Sickle Cell Disease
Conditions
Keywords
SCD, Sickle Cell Disease, Riociguat, Adempas
Brief summary
The proposed study is a Phase 2 multi-center, randomized, double-blind, placebo-controlled, parallel groups study aimed to evaluate the safety, tolerability and the efficacy of riociguat compared with placebo in patients with sickle cell disease (SCD).
Detailed description
This randomized study involves 12 weeks of treatment with riociguat pills or placebo pills, and a follow-up period of 30 days after treatment. The dose is adjusted every 2 weeks based on systolic blood pressure (SBP) and well-being assessed at that visit. Physical examinations, vital signs, blood tests and questionnaires will be performed at 2 week intervals during the double blinded study treatment. Echocardiogram, urine testing, six-minute walk distance and questionnaires will be assessed at the beginning and end of the treatment phase.
Interventions
DRUGRiociguat
Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
DRUGPlacebo
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
Sponsors
Mark Gladwin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Incidence of Treatment Emergent Severe Adverse Events (SAE) | Baseline through 7 days after discontinuation of treatment, up to 13 Weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fatigue Borg Scale | 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. |
| Frequency of SAE Due to Sickle Cell Related Painful Crisis | 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) |
| Overall Incidences of Treatment-emergent Adverse Events (AEs) | Baseline to Week 12 | Proportion of participants that experienced treatment-emergent AEs |
| Incidences of Sickle Cell Related Clinical Complications | Baseline to Week 12 | Incidence of Vaso-occlusive Crisis (VOC) between baseline and week 12 |
| Pain Intensity Using the Brief Pain Inventory | 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. |
| 6-minute Walk Distance | Baseline, 12 weeks | 6-minute walk distance was used to assess functional exercise capacity Mean at 12 weeks assessed using ANCOVA adjusting for baseline. |
| Changes in Blood Pressure as the Main Pharmacodynamic (MAP) | 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. |
| Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography | Baseline, 12 Weeks | Mean TRV at 12 weeks assessed using ANCOVA, adjusting for baseline. |
| End-systolic Volume Using Non-invasive Echocardiography | Baseline,12 weeks | Mean end-systolic volume (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline. |
| Ejection Fraction (Biplane) Using Non-invasive Echocardiography | Baseline, 12 weeks | Mean ejection fraction (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline. |
| Changes in the Dyspnea Borg Scale | 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. |
| Changes in Albumin/Creatinine Ratio | Baseline,12 weeks | Albumin/Creatinine Ratio (ACR) mean change from baseline to 12 weeks using linear regression model. |
| Microalbuminuria | Baseline,12 weeks | Odds ratio per week of microalbuminuria estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope |
| Macroalbuminuria | Baseline,12 weeks | Odds ratio per week of macroalbuminuria estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope. |
| Changes in Glomerular Filtration Rate | 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. |
| Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk | 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 |
| Changes in Hemoglobin | 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. |
| Changes in Reticulocyte Count | 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. |
| Changes in White Blood Cell Count | 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. |
| Changes in Lactate Dehydrogenase (LDH) | 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. |
| Changes in Fetal Hemoglobin | Baseline,12 weeks | Mean change in fetal hemoglobin from baseline to 12 weeks using a linear mixed model |
| Changes in the Levels of Plasma NT-proBNP | Baseline,12 weeks | Mean Change in the levels of plasma NT-proBNP from baseline to 12 weeks using a linear regression model. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 66 |
| 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 | 64 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 8 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Study Burden | 4 | 1 |
| Overall Study | Treatment interruption | 2 | 5 |
Baseline characteristics
| Characteristic | Total | Placebo | Riociguat |
|---|---|---|---|
| 6-Minute Walk Test (6MWT) ≥333 - ≤450 meters | 66 Participants | 35 Participants | 31 Participants |
| 6-Minute Walk Test (6MWT) <333 meters | 35 Participants | 18 Participants | 17 Participants |
| 6-Minute Walk Test (6MWT) >450 meters | 26 Participants | 10 Participants | 16 Participants |
| 6-Minute Walk Test (6MWT) | 395.6 meters STANDARD_DEVIATION 142.7 | 374.0 meters STANDARD_DEVIATION 127.9 | 416.9 meters STANDARD_DEVIATION 154 |
| Age, Continuous | 42.9 years STANDARD_DEVIATION 12.1 | 44.8 years STANDARD_DEVIATION 12.3 | 41.0 years STANDARD_DEVIATION 11.8 |
| Albumin/Creatinine Ratio (ACR) | 305.4 mg/g STANDARD_DEVIATION 657.3 | 361.7 mg/g STANDARD_DEVIATION 849.5 | 249.1 mg/g STANDARD_DEVIATION 379.4 |
| Albuminuria Macroalbuminuria (ACR >300mg/g) | 25 Participants | 13 Participants | 12 Participants |
| Albuminuria Microalbuminuria (ACR 30-300mg/g) | 53 Participants | 28 Participants | 25 Participants |
| Albuminuria Normal (ACR<30mg/g) | 32 Participants | 14 Participants | 18 Participants |
| BMI | 28.1 kg/m² STANDARD_DEVIATION 8.2 | 27.0 kg/m² STANDARD_DEVIATION 6.2 | 29.2 kg/m² STANDARD_DEVIATION 9.7 |
| Clinical Sickle Cell Phenotype (as reported by site) HbSbeta-plus-thalassemia | 4 Participants | 3 Participants | 1 Participants |
| Clinical Sickle Cell Phenotype (as reported by site) HbSbeta-zero-thalassemia | 4 Participants | 1 Participants | 3 Participants |
| Clinical Sickle Cell Phenotype (as reported by site) HbSC | 24 Participants | 11 Participants | 13 Participants |
| Clinical Sickle Cell Phenotype (as reported by site) HbSS | 97 Participants | 48 Participants | 49 Participants |
| Clinical Sickle Cell Phenotype (as reported by site) SCD, subtype not immediately available | 1 Participants | 1 Participants | 0 Participants |
| Diastolic BP | 75.3 mmHg STANDARD_DEVIATION 11.4 | 73.8 mmHg STANDARD_DEVIATION 11.2 | 76.7 mmHg STANDARD_DEVIATION 11.5 |
| Ejection fraction | 60.13 Percentage STANDARD_DEVIATION 6.13 | 60.86 Percentage STANDARD_DEVIATION 6.28 | 59.42 Percentage STANDARD_DEVIATION 5.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 124 Participants | 61 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 3 Participants | 1 Participants |
| Ever had a blood transfusion No | 9 Participants | 2 Participants | 7 Participants |
| Ever had a blood transfusion Yes | 121 Participants | 62 Participants | 59 Participants |
| Ever smoked cigarettes No | 96 Participants | 49 Participants | 47 Participants |
| Ever smoked cigarettes Yes | 34 Participants | 15 Participants | 19 Participants |
| GFR | 110.0 ml/min/1.73 m² STANDARD_DEVIATION 31.5 | 105.4 ml/min/1.73 m² STANDARD_DEVIATION 34.3 | 114.5 ml/min/1.73 m² STANDARD_DEVIATION 28 |
| Heart rate | 82.8 beats per minute STANDARD_DEVIATION 13.2 | 81.2 beats per minute STANDARD_DEVIATION 13.9 | 84.4 beats per minute STANDARD_DEVIATION 12.4 |
| Macroalbuminuria No | 85 Participants | 39 Participants | 46 Participants |
| Macroalbuminuria Yes | 45 Participants | 25 Participants | 20 Participants |
| Mean arterial pressure (MAP) | 92.5 mmHg STANDARD_DEVIATION 11.8 | 91.1 mmHg STANDARD_DEVIATION 11.1 | 94.0 mmHg STANDARD_DEVIATION 12.4 |
| Pain interference score | 3.1 Score on a scale STANDARD_DEVIATION 2.8 | 3.0 Score on a scale STANDARD_DEVIATION 2.8 | 3.1 Score on a scale STANDARD_DEVIATION 2.7 |
| Pain severity score | 3.4 Score on a scale STANDARD_DEVIATION 2.4 | 3.2 Score on a scale STANDARD_DEVIATION 2.5 | 3.5 Score on a scale STANDARD_DEVIATION 2.2 |
| Race/Ethnicity, Customized Race Black or African American | 127 Participants | 64 Participants | 63 Participants |
| Race/Ethnicity, Customized Race Some Other Race | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Unknown | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 72 Participants | 36 Participants | 36 Participants |
| Sex: Female, Male Male | 58 Participants | 28 Participants | 30 Participants |
| Stage 1 hypertension No | 58 Participants | 28 Participants | 30 Participants |
| Stage 1 hypertension Yes | 72 Participants | 36 Participants | 36 Participants |
| Systolic BP | 127.1 mmHg STANDARD_DEVIATION 16.7 | 125.5 mmHg STANDARD_DEVIATION 15.6 | 128.5 mmHg STANDARD_DEVIATION 17.8 |
| TR velocity ≥2.5 - <3 m/s | 37 Participants | 15 Participants | 22 Participants |
| TR velocity <2.5 m/s | 72 Participants | 35 Participants | 37 Participants |
| TR velocity ≥3 m/s | 21 Participants | 14 Participants | 7 Participants |
| TR velocity | 2.41 peak, m/s STANDARD_DEVIATION 0.66 | 2.45 peak, m/s STANDARD_DEVIATION 0.7 | 2.37 peak, m/s STANDARD_DEVIATION 0.61 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 66 | 2 / 64 |
| other Total, other adverse events | 53 / 66 | 45 / 64 |
| serious Total, serious adverse events | 15 / 66 | 20 / 64 |
Outcome results
Primary
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.
Time frame: Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Overall Incidence of Treatment Emergent Severe Adverse Events (SAE) | 15 Participants |
| Placebo | Overall Incidence of Treatment Emergent Severe Adverse Events (SAE) | 20 Participants |
Comparison: P- Value was the exact logistic regression adjusted for clinical site.p-value: 0.19Regression, Logistic
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.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | 6-minute Walk Distance | 391.97 meters |
| Placebo | 6-minute Walk Distance | 431.49 meters |
Comparison: ANCOVA model adjusted for clinic sitep-value: 0.490% CI: [-117.05, 38.02]ANCOVA
Secondary
Changes in Albumin/Creatinine Ratio
Albumin/Creatinine Ratio (ACR) mean change from baseline to 12 weeks using linear regression model.
Time frame: Baseline,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in Albumin/Creatinine Ratio | -56.96 mg/g |
| Placebo | Changes in Albumin/Creatinine Ratio | 25.22 mg/g |
Comparison: Linear regression model adjusted for clinic sitep-value: 0.1490% CI: [-173.69, 9.32]Regression, Linear
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.
Time frame: Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in Blood Pressure as the Main Pharmacodynamic (MAP) | -8.20 mmHg |
| Placebo | Changes in Blood Pressure as the Main Pharmacodynamic (MAP) | -1.24 mmHg |
Comparison: Linear mixed model with random intercept was used to compare the change in MAP as a function of time, the interaction between time and study arm, and clinic site.p-value: <0.00190% CI: [-10.22, -3.69]Mixed Models Analysis
Secondary
Changes in Fetal Hemoglobin
Mean change in fetal hemoglobin from baseline to 12 weeks using a linear mixed model
Time frame: Baseline,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in Fetal Hemoglobin | -1.91 Percentage |
| Placebo | Changes in Fetal Hemoglobin | -0.28 Percentage |
Comparison: Linear regression model adjusted for clinic sitep-value: 0.0790% CI: [-3.13, -0.15]Regression, Linear
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.
Time frame: Baseline, 4 weeks, 8 weeks, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in Glomerular Filtration Rate | -4.13 ml/min/1.73 m² |
| Placebo | Changes in Glomerular Filtration Rate | 0.79 ml/min/1.73 m² |
Comparison: Linear mixed model with random intercept was used to compare the change in GFR as a function of time, the interaction between time and study arm, and clinic site.p-value: 0.0690% CI: [-9.21, -0.62]Mixed Models Analysis
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.
Time frame: Baseline, 4 weeks, 8 weeks,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in Hemoglobin | -0.21 g/dL |
| Placebo | Changes in Hemoglobin | 0.04 g/dL |
Comparison: Linear mixed model with random intercept was used to compare the change in hemoglobin as a function of time, the interaction between time and study arm, and clinic site.p-value: 0.1590% CI: [-0.52, 0.03]Mixed Models Analysis
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.
Time frame: Baseline, 4 weeks, 8 weeks,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in Lactate Dehydrogenase (LDH) | -43.30 U/L |
| Placebo | Changes in Lactate Dehydrogenase (LDH) | -14.02 U/L |
Comparison: Linear mixed model with random intercept was used to compare the change in WBC count as a function of time, the interaction between time and study arm, and clinic site.p-value: 0.1790% CI: [-64.63, 6.08]Mixed Models Analysis
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.
Time frame: Baseline, 4 weeks, 8 weeks,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in Reticulocyte Count | 0.32 percentage |
| Placebo | Changes in Reticulocyte Count | -1.15 percentage |
Comparison: Linear mixed model with random intercept was used to compare the change in reticulocyte count as a function of time, the interaction between time and study arm, and clinic site.p-value: 0.0590% CI: [0.22, 2.72]Mixed Models Analysis
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.
Time frame: Baseline,12 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in the Dyspnea Borg Scale | 0.50 score on a scale |
| Placebo | Changes in the Dyspnea Borg Scale | 0.20 score on a scale |
Comparison: Linear regression model adjusted for clinic sitep-value: 0.2390% CI: [-0.11, 0.73]Regression, Linear
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.
Time frame: Baseline,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in the Levels of Plasma NT-proBNP | 54.67 pg/mL |
| Placebo | Changes in the Levels of Plasma NT-proBNP | -231.89 pg/mL |
Comparison: Linear regression model adjusted for clinic sitep-value: 0.5190% CI: [-429.86, 1002.99]Regression, Linear
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.
Time frame: Baseline, 4 weeks, 8 weeks,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Changes in White Blood Cell Count | -0.28 (x10^9 cells/L) |
| Placebo | Changes in White Blood Cell Count | -0.13 (x10^9 cells/L) |
Comparison: Linear mixed model with random intercept was used to compare the change in WBC count as a function of time, the interaction between time and study arm, and clinic site.p-value: 0.7590% CI: [-0.93, 0.63]Mixed Models Analysis
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
Time frame: Baseline,12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Riociguat | Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk | 0.99 odds ratio |
| Placebo | Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk | 0.95 odds ratio |
Comparison: Generalized linear mixed model (logit link) with random intercept was used to compare CKD stage frequency as a function of time and the interaction between time and study arm.p-value: 0.56Mixed Models Analysis
Secondary
Ejection Fraction (Biplane) Using Non-invasive Echocardiography
Mean ejection fraction (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Ejection Fraction (Biplane) Using Non-invasive Echocardiography | 63.19 percentage |
| Placebo | Ejection Fraction (Biplane) Using Non-invasive Echocardiography | 59.67 percentage |
Comparison: ANCOVA model adjusted for clinic sitep-value: <0.00190% CI: [2, 5.04]ANCOVA
Secondary
End-systolic Volume Using Non-invasive Echocardiography
Mean end-systolic volume (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.
Time frame: Baseline,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | End-systolic Volume Using Non-invasive Echocardiography | 46.40 ml |
| Placebo | End-systolic Volume Using Non-invasive Echocardiography | 53.1 ml |
Comparison: ANCOVA model adjusted for clinic sitep-value: 0.00390% CI: [-10.28, -3.12]ANCOVA
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.
Time frame: Baseline,12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Fatigue Borg Scale | 1.95 score on a scale |
| Placebo | Fatigue Borg Scale | 2.03 score on a scale |
Comparison: ANCOVA model adjusted for clinic sitep-value: -0.890% CI: [-0.62, 0.46]ANCOVA
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)
Time frame: Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Frequency of SAE Due to Sickle Cell Related Painful Crisis | 11 Participants |
| Placebo | Frequency of SAE Due to Sickle Cell Related Painful Crisis | 14 Participants |
Comparison: P- Value was the exact logistic regression adjusted for clinical site.p-value: 0.42Regression, Logistic
Secondary
Incidences of Sickle Cell Related Clinical Complications
Incidence of Vaso-occlusive Crisis (VOC) between baseline and week 12
Time frame: Baseline to Week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Incidences of Sickle Cell Related Clinical Complications | 23 Participants |
| Placebo | Incidences of Sickle Cell Related Clinical Complications | 21 Participants |
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.
Time frame: Baseline,12 weeks
Population: Participants with undetectable ACR or microalbuminuria (30-300 ACR) were excluded
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Riociguat | Macroalbuminuria | 1.03 odds ratio |
| Placebo | Macroalbuminuria | 0.84 odds ratio |
Comparison: Generalized linear mixed model (logit link) with random intercept was used to compare macroalbuminuria frequency as a function of time and the interaction between time and study arm.p-value: 0.3Mixed Models Analysis
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
Time frame: Baseline,12 weeks
Population: Participants with undetectable ACR or macroalbuminuria (\>300 ACR) were excluded
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Riociguat | Microalbuminuria | 0.96 odds ratio |
| Placebo | Microalbuminuria | 0.94 odds ratio |
Comparison: Generalized linear mixed model (logit link) with random intercept was used to compare microalbuminuria frequency as a function of time and the interaction between time and study arm.p-value: 0.78Mixed Models Analysis
Secondary
Overall Incidences of Treatment-emergent Adverse Events (AEs)
Proportion of participants that experienced treatment-emergent AEs
Time frame: Baseline to Week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Riociguat | Overall Incidences of Treatment-emergent Adverse Events (AEs) | 53 Participants |
| Placebo | Overall Incidences of Treatment-emergent Adverse Events (AEs) | 45 Participants |
Comparison: P- Value was the exact logistic regression adjusted for clinical site.p-value: 0.52Regression, Logistic
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.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Pain Intensity Using the Brief Pain Inventory | 3.18 score on a scale |
| Placebo | Pain Intensity Using the Brief Pain Inventory | 3.32 score on a scale |
Comparison: ANCOVA model adjusted for clinic sitep-value: 0.6990% CI: [-0.7, 0.42]ANCOVA
Secondary
Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography
Mean TRV at 12 weeks assessed using ANCOVA, adjusting for baseline.
Time frame: Baseline, 12 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riociguat | Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography | 2.17 m/s |
| Placebo | Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography | 2.31 m/s |
Comparison: ANCOVA model adjusted for clinic sitep-value: 0.1590% CI: [-0.31, 0.02]ANCOVA