An open-label, prospective, single centre study of the effects of Riociguat on RIght VEntricular size and function in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Thoraxklinik Heidelberg gGmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

5 Nov 2021 → 13 Aug 2025

Decision date (initial)

2024-08-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

MSD Sharp & Dohme GmbH

External identifiers

EU CT number

2023-509696-17-00

EudraCT number

2020-005462-34

ClinicalTrials.gov

NCT04954742

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

Investigate the effect of riociguat (MK-4836) on right ventricular (RV) and right atrial (RA) area, measured by echocardiography. The effect of riociguat (MK-4836) on RV and RA area will be compared during therapy in each patient (from baseline to 12 and 24 weeks; primary endpoint baseline vs. 24 weeks riociguat therapy)

Secondary objectives 3

1. Compare the effect of riociguat (MK-4836) on RV and haemodynamic properties in patients with PAH or CTEPH (comparison from baseline to 24 weeks) with right heart catheterization.
2. Secondary efficacy analysis comprises of further echocardiographic measurements and correlation between echocardiography and clinical data such as haemodynamics, vital signs, electrocardiogram, echocardiography, laboratory parameters especially N-terminal pro brain natriuretic peptide (NT-proBNP), pulmonary function, WHO-FC, 6MWD (from baseline to 12 and 24 weeks), cardiopulmonary exercise testing† and quality of life parameters by questionnaire SF-36.
3. Assess the compliance and medication interaction by measurement of plasma drug concentrations of pulmonary hypertension targeted medication.

Conditions and MedDRA coding

Chronic Thromboembolic Pulmonary Hypertension

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Patients with symptomatic PAH with a mean pulmonary artery pressure (mPAP) >20 mmHg and pulmonary vascular resistance (PVR) ≥2 Wood Units (WU), pulmonary arterial wedge pressure (PAWP) ≤15 mmHg (Group I / Nice Clinical Classification of Pulmonary Hypertension) OR [see next criterion]
2. CTEPH (Group IV / Nice Clinical Classification of Pulmonary Hypertension) defined as one of the following options: − inoperable measured at least 3 months after start of full anticoagulation and mPAP >20 mmHg and PVR ≥2 WU, PAWP ≤15 mmHg or − persisting or recurrent PH after pulmonary endarterectomy (mPAP >20 mmHg and PVR ≥2 WU, PAWP ≤15 mmHg measured at least 6 months after surgery (acc. to Simonneau et al. 2018).
3. Patients who are either treatment naïve (with respect to PAH specific medication) OR pre-treated with an endothelin receptor antagonist and/or a prostacyclin and/or a prostacyclin analogue (according to upfront combination treatment) or [see next criterion]
4. pre-treated with phosphodiesterase type 5 inhibitor (PDE-5) with or without combination treatment with an endothelin receptor antagonist and/or prostacyclin analogue. Pre-treated patients need to be stable on PDE5i for at least two months prior to Visit 1. “Stable” is defined as no change in the type of PDE5i and the respective daily dose. PDE5i has to be stopped (sildenafil 24h, tadalafil 48h) before switching to riociguat. The switch from PDE5i to riociguat is due to clinical indication, particularly when the patient´s risk-profile remained in intermediate risk group despite adequate initial treatment including PDE5i (defined as at least 3 of the following parameters: clinical signs of progression, persistent WHO-FC III, 6MWD between 165-440m, peak V02 11-15ml/min/kg (35-65% predicted), NTproBNP 300-1400 ng/l, RA-area 18-26cm2,RAP 8-14mmHg, CI 2,0-2,4 l/min) or in case of PDE5i intolerance.
5. RHC results must not be older than 6 months at screening

Exclusion criteria 12

1. Patients unable to perform a valid 6MWD test (e.g. orthopaedic disease, peripheral artery occlusive disease, which affects the patient´s ability to walk).
2. Moderate to severe bronchial asthma or COPD (Forced Expiratory Volume <60% predicted) or severe restrictive lung disease (Total Lung Capacity < 70% predicted) and/or defined as if high resolution computed tomography shows >20% parenchymal lung disease.
3. Severe congenital abnormalities of the lungs, thorax, and diaphragm.
4. Clinical or radiological evidence of Pulmonary-Veno-Occlusive Disease (PVOD) or Pulmonary Capillary Haemangiomatosis (PCH) or PH and idiopathic interstitial pneumonia (PH-IIP)
5. Uncontrolled arterial hypertension (systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg).
6. Systolic blood pressure <95 mmHg (permitted and monitored closely if due to the study drug side effects).
7. Left heart failure with an ejection fraction less than 40%.
8. Hypertrophic obstructive cardiomyopathy.
9. Severe proven or suspected coronary artery disease according to investigators opinion (patients with Canadian Cardiovascular Society Angina Classification class 2-4, and/or requiring nitrates, and/or myocardial infarction within the last 3 months before Visit 1).
10. Clinical evidence of symptomatic atherosclerotic disease (e.g. peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc).
11. Clinically relevant hepatic dysfunction indicated by: − bilirubin >2 times upper limit normal − and / or hepatic transaminases >3 times upper limit normal − and / or signs of severe hepatic insufficiency (e.g. impaired albumin synthesis with an albumin < 32 g/l, hepatic encephalopathy > grade 1a: West Haven Criteria of Altered Mental Status In Hepatic Encephalopathy)
12. Renal insufficiency (glomerular filtration rate <30 ml/min/m2 e.g. calculated based on the Cockcroft formula).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. the change in RV and RA area from baseline to week 24

Secondary endpoints 52

1. RA and RV area (12 weeks) (echocardiography)
2. Systolic pulmonary artery pressure (sPAP) (echocardiography)
3. RV fractional area change (FAC) (echocardiography)
4. Peak velocity of tricuspid regurgitation (TRV) (echocardiography)
5. Inferior vena cava (IVC) diameter and IVC collapse (echocardiography)
6. Right Ventricle Outflow Tract Velocity Time Integral (RVOT VTI) (echocardiography)
7. Eccentricity index (EI) (echocardiography)
8. Tricuspid Annular Plane Systolic Excursion (TAPSE) (echocardiography)
9. Right and left ventricular pump function (qualitative) (echocardiography)
10. Left Atrial (LA) diameter (echocardiography)
11. LV diastolic function (LV transmitral E wave and A wave, E’ wave of interventricular septum and lateral wall pulsed tissue Doppler, isovolumic relaxation time, mitral deceleration time)
12. Diameters of pulmonary artery (echocardiography)
13. CI in litres per minute per square meter (of body surface area) (RHC)
14. CO in litres per minute (RHC)
15. sPAP, dPAP, mPAP in mmHg (RHC)
16. PAWP in mmHg (RHC)
17. right atrial pressure (RAP) in mmHg (RHC)
18. PVR in Wood Units (RHC)
19. Central venous saturation, via blood gas analysis from pulmonary artery, in % (RHC)
20. 6-minute walking distance from baseline to 12 and 24 weeks of treatment
21. forced vital capacity (FVC) (Body plethysmography)
22. forced expiratory volume in one second (FEV1) (Body plethysmography)
23. FEV1% of maximal vital capacity (VC max) (Body plethysmography)
24. total lung capacity (TLC) (Body plethysmography)
25. residual volume (Body plethysmography)
26. diffusion-limited carbon monoxide (DLCO) and DLCO/VA (Krogh) factor (Diffusion capacity)
27. partial pressure of oxygen and carbon dioxide (blood gas analysis)
28. SaO2 (blood gas analysis)
29. pH values (blood gas analysis)
30. Blood pressure and heart rate (Cardiopulmonary exercise testing)
31. workload (Cardiopulmonary exercise testing)
32. oxygen consumption as total and per kg body weight (Cardiopulmonary exercise testing)
33. exhaled carbon dioxide (VCO2) (Cardiopulmonary exercise testing)
34. oxygen saturation (Cardiopulmonary exercise testing)
35. oxygen pulse (Cardiopulmonary exercise testing)
36. minute ventilation (Cardiopulmonary exercise testing)
37. respiratory equivalents for oxygen and carbon dioxide (Cardiopulmonary exercise testing)
38. respiratory reserve (all values at rest, anaerobic threshold and peak workload) (Cardiopulmonary exercise testing)
39. NT-proBNP
40. hemoglobin
41. hematocrit
42. AST
43. ALT
44. bilirubin
45. CRP
46. Sodium
47. Urea
48. Creatinine
49. plasma drug concentration of PAH-targeted drugs including riociguat and endothelin receptor antagonists
50. WHO functional class from baseline to 12 and 24 weeks of treatment
51. Quality of life parameters by questionnaire SF-36 from baseline value to 24 weeks of treatment
52. Tolerability, safety and survival (Adverse events; vital signs [BP, HR, SaO2], ECG; Need for rescue medication safety parameters)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Thoraxklinik Heidelberg gGmbH

Sponsor organisation

Thoraxklinik Heidelberg gGmbH

Address

Roentgenstrasse 1, Rohrbach Rohrbach

City

Heidelberg

Postcode

69126

Country

Germany

Scientific contact point

Organisation

Thoraxklinik Heidelberg gGmbH

Contact name

Centre for Pulmonary Hypertension

Public contact point

Organisation

Thoraxklinik Heidelberg gGmbH

Contact name

Centre for Pulmonary Hypertension

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications