.3) |
6.8 |
|
Skin,
subcutaneous |
14 (18.9) |
10 (14.3) |
24 (16.7) |
8 (11.6) |
5.1 |
|
Immune |
1 (1.4) |
1 (1.4) |
2 (1.4) |
0 |
1.4 |
|
Infections |
1 (1.4) |
3 (4.3) |
4 (2.8) |
1 (1.4) |
1.4 |
|
GI |
30 (40.5) |
24 (34.3) |
54 (37.5) |
25 (36.2) |
1.3 |
|
Metabolism
and nutrition |
2 (2.7) |
6 (8.6) |
8 (5.6) |
3 (4.3) |
1.3 |
|
Eye |
5 (6.8) |
5 (7.1) |
10 (6.9) |
4 (5.8) |
1.1 |
|
Respiratory,
thoracic, mediastinal |
35 (47.3) |
39 (55.7) |
74 (51.4) |
39 (56.5) |
-5.1 |
|
Cardiac |
34 (45.9) |
23 (32.9) |
57 (39.6) |
31 (44.9) |
-5.3 |
|
Nervous
|
22 (29.7) |
23 (32.9) |
45 (31.3) |
23 (33.3) |
-2.0 |
|
Musculoskeletal,
connective tissue, bone |
15 (20.3) |
14 (20.0) |
29 (20.1) |
19 (27.5) |
-6.9 |
|
General |
5 (6.8) |
10 (14.3) |
15 (10.4) |
9 (13.0) |
-2.6 |
|
Renal
and urinary |
7 (9.5) |
6 (8.6) |
13 (9.0) |
11 (15.9) |
-6.9 |
|
Blood
and lymph |
5 (6.8) |
3 (4.3) |
8 (5.6) |
4 (5.8) |
-0.2 |
|
Reproductive
and breast |
1 (1.4) |
5 (7.1) |
6 (4.2) |
3 (4.3) |
-0.1 |
|
Ear |
2 (2.7) |
2 (2.9) |
4 (2.8) |
2 (2.9) |
-0.1 |
|
Psychiatric |
2 (2.7) |
1 (1.4) |
3 (2.1) |
5 (7.2) |
-5.1 |
|
Injury |
0 |
2 (2.9) |
2 (1.4) |
1 (1.4) |
0 |
|
Endocrine |
0 |
1 (1.4) |
1 (0.7) |
1 (1.4) |
-0.7 |
^from
the all bosentan group
The
body systems with events reported more often by the all bosentan group compared
to the placebo group include vascular, hepatobiliary, skin/subcutanenous,
immune, infections, GI, metabolism/endocrine, and eye. The systems with the
largest placebo subtracted incidence rates were vascular (11%), hepatobiliary
(6.8%), and skin/subcutaneous (5.1%).
Individual
adverse events that were reported a) by more than 2 of “all bosentan” patients
and b) by 1% or more of the “all bosentan” patients than placebo patients are
shown below.
No. and (percent)
of patients
|
|
bosentan |
|
Placebo @subtracted (%) |
||
|
Adverse
event |
125 mg n=74 |
250 mg n=70 |
All n=144 |
Placebo n=69 |
|
|
Any
event |
70 (94.6) |
66 (94.3) |
136 (94.4) |
64 (92.8) |
1.6 |
|
Abnormal
Hepatic function |
4 (5.4) |
10 (14.3) |
14 (9.7) |
2 (2.9) |
6.8 |
|
Edema# |
13 (17.6) |
9 (12.9) |
22 (15.3) |
6 (8.7) |
6.6 |
|
Anemia^ |
5 (6.8) |
2 (2.9) |
7 (4.9) |
0 |
4.9 |
|
Flushing |
7 (9.5) |
6 (8.6) |
13 (9.0) |
3 (4.3) |
4.7 |
|
Fatigue+ |
4 (5.4) |
4 (5.7) |
8 (5.6) |
1 (1.4) |
4.2 |
|
Pruritius |
3 (4.1) |
2 (2.9) |
5 (3.5) |
0 |
3.5 |
|
Syncope |
6 (8.1) |
7 (10.0) |
13 (9.0) |
4 (5.8) |
3.2 |
|
Dyspepsia |
1 (1.4) |
3 (4.3) |
4 (2.8) |
0 |
2.8 |
|
GE
reflux |
1 (1.4) |
3 (4.3) |
4 (2.8) |
0 |
2.8 |
|
Palpitations |
3 (4.1) |
3 (4.3) |
6 (4.2) |
1 (1.4) |
2.8 |
|
Hypotension |
5 (6.8) |
5 (7.1) |
10 (6.9) |
3 (4.3) |
2.6 |
|
Dry
mouth |
3 (4.1) |
2 (2.9) |
5 (3.5) |
1 (1.4) |
2.1 |
|
Pneumonia |
2 (2.7) |
3 (4.3) |
5 (3.5) |
1 (1.4) |
2.1 |
|
Mouth
ulceration |
3 (4.1) |
0 |
3 (2.1) |
0 |
2.1 |
|
Rectal
hemorrhage |
3 (4.1) |
0 |
3 (2.1) |
0 |
2.1 |
|
Blurred
vision |
2 (2.7) |
1 (1.4) |
3 (2.1) |
0 |
2.1 |
|
Headache |
14 (18.9) |
16 (22.9) |
30 (20.8) |
13 (18.8) |
2.0 |
|
Contusion |
3 (4.1) |
1 (1.4) |
4 (2.8) |
1 (1.4) |
1.4 |
|
Dermatitis |
0 |
4 (5.7) |
4 (2.8) |
1 (1.4) |
1.4 |
@the
placebo rate is subtracted from the all bosentan rate
^includes
hematocrit decreased, hemoglobin decreased
+includes
lethargy
#includes
lower limb edema, peripheral edema, edema nos
The
adverse events with the highest placebo subtracted reporting rates were
abnormal hepatic function (6.8%), edema (6.6%), anemia (4.9%), flushing (4.7%),
fatigue (4.2%), pruritus (3.5%), and syncope (3.2%).
2.5.Laboratory
values
The change from
baseline at endpoint for laboratory parameters and including only those
patients with baseline and endpoint values are shown in the table below.
Compared to placebo, the bosentan patients had decreased means for hemoglobin, hematocrit, erythrocyte counts. This is consistent with the increased reports of anemia as an adverse event. The bosentan group also had a decrease in mean leukocytes, neutrophils, lymphocytes, and platelets. Mean eosinophil counts are up slightly compared to placebo.
As
expected, mean LFTs are increased in the bosentan group compared to placebo,
but bilirubin is not. Alk phos is little changed. Changes in creatinine and BUN
and serum electrolytes are similar for both treatment groups.
Number
and percent of patients with marked laboratory abnormalities are shown below.
N.B. Marked abnormalities in LFTs are discussed separately.
Table 17 Incidence of marked laboratory abnormalities in hematology and clinical chemistry variables, safety population
(Table T23 / 04MAY01)
--------------------------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
Laboratory Abnormality (*)
125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
No. % No. % No. % No. %
--------------------------------------------------------------------------------------------------------------------
HEMATOLOGY
Hemoglobin HH 0 / 72
0 / 70 0 /142 0 / 68
LL 3 / 72 4.2% 2 / 70 2.9% 5 /142 3.5% 1 / 68 1.5%
Hematocrit HH 0 / 72
0 / 70 0 /142 0 / 68
LL 2 / 72 2.8% 2 / 70 2.9% 4 /142 2.8% 1 / 68 1.5%
Leukocytes HH 1 / 72 1.4% 0 / 70 1 /142
0.7% 0 / 68
LL 0 / 72 2 / 70 2.9% 2 /142 1.4% 0 / 68
Neutrophils LL 1 / 72 1.4% 2 / 70 2.9% 3 /142 2.1% 1 / 68 1.5%
Eosinophils HH 0 / 72
0 / 70 0 /142 0 / 68
Platelets HH 0 / 72
0 / 69 0 /141 0 / 67
LL 0 / 72 1 / 69 1.4% 1 /141 0.7% 0 / 67
CLINICAL CHEMISTRY
Albumin HH 0 / 73
0 / 70 0 /143 0 / 68
LL 1 / 73 1.4% 0 / 70
1 /143 0.7% 0 / 68
Creatinine HH 0 / 73
0 / 70 0 /143 0 / 68
Sodium HH 0 /
73 0 / 70 0 /143 0 / 68
LL 1 / 73 1.4% 0 / 70
1 /143 0.7% 1 / 68 1.5%
Potassium HH 0 / 73 0 / 70 0 /143 0 / 68
LL 0 / 73 0 / 70 0 /143 0 / 68
Glucose HH 0 / 73
1 / 70 1.4% 1 /143 0.7% 0 / 68
LL 0 / 73 0 / 70 0 /143 0 / 68
BUN HH
1 / 73 1.4% 0 / 70 1 /143
0.7% 0 / 68
--------------------------------------------------------------------------------------------------------------------
Values given are the number of patients with at least one
abnormality/number of patients assessed (%)
HH=above the marked reference range, LL=below the marked reference
range
Consistent
with the other findings, there were more markedly low hemoglobin (3.5%) and/or
hematocrit values (2.8%) compared to placebo (1.5%). In addition, the incidence
rate for abnormally low leukocytes and neutrophils were 1.4% and 2.1%,
respectively, compared to 0% and 1.5%, respectively, for the placebo group.
There was 1 abnormally low platelet count in the bosentan group and none in
placebo.
2.5.1
Hemoglobin/hematocrit abnormalities
Patients with marked hemoglobin and/or hematocrit abnormalities are discussed below.
Bosentan 250 mg bid.
Patient 104 10027 (bosentan 250 mg bid.): 64-year-old white male with pulmonary arterial hypertension due to systemic sclerosis. He had a history of gastro-esophageal reflux, and he was treated with aspirin and warfarin. The hemoglobin concentration dropped gradually from 15.7 to 11.9 g/dl after 205 days of treatment with bosentan (hematocrit dropped from 50% to 35% during the same time period). Ankle edema was reported during the trial, and albumin levels decreased slightly (37 to 35 g/l).
Patient 105 10014 (bosentan 250 mg bid): 48-year-old white female with pulmonary arterial hypertension due to systemic sclerosis. She had a history of lupus erythematosus, anemia, thrombocytopenia, leucopenia and rectal bleeding due to hemorrhoids. After 31 days of treatment with bosentan, hemoglobin concentration dropped from 14.0 to 11.5 g/dl. The low platelet count observed at baseline did not change and the WBC count dropped slightly from 3500 to 2900/ml. The patient was treated with prednisone and aspirin. Patient was decreased to half dose on day 101 and then discontinued on day 115 because of rising LFTs (ALT and AST > 8 x ULN and bilirubin. The lab abnormalities returned to normal after drug was stopped but the patient’s underlying pulmonary disease grew worse and she died 32 days later.
Patient 202 20203 (bosentan 250 mg b.i.d.): 71-year-old white female with pulmonary arterial hypertension due to systemic sclerosis. The hemoglobin concentration dropped from 12.1 to 9.9 g/dl after 111 days of treatment with bosentan. The patient was treated with acenocoumarol, but there was no evidence for bleeding. There was no evidence for hemolysis as bilirubin levels decreased. Platelet count increased, and WBC count, which was high at baseline, decreased to normal levels. The slight increase in body weight associated with leg edema and the decrease in albumin levels from 35 to 32 g/l suggested that hemodilution could be the reason for the drop in hemoglobin.
Bosentan 125 mg b.i.d.
Patient 104 10030 (bosentan 125 mg b.i.d.): 67-year-old white male with pulmonary arterial hypertension due to systemic sclerosis. He had a history of gastro-esophageal reflux, and he was treated with aspirin. The hemoglobin concentration decreased from 11.6 g/dl at baseline to 6.9 g/dl on Day 36. He was treated with 4 units of blood (2 units on each of Days 37 and 38). Hemoglobin concentrations were 10.9 and 9.8 g/dl on Days 40 and 63, respectively, and 13.0 g/dl on Day 117 of treatment. There were no relevant changes in WBC or platelet counts, and bilirubin levels decreased. Black stools (occult gastrointestinal bleeding) were reported as an adverse event in the same month.
Patient 104 10139 (bosentan 125 mg bid.): 63-year-old white female with pulmonary arterial hypertension due to systemic sclerosis. She had a history of anemia, and she received 2 units of blood 1 month before the trial due to a significant drop in hemoglobin concentration. She had gastro-esophageal reflux disease, and she was being treated with warfarin. Her hemoglobin concentration dropped from 11.1 g/dl at baseline to 9.9 and 8.4 g/dl on Days 34 and 48 of treatment, respectively. She was treated with 2 units of blood on Day 51. Platelet count increased, and WBC count remained unchanged. Extensive diverticulosis with diverticulitis was detected during colonscopy, but there was no evidence for bleeding. On Day 111 of treatment, hemoglobin concentration was 12.9 g/dl.
Patient 109 10157 (bosentan 125 mg bid.): 54-year-old white female with pulmonary arterial hypertension due to PPH. She had a history of epistaxis and anemia. During the trial, she continued to suffer from nose bleeds, and her hemoglobin concentration dropped from 10.5 to 8.9 g/dl (Day 30). The patient received 3 units of blood, and on Day 114 her hemoglobin concentration was 11.5 g/dl. Bilirubin, which was high at baseline, dropped; WBC and platelet counts decreased slightly but remained within normal limits. On Day 30, albumin levels were lower than at baseline (29 vs. 35 g/l), and body weight was slightly higher (69 vs 67 kg).
Placebo
Patient 101 10006 (placebo): 66-year-old white female with pulmonary arterial hypertension due to PPH. She had chronic renal failure, and she was being treated with warfarin. Hemoglobin concentration dropped from 12.3 to 8.5 g/dl, which was concomitant with worsening renal function (creatinine increased from 362 mmol/l at baseline to 530 mmol/l). She also had vaginal bleeding and blood in the stool, which were considered related to a hiatal hernia and gastric erosions.
2.5.2 Marked abnormalities in LFTs
Patients with marked abnormalities in LFTs are shown below.
Table 18 Incidence of marked laboratory abnormalities in liver function tests, safety population
(Table T23a / 07MAY01)
--------------------------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
Laboratory Abnormality
(*) 125 mg 250 mg Bosentan
N=74 N=70 N=144 N=69
No. % No. % No. % No. %
--------------------------------------------------------------------------------------------------------------------
LIVER FUNCTION TESTS
SGOT(ASAT)
HH 10 / 73 13.7%
12 / 70 17.1% 22 /143 15.4% 1 / 68 1.5%
SGOT(ASAT) > 3*upper std 7 / 73
9.6% 8 / 70 11.4%
15 /143 10.5% 0 / 68
SGPT(ALAT) HH
14 / 73 19.2% 13 / 70 18.6% 27 /143 18.9% 2 / 68 2.9%
SGPT(ALAT) > 3*upper std 9 / 73
12.3% 10 / 70 14.3%
19 /143 13.3% 0 / 68
ALT or AST > 3*upper std 10 / 73
13.7% 10 / 70 14.3% 20 /143 14.0% 0 / 68
Alkaline Phosphat.
HH 2 / 73 2.7% 3 / 70 4.3% 5 /143 3.5% 0 / 68
Bilirubin
HH 0 / 73 2 / 70 2.9% 2 /143 1.4% 0 / 68
--------------------------------------------------------------------------------------------------------------------
Values given are the
number of patients with at least one abnormality/number of patients assessed
(%)
HH=above the marked
reference range, LL=below the marked reference range
The placebo subtracted incidence rates for AST and ALT abnormalities for the all bosentan group were 13.9 % and 16.0 %, respectively. The placebo subtracted incidence rates for AST and ALT abnormalities >3 x ULN were 10.5% and 13.3%, respectively. Incidence rates for markedly abnormal alk phos values were less common (3.5% for all bosentan and 0 for placebo). Incidence rates for markedly abnormal bilirubin values were 1.4% for all bosentan and 0 for placebo.
There were 10 bosentan patients (10 patients for each of the 2 dose groups) with ALT or AST that were > 3 ´ ULN and of these, 7 had values >8 ULN(5 of 10).
Table 19 Patients with ALT and/or AST > 3 ´ ULN
|
|
Total with |
Patients with ALT and/or AST values |
||
|
Treatment [n
(%)] |
> 3 ´
ULN |
> 3 and Ł
5 ´ ULN |
> 5 and Ł
8 ´ ULN |
> 8 ´
ULN |
|
Bosentan 125 mg b.i.d. |
10 |
6 |
2 |
2 |
|
Bosentan 250 mg b.i.d. |
10 |
4 |
1 |
5 |
Note:
The sponsor's upper limit of the normal range was 30 U/l for ALT and 25
U/l for AST.
ALT = alanine
aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of
normal.
The outcomes for these patients are described below.
Table 20 Outcomes of patients with ALT and/or AST > 3 ´ ULN
|
|
|
|
Continued
to |
|||
|
|
Stable
dosing |
Dose
reduction |
Premature
withdrawn |
End |
|
|
|
Bosentan
125 mg b.i.d. |
6 |
1 |
0 |
3 |
10 |
0 |
|
Bosentan
250 mg b.i.d. |
2‡ |
3 |
3 |
2 |
6 |
4 |
Note: The sponsor's upper limit of the normal
range was 30 U/l for ALT and 25 U/l for AST.
* Transient value = liver
function tests decreased to < 3 ´ ULN while on
treatment.
† Last value = the
last known value on drug before premature discontinuation or interruption of
study drug or the end of the study.
‡ One patient
(115 10117) died due to pneumonia/sepsis.
ALT =
alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit
of normal.
Of the 10 patients on
bosentan 125 mg bid, 6 remained on the randomized dose and 1 had a dose
reduction. There were 3 with an elevated value at the end of the study.
Of the 10 patients on
bosentan 250 mg bid, 1 patient died of pneumonia, 2 remained on randomized dose
and 3 had a dose reduction. Three patients were withdrawn early (with
values> 8xULN) and 2 had dose reduction. Six patients continued into the
open label study and 4 did not.
2.5.3. Eosinophils
The following figure shows a
plot of individual eosinophil values at baseline and at endpoint. There is a
suggestion that there are more bosentan patients with higher values at endpoint
compared to placebo patients.
If this is true, this
phenomenon is not well understood.
Mean
values at baseline and endpoint as well as mean changes from baseline at endpoint
for heart rate, blood pressure, respiratory rate and weight are shown below.
Table 21 Vital signs: Change from baseline to study end, safety population
(Table T32 / 04MAY01)
----------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125
mg 250 mg Bosentan
N=74 N=70
N=144 N=69
----------------------------------------------------------------------------------------------------
Pulse Rate
(bpm)
n 74 68 142 68
Baseline 82.2 ±
14.0 83.8 ± 13.0
83.0 ± 13.5 80.9 ±
12.0
Last up to end of study 79.5 ± 13.3 85.1 ± 13.5
82.2 ± 13.6 84.2 ±
13.2
Change from baseline -2.7 ± 13.3 1.4 ±
13.8 -0.8 ± 13.6
3.4 ± 13.7
% Change from baseline -1.9 ± 17.4 3.2 ± 20.4
0.5 ± 19.0 5.6 ±
18.5
Systolic BP
(mmHg)
n 73 68
141 68
Baseline 116.9 ±
20.5 117.1 ± 15.9
117.0 ± 18.4 121.5 ±
19.2
Last up to end of study 116.5 ± 16.1 110.6 ± 14.8
113.6 ± 15.7 117.1 ±
17.2
Change from baseline -0.4 ± 19.0 -6.5 ± 14.9
-3.4 ± 17.4 -4.4 ±
16.4
% Change from baseline 1.3 ± 15.6 -4.8 ± 12.3
-1.7 ± 14.4 -2.7 ±
12.8
Diastolic BP
(mmHg)
n 73 68 141 68
Baseline 72.9 ±
11.4 73.8 ± 12.4
73.3 ± 11.8 75.0 ±
10.6
Last up to end of study 70.6 ± 12.2 70.6 ± 10.2
70.6 ± 11.2 75.6 ±
11.3
Change from baseline -2.3 ± 13.0 -3.2 ± 12.3
-2.7 ± 12.6 0.6 ±
10.4
% Change from baseline -1.6 ± 19.4 -2.7 ± 16.3
-2.1 ± 17.9 1.7 ±
14.2
Respiration
Rate (per min)
n 67
64 131 59
Baseline 19.6 ±
3.2 19.0 ± 3.3
19.3 ± 3.3 19.7 ±
3.8
Last up to end of study 20.1 ± 4.0 22.0 ± 10.0
21.0 ± 7.6 19.8 ±
3.1
Change from baseline 0.5 ± 4.6 3.0 ± 9.5
1.7 ± 7.5 0.1 ±
3.9
% Change from baseli 4.4 ± 21.0 16.6 ± 42.1
10.4 ± 33.5 3.0 ±
19.6
Weight (Kg)
n 74
70 144 67
Baseline 71.5 ±
21.0 70.2 ± 18.0
70.9 ± 19.6 74.0 ±
18.2
Last up to end of study 72.2 ± 21.2 70.8 ± 18.0
71.5 ± 19.7 74.6 ±
18.2
Change from baseline 0.7 ± 3.7 0.6 ± 3.5
0.7 ± 3.6 0.6 ±
4.0
% Change from baseline 1.2 ± 5.0 1.0 ± 4.6
1.1 ± 4.8 1.0 ±
5.7
----------------------------------------------------------------------------------------------------
Note: Values are mean ± standard deviation.
BP = blood
pressure.
Heart
rate and weight remained basically unchanged while blood pressure decreased
slightly and respiration increased.
2.7 ECG
Changes in ECG intervals are
shown below.
Table 22 Change from
baseline to study end in quantitative 12‑lead ECG parameters,
safety population
(Table T30 / 04MAY01)
----------------------------------------------------------------------------------------------------
Bosentan Bosentan All Placebo
125
mg 250 mg Bosentan
N=74 N=70 N=144
N=69
----------------------------------------------------------------------------------------------------
PQ (PR)
Interval (ms)
n 65 67
132 66
Baseline 166.3 ±
23.7 172.7 ± 33.4
169.5 ± 29.1 169.5 ±
29.1
Last up to end of study 167.4 ± 25.1 170.2 ± 42.5
168.8 ± 34.9 171.3 ±
34.4
Change from baseline 1.1 ± 22.2 -2.5 ±
37.2 -0.7 ± 30.7
1.8 ± 22.1
% Change from baseline 1.5 ± 14.6 -0.5 ± 19.2
0.5 ± 17.1 1.6 ±
13.3
QRS Interval
(ms)
n 73 68 141 67
Baseline 93.0 ±
20.6 94.3 ± 20.3
93.6 ± 20.4 90.1 ±
15.6
Last up to end of study 91.8 ± 20.6 94.6 ± 20.5
93.2 ± 20.6 92.4 ±
14.9
Change from baseline -1.2 ± 11.8 0.3 ±
13.9 -0.5 ± 12.8
2.4 ± 15.0
% Change from baseline -0.4 ± 12.9 1.8 ± 18.1
0.7 ± 15.6 5.2 ±
27.4
QT Interval
(ms)
n 73 68 141 67
Baseline 384.5 ±
43.2 375.3 ± 45.9
380.0 ± 44.6 377.0 ±
44.0
Last up to end of study 386.1 ± 42.4 373.7 ± 47.8
380.1 ± 45.4 375.6 ±
44.1
Change from baseline 1.7 ± 40.1 -1.6 ± 45.1
0.1 ± 42.5 -1.4 ±
37.8
% Change from baseline 1.0 ± 11.1 0.3 ± 13.0
0.7 ± 12.0 0.1 ±
10.3
Heart Rate
(bpm)
n 73 68 141 67
Baseline 80.2 ±
13.0 83.0 ± 16.2
81.5 ± 14.6 79.9 ±
12.0
Last up to end of study 77.5 ± 13.6 82.0 ± 14.2
79.7 ± 14.0 81.7 ±
14.0
Change from baseline -2.7 ± 10.4 -0.9 ± 12.9
-1.8 ± 11.6 1.8 ±
11.5
% Change from baseline -2.8 ± 12.5 0.7 ± 18.3
-1.1 ± 15.6 2.9 ±
14.6
----------------------------------------------------------------------------------------------------
Note: Values are mean ± standard deviation.
There
are no signals that bosentan has an adverse effect on cardiac conduction.
The
reported ECG abnormalities are shown below.
Slightly
more total ECG abnormalities were reported for placebo (39.1%) than for all
bosentan (31.9%). Compared to placebo, all bosentan had more reports of
intra-ventricular conduction defects, atrial fibrillation/flutter, and right
ventricular hypertrophy. There is no indication that these reports are anything
other than random variation.
Protocol AC 052-351
AC-052-351
was designed as a small pilot efficacy study. The original protocol is dated
May 6, 1999. The study was conducted between September 8, 1999 and April 3,
2000.
3.1.1
Study Design
This was a small double‑blind, multicenter,
parallel, study with a 2 (drug): 1 (placebo) randomization scheme. Subjects
with either symptomatic severe primary pulmonary hypertension (PPH) or
pulmonary hypertension secondary to scleroderma (SSc/PH), who were ambulatory
and were in functional class III-IV ( 1998 WHO classification) were eligible to
be enrolled.
Subjects were allowed to be receiving any of the
following: oral vasodilators, anticoagulants, diuretics, cardiac glycosides and
supplemental oxygen provided that none of the treatments was started or stopped
within 1 month of screening. Subjects could neither have received prostacyclin
therapy within 3 months prior to screening nor have been scheduled to receive
prostacyclin therapy for 3 months following randomization.
3.1.2
Study Objective
The
objective of this study was to determine if bosentan, compared to placebo,
increases peak[8] exercise
capacity in study subjects.
3.1.3. Patient Type
3.1.3.1. Inclusion Criteria
Subjects who were
- 18 years or older;
- either male or non-pregnant female (only
those who were post menopausal, surgically sterile or practicing an acceptable
method of contraception).
- diagnosed with PPH or SSc/PH and remained
in functional class III-IV (1998 WHO classification) despite optimal therapy
with oral vasodilators, cardiac glycosides, anticoagulants, diuretics and/or
supplemental oxygen for at least one month.
- able to demonstrate a baseline 6-minute
walk test of > 150 m and < 500 m.
At randomization
visit (visit 2), subjects had to meet the following criteria:
-
no
change in nature or dosage of background medication for PAH within 7 days prior
to randomization;
-
the
second 6-minute walk test was within 15 % of thc screening walk test, or the
third 6-minute walk test was within 15% of the second walk test;
- baseline
mean PAP > 25 mm Hg (mean of two repeated measures during expiration) and
PVR > 3 mm Hg/liter/min (mean of two repeated measures during expiration)
and PCWP < 15 mm Hg (measured once only);
- Systolic blood pressure was > 85
mm Hg.
3.1.3.2
Exclusion Criteria
Subjects were
excluded if they had
- pulmonary
hypertension as the result of conditions other than PPH or SSc/PH;
- SSc/PH with
moderate to severe interstitial disease;
-
stopped treatment with oxygen, diuretics, oral vasodilators, cardiac glycosides
or anticoagulants within one month of screening;
-
started a new treatment with oxygen, diuretics, oral vasodilators, cardiac
glycosides or anticoagulants within one month of screening;
-
received prostacyclin therapy within 3 months of study screening;
- been scheduled
to receive proslacyclin therapy within 3 months of randomization.
-
a musculoskeletal disorder or any other condition that limited his/her ability
to perform the 6-minute walk tests;
- hypotension, defined as
systolic blood pressure < 85 mm Hg;
- hemoglobin, hematocrit or
leucocyte count of more than 30% outside the normal range. (Subjects with
secondary polycythemia were permitted in the study.)
- ASAT and/or ALAT values
greater than 3 times the upper limit of normal.
- received glibenclamide (glyburide) or cyclosporine-A within one
month of entry into the study or expected to receive glibenclamide (glyburide)
or cyclosporine A during the study period.
-received therapy with
another investigational drag within one month.
-a known drug or alcohol
dependence or any other factors which would interfere with the study conduct or
interpretation of the results.
- any illness
other than PAH which might reduce life expectancy to less than 6 months.
3.1.4
Sample Size
The
sample size of 30 subjects (20 bosentan and 10 placebo) was based on an assumed
change from baseline in walking distance of 50 meters with standard deviation
of 50 meters. A total of 32 subjects were randomized (21 received bosentan and
11 received placebo).
3.1.5 Duration
Phase I (double blind phase)
Each subject received a minimum of 12 weeks (between 70
and 98 days) of double blind treatment. In other words, all subjects received
double blind treatment until the last enrolled subject, not prematurely
withdrawn, completed week 12.
Phase II
All subjects who completed the double blind treatment
phase (12 weeks) as well as subjects who dropped out of the study prematurely
had the option of entering an open label, uncontrolled phase.
3.1.6
Treatments
Subjects
were randomized to placebo bid or bosentan 62.5 mg bid for 4 weeks. The dose of
bosentan was then increased to 125 mg bid for at least an additional 8 weeks.
Subjects were down titrated to 1 tablet once daily if they experienced intolerable
side effects thought to be attributed to study drug. The higher dose was reintroduced if the investigator thought it
could be tolerated.
3.1.7
Study Procedure
The
flow chart (includes amendments) below outlines study procedures at each clinic
visit.
3.1.8
Protocol define study hypotheses and efficacy endpoints:
3.1.8.1 the primary endpoint: change
from baseline in exercise capacity at 12 weeks as determined by the 6-minute
walk test.
Subjects who died, underwent lung
transplantation during the study, or discontinued study medications because of
worsening condition were analyzed using their last assessment. In the event
that no assessment of walk distance was obtained at the time of premature
withdrawal, subjects were assigned a walk distance of 0 meter at the 12-week
time point.
All other subjects without a week
12 assessment of the primary endpoint were to have their last assessment
carried forward. If no assessment was obtained during the treatment period, the
subject was assigned "no change" (0 change from baseline, equivalent
to carrying forward the baseline value).
