Trial Outcomes & Findings for A Multi-Center Study of Riociguat in Patients With Sickle Cell Diseases (NCT NCT02633397)

Last Updated: 2023-07-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

130 participants

Primary outcome timeframe

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

Results posted on

2023-07-19

Participant Flow

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	66	64
Overall Study COMPLETED	50	47
Overall Study NOT COMPLETED	16	17

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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
Overall Study Adverse Event	8	8
Overall Study Study Burden	4	1
Overall Study Treatment interruption	2	5
Overall Study Death	2	2
Overall Study Physician Decision	0	1

Baseline Characteristics

Four participants had a missing result

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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	Total n=130 Participants Total of all reporting groups
Stage 1 hypertension No	30 Participants n=66 Participants	28 Participants n=64 Participants	58 Participants n=130 Participants
Stage 1 hypertension Yes	36 Participants n=66 Participants	36 Participants n=64 Participants	72 Participants n=130 Participants
Heart rate	84.4 beats per minute STANDARD_DEVIATION 12.4 • n=66 Participants	81.2 beats per minute STANDARD_DEVIATION 13.9 • n=64 Participants	82.8 beats per minute STANDARD_DEVIATION 13.2 • n=130 Participants
Mean arterial pressure (MAP)	94.0 mmHg STANDARD_DEVIATION 12.4 • n=66 Participants	91.1 mmHg STANDARD_DEVIATION 11.1 • n=64 Participants	92.5 mmHg STANDARD_DEVIATION 11.8 • n=130 Participants
Age, Continuous	41.0 years STANDARD_DEVIATION 11.8 • n=66 Participants	44.8 years STANDARD_DEVIATION 12.3 • n=64 Participants	42.9 years STANDARD_DEVIATION 12.1 • n=130 Participants
Sex: Female, Male Female	36 Participants n=66 Participants	36 Participants n=64 Participants	72 Participants n=130 Participants
Sex: Female, Male Male	30 Participants n=66 Participants	28 Participants n=64 Participants	58 Participants n=130 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=66 Participants	0 Participants n=64 Participants	2 Participants n=130 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	63 Participants n=66 Participants	61 Participants n=64 Participants	124 Participants n=130 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=66 Participants	3 Participants n=64 Participants	4 Participants n=130 Participants
Race/Ethnicity, Customized Race · Black or African American	63 Participants n=66 Participants	64 Participants n=64 Participants	127 Participants n=130 Participants
Race/Ethnicity, Customized Race · Some Other Race	2 Participants n=66 Participants	0 Participants n=64 Participants	2 Participants n=130 Participants
Race/Ethnicity, Customized Race · Unknown	1 Participants n=66 Participants	0 Participants n=64 Participants	1 Participants n=130 Participants
Clinical Sickle Cell Phenotype (as reported by site) SCD, subtype not immediately available	0 Participants n=66 Participants	1 Participants n=64 Participants	1 Participants n=130 Participants
Clinical Sickle Cell Phenotype (as reported by site) HbSS	49 Participants n=66 Participants	48 Participants n=64 Participants	97 Participants n=130 Participants
Clinical Sickle Cell Phenotype (as reported by site) HbSC	13 Participants n=66 Participants	11 Participants n=64 Participants	24 Participants n=130 Participants
Clinical Sickle Cell Phenotype (as reported by site) HbSbeta-zero-thalassemia	3 Participants n=66 Participants	1 Participants n=64 Participants	4 Participants n=130 Participants
Clinical Sickle Cell Phenotype (as reported by site) HbSbeta-plus-thalassemia	1 Participants n=66 Participants	3 Participants n=64 Participants	4 Participants n=130 Participants
BMI	29.2 kg/m² STANDARD_DEVIATION 9.7 • n=64 Participants • Four participants had a missing result	27.0 kg/m² STANDARD_DEVIATION 6.2 • n=62 Participants • Four participants had a missing result	28.1 kg/m² STANDARD_DEVIATION 8.2 • n=126 Participants • Four participants had a missing result
Systolic BP	128.5 mmHg STANDARD_DEVIATION 17.8 • n=66 Participants	125.5 mmHg STANDARD_DEVIATION 15.6 • n=64 Participants	127.1 mmHg STANDARD_DEVIATION 16.7 • n=130 Participants
Diastolic BP	76.7 mmHg STANDARD_DEVIATION 11.5 • n=66 Participants	73.8 mmHg STANDARD_DEVIATION 11.2 • n=64 Participants	75.3 mmHg STANDARD_DEVIATION 11.4 • n=130 Participants
Pain severity score	3.5 Score on a scale STANDARD_DEVIATION 2.2 • n=66 Participants	3.2 Score on a scale STANDARD_DEVIATION 2.5 • n=64 Participants	3.4 Score on a scale STANDARD_DEVIATION 2.4 • n=130 Participants
Pain interference score	3.1 Score on a scale STANDARD_DEVIATION 2.7 • n=66 Participants	3.0 Score on a scale STANDARD_DEVIATION 2.8 • n=64 Participants	3.1 Score on a scale STANDARD_DEVIATION 2.8 • n=130 Participants
6-Minute Walk Test (6MWT)	416.9 meters STANDARD_DEVIATION 154.0 • n=64 Participants • three participants are missing results.	374.0 meters STANDARD_DEVIATION 127.9 • n=63 Participants • three participants are missing results.	395.6 meters STANDARD_DEVIATION 142.7 • n=127 Participants • three participants are missing results.
6-Minute Walk Test (6MWT) <333 meters	17 Participants n=64 Participants • three participants are missing results.	18 Participants n=63 Participants • three participants are missing results.	35 Participants n=127 Participants • three participants are missing results.
6-Minute Walk Test (6MWT) ≥333 - ≤450 meters	31 Participants n=64 Participants • three participants are missing results.	35 Participants n=63 Participants • three participants are missing results.	66 Participants n=127 Participants • three participants are missing results.
6-Minute Walk Test (6MWT) >450 meters	16 Participants n=64 Participants • three participants are missing results.	10 Participants n=63 Participants • three participants are missing results.	26 Participants n=127 Participants • three participants are missing results.
TR velocity	2.37 peak, m/s STANDARD_DEVIATION 0.61 • n=66 Participants	2.45 peak, m/s STANDARD_DEVIATION 0.70 • n=64 Participants	2.41 peak, m/s STANDARD_DEVIATION 0.66 • n=130 Participants
TR velocity <2.5 m/s	37 Participants n=66 Participants	35 Participants n=64 Participants	72 Participants n=130 Participants
TR velocity ≥2.5 - <3 m/s	22 Participants n=66 Participants	15 Participants n=64 Participants	37 Participants n=130 Participants
TR velocity ≥3 m/s	7 Participants n=66 Participants	14 Participants n=64 Participants	21 Participants n=130 Participants
Ejection fraction	59.42 Percentage STANDARD_DEVIATION 5.95 • n=65 Participants • Two participants are missing results.	60.86 Percentage STANDARD_DEVIATION 6.28 • n=63 Participants • Two participants are missing results.	60.13 Percentage STANDARD_DEVIATION 6.13 • n=128 Participants • Two participants are missing results.
Macroalbuminuria No	46 Participants n=66 Participants	39 Participants n=64 Participants	85 Participants n=130 Participants
Macroalbuminuria Yes	20 Participants n=66 Participants	25 Participants n=64 Participants	45 Participants n=130 Participants
Albumin/Creatinine Ratio (ACR)	249.1 mg/g STANDARD_DEVIATION 379.4 • n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	361.7 mg/g STANDARD_DEVIATION 849.5 • n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	305.4 mg/g STANDARD_DEVIATION 657.3 • n=110 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.
Albuminuria Normal (ACR<30mg/g)	18 Participants n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	14 Participants n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	32 Participants n=110 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.
Albuminuria Microalbuminuria (ACR 30-300mg/g)	25 Participants n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	28 Participants n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	53 Participants n=110 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.
Albuminuria Macroalbuminuria (ACR >300mg/g)	12 Participants n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	13 Participants n=55 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.	25 Participants n=110 Participants • Unavailable data for Twenty participants. ACR was undetectable in 11 participants, while 9 participants had missing data.
GFR	114.5 ml/min/1.73 m² STANDARD_DEVIATION 28.0 • n=66 Participants	105.4 ml/min/1.73 m² STANDARD_DEVIATION 34.3 • n=64 Participants	110.0 ml/min/1.73 m² STANDARD_DEVIATION 31.5 • n=130 Participants
Ever smoked cigarettes No	47 Participants n=66 Participants	49 Participants n=64 Participants	96 Participants n=130 Participants
Ever smoked cigarettes Yes	19 Participants n=66 Participants	15 Participants n=64 Participants	34 Participants n=130 Participants
Ever had a blood transfusion No	7 Participants n=66 Participants	2 Participants n=64 Participants	9 Participants n=130 Participants
Ever had a blood transfusion Yes	59 Participants n=66 Participants	62 Participants n=64 Participants	121 Participants n=130 Participants

PRIMARY outcome

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)	15 Participants	20 Participants

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Frequency of SAE Due to Sickle Cell Related Painful Crisis	11 Participants	14 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Proportion of participants that experienced treatment-emergent AEs

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Overall Incidences of Treatment-emergent Adverse Events (AEs)	53 Participants	45 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Incidences of Sickle Cell Related Clinical Complications	23 Participants	21 Participants

SECONDARY outcome

Timeframe: Baseline, 12 weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Pain Intensity Using the Brief Pain Inventory	3.18 score on a scale Interval 2.75 to 3.62	3.32 score on a scale Interval 2.88 to 3.75

SECONDARY outcome

Timeframe: Baseline, 12 weeks

6-minute walk distance was used to assess functional exercise capacity Mean at 12 weeks assessed using ANCOVA adjusting for baseline.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
6-minute Walk Distance	391.97 meters Interval 332.29 to 451.66	431.49 meters Interval 369.61 to 493.37

SECONDARY outcome

Timeframe: Baseline,12 Weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in the Dyspnea Borg Scale	0.50 score on a scale Interval 0.17 to 0.83	0.20 score on a scale Interval -0.14 to 0.53

SECONDARY outcome

Timeframe: Baseline,12 weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Fatigue Borg Scale	1.95 score on a scale Interval 1.53 to 2.37	2.03 score on a scale Interval 1.6 to 2.46

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in Blood Pressure as the Main Pharmacodynamic (MAP)	-8.20 mmHg Interval -10.48 to -5.91	-1.24 mmHg Interval -3.58 to 1.1

SECONDARY outcome

Timeframe: Baseline, 12 Weeks

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography	2.17 m/s Interval 2.04 to 2.3	2.31 m/s Interval 2.19 to 2.44

SECONDARY outcome

Timeframe: Baseline,12 weeks

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
End-systolic Volume Using Non-invasive Echocardiography	46.40 ml Interval 43.59 to 49.22	53.1 ml Interval 50.33 to 55.88

SECONDARY outcome

Timeframe: Baseline, 12 weeks

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Ejection Fraction (Biplane) Using Non-invasive Echocardiography	63.19 percentage Interval 62.01 to 64.37	59.67 percentage Interval 58.51 to 60.83

SECONDARY outcome

Timeframe: Baseline,12 weeks

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in the Levels of Plasma NT-proBNP	54.67 pg/mL Interval -477.91 to 587.2	-231.89 pg/mL Interval -780.36 to 316.5

SECONDARY outcome

Timeframe: Baseline,12 weeks

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in Albumin/Creatinine Ratio	-56.96 mg/g Interval -126.1 to 12.17	25.22 mg/g Interval -44.66 to 95.11

SECONDARY outcome

Timeframe: Baseline,12 weeks

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

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

Outcome measures

Outcome measures
Measure	Riociguat n=43 Participants 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	Placebo n=42 Participants 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
Microalbuminuria	0.96 odds ratio Interval 0.87 to 1.06	0.94 odds ratio Interval 0.85 to 1.04

SECONDARY outcome

Timeframe: Baseline,12 weeks

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

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

Outcome measures

Outcome measures
Measure	Riociguat n=30 Participants 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	Placebo n=27 Participants 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
Macroalbuminuria	1.03 odds ratio Interval 0.81 to 1.31	0.84 odds ratio Interval 0.66 to 1.08

SECONDARY outcome

Timeframe: Baseline, 4 weeks, 8 weeks, 12 weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in Glomerular Filtration Rate	-4.13 ml/min/1.73 m² Interval -7.11 to -1.14	0.79 ml/min/1.73 m² Interval -2.29 to 3.87

SECONDARY outcome

Timeframe: Baseline,12 weeks

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk	0.99 odds ratio Interval 0.9 to 1.08	0.95 odds ratio Interval 0.86 to 1.04

SECONDARY outcome

Timeframe: Baseline, 4 weeks, 8 weeks,12 weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in Hemoglobin	-0.21 g/dL Interval -0.4 to -0.01	0.04 g/dL Interval -0.16 to 0.24

SECONDARY outcome

Timeframe: Baseline, 4 weeks, 8 weeks,12 weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in Reticulocyte Count	0.32 percentage Interval -0.54 to 1.19	-1.15 percentage Interval -2.05 to -0.24

SECONDARY outcome

Timeframe: Baseline, 4 weeks, 8 weeks,12 weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in White Blood Cell Count	-0.28 (x10^9 cells/L) Interval -0.83 to 0.26	-0.13 (x10^9 cells/L) Interval -0.69 to 0.43

SECONDARY outcome

Timeframe: Baseline, 4 weeks, 8 weeks,12 weeks

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.

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in Lactate Dehydrogenase (LDH)	-43.30 U/L Interval -67.49 to -19.1	-14.02 U/L Interval -39.8 to 11.76

SECONDARY outcome

Timeframe: Baseline,12 weeks

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

Outcome measures

Outcome measures
Measure	Riociguat n=66 Participants 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	Placebo n=64 Participants 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
Changes in Fetal Hemoglobin	-1.91 Percentage Interval -3.05 to -0.78	-0.28 Percentage Interval -1.44 to 0.88

Adverse Events

Riociguat

Serious events: 15 serious events

Other events: 53 other events

Deaths: 2 deaths

Placebo

Serious events: 20 serious events

Other events: 45 other events

Deaths: 2 deaths

Serious adverse events

Serious adverse events
Measure	Riociguat n=66 participants at risk 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	Placebo n=64 participants at risk 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
General disorders VOC	16.7% 11/66 • Number of events 17 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	21.9% 14/64 • Number of events 23 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Cardiac disorders Cardiac Arrest	1.5% 1/66 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	0.00% 0/64 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Cardiac disorders Mitral Valve Disease	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Cardiac disorders Supraventricular Tachycardia	1.5% 1/66 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	0.00% 0/64 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Infections and infestations Lung Infection	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Infections and infestations Skin Infection	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Infections and infestations Upper Respiratory Infection	1.5% 1/66 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	0.00% 0/64 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Renal and urinary disorders Acute Kidney Injury	1.5% 1/66 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	0.00% 0/64 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Renal and urinary disorders Other - Pyelonephritis	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Blood and lymphatic system disorders Thrombotic Thrombocytopenic Purpura	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Endocrine disorders Other - Dizziness	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Nervous system disorders Lethargy	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Respiratory, thoracic and mediastinal disorders Cough	1.5% 1/66 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	0.00% 0/64 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Vascular disorders Other - Papilledema	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.

Other adverse events

Additional Information

Mark Gladwin

Dean, University of Maryland School of Medicine, Vice President for Medical Affairs, University of Maryland, Baltimore

Phone: 410-706-7410

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Riociguat n=66 participants at risk 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	Placebo n=64 participants at risk 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
General disorders VOC	34.8% 23/66 • Number of events 65 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	32.8% 21/64 • Number of events 46 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
General disorders Malaise	4.5% 3/66 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	4.7% 3/64 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
General disorders Fatigue	4.5% 3/66 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	3.1% 2/64 • Number of events 2 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
General disorders Edema Limbs	6.1% 4/66 • Number of events 4 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	0.00% 0/64 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Diarrhea	13.6% 9/66 • Number of events 11 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	12.5% 8/64 • Number of events 9 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Nausea	10.6% 7/66 • Number of events 8 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	4.7% 3/64 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Abdominal Pain	6.1% 4/66 • Number of events 5 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	6.2% 4/64 • Number of events 5 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Gastroesophageal Reflux Disease	12.1% 8/66 • Number of events 8 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Vomiting	9.1% 6/66 • Number of events 6 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	3.1% 2/64 • Number of events 2 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Dry Mouth	4.5% 3/66 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	3.1% 2/64 • Number of events 2 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Constipation	4.5% 3/66 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Gastrointestinal disorders Other	4.5% 3/66 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Nervous system disorders Headache	21.2% 14/66 • Number of events 16 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	9.4% 6/64 • Number of events 7 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Nervous system disorders Dizziness	12.1% 8/66 • Number of events 9 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	4.7% 3/64 • Number of events 4 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Musculoskeletal and connective tissue disorders Other	13.6% 9/66 • Number of events 15 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	15.6% 10/64 • Number of events 14 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Musculoskeletal and connective tissue disorders Pain In Extremity	3.0% 2/66 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	4.7% 3/64 • Number of events 4 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Musculoskeletal and connective tissue disorders Myalgia	4.5% 3/66 • Number of events 5 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	4.7% 3/64 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Respiratory, thoracic and mediastinal disorders Cough	7.6% 5/66 • Number of events 5 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	1.6% 1/64 • Number of events 1 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Respiratory, thoracic and mediastinal disorders Dyspnea	4.5% 3/66 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	0.00% 0/64 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Cardiac disorders Palpitations	7.6% 5/66 • Number of events 5 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	3.1% 2/64 • Number of events 2 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.
Cardiac disorders Chest Pain - Cardiac	0.00% 0/66 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.	4.7% 3/64 • Number of events 3 • Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks Adverse events and deaths were not collected by dose level.