Efficacy and Safety of Riociguat in Patients With Systemic Sclerosis

Scleroderma, Systemic Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02283762
• Other study ID #: 16277
• Secondary ID: 2014-001353-16
• Status: Completed
• Phase: Phase 2
• Start date: January 15, 2015
• Est. completion date: March 28, 2019

Study information

• Verified date: January 2020
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: March 28, 2019
• Est. primary completion date: December 15, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Scleroderma, Diffuse
• Scleroderma, Systemic

Intervention

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
Sham-titration

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Monash Medical Centre	Clayton	Victoria
Australia	St Vincent's Hospital	Fitzroy	Victoria
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Royal Perth Hospital	Perth	Western Australia
Belgium	CU Saint-Luc/UZ St-Luc	Bruxelles - Brussel
Belgium	UZ Gent	Gent
Belgium	UZ Leuven Gasthuisberg	Leuven
Canada	St. Joseph's Healthcare - Hamilton	Hamilton	Ontario
Canada	Sir Mortimer B. Davis Jewish General Hospital	Montreal	Quebec
Canada	Arthritis Program Research Group, Inc.	Newmarket	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Czechia	Revmatologicky ustav	Praha 2
France	Hôpital Pellegrin - Bordeaux	Bordeaux
France	Centre Hospitalier Universitaire - Grenoble	Grenoble
France	Hopital Claude-Huriez CHRU	Lille
France	Cochin - Paris	Paris
France	CHU STRASBOURG - Hôpital de Hautepierre	Strasbourg
Germany	Kerckhoff-Klinik GmbH	Bad Nauheim	Hessen
Germany	Universitätsklinikum Erlangen	Erlangen	Bayern
Germany	Universitätsklinikum Köln	Köln	Nordrhein-Westfalen
Germany	Universitätsklinikum Ulm	Ulm	Baden-Württemberg
Hungary	Debreceni Egyetem Klinikai Kozpont	Debrecen
Hungary	Pecsi Tudomanyegyetem Klinikai Kozpont	Pecs
Italy	A.O.U. di Cagliari	Cagliari	Sardegna
Italy	A.O.U. Careggi	Firenze	Toscana
Italy	A.O. di Padova	Padova	Veneto
Italy	A.O.U. Pisana	Pisa	Toscana
Italy	A.O.U. Policlinico Umberto I	Roma	Lazio
Japan	Nippon Medical School Hospital	Bunkyo-ku	Tokyo
Japan	Gunma University Hospital	Maebashi	Gunma
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Japan	Tohoku University Hospital	Sendai	Miyagi
Japan	Institute of Rheumatology Tokyo Women's Medical University	Shinjuku-ku	Tokyo
Netherlands	Universitair Medisch Centrum St. Radboud	Nijmegen
Netherlands	University Medical Center Utrecht	Utrecht
New Zealand	Wellington Hospital	Wellington
Switzerland	Universitätsspital Basel	Basel
Switzerland	Kantonsspital St. Gallen	St. Gallen	Sankt Gallen
Switzerland	UniversitätsSpital Zürich	Zürich
Turkey	Cukurova Univ. Tip. Fak. Balcali Hastanesi	Adana
Turkey	Hacettepe Universitesi Tip Fakultesi	Ankara
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi	Istanbul
Turkey	Dokuz Eylul Universitesi Tip Fakultesi	Izmir
United Kingdom	Ninewells Hospital	Dundee
United Kingdom	Aintree University Hospital	Liverpool
United Kingdom	Royal Free Hospital	London
United Kingdom	Freeman Hospital	Newcastle Upon Tyne	Tyne And Wear
United Kingdom	Hope Hospital	Salford	Manchester
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Medical University of South Carolina Medical Center	Charleston	South Carolina
United States	University of Connecticut Health Center	Farmington	Connecticut
United States	Memorial Hermann-Texas Medical Center	Houston	Texas
United States	UCLA David Geffen School of Medicine	Los Angeles	California
United States	Rutgers Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Stanford University School of Medicine	Palo Alto	California
United States	University of Utah Health Care	Salt Lake City	Utah
United States	Mayo Clinic - Scottsdale	Scottsdale	Arizona
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  France,  Germany,  Hungary,  Italy,  Japan,  Netherlands,  New Zealand,  Switzerland,  Turkey,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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