TEMPO: Study of Placebo or Bosentan to Treat Patients With Single Ventricle Physiology.

Sponsor

Rigshospitalet, Denmark (Other)

Overall Status

Completed

CT.gov ID

NCT01292551

Collaborator

Aarhus University Hospital (Other), Bispebjerg Hospital (Other), Actelion (Industry)

Enrollment

Locations

Arms

24.9

Duration (Months)

18.8

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether Bosentan is an effective and safe treatment to adolescent and adult (15 years and older) patients, born with one ventricle of the heart instead of two (single ventricle physiology) and who have undergone TCPC as a palliative surgical treatment. The aim of the TCPC operation is to use the one functioning ventricle to pump the blood flow to the body, while the blood to the lungs is received directly from the caval veins, and is thus a passive flow, without the aid of a ventricle to actively pump the blood through the pulmonary circulation. The resistance in the pulmonary circulation is therefore critical to these patients. These patients have markedly lower work capacity in bicycle test than the general public. Furthermore they have a high risk of developing complications e.g. loss of protein from the intestines.

Bosentan is a medication that lowers the resistance in the pulmonary circulation. It is routinely used for patients with pulmonary hypertension. Some studies have shown that drugs that lower the pulmonary resistance can increase exercise capacity significantly in patients with single ventricle physiology.

In this study 80 patients will receive either placebo or Bosentan for 14 weeks. Before and after the treatment, bicycle test along with blood samples, stool samples and quality of life interviews will be performed. Every four weeks during the study blood samples, physical exam and interviews will be performed to ensure the safety of the treatment.

The investigators expect to find a significant increase in work capacity after 14 weeks in the treatment group compared with the placebo group.

Moreover the investigators hope to find a decrease in intestinal protein loss and an improved quality of life.

Condition or Disease	Intervention/Treatment	Phase
Hypoplastic Left Heart Syndrome Tricuspid Atresia Other Specified Congenital Anomalies of Heart	Drug: Bosentan Drug: Placebo	Phase 2

Detailed Description

In the statistical analysis the investigators wish to analyse interactions between the primary endpoint and predefined subgroups in order to distinguish responders from non-responders to the treatment. The predefined subgroups are:

NT-proBNP > 100 (yes/no) Ventricular anatomy (RV/LV) CT-proEndothelin-1. In the latter, the investigators do not wish to predefine a specific value, due to limited experience with this analysis. We wish to use the data from the study to find a cut-off value, that is able to predict positive response to treatment.

Study Design

Study Type:

Interventional

Actual Enrollment :

75 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Treatment With Endothelin Antagonist to Tcpc Patients; a Multicenter, Randomized, Prospective Study Measuring Maximal O2 Uptake in Ergometer Bicycle Test

Study Start Date :

Feb 1, 2011

Actual Primary Completion Date :

Mar 1, 2013

Actual Study Completion Date :

Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bosentan	Drug: Bosentan tablets Bosentan 62,5 mg x 2 daily for two weeks, then 125 mg x 2 daily for 12 weeks Other Names: Bosentan: Tracleer
Placebo Comparator: Placebo	Drug: Placebo Placebo tablets 2 x daily for 2 weeks, then change to different placebo tablets to match Bosentan group, 2 x daily for 12 weeks

Arm

Intervention/Treatment

Active Comparator: Bosentan

Drug: Bosentan

tablets Bosentan 62,5 mg x 2 daily for two weeks, then 125 mg x 2 daily for 12 weeks

Other Names:

Bosentan: Tracleer

Placebo Comparator: Placebo

Drug: Placebo

Placebo tablets 2 x daily for 2 weeks, then change to different placebo tablets to match Bosentan group, 2 x daily for 12 weeks

Outcome Measures

Primary Outcome Measures

Change from baseline in VO2max at 14 weeks [Baseline and 14 weeks]
Maximal O2 uptake in ml/min/kg in ergometer bicycle test

Secondary Outcome Measures

Change from baseline in blood samples at 14 weeks [Baseline and 14 weeks]
blood samples measured: plasma CT pro endothelin-1, IgG, IgA, NT pro BNP, albumin, free protein
Change from baseline in SF36 questionnaire score at 14 weeks [Baseline and 14 weeks]
SF36 quality of life interview
Change from baseline in feces alfa 1 antitrypsin at 14 weeks [Baseline and 14 weeks]
Fecal alfa 1 antitrypsin in mg/g
Number of participants with adverse events [2, 6, 10 and 14 weeks after start of treatment]
general interview on adverse effects, and questions with special focus on typical adverse effects in Bosentan
Change from baseline in vital signs [Baseline, 2, 6, 10 and 14 weeks]
Systemic bloodpressure in mmHg, Pulse in min-1, Oxygen saturation in percent
Change from baseline in control blood samples [Baseline, 2, 6, 10 and 14 weeks]
Liver and renal biomarkers, Hb, PCV, trc and hCG for women
Change from baseline in cardiac output/pulmonary blood flow [Baseline and 14 weeks]
CO measured by Stringer Wassermann method during ergometer bicycle test

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

TCPC operated
Age > 15 years old
Clinical stability > 3 months, evaluated by investigator from clinical record
For women: Negative s-hCG and use of contraception

Exclusion Criteria:

Severe heart failure (NYHA-class IV)
Oxygen saturation < 85 % at rest
Pre-existing liver condition (transaminases 2x > reference)
Renal failure (creatinin > 150 mmol/l)
Obstruction of TCPC circulation
History of work induced severe arrhythmia
Systolic blood pressure below 80% of reference (BT < 88 mmHg)
Use of any of following drugs: Fluconazol, Ketoconazole, CiclosporinA, Lopinavir, Ritonavir, Rifampicin, Carbamazepin and Phenytoin
Significant extra-cardiac condition e.g. neurological impairment

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Aarhus University Hospital	Aarhus	Denmark	8200
2	Rigshospitalet	Copenhagen	Denmark	2100
3	Lund University Hospital	Lund	Sweden
4	Karolinska Institutet	Stockholm	Sweden