A Multi-Center Study of Riociguat in Patients With Sickle... | NCT02633397

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Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Label	Type	Description	Intervention Names
Riociguat	Experimental	Treatment Arm	Drug: Riociguat
Placebo	Placebo Comparator	Placebo Arm	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Riociguat	Drug	Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks	Riociguat

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)	The primary endpoint was the proportion of participants who experienced at least 1 treatment-emergent serious adverse event (SAE), which was defined as any event occurring after the baseline visit (i.e., after initiation of study drug), adjudicated by a designated committee of protocol investigators and outside experts. SAEs were considered to be treatment-emergent if they started or worsened after the first dose of study medication and up to 7 days after end of study treatment.	Baseline through 7 days after discontinuation of treatment, up to 13 Weeks

Secondary Outcomes

Measure	Description	Time Frame
Frequency of SAE Due to Sickle Cell Related Painful Crisis	The proportion of participants with treatment-emergent SAE for sickle-cell related crises (Vaso-occlusive crises)	Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
Overall Incidences of Treatment-emergent Adverse Events (AEs)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Age ≥ 18 years
Sickling disorder (HbSS, HbSC, HbSbeta-thalassemia, HbSD, HbSO-Arab documented by hemoglobin electrophoresis or HPLC fractionation)
At least one of the following findings: a. Systolic blood pressure ≥ 130 mm Hg on at least two occasions at least 1 day apart (one of these may be by history), b. Macroalbuminuria as manifested by urine albumin to creatinine ratio > 300 mg/g, c. Tricuspid regurgitant velocity (TRV) > 2.9 m/sec measured by echocardiography d. NT-proBNP level ≥ 160 pg/mL e. Urinalysis protein 1 + or higher.
Females of reproductive potential (FRP) must have a negative, pre-treatment pregnancy test. Post-menopausal women (defined as no menses for at least 1 year or post-surgical from bilateral oophorectomy) are not required to undergo a pregnancy test.
Females of reproductive potential must agree to use reliable contraception when sexually active. Adequate contraception is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required beginning at the signing of the informed consent form until one month after the last dose of riociguat.
Patients must be willing to provide a blood sample for DNA analysis.

Exclusion Criteria:

Pregnant or breast feeding women
Patients with severe hepatic impairment defined as Child Pugh C
End stage renal disease requiring dialysis
Patients with eGFR <30 mL/min/1.73m, where GFR is estimated based on CKD-epi equation
Patients on phosphodiesterase type 5 inhibitors (PDE-5) (such as sildenafil, tadalafil, vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline) or nitrates
Patients on strong cytochrome P450 (CYP) and P-glycoprotein 1(P-gp)/BCRP inhibitors such as systemic azole antimycotics (eg: ketoconazole, itraconazole), or HIV protease inhibitors (such as ritonavir)
Patients on St. John's Wort
If patients are taking antihypertensive drugs, hydroxyurea, L-glutamine, crizanlizumab, or voxelotor prior to enrollment, they are excluded until the dose level is stable for at least three months
Systolic blood pressure <95 mm Hg at Screening Visit 1 or 2 or Week 0 before randomization
Current enrollment in an investigational new drug trial. Patients are eligible for enrollment 30 days after the last dose of an investigational drug has been received
Evidence of qualitative urine drug test at screening for cocaine, phencyclidine (PCP), heroin, or amphetamines within three months prior to enrollment
Patients who have recently (last six months) experienced serious bleeding from the lung or have undergone a bronchial arterial embolization procedure.
Pulmonary hypertension associated with Idiopathic Interstitial Pneumonias
Medical disorder, condition, or history that in the investigator's judgment would impair the patient's ability to participate or complete this study or render the patient to be inappropriate for enrollment

Contacts/Locations Module

Name	Affiliation	Role
Mark Gladwin, MD	University of Pittsburgh	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
UCSF Benioff Children's Hospital Oakland		Oakland	California	94609	United States
Howard University

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
42418684	Derived	Wood KC, Nouraie SM, Gladwin MT, Novelli EM, Gordeuk VR, Morris CR, Minniti CP, Ataga KI, Desai PC, Abebe KZ, Straub AC. The CYB5R3 T117S Missense Variant is Associated with Attenuated Riociguat Efficacy in Sickle Cell Disease. Blood. 2026 Jul 8:blood.2026034193. doi: 10.1182/blood.2026034193. Online ahead of print.
38554715	Derived

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
FG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Jan 7, 2020

Derived Section

Miscellaneous Info Module

Submission Tracking

Condition Browse Module

Intervention Browse Module

Masking Info

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
BG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Age at screening

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG00015 OG00120

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	P- Value was the exact logistic regression adjusted for clinical site.	Regression, Logistic		0.19														Superiority

Secondary

Frequency of SAE Due to Sickle Cell Related Painful Crisis

The proportion of participants with treatment-emergent SAE for sickle-cell related crises (Vaso-occlusive crises)

Posted

Count of Participants

Participants

Baseline through 7 days after discontinuation of treatment, up to 13 Weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Overall Incidences of Treatment-emergent Adverse Events (AEs)

Proportion of participants that experienced treatment-emergent AEs

Posted

Count of Participants

Participants

Baseline to Week 12

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Incidences of Sickle Cell Related Clinical Complications

Incidence of Vaso-occlusive Crisis (VOC) between baseline and week 12

Posted

Count of Participants

Participants

Baseline to Week 12

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Pain Intensity Using the Brief Pain Inventory

Brief Pain Inventory (BPI) short form - score ranges from 0 (no pain) to 10 (Pain as bad as you can imagine)

Mean at 12 weeks assessed using ANCOVA adjusting for baseline.

Posted

Mean

90% Confidence Interval

score on a scale

Baseline, 12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

6-minute Walk Distance

6-minute walk distance was used to assess functional exercise capacity

Mean at 12 weeks assessed using ANCOVA adjusting for baseline.

Posted

Mean

90% Confidence Interval

meters

Baseline, 12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in the Dyspnea Borg Scale

Baseline to 12 weeks mean change of the Borg dyspnea scores, post 6MWT, using a linear regression model.

Dyspnea Borg score was used to measure the level of severity of breathlessness perceived by the patient at the end of the 6MWD Test. The severity is measured on a 10-point scale with 0= nothing at all and 10=maximum severity of breathlessness.

Posted

Mean

90% Confidence Interval

score on a scale

Baseline,12 Weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Fatigue Borg Scale

Fatigue Borg score was used to rank the participant's exertion at the end of the 6MWD Test. The rate of exertion was given according to a scale ranging from 0 (nothing at all) to 10=maximum severity of exertion

Mean at 12 weeks assessed using ANCOVA adjusting for baseline.

Posted

Mean

90% Confidence Interval

score on a scale

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in Blood Pressure as the Main Pharmacodynamic (MAP)

Baseline to 12 weeks mean change of MAP, estimated with a repeated measures analysis (Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks) using a linear mixed model.

Posted

Mean

90% Confidence Interval

mmHg

Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography

Mean TRV at 12 weeks assessed using ANCOVA, adjusting for baseline.

Posted

Mean

90% Confidence Interval

m/s

Baseline, 12 Weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

End-systolic Volume Using Non-invasive Echocardiography

Mean end-systolic volume (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.

Posted

Mean

90% Confidence Interval

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Ejection Fraction (Biplane) Using Non-invasive Echocardiography

Mean ejection fraction (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.

Posted

Mean

90% Confidence Interval

percentage

Baseline, 12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in the Levels of Plasma NT-proBNP

Mean Change in the levels of plasma NT-proBNP from baseline to 12 weeks using a linear regression model.

Posted

Mean

90% Confidence Interval

pg/mL

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in Albumin/Creatinine Ratio

Albumin/Creatinine Ratio (ACR) mean change from baseline to 12 weeks using linear regression model.

Posted

Mean

90% Confidence Interval

mg/g

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Microalbuminuria

Odds ratio per week of microalbuminuria estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope

Participants with undetectable ACR or macroalbuminuria (>300 ACR) were excluded

Posted

Number

90% Confidence Interval

odds ratio

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Macroalbuminuria

Odds ratio per week of macroalbuminuria estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope.

Participants with undetectable ACR or microalbuminuria (30-300 ACR) were excluded

Posted

Number

90% Confidence Interval

odds ratio

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in Glomerular Filtration Rate

Mean change in GFR to 12 weeks, estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.

Posted

Mean

90% Confidence Interval

ml/min/1.73 m²

Baseline, 4 weeks, 8 weeks, 12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk

Odds ratio (OR) per week of low-risk CKD stage versus at least moderately increased risk (includes moderately increased risk CKD, high increased risk CKD, and very high increased risk CKD) estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope

Posted

Number

90% Confidence Interval

odds ratio

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in Hemoglobin

Mean change in hemoglobin to 12 weeks, estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.

Posted

Mean

90% Confidence Interval

g/dL

Baseline, 4 weeks, 8 weeks,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in Reticulocyte Count

Mean change in reticulocyte count to 12 weeks, estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.

Posted

Mean

90% Confidence Interval

percentage

Baseline, 4 weeks, 8 weeks,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in White Blood Cell Count

Mean change in White Blood Cell count to 12 weeks estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.

Posted

Mean

90% Confidence Interval

(x10^9 cells/L)

Baseline, 4 weeks, 8 weeks,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in Lactate Dehydrogenase (LDH)

Mean change in LDH to 12 weeks estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.

Posted

Mean

90% Confidence Interval

U/L

Baseline, 4 weeks, 8 weeks,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

Secondary

Changes in Fetal Hemoglobin

Mean change in fetal hemoglobin from baseline to 12 weeks using a linear mixed model

Posted

Mean

90% Confidence Interval

Percentage

Baseline,12 weeks

ID	Title	Description
OG000	Riociguat	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
OG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks

Units	Counts
Participants	OG000

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	Treatment Arm Riociguat: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks	2	66	15	66	53	66
EG001	Placebo	Placebo Arm Placebo: Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks	2	64	20	64	45	64

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
VOC	General disorders	Non-systematic Assessment	EG00017 events11 affected66 at risk EG00123 events14 affected64 at risk
Cardiac Arrest	Cardiac disorders	Non-systematic Assessment	EG0001 events1 affected66 at risk EG0010 events0 affected64 at risk
Mitral Valve Disease	Cardiac disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk
Supraventricular Tachycardia	Cardiac disorders	Non-systematic Assessment	EG0001 events1 affected66 at risk EG0010 events0 affected64 at risk
Lung Infection	Infections and infestations	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk
Skin Infection	Infections and infestations	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk
Upper Respiratory Infection	Infections and infestations	Non-systematic Assessment	EG0001 events1 affected66 at risk EG0010 events0 affected64 at risk
Acute Kidney Injury	Renal and urinary disorders	Non-systematic Assessment	EG0001 events1 affected66 at risk EG0010 events0 affected64 at risk
Other - Pyelonephritis	Renal and urinary disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk
Thrombotic Thrombocytopenic Purpura	Blood and lymphatic system disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk
Other - Dizziness	Endocrine disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk
Lethargy	Nervous system disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk
Cough	Respiratory, thoracic and mediastinal disorders	Non-systematic Assessment	EG0001 events1 affected66 at risk EG0010 events0 affected64 at risk
Other - Papilledema	Vascular disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0011 events1 affected64 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
VOC	General disorders	Non-systematic Assessment	EG00065 events23 affected66 at risk EG00146 events21 affected64 at risk
Malaise	General disorders	Non-systematic Assessment	EG0003 events3 affected66 at risk EG0013 events3 affected64 at risk
Fatigue	General disorders	Non-systematic Assessment	EG0003 events3 affected66 at risk EG0012 events2 affected64 at risk
Edema Limbs	General disorders	Non-systematic Assessment	EG0004 events4 affected66 at risk EG0010 events0 affected64 at risk
Diarrhea	Gastrointestinal disorders	Non-systematic Assessment	EG00011 events9 affected66 at risk EG0019 events8 affected64 at risk
Nausea	Gastrointestinal disorders	Non-systematic Assessment	EG0008 events7 affected66 at risk EG0013 events3 affected64 at risk
Abdominal Pain	Gastrointestinal disorders	Non-systematic Assessment	EG0005 events4 affected66 at risk EG0015 events4 affected64 at risk
Gastroesophageal Reflux Disease	Gastrointestinal disorders	Non-systematic Assessment	EG0008 events8 affected66 at risk EG0011 events1 affected64 at risk
Vomiting	Gastrointestinal disorders	Non-systematic Assessment	EG0006 events6 affected66 at risk EG0012 events2 affected64 at risk
Dry Mouth	Gastrointestinal disorders	Non-systematic Assessment	EG0003 events3 affected66 at risk EG0012 events2 affected64 at risk
Constipation	Gastrointestinal disorders	Non-systematic Assessment	EG0003 events3 affected66 at risk EG0011 events1 affected64 at risk
Other	Gastrointestinal disorders	Non-systematic Assessment	EG0003 events3 affected66 at risk EG0011 events1 affected64 at risk
Headache	Nervous system disorders	Non-systematic Assessment	EG00016 events14 affected66 at risk EG0017 events6 affected64 at risk
Dizziness	Nervous system disorders	Non-systematic Assessment	EG0009 events8 affected66 at risk EG0014 events3 affected64 at risk
Other	Musculoskeletal and connective tissue disorders	Non-systematic Assessment	EG00015 events9 affected66 at risk EG00114 events10 affected64 at risk
Pain In Extremity	Musculoskeletal and connective tissue disorders	Non-systematic Assessment	EG0003 events2 affected66 at risk EG0014 events3 affected64 at risk
Myalgia	Musculoskeletal and connective tissue disorders	Non-systematic Assessment	EG0005 events3 affected66 at risk EG0011 events1 affected64 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0013 events3 affected64 at risk
Cough	Respiratory, thoracic and mediastinal disorders	Non-systematic Assessment	EG0005 events5 affected66 at risk EG0011 events1 affected64 at risk
Dyspnea	Respiratory, thoracic and mediastinal disorders	Non-systematic Assessment	EG0003 events3 affected66 at risk EG0010 events0 affected64 at risk
Palpitations	Cardiac disorders	Non-systematic Assessment	EG0005 events5 affected66 at risk EG0012 events2 affected64 at risk
Chest Pain - Cardiac	Cardiac disorders	Non-systematic Assessment	EG0000 events0 affected66 at risk EG0013 events3 affected64 at risk

Point of Contact

Title	Organization	Phone	Extension	Email
Mark Gladwin	Dean, University of Maryland School of Medicine, Vice President for Medical Affairs, University of Maryland, Baltimore	410-706-7410		mgladwin@som.umaryland.edu

First MCP Posted Date

ID	Term
D000755	Anemia, Sickle Cell

Ancestor Terms

ID	Term
D000745	Anemia, Hemolytic, Congenital
D000743	Anemia, Hemolytic
D000740	Anemia
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D006453	Hemoglobinopathies
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities

ID	Term
C542595	riociguat