Efficacy and safety of riociguat (MK-4836) in incipient pulmonary vascular disease as an indicator for early pulmonary arterial hypertension Double-blind, randomized, multicenter, multinational, placebo-controlled phase IIa study

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

25 Jul 2022 → 31 Jul 2025

Decision date (initial)

2024-12-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

MSD SHARP & DOHME GmbH

External identifiers

EU CT number

2023-509695-42-00

EudraCT number

2021-001633-40

ClinicalTrials.gov

NCT05339087

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To investigate the change pulmonary vascular resistance among patients with early pulmonary vascular disease treated with riociguat (MK-4836) versus placebo for 24 weeks.

Secondary objectives 2

1. To investigate, whether treatment with riociguat (MK-4836) may improve further hemodynamic and clinical parameters, defined as change from baseline to 24 weeks of treatment
2. To assess safety and tolerability of riociguat (MK-4836) treatment in patients with early pulmonary vascular disease

Conditions and MedDRA coding

Pulmonary vascular disease

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male and female patients with early pulmonary vascular disease, defined as either a) mean pulmonary arterial pressure (mPAP) ≥25 mmHg with pulmonary vascular resistance (PVR) ≥2 to <3 WU and pulmonary arterial wedge pressure (PAWP) ≤15 mmHg (group I PAH according to 2022 ERS/ESC guidelines) or b) mPAP 21-<25 mmHg with PVR ≥2 WU, and PAWP ≤15 mmHg associated with connective tissue disease (CTD) or as idiopathic/heritable form
2. Treatment naïve patients (with respect to PAH specific medication)
3. Unspecific treatments which may also be used for the treatment of pulmonary hypertension such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. Permitted are also treatments of the rheumatologic disease. However, these drugs must have been started at least 1 month before right heart catheterization.
4. Right-heart catheterization results must not be older than 1 month at Visit 1 (will be considered as baseline values, the time frame can be prolonged up to 6 months, if the patient has had no signs of clinical changes defined as >20% change of 6MWD, WHO FC, > 30% change in NT-proBNP) and must have been measured in the participating center under standardized conditions (refer to the study specific Swan Ganz catheterization manual).

Exclusion criteria 8

1. Patients with systemic lupus erythematosus.
2. Concomitant PAH-targeted treatment is not allowed during the study. Accordingly, patients scheduled to receive another investigational drug during the course of this study cannot participate (see exclusion criterion 12). Patients already receiving or having received any PAH targeted therapy will therefore not be included into the study. Such treatment may not be discontinued to enable inclusion into the study.
3. Concomitant treatment with phosphodiesterase 5 inhibitors, endothelin receptor antagonists and prostacyclin analogues due to digital ulcers is contraindicated and must notbe taken during the study period. Such drugs must have a washout-phase of 3 days at the time of right heart catheterization at screening. Intravenous treatment with prostacyclin analogues should not be performed within 1 week of right heart catheterization.
4. Pulmonary hypertension explained by other cause including group 2, 3, 4 and 5 PH according to the current guidelines.
5. Cardiac comorbidity, defined with three or more of the following conditions: uncontrolled arterial hypertension, diabetes mellitus, body mass index >35, left atrial enlargement >20 cm², atrial fibrillation, left ventricular ejection fraction <50%.
6. Pulmonary comorbidity, defined as forced vital capacity (FVC) ≤70; forced expiratory volume in 1 second (FEV1) ≤50%; diffusion capacity of the lung (DLCO) ≤30%.
7. Contraindications according to summary of product characteristics of riociguat (e.g. arterial hypotension with systolic blood pressure <95 mmHg; nitrates or nitric oxide donors (such as amyl nitrite) in any form including recreational drugs)
8. Background therapy with highly anti-fibrotic drugs (pirfenidone) or nintedanib, prednisolone >10 mg/day

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pulmonary vascular resistance, change from baseline to 24 weeks

Secondary endpoints 6

1. change of cardiac index at rest (baseline to 24 weeks)
2. change of total pulmonary resistance (baseline to 24 weeks)
3. change of diffusion capacity of the lung (baseline to 24 weeks)
4. change of 6-minute walking distance (baseline to 24 weeks)
5. change of WHO functional class (baseline to 24 weeks)
6. change in QoL (SF-36, physical summation score; baseline to 24 weeks)

Investigational products

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

Test 5

Placebo 1

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 of Pulmonary Hypertension

Public contact point

Organisation

Thoraxklinik Heidelberg gGmbH

Contact name

Centre of Pulmonary Hypertension

Locations

4 EU/EEA countries · 6 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 19 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