Bosentan, an endothelin-receptor antagonist, in the treatment of pulmonary hypertension in severe chronic obstructive pulmonary disease: a prospective, double-blind, placebo-controlled trial

ISRCTN ISRCTN98252311
DOI https://doi.org/10.1186/ISRCTN98252311
Secondary identifying numbers N/A
Submission date
22/03/2006
Registration date
20/04/2006
Last edited
07/05/2008
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Respiratory
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Michael Tamm
Scientific

University Hospital Basel
Petersgraben 4
Basel
4031
Switzerland

Phone +41 (0)61 265 5184
Email stolzd@uhbs.ch

Study information

Study designInterventional, prospective, randomised, double-blind, placebo-controlled study
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Not specified
Study typeTreatment
Scientific title
Study acronymTOP Study
Study objectivesWe hypothesise that the orally administered dual endothelin-receptor antagonist bosentan improves exercise capacity (as measured by the six-minute walk test, mobile spiroergometry) and pulmonary perfusion (as measured by computed tomography single photon emission computed tomography [CT SPECT]) and is well tolerated at a dose of 125 mg, twice daily, in patients with pulmonary hypertension due to severe chronic obstructive pulmonary disease (COPD)
Ethics approval(s)Approved by Ethics Committee of Basel (EKBB) on 20/03/2006, reference number: 317/05. This trial was also approved by the Swiss Federal Authority (Swiss Agency for Therapeutic Products [SWISSMEDIC]), protocol reference number: 2006 DR 2086.
Health condition(s) or problem(s) studiedChronic obstructive pulmonary disease
InterventionBosentan dose increases from 62.5 mg twice a day (BID) to 125 mg DIB after 14 days, if there is no increase in AST/ALT greater than 3 x normal values. If there is an increase of AST/ALT greater than 3 times but less than 5 times that of the normal values, the dosage is maintained at 62.5 mg BID. If the increase if greater than 5 times the normal value, therapy with bosentan has to be discontinued. The control group will receive a placebo.
Intervention typeDrug
Pharmaceutical study type(s)
PhaseNot Specified
Drug / device / biological / vaccine name(s)Bosentan
Primary outcome measureImprovement in six feet walking distance after three months therapy.
Secondary outcome measuresImprovement or change after three months in regard to:
1. Partial pressure of Oxygen (pO2) measured in the Arterial Blood Gas Analysis (ABGA)
2. Maximal oxygen uptake (VO2 max), Saturation of Oxygen in arterial blood (SaO2) as measured by mobile exercise test
3. Perfusion pattern on the thorax SPECT-CT (SYMBIA T2), comparing different morphologic types of emphysema
4. Systolic pulmonary pressure, right-ventricular enlargement and right-ventricular ejection fraction as measured by echocardiography
5. Bodyplethysmography and Carbon Dioxide (CO2) diffusion capacity
6. Brain natriuretic peptide
7. Liver enzymes (AST, ALT)
Overall study start date01/04/2006
Completion date01/12/2006

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participants24
Key inclusion criteria1. Patients with a diagnosis of severe (forced expiratory volume in one second [FEV1] less than 50%), or very severe (FEV1 less than 30%) COPD and/or severe emphysema (markedly impaired diffusion capacity), according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines will be included in the study. Post-bronchodilator lung function test will be appreciated, as suggested in the guidelines. Patients will be screened in regard to echocardiographical technical feasibility. Moreover, patients will undergo routine clinical, land laboratory evaluation as well as full lung function testing.
2. Greater than 18 years of age
3. Postmenopausal women or women with negative pre-treatment pregnancy test as well as a reliable method of contraception during study treatment and for at least three months after study treatment termination. Reliable methods of contraception are:
3.1. Barrier type devices (e.g. female condom, diaphragm, contraceptive sponge) only in combination with a spermicide
3.2. Intra-uterine devices
3.3. Oral, injectable or implantable contraceptives only in combination with a barrier method
3.4. Hormone-based contraceptives alone, regardless of the route of administration, are not considered as reliable methods of contraception
3.5. Abstention, rhythm method, and contraception by the partner alone are not acceptable methods of contraception
Key exclusion criteria1. Mental disorder preventing appropriate judgment concerning study participation
2. Significant comorbidity resulting in reduced life expectancy
3. Infectious or non-infections hepatitis
4. Known intolerance to bosentan
5. Significant exacerbation of COPD within the last month
6. Insufficient technical quality in the echocardiographic evaluation
7. Systolic Blood Pressure (BP) less than 85 mmHg
8. Body weight less than 40 kg
9. Hemoglobin concentration less than 75% of the lower limit of the normal range
10. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) values greater than 3 times the upper limit of normal
11. Moderate to severe hepatic impairment (Child-Pugh B or C)
12. Patients with decompensated and/or not corrected right heart failure
13. Concomitant treatment with:
13.1. Calcineurin-inhibitors (e.g. cyclosporine A and tacrolimus, everolimus, sirolimus)
13.2. CYP2C9 and CYP3A4 inhibitors (e.g. fluconazole, amiodarone, miconazole, ketoconazole, itraconazole, ritonavir, voriconazole, metronidazole)
13.3. Protease inhibitors (e.g. ritonavir) or glibenclamide (glyburide) within 1 week of randomisation
Date of first enrolment01/04/2006
Date of final enrolment01/12/2006

Locations

Countries of recruitment

  • Switzerland

Study participating centre

University Hospital Basel
Basel
4031
Switzerland

Sponsor information

University Hospital Basel (USB) (Switzerland)
University/education

Division of Pneumology
Petersgraben 4
Basel
4031
Switzerland

Phone +41 (0)61 265 5184
Email stolzd@uhbs.ch
Website http://www.unispital-basel.ch/
ROR logo "ROR" https://ror.org/04k51q396

Funders

Funder type

University/education

University Hospital Basel (USB) (Switzerland) - Department of Pneumology

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article Results 01/09/2008 Yes No