The aim of this Phase II proof of concept study is to assess efficacy, haemodynamics and safety of Terguride vs. placebo in patients with pulmonary arterial hypertension (PAH). Having finished this proof-of-concept study it is intended that patients…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint is the investigation into:
Pulmonary vascular resistance at final right heart catheterisation (15 weeks
from initial right heart catheterisation) as objective measure
Benchmark: significant reduction (20% vs. baseline) of pulmonary vascular
resistance
In the open-label extension procedure safety parameters and time to clinical
worsening will be addressed.
Secondary outcome
Secondary endpoints are to evaluate the effects of the treatment regimen on:
1. Time from randomisation to clinical worsening (defined as the combined end
point of death, lung transplantation, hospitalisation for pulmonary
hypertension, leading to discontinuation or need for additional specific PAH
therapy)
2. Change in six minutes walk distance (baseline/ 15. week)
3. Change in Borg Dyspnea Index (baseline/ 15.week)
4. Change in WHO functional class (a modification of the New York Heart
Association class; baseline/15. week)
5. Change in cardiac output-index
6. Change in PA pressure
7. Circulating levels of NT-pro-BNP (baseline/ 15. week)
8. Quality of life questionnaire (SF 36, baseline/ 15. week)
9. Adverse events
10. Concomitant medication
Background summary
Terguride is a high affinity antagonist at the 5-HT2B receptor and
non-competitively inhibits the 5-HT2A receptor under physiological conditions.
In a rodent model of monocrotaline induced PAH Terguride dose-dependently
ameliorated the rise in pulmonary pressure, right heart hypertrophy and the
extent of lesion-induced muscularisation of pulmonary arterioles. In the
bleomycin mouse model of lung fibrosis Terguride attenuated the increase in
collagen deposition as assessed by hydroxyproline determination.
Study objective
The aim of this Phase II proof of concept study is to assess efficacy,
haemodynamics and safety of Terguride vs. placebo in patients with pulmonary
arterial hypertension (PAH). Having finished this proof-of-concept study it is
intended that patients will continuously be traeted in an open label extension
procedure with Terguride (05mg) on a voluntary basis.
Study design
The study is a prospective, randomised, double-blind trial with 3 different
treatment phases
- Up-titration over 3 weeks
- 12 weeks treatment on constant dosage (minimal dosage 1,5 mg,
max 3 mg per day)
- Down titration over 5 days to 1 week
Having finished this proof-of-concept study it is intended that patients will
continuously be traeted in an open label extension procedure with Terguride
(05mg) on a voluntary basis. Patients having finished the proof-of-concept
study *after Visit 6- will continuously be treated in an open label extension
procedure on a voluntary basis. On investigator*s responsibility and on
patient*s agreement treatment with the active drug substance Terguride will be
continued on sponsor*s expenses starting again with up-titration schedule. The
Study Extension will be covered by an insurance. The foreseen duration of the
treatment is *up to know- until 31 March 2011 (proof-of-concept study plus open
label extension procedure). A seperate informed consent has to be signed by the
patients.
Intervention
The patient will undergo several special investigations (Pulmonary Function
Test, Diffusion-Limited Carbon Monoxide, ECG, Echocardiogram, Oxygen
Saturation, Right Heart Catheterisation (under local anaesthesia), Laboratory
Assessments (approx 16 x 14 ml during the full duration of participation) which
are part of the clinical routine.
Study burden and risks
Patients may benefit directly from the inhibition of trophic effects of
Terguride by ameliorating, stopping or possibly reversing remodelling processes.
Possible risks may be the side-effects of Terguride which are already known
(nausea, vomiting, dizziness, vertigo, headache, reduction in blood pressure),
reactions to the heart catherisation (problems at the puncture site, cardiac
dysrhythmias, allergic reactions to the contrast agent), reactions to the skin
puncture for blood sampling (bruise, local irritation, local pain or in rare
cases, an infection, nerve damage or venous inflammation in the area of the
puncture site) and self-sticking ECG electrodes on patients with sensitive skin
can lead to itching and redness under the electrodes.
Rütistraße 20
9050 Appenzell
CH
Rütistraße 20
9050 Appenzell
CH
Listed location countries
Age
Inclusion criteria
1. Female and male patients of any racial origin with PAH (WHO classification II-IV)
2. On stable treatment with best supportive care with anticoagulant drugs, diuretics, cardiac glycosides, supplemental oxygen and calcium channels blockers, adjusted to the individual need of the respective patient. Specific PAH mono-therapy (or combination-therapy not exceeding two PAH specific drugs) with either endothelin receptor antagonists or phosphodiesterase type 5 inhibitors or non-parenteral prostanoids (i.e. inhaled, oral, s.c.) is allowed (pre-treated patients) but not mandatory (treatment naive patients). Patients already on PAH specific drugs must be receiving a stable dose of the medication for at least 3 months
3. Having fulfilled his/her 18th birthday on Day 1 of the study but not older than 80 years (up to the patient*s 81st birthday).
4. PAH due to idiopathic pulmonary arterial hypertension or connective tissue disease associated PAH
5. Right heart catheterisation 4 weeks prior to screening or at screening with PAH, specifically PAPm *25 mmHg (at rest), Pulmonary capillary wedge pressure (PCWP) *16 mmHg, pulmonary vascular resistance *500 dyn x sec x cm-5. Echocardiogram at screening consistent with PAH, specifically evidence of right ventricular hypertrophy or dilation, evidence of normal left ventricular function, and absence of mitral valve stenosis
6. Six minutes walk distance above 150 m
7. Receiving conventional PAH therapy, stable for one month.
8. Presentation of negative test results in regard to HIV, Hepatitis C/B, not older than 4 weeks.
9. Able to understand and willing to sign the Informed Consent Form.
Exclusion criteria
1. PAH of any cause other than permitted in the entry criteria
2. Contraindication for heart catheterisation
3. Any change in disease-targeted therapy within the last month before screening
4. Patients requiring intravenous prostanoid therapy within 3 months prior to study start
5. Any subject who had received any investigational medication within 1 month prior to the start of this study or who is scheduled to receive another investigational drug during the course of this study
6. Known intolerance to Terguride
7. Active liver disease, porphyria or elevations of serums transaminases >3 x ULN (upper limit of normal) or bilirubin > 1.5 x ULN
8. History or suspicion of inability to cooperate adequately.
9. Cancer or other malign haematological disease
10. Pulmonary Hypertension caused by left heart disease
11. Pulmonary Arterial Hypertension associated with congenital heart disease (PAH-CHD)
12. Pulmonary Arterial Hypertension associated with human immunodeficiency virus infection (PAH-HIV)
13. Portopulmonary Hypertension (PPHT)
14. CTEPH Chronic Thromboembolic Pulmonary Hypertension
15. Pulmonary Hypertension associated with other diseases excluding aforementioned: PAH due to idiopathic pulmonary arterial hypertension or tissue disease associated PAH, PAH associated with connective tissue disease including systemic sclerosis (sclerodermia) and systemic lupus erythematosus (SLE).
16. Pulmonary Hypertension associated with other chronic lung diseases
17. Additionally, women with child bearing potential must be excluded if:
* They have not used reliable contraception in the cycle before
the study. According to CPMP/ICH/286/95 (modification) highly
effective methods of birth control (defined by a failure rate
< 1% per year) include the consistent and correct use of
implants, injectables combined oral contraceptives, selected
intrauterine devices (IUD), sexual abstinence or vasectomised
partner. The subject has to agree to continue using such highly
reliable contraception during the entire study period and the
cycle after the study
* They are pregnant or lactating. (A negative pregnancy test must be provided for all patients)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-003975-38-NL |
| CCMO | NL19715.029.07 |