Safety and Tolerability of bosentan in Idiopathic Pulmonary Fibrosis: an
open label study
Andreas Günther1, Beate Enke1, Philipp Markart1, Peter Hammerl1, Harald Morr2, Jürgen
Behr4, Gerd Stähler5, Werner Seeger1, Friedrich Grimminger1, Isabelle Leconte3, Sebastien
Roux3 and Hossein-Ardeschir Ghofrani1
Online Data Supplement
Materials and Methods
PATIENTS
12 patients were enrolled into this study at the Medical Clinic of the Justus-Liebig-University
Giessen between February 2002 and January 2003. The following inclusion criteria needed to
be met: diagnosis of IPF according to the ATS / ERJ Consensus Criteria for diagnosis of IPF
[E1], 18 years of age, forced vital capacity FVC between 50 and 90% of predicted, decline
of FVC values by  10% in the previous year despite steroid/immunosuppressive treatment,
diffusion capacity for carbon dioxide (DLco) > 35% or predicted, partial pressure of arterial
oxygen (PaO2) > 55mmHg and systolic blood pressure  85mmHg.
Major exclusion criteria included pregnancy, breast feeding, underlying severe liver or
systemic collagen/vascular disease and current treatment with glibenclamid (glyburide),
tacrolimus or cyclosporine A (see table E1).
In one patient IPF had been diagnosed on the basis of an open lung biopsy for which an
external pathologist had described a Usual Interstitial Pneumonitis (UIP) pattern. The biopsies
of this patient were re-evaluated by our local interdisciplinary conference at a time he had
already passed by the 3month study period. It was found that the changes seen in the biopsies
would rather resemble morphological aspects of hypersensitivity pneumonitis (giant cells,
bronchiolocentric distribution) than a usual interstitial pneumonia pattern and the diagnosis
was therefore changed retrospectively.
STUDY DESIGN
This was an open-label; single center, non-comparative study, which consisted of a screening
phase (maximum of 2 weeks), a three-part treatment phase (maximum of 12 weeks in total)
and an optional extension phase (see figure E1). The planned sample size was 12 patients
based on purely empirical considerations. The local ethics committee approved the study and
informed consent was obtained from all participants prior to inclusion.
Study course
Patients were screened for preliminary eligibility prior to start of treatment. After finishing
baseline, patients underwent right heart catheterization in combination with multiple inert gas
elimination technique (MIGET) on day 1 (first part of treatment), under which first bosentan
administration took place. During this right heart catheter the pulmonary vascular
responsibility was also assessed by a short term inhalative nitric oxide (NO) run. For this
purpose NO inhalation was started with 5ppm and stepwise increased until no further
improvement of hemodynamics or gas exchange was encountered, adverse events such as
hypoxemia developed or 40ppm were reached. Using this algorithm, ~ 10-15ppm were used
in the study subjects. After this NO challenge, patients received a single dose of bosentan for
assessment of ventilation/perfusion distribution (VA/Q) and hemodynamics. Patients still
eligible for further treatment (see below), received oral bosentan at 62.5mg twice daily during
the first week (second part of treatment) and bosentan was up-titrated to 125mg twice daily
with the beginning of the second week. Treatment was continued until 12 weeks were
completed (third part of treatment), after which patients could enter an extension period.
Study parameters
After informed consent was obtained, medical history, body weight and concomitant
medication were recorded and a physical examination, a 12 lead electrography, a lung
function test including assessment of CO diffusion capacity, an exercise test (6min walk)
including assessment of Borg scale was performed and quality of life ((EQ-5D [E2] and
Mahler questionnaires [E3]), vital signs (blood pressure, heart rate) and oxygen saturation
were monitored. The European Quality of Life Dimension (EQ-5D) questionnaire consists of
two elements, a Visual Analogue Scale (EQ5D VAS), in which the patient can draw a line to
a point between the best (100%) and the worst (0%) conceivable health condition, and a self
classifier, in which the patient is asked to categorize his / her condition in view of “mobility”,
“self-care”, “usual activities”, “pain/discomfort” and “anxiety/depression” (each consisting of
three categories). Using the Mahler Dyspnea Index the patient is asked to categorize the
extend of dyspnea in view of “functional impairement”, “magnitude of task” and “magnitude
of effort” (each 5 categories).
Blood was withdrawn and analysed for the following compounds: hemoglobin, hematocrit,
erythrocytes, leucocytes (total), neutrophils, lymphocytes, monocytes, eosinophils, basophils,
other leucocytes, platelets, red cell distribution width, reticulocytes, prothrombin time (PT),
partial thromboplastin time (PTT), International normalized ratio (INR), mean corpuscular
volume (MCV), mean corpuscular hemoglobin concentration (MCHC) and mean corpuscular
hemoglobin (MCH). In addition serum was obtained at screening and at the end of the 3month
study period for analysis of the concentration of Surfactant Protein D. Furthermore, a
pregnancy test was conducted, if participating women were in child-bearing age.
Invasive testing
On the first day, right heart catheterization was undertaken, employing a Swan Ganz Catheter
[E4] (Baxter Health care, Irvine, California) and conventional thermodilution technique [E5].
Moreover, ventilation-perfusion matching was assessed using the multiple inert gas
elimination technique (MIGET) as previously described [E6]. Patients remained in bed and
thus at rest during the entire testing procedure. Parameters obtained by these techniques
included: cardiac output (CO), cardiac index (CI), central venous pressure (CVP), pulmonary
vascular resistance (PVR, calculated as follows: PVR (dyn/sec/cm5) = (mean PAP – PCWP) x
80 cardiac output), systemic arterial resistance (SAR), pulmonary capillary wedge pressure
(PCWP), heart rate (HR), mean pulmonary artery pressure (MPAP), mean systemic arterial
pressure (MSAP), oxygen saturation (O2-Sat), minute ventilation (MV), pulmonary shunt
flow, perfusion of low VA/Q, normal VA/Q and high VA/Q areas (in % of total perfusion),
arterial blood gas analysis including paO2, paCO2, pH, BE.
Treatment phase and extension
At day 1 and week 12, body weight, lab tests, vital signs, pulmonary function and oxygen
saturation were recorded. On occasion of the last visit in week 12 or at premature withdrawal
all measures as detailed for screening and base-line had to be repeated.
After completion of week 12, patients could be enrolled into a study extension phase, in
which visits were performed every 3months. On these occasions, lung function tests including
CO diffusion capacity, a 6minute walk distance, vital parameters and oxygen saturation were
assessed.
Primary safety endpoint
The primary safety endpoint was a combined one, which was assessed at day 1 and at the end
of week 2. Bosentan was considered as well tolerated if the following criteria were NOT met:
- The arterial PaO2 decreased by > 10% or the cardiac output decreased by > 20% below their
respective baseline values (day 1). Prior to amendment 1 an increase in perfusion of low VA/Q
areas or shunt flow by more than 20% was defined as criterion, but later omitted in order not
to needlessly discontinuate patients who had variable MIGET measurements but no consistent
evidence for clinically relevant VA/Q mismatch.
- The minute ventilation increased by > 20% from the baseline value (within first 2 weeks).
- The oxygen saturation (at rest) decreased by > 5% from the baseline value (within first 2
weeks).
Patients who met the mentioned criteria had to be withdrawn from bosentan. If thereafter, a
patient had a sustained deterioration in minute ventilation (increase) and/or SaO2 (decrease),
study medication had to be temporarily discontinued (4 to 5 days) and the patient’s minute
ventilation and SaO2 re-evaluated at a later date. If, as judged from an improvement of minute
ventilation or SaO2 after withdrawal of bosentan, the deterioration had to be attributed to the
preceding intake of bosentan, the drug had to be permanently discontinued. If no
improvement occurred treatment with bosentan could be re-initiated.
Secondary endpoints
Endpoints assessing additional safety parameters included changes in the MIGET data
obtained during right heart catheter testing on day 1 (% shunt perfusion, % perfusion of low
VA/Q areas, standard deviation of perfusion and ventilation), changes in minute ventilation,
oxygen saturation, heart rate and blood pressure, body weight and incidence of adverse events
and serious adverse events (SAE) and laboratory abnormalities. In addition, aspartate and
alanine aminotransferase (AST and ALT) had to be closely monitored according to the
protocol, which were in line with the guidelines in the summary of product characteristics.
Secondary efficacy endpoints
Endpoints assessing efficacy included changes in lung function (TLC, VC, FVC, FEV1, RV),
CO diffusion capacity, 6-minute walk distance and Borg dyspnea score (exercise capacity) as
well as quality of life (measured with the EQ-5D questionnaire and Mahler index).
Serum concentration of SP-D as pulmonary fibrosis marker was determined using a sandwich
type ELISA system with two monoclonal antibodies (IE11, VI F11-Biotin, BMA, Heidelberg,
Germany). Human SP-D standard was prepared as described previously [E7]. Purity was
checked by SDS-PAGE and concentration was determined using a commercial assay (BCA,
Pierce, Bonn, Germany). Detection of bound antibody was accomplished by sequential
incubation with avidin-biotin complex / HRP (DakoCytomation, Hamburg, Germany) and
ABTS as substrate. The detection limit ranged at 100 pg SP-D per ml serum. Assays were
performed in duplicate for each sample.
Statistics:
The sample size of 12 patients was based on empirical considerations and on previous
publications in the field. Intention to treat analysis was performed. For this purpose,
quantitative secondary safety and efficacy endpoints were summarized using location and
scale statistics together with 95% confidence limits (CL) for the mean. Qualitative variables
were summarized using frequency counts and proportions. Exploratory p-values were
provided using the paired signed rank test. Observed p-values were compared to the standard
nominal two-sided 0.05 alpha level with no corrections for multiplicity of endpoints due to the
exploratory nature of the testing.
Demographics, baseline characteristics, and safety data were summarized descriptively, using
summary statistics for continuous variables and frequency counts for categorical variables.
All parameters were analyzed on a single analysis population including all patients who
received any trial treatment. For O2 sat, MV, pulmonary function tests, walk test and Borg
scale, missing values at week 12 were replaced by carrying forward the last post-baseline
value (“last value carried forward technique”) observed prior to the time point of the missing
assessment, an established statistical technique for reduction of nonresponse bias [E8]. For the
above-mentioned analyses, patients who died were analyzed assigning at each parameter
analyzed the “worst” assessment observed in the study population during the study period.
Statistical Analysis System software (SAS Institute, Cary, NC, USA) was used for the
analysis of the efficacy and safety data.
Narratives for the two patients dying from pneumonia:
Two patients died during the regular study course because of pneumonia and these cases are
discussed in more depth in the following:
The one patient was a 62 year old male with advanced (FVC 48% and DLco 33% of
predicted) and accelerated (loss of 0.91 l of FVC within the preceding year) IPF. He also had
coronary heart disease. His baseline Mahler functional grade was 1 and the walking distance
on the 6 min walk test (6MWT) was 249 m with a grade 4 on the Borg dyspnea index after the
6MWT. His baseline blood gases were normal under Long term oxygen therapy (LTOT),
there was no pulmonary hypertension during right heart catheterisation and cardiac index and
PCWP were normal. When acutely administered, bosentan 125 mg did not elicit a V/Q
mismatch on the MIGET. In detail, shunt flow was 6.1% of total perfusion prior to and 6.7%
of total perfusion after bosentan administration. Concomitant medication was LTOT 2l/min,
an immunosuppressive therapy consisting of prednisone and azathioprine, molsidomine,
isosorbide mononitrate, ipratropium, fenoterol, N-acetyl cysteine and 125 mg b.i.d of
bosentan. He was hospitalized suffering from progressive and severe dyspnea on day 32 after
enrollment. On the day of admission, CRP values were already increased (26 mg/l). An
intravenous antibiotic treatment was started with moxifloxacin 1x1 400mg, oxygen saturation
was 49% without nasal O2 and patient still had dyspnea under high doses of nasal O2.
Therefore, high flow CPAP was initiated one day after admission. Despite i.v. antibiotics,
CRP kept on rising. Application of bosentan was interrupted in the first week after admission,
without any significant change in the clinical status of the patient or the laboratory data.
Intravenous antibiotic treatment was therefore changed to 1x2g ceftriaxon and 3x600mg
clindamycin on day 34 after admission and amphotericin B was started on day 37 day after
admission because of candida species proven in sputum samples. On day 38
ceftriaxon/clindamycin treatment was switched to 3x1g meronem, 2x1g vancomycin and
500mg azithromycin p.o. in view of rising CRP values (56mg/l) and progressive bilateral
alveolar as well as reticular infiltrates. On day 41 gancyclovir treatment was initiated because
of detection of CMV DNA in serum (nested PCR) and a shift in CMV IgM antibodies. No
serological sign of an infection with Chlamydia, Legionella or Mycoplasma was obtained.
Despite these efforts, the respiratory situation of the patient further worsened and the patient
needed to be intubated and mechanically ventilated starting at d9 after admission In response
to the onset of mechanical ventilation, CRP was further increased, but gradually declined until
day 47 (37mg/l), when the patient started to develop severe sepsis and CRP increased again
(peak 109mg/l). Despite high dose steroid and catecholamine treatment the patient got more
and more unstable. Dialysis was not possible anymore and the patient died on day 49 due to
septic shock. An autopsy was performed in this patient and both, the macroscopic as well as
the microscopic examination of the lung strongly suggested severe pneumonia. No other
source of sepsis was identified.
The other, 58 year old patient also had advanced (FVC 47% and DLco 30% of predicted) and
progressive (loss of 1.14l of FVC during the preceding 21months) IPF. This patient already
reported of one episode of pneumonia necessitating hospital treatment before participating in
the trial. Besides, he also had a gastric ulcer, coxarthrosis and hypercholesterolemia. At
screening, his baseline Mahler functional grade was maximal (0) and the walking distance on
the 6 min walk test (6MWT) was 260m, with a grade 3 on the Borg dyspnea index after the
6MWT. His baseline blood gas were normal under long term oxygen therapy (LTOT), a
moderate pulmonary hypertension (mPAP 30 mmHg) was evident during right heart
catheterisation and cardiac index and PCWP were normal. When acutely administered during
right heart catheterization, bosentan 125 mg did not elicit a V/Q mismatch on the MIGET.
Concomitant medication included LTOT 1l/min, immunosuppressive treatment with
prednisolone,
atorvastatin,
omeprazole,
calcium,
magnesium,
beclometasone,
dihydroergotamine, natamycin and 125 mg bid of bosentan. On day 13, the patient reported of
colored sputum and increased dyspnoe. Accordingly, CRP was elevated to 32mg/l and,
although no infiltrate was seen on chest X-ray, respiratory tract infection was diagnosed. A
pharyngeal smear revealed streptococci, and the patient improved under an intravenous, later
oral treatment with sultamicillin (3x3g). 4 days after admission the patient was discharged
from hospital with reduced greatly CRP values and in improved condition. He was then
hospitalized again on day 28 due to now a profound dyspnea and highly elevated CRP values
(65mg/l). Bosentan treatment was permanently discontinued 5 days later. The patient was
transferred to the ICU due to progressive dyspnea, and a non-invasive CPAP ventilation was
started. Despite extensive i.v. antibiotics (imipenem, vancomycin, fluconazole and
moxifloxacin), the overall condition of the patient deteriorated progressively. Repetitive
specimen obtained from blood, sputum and urine did not forward an identification of a
microbial agent. However, in the beginning of this episode, sputum as well as pharyngeal
smears forwarded hemolytic streptococci of group G. Infection with Legionella, Chlamydia or
Mycoplasma was excluded on the basis or serologic tests. Similarly. CMV DNA was not
identified and anti-CMV IgM could not be detected. Regardless of the inability to isolate the
responsible pathogen, the clinical course, the radiographic findings (bilateral consolidations)
and the course of infection parameters strongly suggested lung infection. CRP rised from 65
mg/l on day 28 to 345 mg/l on day 34. Since the patient had determined in advance that he
would never like to receive mechanical ventilation he was not intubated and died from
respiratory failure on day 35due to sepsis and multiorgan failure.
References
E1. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment.
International consensus statement. American Thoracic Society (ATS), and the
European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: 646-664.
E2. EuroQol - a new facility for the measurement of health-related quality of life. Health
Policy 1990; 16: 199-208.
E3. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea:
contents, interobserver agreement, and physiologic correlates of two new clinical
indexes. Chest 1984; 85: 751-758.
E4. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N,
Seeger W, Grimminger F. Combination therapy with oral Sildenafil and inhaled
Iloprost for severe Pulmonary Hypertension. Ann Intern Med 2002; 136: 515-522.
E5. Walmrath D, Grimminger F, Pappert D, Knothe C, Obertacke U, Benzing A, Gunther
A, Schmehl T, Leuchte H, Seeger W. Bronchoscopic administration of bovine natural
surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics.
Eur Respir J 2002; 19: 805-810
E6. Walmrath D, Gunther A, Ghofrani HA, Schermuly R, Schneider T, Grimminger F,
Seeger W. Bronchoscopic surfactant administration in patients with severe adult
respiratory distress syndrome and sepsis. Am J Respir Crit Care Med 1996; 154: 5762.
E7. Strong P, Kishore U, Morgan C, Lopez Bernal A, Singh M, Reid KB. A novel method
of purifying lung surfactant proteins A and D from the lung lavage of alveolar
proteinosis patients and from pooled amniotic fluid. J Immunol Methods 1998; 220:
139-149.
E8. Wood AM, White IR, Thompson SG. Are missing outcome data adequately handled.
A review of published randomized controlled trials in major medical journals. Clin
Trials 2004; 4: 368-376.
Table E1: Inclusion and Exclusion Criteria
Inclusion Criteria
Exclusion Criteria
Signed informed consent prior to any study
Interstitial Lung disease due to conditions
other than IPF
procedure
Patients of either sex, aged 18 or older, body
Associated Connective Tissue Disorder (e.g.
scleroderma)
weight > 40 kg
History of clinically significant environmental
exposure known to cause pulmonary fibrosis
Female patients with a high likeliness for not
Pulmonary alveolitis
being pregnant
Systolic blood pressure < 85mmHG
IPF diagnosis made from open-lung biopsy or
Hemoglobin or hematocrit > 30% below the
normal ranges
video-assisted thoracic surgery or by clinical
diagnosis according to Consensus Statement of
ATS / ERS [E1]
50% ≤ FVC ≤ 90% of predicted value
Worsening during the past year (at least 10%
decline in FVC)
DLco > 35% of predicted value
Capillary paO2 > 55 mmHg either in absence
or presence of nasal oxygen
Alanine aminotransferase (ALT) and/or
aspartate aminotransferase (AST) values > 3
times the upper limit of normal (ULN),
moderate to severe liver failure
Evidence of acute infectious lung disease, HIV
infection
Taking or planning to take other
investigational drugs during the study
Taking or planning to take prostanoids (e.g.,
ilomedine, epoprostenol) during the study
Receiving therapy with agents known or likely
to interact with study drug (glibenclamide
[glyburide], cyclosporine A, and tacrolimus).
Previously received bosentan therapy or
known hypersensitivity to bosentan
Left ventricular dysfunction (ejection fraction
< 35%)
Life expectancy < 6 months
Evidence or history of drug or alcohol abuse
Mental or physical impairment limiting the
ability to comply with study requirements
Breast feeding
Table E2: Concomitant medication
n
%
SYSTEMIC CORTICOSTEROIDS
Total pts with at least one TRT
10
83.3%
PREDNISOLONE
7
58.3%
PREDNISONE
2
16.7%
METHYLPREDNISOLONE
1
8.3%
--------------------------------------------------------MINERAL SUPPLEMENTS
Total pts with at least one TRT
7
58.3%
CALCIUM
4
33.3%
MAGNESIUM
3
25.0%
POTASSIUM
2
16.7%
LEKOVIT CA
1
8.3%
--------------------------------------------------------ANTACIDS, DRUGS FOR TREATMENT OF PEPTIC
ULCER AND FLATULENCE
Total pts with at least one TRT
4
33.3%
OMEPRAZOLE
2
16.7%
RANITIDINE
2
16.7%
LANSOPRAZOLE
1
8.3%
--------------------------------------------------------IMMUNOSUPPRESSIVE AGENTS
Total pts with at least one TRT
4
33.3%
AZATHIOPRINE
2
16.7%
CYCLOPHOSPHAMIDE
2
16.7%
--------------------------------------------------------SERUM LIPID REDUCING AGENTS
Total pts with at least one TRT
4
33.3%
ATORVASTATIN
3
25.0%
SIMVASTATIN
1
8.3%
--------------------------------------------------------AGENTS ACTING ON THE RENIN-ANGIOTENSIN
SYSTEM
Total pts with at least one TRT
3
25.0%
IRBESARTAN
2
16.7%
VALSARTAN
1
8.3%
--------------------------------------------------------ANTI-ASTHMATICS
Total pts with at least one TRT
3
25.0%
IPRATROPIUM
2
16.7%
BECLOMETASONE
1
8.3%
FENOTEROL
1
8.3%
FLUTICASONE
1
8.3%
--------------------------------------------------------COUGH AND COLD PREPARATIONS
Total pts with at least one TRT
3
25.0%
ACETYLCYSTEINE
2
16.7%
NOSCAPINE
1
8.3%
POTASSIUM IODIDE
1
8.3%
--------------------------------------------------------LOW CEILING DIURETICS, THIAZIDES
Total pts with at least one TRT
3
25.0%
HYDROCHLOROTHIAZIDE
3
25.0%
--------------------------------------------------------VITAMINS
Total pts with at least one TRT
3
25.0%
COLECALCIFEROL
2
16.7%
ERGOCALCIFEROL
1
8.3%
--------------------------------------------------------ANALGESICS
Total pts with at least one TRT
2
16.7%
DIHYDROERGOTAMINE
1
8.3%
TRAMADOL
1
8.3%
--------------------------------------------------------ANTITHROMBOTIC AGENTS
Total pts with at least one TRT
2
16.7%
ACETYLSALICYLIC ACID
1
8.3%
PHENPROCOUMON
1
8.3%
---------------------------------------------------------
n
%
BETA BLOCKING AGENTS
Total pts with at least one TRT
2
16.7%
BISOPROLOL
1
8.3%
METOPROLOL
1
8.3%
--------------------------------------------------------CALCIUM CHANNEL BLOCKERS
Total pts with at least one TRT
2
16.7%
NITRENDIPINE
1
8.3%
VERAPAMIL
1
8.3%
--------------------------------------------------------DRUGS USED IN DIABETES
Total pts with at least one TRT
2
16.7%
INSULIN
2
16.7%
--------------------------------------------------------DIURETICS
Total pts with at least one TRT
2
16.7%
FUROSEMIDE
2
16.7%
--------------------------------------------------------ORGANIC NITRATES
Total pts with at least one TRT
2
16.7%
ISOSORBIDE MONONITRATE
1
8.3%
PENTAERITHRITYL TETRANITRATE 1
8.3%
--------------------------------------------------------ANTIGOUT PREPARATIONS
Total pts with at least one TRT
1
8.3%
ALLOPURINOL
1
8.3%
--------------------------------------------------------ANTIMYCOTICS FOR SYSTEMIC USE
Total pts with at least one TRT
1
8.3%
FLUCONAZOLE
1
8.3%
--------------------------------------------------------CARDIAC GLYCOSIDES
Total pts with at least one TRT
1
8.3%
BETA-ACETYLDIGOXIN
1
8.3%
--------------------------------------------------------DRUGS FOR TREATMENT OF BONE DISEASES
Total pts with at least one TRT
1
8.3%
CLODRONIC ACID
1
8.3%
--------------------------------------------------------LAXATIVES
Total pts with at least one TRT
1
8.3%
LACTULOSE
1
8.3%
--------------------------------------------------------OTHER VASODILATORS USED IN CARDIAC
DISEASES
Total pts with at least one TRT
1
8.3%
MOLSIDOMINE
1
8.3%
--------------------------------------------------------PERIPHERAL VASODILATORS
Total pts with at least one TRT
1
8.3%
GINKGO BILOBA
1
8.3%
--------------------------------------------------------POTASSIUM SPARING AGENTS
Total pts with at least one TRT
1
8.3%
TRIAMTERENE
1
8.3%
--------------------------------------------------------THYROID THERAPY
Total pts with at least one TRT
1
8.3%
LEVOTHYROXINE
1
8.3%
--------------------------------------------------------UROLOGICALS
Total pts with at least one TRT
1
8.3%
URALYT-U
1
8.3%
---------------------------------------------------------
TABLE E3: Minute ventilation, oxygen saturation and Quality of Life
Minute ventilation [l/min]
Oxygen saturation [%]
(at rest)
EQ-5D Score
(full health = 1; death = 0)
EQ-5D VAS Scale
(best imaginable state = 100%
worst imaginable state = 0%)
Mahler Dyspnoe Index
(dyspnoe rate in 5 grades
0 = severe; 12 – unimpaired)
Baseline
(n = 11)
Week 2
(n = 11)
11.61
(9.04;14.17)
94.45
(92.06;96.85)
12.39
(10.62;14.15)
94.36
(91.92;96.81)
Baseline
(n = 11)
Week 12
(n = 11)
0.553
(0.323;0.783)
47
(31;63)
0.589
(0.435;0.742)
41
(27;54)
4.7
(3.4; 5.9)
4.2
(3.2; 5.3)
Study Course
HR
PVR
SVR
O2 Sat
PCWP
CVP
MIGET
X
X
X
X
125 mg bosentan
-2h
0
1h
2h
4h
8h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
wk12
wk6
X
X
X
NO trial
t=
d1
X
X
125 mg
wk2
Lung function
X
6 min walk
X
QOL questionnaires
X
ECG
X
Rightheart Cath-MIGET
62,5 mg
d0 baseline
screening
0
wk1
Figure E1
X
X
X
X