E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
An increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037400 |
E.1.2 | Term | Pulmonary hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
There is one main aim: 1. To confirm that when racecadotril is administered to patients with pulmonary hypertension taking sildenafil, it inhibits the enzyme, neutral endopeptidase. |
|
E.2.2 | Secondary objectives of the trial |
There are three main secondary aims: 1. To measure the effect of racecadotril, when administered to patients taking sildenafil, on blood pressure, including the blood pressure of the lungs (pulmonary artery pressure). 2. To measure the effect of racecadotril, when administered to patients taking sildenafil,on related blood biomarkers. 3. To assess the safety of racecadotril when administered to patients taking sildenafil. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. WHO Group I pulmonary hypertension(i.e. idiopathic, familial or associated with connective tissue diseases) 2. 18-80 years old 3. Technically satisfactory right heart catheterisation (Step 1 only) 4. On sildenafil (20-100 mg; t.i.d.) 5. Six minute walk distance of equal to or >150 m at entry 6. No changes to PH specific therapies for 1 month 7. Not pregnant (women only). Women of childbearing potential only: Women must have a negative pregnancy test within seven days prior to being registered for trial treatment on day 0; they must be willing to use an effective method of contraception (including hormonal or barrier method of birth control) from the time consent is signed until six weeks after treatment discontinuation 8. Able to provide consent for the trial |
|
E.4 | Principal exclusion criteria |
1. Known sensitivity to racecadotril 2. Clinical diagnosis of liver cirrhosis or ALT/AST >two times the upper limit of normal 3. Kidney disease with an eGFR of <50 ml/min 4. History of angioedema 5. Systolic blood pressure <85 mmHg 6. Known history of drug or alcohol abuse within six months of enrolment 7. Participation in a clinical study involving another investigational drug 8. Women who are breastfeeding 9. Any clinical condition for which the investigator would consider the patient unsuitable for the trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Maximum percentage change from baseline in plasma atrial natriuretic peptide (ANP) concentration (nM). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Step 1: Blood samples taken at 0,1,2,3 and 6 hours (+/- 15 minutes/time point). Step 2: Blood samples taken on day 0 and on the 12th, or 13th, or 14th day of treatment. |
|
E.5.2 | Secondary end point(s) |
Step 1 In patients with PH to determine the effect of a single dose of racecadotril or placebo (either 100 mg or 200 mg p.o). Racecadotril or placebo will be co-administered concurrently with sildenafil (20-100 mg; p.o.). 1. Pulmonary haemodynamic assessments: Maximum change in: 1. Pulmonary vascular resistance (dynes. sec/cm-5) 2. Stroke volume (ml) 3. Pulmonary artery occlusion pressure (mmHg) 4. Arterial saturation (%) 5. Mean arterial pressure (mmHg) 2. Systemic haemodynamic assessments: 1. Systolic and diastolic blood pressure (mmHg) and Heart Rate (BPM) 3. Additional biomarkers in the blood: Brain-type Natriuretic Peptide (BNP)(nM), N-terminal pro brain-type natriuretic peptide (NT-proBNP) (nM), C-type natriuretic peptide (CNP) (pM),Cyclic guanosine-3’,5’-monophosphate (cGMP) (nM), endothelin 1(ET-1) (nM), Nitrite and Nitrate (NOx) (nM) 4. Safety assessment: Adverse events Step 2 In patients with PH, to determine the effects of racecadotril or placebo administered in repeat dosing (100 or 200 mg t.i.d.) concurrently with sildenafil (20-100 mg; p.o.; t.i.d.) for 12, or 13, or 14 days, on; 1. Systemic haemodynamic assessments: Systolic and diastolic blood pressure (mmHg) and heart rate (BPM) 2. Additional biomarkers in the blood: Brain-type Natriuretic Peptide (BNP)(nM), N-terminal pro brain-type natriuretic peptide (NT-proBNP) (nM), C-type natriuretic peptide (CNP) (pM), Cyclic guanosine-3’,5’-monophosphate (cGMP) (nM) , endothelin 1(ET-1) (nM), Nitrite and Nitrate (NOx) (nM) 3. Safety assessment: Adverse events 4. Six minute walk test (m) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Step 1: Pulmonary haemodynamics measured at 0, 1.5 and 2 hours (+/- 10 minutes /time point) Systemic haemodynamics measured at 0 and then every 30 minutes up to 6 hours (+/- 15 minutes /time point) Blood samples taken at 0,1,2,3 and 6 hours (+/- 15 minutes /time point). Step 2: Blood samples taken on day 0 and on the 12th, or 13th, or 14th day of treatment. Systemic haemodynamics measured on day 0 and on the 12th, or 13th, or 14th day of treatment. Six minute walk test measured on day 0 and on the 12th, or 13th, or 14th day of treatment. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the trial is defined as being upon 30 days after the completion of all clinical data entry of the data received at the UCL CTU and the resolution of all clinical data queries. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |