Efficacy and Safety of Riociguat in Patients With Systemi... | NCT02283762

ID	Type	Description	Link
2014-001353-16	EudraCT Number

Label	Type	Description	Intervention Names
Riociguat	Experimental	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)
Placebo	Placebo Comparator	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

Name	Type	Description	Arm Group Labels	Other Names
Riociguat (Adempas, BAY63-2521)	Drug	Starting dose 0.5 mg TID, increase by 0.5 mg every 2 weeks until highest possible dose of 2.5 mg TID	Riociguat

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

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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
Bayer Study Director	Bayer	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic - Scottsdale		Scottsdale	Arizona	85259-5404	United States
UCLA David Geffen School of Medicine

PubMed Identifier	Type	Citation	Retractions
27746061	Background	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.
38460548	Derived	Khanna D, Kramer F, Hofler J, Ghadessi M, Sandner P, Allanore Y, Denton CP, Kuwana M, Matucci-Cerinic M, Pope JE, Atsumi T, Becvar R, Czirjak L, De Langhe E, Hachulla E, Ishii T, Ishikawa O, Johnson SR, Riccieri V, Schiopu E, Silver RM, Smith V, Stagnaro C, Steen V, Stevens W, Szucs G, Truchetet ME, Wosnitza M, Distler O. Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis. Rheumatology (Oxford). 2024 Nov 1;63(11):3124-3134. doi: 10.1093/rheumatology/keae150.

Label	URL
Click here to find information about studies related to Bayer Healthcare products conducted in Europe.	View source

ID	Title	Description
FG000	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 17, 2018	Nov 29, 2018

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Full analysis set (FAS: all participants randomized and treated with study medication) with evaluable data for this outcome measure.

Posted

Mean

Standard Deviation

score on a scale

Baseline to week 52

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants	OG00057 OG00152

Title

Denominators

Categories

Title	Measurements
	OG000-2.088± 5.658 OG001-0.769± 8.243

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		MMRM (Method 1)		0.0815		Difference of LS means	-2.34			2-Sided	95	-4.99	0.30					Superiority

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.

Full analysis set (FAS)

Posted

Count of Participants

Participants

Week 52

ID	Title	Description
OG000	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.
OG001	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.

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).

FAS with evaluable data for this outcome measure.

Posted

Mean

Standard Deviation

score on a scale

Baseline to week 52

ID	Title	Description
OG000	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.
OG001

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.

FAS with evaluable data for this outcome measure.

Posted

Mean

Standard Deviation

score on a scale

Baseline to week 52

ID	Title	Description
OG000	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.
OG001	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.

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.

FAS with evaluable data for this outcome measure.

Posted

Mean

Standard Deviation

score on a scale

Baseline to week 52

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted to Week 52

Negative change in FVC percent predicted indicates worsening.

FAS with evaluable data for this outcome measure.

Posted

Mean

Standard Deviation

FVC percent predicted

Baseline to week 52

ID	Title	Description
OG000	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.
OG001	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Riociguat-Riociguat (LTE Phase)	Main treatment phase: 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 from Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.	0	42	10	42	38	42
EG001	Placebo-Riociguat (LTE Phase)	Main treatment phase: 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 from 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.	0	45	11	45	39	45
EG002	Riociguat (Main Treatment Phase)	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.	1	60	9	60	55	60
EG003	Placebo (Main Treatment Phase)	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.	1	61	15	61	49	61

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG0031 events1 affected61 at risk
Angina pectoris	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0002 events1 affected42 at risk EG0010 events0 affected45 at risk EG0022 events1 affected60 at risk EG003
Left ventricular failure	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Pericarditis	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Ventricular tachycardia	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0023 events1 affected60 at risk EG003
Gastric haemorrhage	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Intestinal pseudo-obstruction	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Inflammation	General disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Infected skin ulcer	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Pneumonia	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0012 events1 affected45 at risk EG0021 events1 affected60 at risk EG003
Lung infection	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Exposure during pregnancy	Injury, poisoning and procedural complications	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Osteolysis	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Scleroderma	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Musculoskeletal discomfort	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Adenocarcinoma gastric	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Ovarian cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Intraductal proliferative breast lesion	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Cerebellar infarction	Nervous system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Syncope	Nervous system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Scleroderma renal crisis	Renal and urinary disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Acute pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Skin ulcer	Skin and subcutaneous tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Prophylaxis	Surgical and medical procedures	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Raynaud's phenomenon	Vascular disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Cardiac failure	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0012 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Extrasystoles	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Tachycardia	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Diverticulum intestinal	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Haematemesis	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Ileus	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0013 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Intestinal obstruction	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0002 events1 affected42 at risk EG0012 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Subileus	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0012 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Appendicitis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Localised infection	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Postoperative wound infection	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Salpingitis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Sepsis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Staphylococcal infection	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0002 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Bursitis infective	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Device related sepsis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Medical device site joint infection	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Hand fracture	Injury, poisoning and procedural complications	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Ultrasound kidney abnormal	Investigations	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Fluid overload	Metabolism and nutrition disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Cervical spinal stenosis	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Spinal osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Chondropathy	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Systemic scleroderma	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0016 events2 affected45 at risk EG0020 events0 affected60 at risk EG003
Tongue neoplasm malignant stage unspecified	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0011 events1 affected45 at risk EG0020 events0 affected60 at risk EG003
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Rhinoplasty	Surgical and medical procedures	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Large intestinal polypectomy	Surgical and medical procedures	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Hypertension	Vascular disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Palpitations	Cardiac disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0011 events1 affected45 at risk EG0028 events8 affected60 at risk EG0033 events3 affected61 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0016 events4 affected45 at risk EG0025 events4 affected60 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0013 events1 affected45 at risk EG0022 events2 affected60 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0005 events4 affected42 at risk EG0012 events2 affected45 at risk EG0023 events3 affected60 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG00011 events5 affected42 at risk EG00123 events8 affected45 at risk EG00215 events10 affected60 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0012 events2 affected45 at risk EG0024 events4 affected60 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0013 events2 affected45 at risk EG0027 events7 affected60 at risk EG003
Dysphagia	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0011 events1 affected45 at risk EG0027 events6 affected60 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0007 events7 affected42 at risk EG0018 events8 affected45 at risk EG00216 events15 affected60 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0005 events2 affected42 at risk EG0017 events6 affected45 at risk EG0029 events7 affected60 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG00011 events7 affected42 at risk EG00114 events4 affected45 at risk EG00214 events8 affected60 at risk EG003
Asthenia	General disorders	MedDRA (20.1)	Non-systematic Assessment	EG0002 events2 affected42 at risk EG0011 events1 affected45 at risk EG0026 events3 affected60 at risk EG003
Fatigue	General disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0014 events4 affected45 at risk EG0027 events7 affected60 at risk EG003
Oedema peripheral	General disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0013 events3 affected45 at risk EG0027 events6 affected60 at risk EG003
Pain	General disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0011 events1 affected45 at risk EG0024 events3 affected60 at risk EG003
Pyrexia	General disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0011 events1 affected45 at risk EG0022 events2 affected60 at risk EG003
Peripheral swelling	General disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0026 events5 affected60 at risk EG003
Bronchitis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0006 events5 affected42 at risk EG0010 events0 affected45 at risk EG0023 events3 affected60 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG00013 events11 affected42 at risk EG00110 events10 affected45 at risk EG0027 events5 affected60 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG00010 events7 affected42 at risk EG0017 events6 affected45 at risk EG0025 events4 affected60 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0007 events2 affected42 at risk EG0014 events3 affected45 at risk EG0025 events4 affected60 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0005 events4 affected42 at risk EG0016 events6 affected45 at risk EG00214 events12 affected60 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0002 events2 affected42 at risk EG0011 events1 affected45 at risk EG0023 events3 affected60 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events2 affected42 at risk EG0012 events2 affected45 at risk EG0026 events4 affected60 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0004 events4 affected42 at risk EG0013 events2 affected45 at risk EG0026 events4 affected60 at risk EG003
Dizziness	Nervous system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0017 events6 affected45 at risk EG00221 events13 affected60 at risk EG003
Headache	Nervous system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0004 events3 affected42 at risk EG0014 events4 affected45 at risk EG00212 events11 affected60 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0012 events2 affected45 at risk EG0021 events1 affected60 at risk EG003
Insomnia	Psychiatric disorders	MedDRA (20.1)	Non-systematic Assessment	EG0002 events2 affected42 at risk EG0010 events0 affected45 at risk EG0023 events3 affected60 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0006 events6 affected42 at risk EG0014 events3 affected45 at risk EG0029 events9 affected60 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0014 events3 affected45 at risk EG0029 events8 affected60 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0002 events2 affected42 at risk EG0011 events1 affected45 at risk EG0025 events4 affected60 at risk EG003
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0006 events5 affected42 at risk EG0015 events5 affected45 at risk EG0024 events4 affected60 at risk EG003
Eczema	Skin and subcutaneous tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0002 events2 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Erythema	Skin and subcutaneous tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0024 events3 affected60 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0026 events5 affected60 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0001 events1 affected42 at risk EG0010 events0 affected45 at risk EG0024 events3 affected60 at risk EG003
Skin ulcer	Skin and subcutaneous tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0007 events6 affected42 at risk EG0014 events4 affected45 at risk EG0024 events4 affected60 at risk EG003
Hypertension	Vascular disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Hypotension	Vascular disorders	MedDRA (20.1)	Non-systematic Assessment	EG0006 events5 affected42 at risk EG0019 events7 affected45 at risk EG0027 events7 affected60 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0014 events4 affected45 at risk EG0022 events2 affected60 at risk EG003
Iron deficiency anaemia	Blood and lymphatic system disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0010 events0 affected45 at risk EG0021 events1 affected60 at risk EG003
Mouth ulceration	Gastrointestinal disorders	MedDRA (20.1)	Non-systematic Assessment	EG0004 events3 affected42 at risk EG0010 events0 affected45 at risk EG0020 events0 affected60 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0002 events2 affected42 at risk EG0016 events5 affected45 at risk EG0021 events1 affected60 at risk EG003
Influenza	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0015 events4 affected45 at risk EG0022 events2 affected60 at risk EG003
Pneumonia	Infections and infestations	MedDRA (20.1)	Non-systematic Assessment	EG0003 events3 affected42 at risk EG0010 events0 affected45 at risk EG0022 events1 affected60 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA (20.1)	Non-systematic Assessment	EG0002 events2 affected42 at risk EG0013 events3 affected45 at risk EG0021 events1 affected60 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0014 events3 affected45 at risk EG0020 events0 affected60 at risk EG003
Bursitis	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0003 events2 affected42 at risk EG0013 events3 affected45 at risk EG0022 events2 affected60 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0005 events4 affected42 at risk EG0012 events2 affected45 at risk EG0021 events1 affected60 at risk EG003
Urticaria	Skin and subcutaneous tissue disorders	MedDRA (20.1)	Non-systematic Assessment	EG0000 events0 affected42 at risk EG0014 events3 affected45 at risk EG0022 events2 affected60 at risk EG003

ID	Term
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases
D012871	Skin Diseases

ID	Title	Description
BG000	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.
BG001	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.
BG002	Total	Total of all reporting groups