Other Systemic Involvement of Connective Tissue, Primary Pulmonary Hypertension, Pulmonary Vascular Disorder, Systemic Sclerosis
Conditions
Keywords
early pulmonary vascular disease, riociguat, pulmonary hypertension
Brief summary
This is a randomized, double-blind, placebo-controlled, multicenter, multinational study investigating the effect of riociguat (MK-4836) in patients with early pulmonary vascular disease.
Detailed description
Chronic pulmonary arterial hypertension (PAH) is associated with impaired exercise capacity, quality of life and right ventricular function characterized by an increase of pulmonary vascular resistance (PVR) and pulmonary arterial pressure, leading to right heart insufficiency. Riociguat tratment is approved for both PAH and chronic thromboembolic pulmonary hypertension (CTEPH). Data on early treatment of patients with mildly elevated pulmonary arterial pressures is still scarce but there is evindence that such patients may benefit from early targeted therapy. For instance, in a trial on systemic sclerosis (SSc)-patients with mildly elevated mean pulmonary artery pressure (mPAP) and/or exercise pulmonary hypertension, without significant left heart or lung disease, ambrisentan, an endothelin receptor antagonist resulted in an improvement of PVR as secondary endpoint, which may be of prognostic relevance in this patient cohort and requires further research. Besides its prognostic significance among patients with SSc-APAH, PVR may be an indicator of early pulmonary vascular disease and previous studies proved the positive effects of riociguat on right heart size and PVR (secondary endpoint in phase III studies). Thus, PVR was chosen as primary endpoint of this study aiming to investigate the effect of riociguat (MK-4836) on PVR, clinical parameters, safety and tolerability in patients with early pulmonary vascular disease. Eligible subjects will be randomized in a 1:1 ratio to receive either riociguat or placebo. Medical examinations include medical history, physical examination, electrocardiogram, blood gas analyses, lung function tests, laboratory testing (including NT-proBNP), echocardiography at rest, and right heart catheterization. The prospective period of data collection comprises a 24-week treatment phase diveded into an 8-week titration phase followed by a 16-week main study phase as well as a safety follow-up of 30±14 days.
Interventions
Riociguat Oral Tablet (1 mg, 1.5 mg, 2.0 mg or 2.5 mg three times daily) Titration phase: dose will be individually adjusted in accordance with the in-label titration regimen. Dose adjustment will be performed every two weeks by phone taking the systemic blood pressure of the patient, the subjects and physicians' subjective estimation and occurrence of adverse reactions into account. At week 8 the maintenance dose will be established and continued for the rest of the study
OTHERPlacebo
Sham titration and adjustment to maintenance dose will be performed according to individual tolerability as in the experimental arm.
Sponsors
Heidelberg University
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ≥18 years of age at time of inclusion. 2. 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 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 (see Group I / Nice Clinical Classification of Pulmonary Hypertension) (acc. to Simonneau et al. 2019). Patients with rheumatoid arthritis or connective tissue disease of any kind, except systemic lupus erythematosus, may also be included. Patients in group b will be mainly enrolled as long as patients in group a are not defined as having pulmonary arterial hypertension according to European pulmonary hypertension guidelines. 3. Treatment naïve patients (with respect to PAH specific medication) 4. 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. 5. 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 \>10% 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). If the respective measurements have not been performed in context with the patient's regular diagnostic work up, they have to be performed as a part of the study during the pre-study phase (after the patient signed the informed consent). 6. Women without childbearing potential defined as postmenopausal women aged 55 years or older, women with bilateral tubal ligation, women with bilateral ovariectomy, and women with hysterectomy can be included in the study. 7. Women of childbearing potential can only be included in the study if all of the following applies (listed below): 1. Negative serum pregnancy test at screening and at study start (visit 1). 2. Agreement to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation. These tests should be performed by the patient at home. 3. Agreement to use a highly effective contraception method as specified from screening until at least 30 days after last dose of study medication. 8. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period. 9. Patients must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures.
Exclusion criteria
1. Patients with systemic lupus erythematosus. 2. Concomitant PAH-targeted treatment is not allowed during the study. 3. Concomitant treatment with phosphodiesterase 5 inhibitors, endothelin receptor antagonists and prostacyclin analogues due to digital ulcers is contraindicated and must not be 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. Any decision to discontinue above-mentioned drugs will be made by the clinicians and the patient at screening, which takes part during the patients' regular routine visit. The discontinuation of above-mentioned drugs will be evaluated by considering the presence or absence of digital ulcers and their frequency of appearance in the patient's medical history. 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) ≤40%. FVC may be \<70/ if high resolution computed tomography shows \<20% lung fibrosis. 7. Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator. 8. Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g. active cancer disease with localized and/or metastasized tumor mass). 9. Patients with a history of severe or multiple drug allergies (defined as allergic reactions to three or more structurally unrelated drugs). 10. Patients with hypersensitivity to the investigational drug or any of the excipients. 11. Contraindications according to summary of product characteristics of riociguat (e.g. arterial hypotension with systolic blood pressure \<95 mmHg; nitrates) 12. Participation in any clinical drug trial within 4 weeks prior to screening of this study and/or patient, who is scheduled to receive an investigational medicinal product (IMP) during the course of this study 13. Background therapy with highly anti-fibrotic drugs (pirfenidone) or nintedanib, prednisolone \>10 mg/day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Pulmonary Vascular Resistance (PVR) | baseline, 24 weeks | Change in pulmonary hemodynamics assessed by right heart catheterization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of Cardiac Index (CI) at Rest From Baseline at 24 Weeks | baseline, 24 weeks | Change in pulmonary hemodynamics assessed by right heart catheterization |
| Change of Total Pulmonary Resistance (TPR) From Baseline at 24 Weeks | baseline, 24 weeks | Change in Pulmonary hemodynamics assessed by right heart catheterization Hierarchical testing of secondary endpoints stopped after first step. |
| Change of Diffusion Capacity of the Lung (DLCO) From Baseline at 24 Weeks | baseline, 24 weeks | Change assessed by lung function tests. Hierarchical testing of secondary endpoints stopped after first step. |
| Change in 6-minute Walking Distance (6MWD) | baseline, 24 weeks | Change in exercise capacity assessed by 6-minute walking distance test Hierarchical testing of secondary endpoints stopped after first step. |
| Change of World Health Organization- Functional Class (WHO-FC) From Baseline at 24 Weeks | baseline, 24 weeks | Change of WHO functional class, change score The World Health Organization (WHO) functional class (FC) describes the severity of pulmonary hypertension (PH) symptoms. FC I is considered the mildest and FC IV the most severe form of PH. |
Countries
Austria, France, Germany, Italy, Switzerland, United Kingdom
Contacts
PRINCIPAL_INVESTIGATOREkkehard Grünig, MD
Thoraxklinik at the University of Heidelberg
Participant flow
Recruitment details
Participants were recruited at 6 study centres between October 2022 and May 2025. The first participant was enrolled on 24 October 2022, the last on 30 May 2025.
Pre-assignment details
Overall, 35 participants met the eligibility criteria and were randomized to treatment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 65.89 years STANDARD_DEVIATION 6.64 |
| Blood gas analysis - bicarbonates | 22.34 mmol/L STANDARD_DEVIATION 1.76 |
| Blood gas analysis - Partial Pressure of Carbon Dioxide (PaCO2) | 36.37 mmHg STANDARD_DEVIATION 3.92 |
| Blood gas analysis - Partial Pressure of Oxygen (PaO2) | 75.57 mmHg STANDARD_DEVIATION 9.6 |
| Blood gas analysis - pH | 7.41 pH STANDARD_DEVIATION 0.01 |
| Blood gas analysis - Saturation of Arterial Oxygen (SaO2) | 95.97 percent STANDARD_DEVIATION 1.53 |
| Concomitant diseases Autoimmune rheumatic diseases - Mixed connective tissue disease | 2 Participants |
| Concomitant diseases Autoimmune rheumatic diseases - other | 3 Participants |
| Concomitant diseases Autoimmune rheumatic diseases - Sjögren Syndrome | 1 Participants |
| Concomitant diseases Autoimmune rheumatic diseases - Systemic Sclerosis (SSc) - diffuse cutaneous SSc | 1 Participants |
| Concomitant diseases Autoimmune rheumatic diseases - Systemic Sclerosis (SSc)- limited cutaneous SSc | 6 Participants |
| Concomitant diseases Autoimmune rheumatic diseases - Systemic Sclerosis (SSc) - other subtypes | 6 Participants |
| Concomitant diseases Degenerative bone disease | 12 Participants |
| Concomitant diseases Diabetes mellitus | 2 Participants |
| Concomitant diseases Dyslipidemia | 6 Participants |
| Concomitant diseases Iron deficiency | 4 Participants |
| Concomitant diseases Mild interstitial lung disease | 7 Participants |
| Concomitant diseases Mild obstructive lung disease | 3 Participants |
| Concomitant diseases Oesophagus disease | 4 Participants |
| Concomitant diseases Osteoporosis | 4 Participants |
| Concomitant diseases Thyroid dysfunction | 5 Participants |
| Concomitant diseases Treated arterial hypertension | 20 Participants |
| Concomitant diseases Treated coronary heart disease | 1 Participants |
| Duration of pulmonary hypertension (PH) | 0.56 months STANDARD_DEVIATION 1.65 |
| Echocardiography at rest - Estimated Systolic Pulmonary Artery Pressure (sPAP) | 33.55 mmHg STANDARD_DEVIATION 7.52 |
| Echocardiography at rest - left ventricular eccentricity index (LV-EI) | 1.00 index STANDARD_DEVIATION 0 |
| Echocardiography at rest - Left ventricular ejection fraction | 64.09 percent STANDARD_DEVIATION 6.28 |
| Echocardiography at rest - right atrial (RA) area | 12.47 cm2 STANDARD_DEVIATION 3.04 |
| Echocardiography at rest - right ventricular (RV) area | 12.53 cm2 STANDARD_DEVIATION 2.85 |
| Echocardiography at rest - Tricuspid Annular Plane Systolic Excursion (TAPSE) | 2.37 cm STANDARD_DEVIATION 0.41 |
| Height | 161.94 cm STANDARD_DEVIATION 7.28 |
| Hemodynamics at rest - cardiac index (CI) | 2.70 l/min/m2 STANDARD_DEVIATION 0.43 |
| Hemodynamics at rest - cardiac output (CO) | 4.62 l/min STANDARD_DEVIATION 0.93 |
| Hemodynamics at rest - diastolic pulmonary artery pressure (dPAP) | 14.44 mmHg STANDARD_DEVIATION 2.25 |
| Hemodynamics at rest - mean pulmonary arterial pressure (mPAP) | 23.86 mmHg STANDARD_DEVIATION 2.69 |
| Hemodynamics at rest - pulmonary artery wedge pressure (PAWP) | 10.00 mmHg STANDARD_DEVIATION 2.98 |
| Hemodynamics at rest - Pulmonary Vascular Resistance (PVR) | 3.01 WU STANDARD_DEVIATION 0.73 |
| Hemodynamics at rest - Right Arterial Pressure (RAP) | 6.71 mmHg STANDARD_DEVIATION 3.12 |
| Hemodynamics at rest - Systolic Pulmonary Artery Pressure (sPAP) | 36.61 mmHg STANDARD_DEVIATION 3.85 |
| Hemodynamics at rest - Venous Oxygen Saturation (SVO2) | 59.89 percent STANDARD_DEVIATION 5.9 |
| Laboratory - C-reactive protein (CRP) | 6.15 mg/L STANDARD_DEVIATION 8.5 |
| Laboratory - Creatinine | 0.79 mg/dl STANDARD_DEVIATION 0.21 |
| Laboratory - Hemoglobin | 13.26 g/dl STANDARD_DEVIATION 1.29 |
| Laboratory - N-terminal prohormone of brain natriuretic peptide (NTproBNP) | 316.73 pg/ml STANDARD_DEVIATION 342.13 |
| Laboratory - Serum Glutamic Pyruvic Transaminase (SGPT) | 20.48 U/L STANDARD_DEVIATION 14.28 |
| Laboratory - Urea | 25.82 mg/dl STANDARD_DEVIATION 6.68 |
| Laboratory - Uric acid | 4.93 mg/dl STANDARD_DEVIATION 2.1 |
| Lung function - Diffusion limited carbon monoxide/alevolar volume (DLCO/VA) | 70.99 percent predicted STANDARD_DEVIATION 15.12 |
| Lung function - Diffusion limited carbon monoxide (DLCO) | 58.83 percent predicted STANDARD_DEVIATION 10.15 |
| Lung function - Forced expiratory volume in the first second (FEV1) | 90.90 percent predicted STANDARD_DEVIATION 15.74 |
| Lung function - Forced Vital Capacity (FVC) | 92.18 L STANDARD_DEVIATION 12.54 |
| Lung function - Residual volume | 88.54 percent predicted STANDARD_DEVIATION 21.67 |
| Lung function - total lung capacity (TLC) | 92.28 percent (predicted) STANDARD_DEVIATION 12.48 |
| Pulmonary hypertension (PH) Etiology CTD-associated | 11 Participants |
| Pulmonary hypertension (PH) Etiology Heritable | 0 Participants |
| Pulmonary hypertension (PH) Etiology Idiopathic | 6 Participants |
| Pulmonary hypertension (PH) Etiology other | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 0 Participants |
| Short Form-36 Health Survey - Emotional role function | 43.15 scores on a scale STANDARD_DEVIATION 50.3 |
| Short Form-36 Health Survey - General health perception | 53.06 scores on a scale STANDARD_DEVIATION 23.67 |
| Short Form-36 Health Survey - Mental summation score | 55.22 scores on a scale STANDARD_DEVIATION 19.44 |
| Short Form-36 Health Survey - Mental well-being | 64.47 scores on a scale STANDARD_DEVIATION 16.41 |
| Short Form-36 Health Survey - Pain | 63.15 scores on a scale STANDARD_DEVIATION 22.94 |
| Short Form-36 Health Survey - Physical functioning | 59.26 scores on a scale STANDARD_DEVIATION 23.1 |
| Short Form-36 Health Survey - Physical role function | 39.71 scores on a scale STANDARD_DEVIATION 46.66 |
| Short Form-36 Health Survey - Physical summation score | 50.56 scores on a scale STANDARD_DEVIATION 23.36 |
| Short Form-36 Health Survey - Social functioning | 72.39 scores on a scale STANDARD_DEVIATION 22.05 |
| Short Form-36 Health Survey - Vitality | 43.38 scores on a scale STANDARD_DEVIATION 18.25 |
| Six-minute walking distance (6MWD) test - 6MWD | 387.11 m STANDARD_DEVIATION 81.94 |
| Six-minute walking distance (6MWD) test - Borg dyspnea score | 3.09 scores on a scale STANDARD_DEVIATION 2.1 |
| Six-minute walking distance (6MWD) test - Peripheral Oxygen Saturation (SpO2) (test end) | 89.39 percent STANDARD_DEVIATION 11.61 |
| Vial signs - Heart rate | 73.44 beats/min STANDARD_DEVIATION 8.82 |
| Vital signs - Diastolic blood pressure | 77.13 mmHg STANDARD_DEVIATION 9.56 |
| Vital signs - Peripheral Oxygen Saturation (SpO2) | 96.56 percent STANDARD_DEVIATION 1.41 |
| Vital signs - Systolic blood pressure | 119.50 mmHg STANDARD_DEVIATION 15.27 |
| Weight | 66.84 kg STANDARD_DEVIATION 11.64 |
| World Health Organization Functional Class (WHO FC) I | 0 Participants |
| World Health Organization Functional Class (WHO FC) II | 25 Participants |
| World Health Organization Functional Class (WHO FC) III | 1 Participants |
| World Health Organization Functional Class (WHO FC) IV | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 16 / 17 | 16 / 18 |
| serious Total, serious adverse events | 2 / 17 | 1 / 18 |
Outcome results
None listed