Efficacy and Safety of Riociguat in Patients With Systemic Sclerosis
- Conditions
- Scleroderma, Systemic
- Interventions
- Drug: Riociguat (Adempas, BAY63-2521)Drug: Placebo
- Registration Number
- NCT02283762
- Lead Sponsor
- Bayer
- Brief Summary
To investigate if Riociguat is effective in the treatment of systemic sclerosis
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 121
- Men or women aged 18 years and older
- Systemic sclerosis, as defined by ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) 2013 criteria
- dcSSc (diffuse cutaneous systemic sclerosis) according to the LeRoy criteria, ie, skin fibrosis proximal to the elbows and knees in addition to acral fibrosis
- Disease duration of ≤ 18 months (defined as time from the first non-Raynaud's phenomenon manifestation)
- ≥ 10 and ≤ 22 mRSS (modified Rodnan skin score) units at the screening visit
- FVC (forced vital capacity) ≥ 45% of predicted at screening
- DLCO (diffusion capacity of the lung for carbon monoxide) ≥ 40% of predicted (hemoglobin-corrected) at screening
- Negative serum pregnancy test in a woman of childbearing potential at the screening visit
- Women of childbearing potential must agree to use adequate contraception when sexually active. "Adequate contraception" is defined as any combination of at least 2 effective methods of birth control, of which at least 1 is a physical barrier (e.g. condom with hormonal contraception like implants or combined oral contraceptives, condom with intrauterine devices). This applies since signing of the informed consent form until 30 (+5) days after the last study drug administration.
- Limited cutaneous SSc (systemic sclerosis) at screening
- Major surgery (including joint surgery) within 8 weeks prior to screening
- Hepatic insufficiency classified as Child-Pugh C
- Patients with isolated AST or ALT >3xULN or bilirubin >2xULN can be included in the trial under the condition of additional monitoring during the trial
- Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m^2 (Modification of Diet in Renal Disease formula) or on dialysis at the screening visit. Patients entering the trial with eGFR 15-29 mL/min/1.73 m^2 will be undergo additional monitoring of renal function
- Any prior history of renal crisis
- Sitting SBP (systolic blood pressure) < 95 mmHg at the screening visit
- Sitting heart rate < 50 beats per minute (BPM) at the screening visit
- Left ventricular ejection fraction < 40% prior to screening
- Any form of pulmonary hypertension as determined by right heart catheterization
- Pulmonary disease with FVC < 45% of predicted or DLCO (hemoglobin-corrected) < 40% of predicted at screening
- Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization
- Not permitted prior and concomitant medication
- Pregnant or breast feeding women
- Women of childbearing potential not willing to use adequate contraception and not willing to agree to 4-weekly pregnancy testing from Visit 1 (first administration of study drug) onwards until 30 (+5) days after last study drug intake.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Riociguat Riociguat (Adempas, BAY63-2521) Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period. Placebo Placebo Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.
- Primary Outcome Measures
Name Time Method Change From Baseline in Modified Rodnan Skin Score (mRSS) to Week 52 Baseline to week 52 The mRSS is a validated physical examination method for estimating skin thickness. It correlates with biopsy measures of collagen in the dermis and reflects prognosis and visceral involvement, especially in early disease. It is scored on 0 (normal) to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 (higher score means worse situation) and is used to categorize severity of SSc. A decrease in the mean change of mRSS shows mRSS improved.
- Secondary Outcome Measures
Name Time Method CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 Reported as Number of Participants With a CRISS Probability >=0.60 or <0.60 From Baseline to Week 52 Week 52 CRISS forms a composite response index consisting of SSc-related organ involvement and the following five variables: mRSS, FVC percent predicted, physician's and patient's global assessments, and HAQ-DI score (from SHAQ patient-reported outcome). The resulting index is a 2-step process that captures clinically meaningful worsening of internal organ involvement and the core variables that show change. Patients for whom the predicted CRISS probability was ≥ 0.60 were considered improved, while patients for whom the predicted probability was \< 0.60 were considered not improved.
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score to Week 52 Baseline to week 52 The HAQ-DI is a composite measure from which a 'Standard Disability Index' score can be computed to assess a patient's disability level. Generally, a score of 0-1 represents mild to moderate difficulty, 1-2 moderate to severe disability and 2-3 severe to very severe disability. The HAQ-DI comprises 20 items that assess patient abilities across 8 functional activities: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. Each item is rated on a 4-point scale: 0=Without ANY difficulty, 1=With SOME difficulty, 2=With MUCH difficulty, 3=UNABLE to do. The 8 scores of the 8 sections are summed and divided by 8. In the event that one section is not completed by a subject then the summed score would be divided by 7. The final overall HAQ-DI score ranges from 0 to 3 and positive change indicates worse health-related quality of life (HRQoL).
Change From Baseline in Patient's Global Assessment Score to Week 52 Baseline to week 52 The patient's global assessments (a self-report) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the patient's global assessments score indicates worsening.
Change From Baseline in Physician's Global Assessment Score to Week 52 Baseline to week 52 The physician's global assessments (reported by the physician) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the physician's global assessments score indicates worsening.
Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted to Week 52 Baseline to week 52 Negative change in FVC percent predicted indicates worsening.
Trial Locations
- Locations (59)
Mount Sinai Hospital
🇨🇦Toronto, Ontario, Canada
Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
Hope Hospital
🇬🇧Salford, Manchester, United Kingdom
CU Saint-Luc/UZ St-Luc
🇧🇪Bruxelles - Brussel, Belgium
UZ Leuven Gasthuisberg
🇧🇪Leuven, Belgium
Universitätsspital Basel
🇨🇭Basel, Switzerland
UniversitätsSpital Zürich
🇨🇭Zürich, Switzerland
UZ Gent
🇧🇪Gent, Belgium
Universitätsklinikum Ulm
🇩🇪Ulm, Baden-Württemberg, Germany
Rutgers Robert Wood Johnson Medical School
🇺🇸New Brunswick, New Jersey, United States
St Vincent's Hospital
🇦🇺Fitzroy, Victoria, Australia
Monash Medical Centre
🇦🇺Clayton, Victoria, Australia
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
Debreceni Egyetem Klinikai Kozpont
🇭🇺Debrecen, Hungary
Institute of Rheumatology Tokyo Women's Medical University
🇯🇵Shinjuku-ku, Tokyo, Japan
Memorial Hermann-Texas Medical Center
🇺🇸Houston, Texas, United States
University of Utah Health Care
🇺🇸Salt Lake City, Utah, United States
University of Connecticut Health Center
🇺🇸Farmington, Connecticut, United States
UCLA David Geffen School of Medicine
🇺🇸Los Angeles, California, United States
Mayo Clinic - Scottsdale
🇺🇸Scottsdale, Arizona, United States
Stanford University School of Medicine
🇺🇸Palo Alto, California, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
Hôpital Pellegrin - Bordeaux
🇫🇷Bordeaux, France
CHU STRASBOURG - Hôpital de Hautepierre
🇫🇷Strasbourg, France
Cochin - Paris
🇫🇷Paris, France
Kerckhoff-Klinik GmbH
🇩🇪Bad Nauheim, Hessen, Germany
Universitätsklinikum Köln
🇩🇪Köln, Nordrhein-Westfalen, Germany
A.O.U. Careggi
🇮🇹Firenze, Toscana, Italy
Gunma University Hospital
🇯🇵Maebashi, Gunma, Japan
Hacettepe Universitesi Tip Fakultesi
🇹🇷Ankara, Turkey
Aintree University Hospital
🇬🇧Liverpool, United Kingdom
A.O. di Padova
🇮🇹Padova, Veneto, Italy
Liverpool Hospital
🇦🇺Liverpool, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
St. Joseph's Healthcare - Hamilton
🇨🇦Hamilton, Ontario, Canada
Sir Mortimer B. Davis Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Revmatologicky ustav
🇨🇿Praha 2, Czechia
Arthritis Program Research Group, Inc.
🇨🇦Newmarket, Ontario, Canada
Centre Hospitalier Universitaire - Grenoble
🇫🇷Grenoble, France
Hopital Claude-Huriez CHRU
🇫🇷Lille, France
Universitätsklinikum Erlangen
🇩🇪Erlangen, Bayern, Germany
A.O.U. di Cagliari
🇮🇹Cagliari, Sardegna, Italy
A.O.U. Policlinico Umberto I
🇮🇹Roma, Lazio, Italy
Pecsi Tudomanyegyetem Klinikai Kozpont
🇭🇺Pecs, Hungary
A.O.U. Pisana
🇮🇹Pisa, Toscana, Italy
Hokkaido University Hospital
🇯🇵Sapporo, Hokkaido, Japan
Tohoku University Hospital
🇯🇵Sendai, Miyagi, Japan
Nippon Medical School Hospital
🇯🇵Bunkyo-ku, Tokyo, Japan
Universitair Medisch Centrum St. Radboud
🇳🇱Nijmegen, Netherlands
Wellington Hospital
🇳🇿Wellington, New Zealand
Kantonsspital St. Gallen
🇨🇭St. Gallen, Sankt Gallen, Switzerland
Cukurova Univ. Tip. Fak. Balcali Hastanesi
🇹🇷Adana, Turkey
Dokuz Eylul Universitesi Tip Fakultesi
🇹🇷Izmir, Turkey
Istanbul Universitesi Istanbul Tip Fakultesi
🇹🇷Istanbul, Turkey
Freeman Hospital
🇬🇧Newcastle Upon Tyne, Tyne And Wear, United Kingdom
Ninewells Hospital
🇬🇧Dundee, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
Medical University of South Carolina Medical Center
🇺🇸Charleston, South Carolina, United States
University Medical Center Utrecht
🇳🇱Utrecht, Netherlands