Contact information
Type
Scientific
Primary contact
Prof Michael Tamm
ORCID ID
Contact details
University Hospital Basel
Petersgraben 4
Basel
4031
Switzerland
+41 (0)61 265 5184
stolzd@uhbs.ch
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
N/A
Study information
Scientific title
Acronym
TOP Study
Study hypothesis
We 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
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.
Study design
Interventional, prospective, randomised, double-blind, placebo-controlled study
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Chronic obstructive pulmonary disease
Intervention
Bosentan 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 type
Drug
Phase
Not Specified
Drug names
Bosentan
Primary outcome measure
Improvement in six feet walking distance after three months therapy.
Secondary outcome measures
Improvement 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 trial start date
01/04/2006
Overall trial end date
01/12/2006
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. 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
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
24
Participant exclusion criteria
1. 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
Recruitment start date
01/04/2006
Recruitment end date
01/12/2006
Locations
Countries of recruitment
Switzerland
Trial participating centre
University Hospital Basel
Basel
4031
Switzerland
Sponsor information
Organisation
University Hospital Basel (USB) (Switzerland)
Sponsor details
Division of Pneumology
Petersgraben 4
Basel
4031
Switzerland
+41 (0)61 265 5184
stolzd@uhbs.ch
Sponsor type
University/education
Website
Funders
Funder type
University/education
Funder name
University Hospital Basel (USB) (Switzerland) - Department of Pneumology
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
Results in http://www.ncbi.nlm.nih.gov/pubmed/18448495
Publication citations
-
Results
Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, Tamm M, A randomised, controlled trial of bosentan in severe COPD., Eur. Respir. J., 2008, 32, 3, 619-628, doi: 10.1183/09031936.00011308.