Efficacy and Safety of Riociguat in Patients With Systemic Sclerosis

Phase 2

Completed

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

Inclusion Criteria

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.

Exclusion Criteria

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): Mayo Clinic - Scottsdale
🇺🇸
Scottsdale, Arizona, United States
UCLA David Geffen School of Medicine
🇺🇸
Los Angeles, California, United States
Stanford University School of Medicine
🇺🇸
Palo Alto, California, United States
University of Connecticut Health Center
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Farmington, Connecticut, United States
Georgetown University Medical Center
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Washington, District of Columbia, United States
University of Michigan Health System
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Ann Arbor, Michigan, United States
Rutgers Robert Wood Johnson Medical School
🇺🇸
New Brunswick, New Jersey, United States
Medical University of South Carolina Medical Center
🇺🇸
Charleston, South Carolina, United States
Memorial Hermann-Texas Medical Center
🇺🇸
Houston, Texas, United States
University of Utah Health Care
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Salt Lake City, Utah, United States
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Mayo Clinic - Scottsdale
🇺🇸Scottsdale, Arizona, United States