Efficacy and Safety of Riociguat in Patients With Systemic Sclerosis

A Randomized, Double-Blind, Placebo-Controlled Phase II Study to Investigate the Efficacy and Safety of Riociguat in Patients With Diffuse Cutaneous Systemic Sclerosis (dcSSc)

To investigate if Riociguat is effective in the treatment of systemic sclerosis

Study Overview

• Status: Completed
• Conditions: Scleroderma, Systemic
• Intervention / Treatment: Drug: Riociguat (Adempas, BAY63-2521); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Belgium
  • Bruxelles - Brussel, Belgium, 1200
    • CU Saint-Luc/UZ St-Luc
  • Gent, Belgium, 9000
    • UZ Gent
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 1Y2
      • St. Joseph's Healthcare - Hamilton
    • Newmarket, Ontario, Canada, L3Y 3R7
      • Arthritis Program Research Group, Inc.
    • Toronto, Ontario, Canada, M5T 3L9
      • Mount Sinai Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T1E2
      • Sir Mortimer B. Davis Jewish General Hospital
• Czechia
  • Praha 2, Czechia, 128 50
    • Revmatologicky ustav
• France
  • Bordeaux, France, 33000
    • Hôpital Pellegrin - Bordeaux
  • Grenoble, France, 38043
    • Centre Hospitalier Universitaire - Grenoble
  • Lille, France, 59037
    • Hopital Claude-Huriez CHRU
  • Paris, France, 75674
    • Cochin - Paris
  • Strasbourg, France, 67098
    • Chu Strasbourg - Hôpital de Hautepierre
• Germany
  • Baden-Württemberg
    • Ulm, Baden-Württemberg, Germany, 89081
      • Universitätsklinikum Ulm
  • Bayern
    • Erlangen, Bayern, Germany, 91054
      • Universitätsklinikum Erlangen
  • Hessen
    • Bad Nauheim, Hessen, Germany, 61231
      • Kerckhoff-Klinik GmbH
  • Nordrhein-Westfalen
    • Köln, Nordrhein-Westfalen, Germany, 50937
      • Universitätsklinikum Köln
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont
  • Pecs, Hungary, 7632
    • Pecsi Tudomanyegyetem Klinikai Kozpont
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00161
      • A.O.U. Policlinico Umberto I
  • Sardegna
    • Cagliari, Sardegna, Italy, 09042
      • A.O.U. di Cagliari
  • Toscana
    • Firenze, Toscana, Italy, 50139
      • A.O.U. Careggi
    • Pisa, Toscana, Italy, 56126
      • A.O.U. Pisana
  • Veneto
    • Padova, Veneto, Italy, 35128
      • A.O. di Padova
• Japan
  • Gunma
    • Maebashi, Gunma, Japan, 371-8511
      • Gunma University Hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University Hospital
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8603
      • Nippon Medical School Hospital
    • Shinjuku-ku, Tokyo, Japan, 162-0054
      • Institute of Rheumatology Tokyo Women's Medical University
• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • Universitair Medisch Centrum St. Radboud
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• New Zealand
  • Wellington, New Zealand, 6021
    • Wellington Hospital
• Switzerland
  • Basel, Switzerland
    • Universitätsspital Basel
  • Zürich, Switzerland, 8091
    • Universitatsspital Zurich
  • Sankt Gallen
    • St. Gallen, Sankt Gallen, Switzerland, 9007
      • Kantonsspital St. Gallen
• Turkey
  • Adana, Turkey, 01330
    • Cukurova Univ. Tip. Fak. Balcali Hastanesi
  • Ankara, Turkey
    • Hacettepe Universitesi Tip Fakultesi
  • Istanbul, Turkey, 34093
    • Istanbul Universitesi Istanbul Tip Fakultesi
  • Izmir, Turkey, 35340
    • Dokuz Eylul Universitesi Tip Fakultesi
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Ninewells Hospital
  • Liverpool, United Kingdom, L9 7AL
    • Aintree University Hospital
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • Manchester
    • Salford, Manchester, United Kingdom, M6 8HD
      • Hope Hospital
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN
      • Freeman Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259-5404
      • Mayo Clinic - Scottsdale
  • California
    • Los Angeles, California, United States, 90095-1670
      • UCLA David Geffen School of Medicine
    • Palo Alto, California, United States, 94304
      • Stanford University School of Medicine
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Robert Wood Johnson Medical School
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Memorial Hermann-Texas Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Riociguat; 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.	Drug: Riociguat (Adempas, BAY63-2521); Starting dose 0.5 mg TID, increase by 0.5 mg every 2 weeks until highest possible dose of 2.5 mg TID
Placebo Comparator: 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.	Drug: Placebo; Sham-titration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Modified Rodnan Skin Score (mRSS) 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.	Baseline to week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Week 52
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score 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).	Baseline to week 52
Change From Baseline in Patient's Global Assessment Score 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.	Baseline to week 52
Change From Baseline in Physician's Global Assessment Score 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.	Baseline to week 52
Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted to Week 52	Negative change in FVC percent predicted indicates worsening.	Baseline to week 52

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Distler O, Pope J, Denton C, Allanore Y, Matucci-Cerinic M, de Oliveira Pena J, Khanna D. RISE-SSc: Riociguat in diffuse cutaneous systemic sclerosis. Respir Med. 2017 Jan;122 Suppl 1:S14-S17. doi: 10.1016/j.rmed.2016.09.011. Epub 2016 Sep 28.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
• Click here to find results for studies related to Bayer products

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2015
• Primary Completion (Actual): December 15, 2017
• Study Completion (Actual): March 28, 2019

Study Registration Dates

• First Submitted: November 3, 2014
• First Submitted That Met QC Criteria: November 3, 2014
• First Posted (Estimate): November 5, 2014

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: January 17, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Connective Tissue Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: 16277; 2014-001353-16 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No