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CompletedNCT02633397Updated Jul 19, 2023Results posted

A Multi-Center Study of Riociguat in Patients With Sickle Cell Diseases

A Phase 2 interventional study of Riociguat and Placebo in Sickle Cell Disease, sponsored by Mark Gladwin. Completed at 20 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-07-19.

Sponsored by Mark Gladwin · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
130
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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).

Read the 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.

02

Conditions studied

  • Sickle Cell Disease

Browse trials for

Keywords

  • SCD
  • Sickle Cell Disease
  • Riociguat
  • Adempas
03

In context

Anemia, Sickle Cell

1,103 studies on the registry are indexed under Anemia, Sickle Cell; 235 are open to participants now.

This study's enrollment of 130 is above the median of 40 across 750 interventional studies indexed under Anemia, Sickle Cell.

Browse Anemia, Sickle Cell studies →

Lead sponsor

Mark Gladwin is the lead sponsor of 2 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts 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

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
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
130 participants (actual)

Study arms

  • Experimental
    Riociguat

    Treatment Arm

    Drug: Riociguat

  • Placebo comparator
    Placebo

    Placebo Arm

    Drug: Placebo

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

    Also known as: Adempas

  • 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

06

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. Overall Incidences of Treatment-emergent Adverse Events (AEs)

    Proportion of participants that experienced treatment-emergent AEs

    Time frame: Baseline to Week 12

  3. Incidences of Sickle Cell Related Clinical Complications

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

    Time frame: Baseline to Week 12

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography

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

    Time frame: Baseline, 12 Weeks

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. Changes in Fetal Hemoglobin

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

    Time frame: Baseline,12 weeks

07

Results

Posted Jul 19, 2023

Participant flow

Participant flow — Overall Study
MilestoneRiociguatPlacebo
Started6664
Completed5047
Not completed1617
Withdrew: Adverse event88
Withdrew: Study burden41
Withdrew: Treatment interruption25
Withdrew: Death22
Withdrew: Physician decision01

Outcome measures

PrimaryOverall 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
Reported as:
Count of participants · Participants
Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)
ParticipantsRiociguatPlacebo
Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)1520
Statistical analysis
  • Riociguat vs Placebo · Regression, Logistic · p = 0.19
SecondaryFrequency 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
Reported as:
Count of participants · Participants
Frequency of SAE Due to Sickle Cell Related Painful Crisis
ParticipantsRiociguatPlacebo
Frequency of SAE Due to Sickle Cell Related Painful Crisis1114
Statistical analysis
  • Riociguat vs Placebo · Regression, Logistic · p = 0.42
SecondaryOverall Incidences of Treatment-emergent Adverse Events (AEs)

Proportion of participants that experienced treatment-emergent AEs

Time frame:
Baseline to Week 12
Reported as:
Count of participants · Participants
Overall Incidences of Treatment-emergent Adverse Events (AEs)
ParticipantsRiociguatPlacebo
Overall Incidences of Treatment-emergent Adverse Events (AEs)5345
Statistical analysis
  • Riociguat vs Placebo · Regression, Logistic · p = 0.52
SecondaryIncidences of Sickle Cell Related Clinical Complications

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

Time frame:
Baseline to Week 12
Reported as:
Count of participants · Participants
Incidences of Sickle Cell Related Clinical Complications
ParticipantsRiociguatPlacebo
Incidences of Sickle Cell Related Clinical Complications2321
SecondaryPain 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
Reported as:
Mean · score on a scale
Pain Intensity Using the Brief Pain Inventory
score on a scaleRiociguatPlacebo
Pain Intensity Using the Brief Pain Inventory3.18 (2.75 to 3.62)3.32 (2.88 to 3.75)
Statistical analysis
  • Riociguat vs Placebo · ANCOVA · p = 0.69 · Mean difference (final values): -0.14 · 90% CI -0.70 to 0.42
Secondary6-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
Reported as:
Mean · meters
6-minute Walk Distance
metersRiociguatPlacebo
6-minute Walk Distance391.97 (332.29 to 451.66)431.49 (369.61 to 493.37)
Statistical analysis
  • Riociguat vs Placebo · ANCOVA · p = 0.40 · Mean difference (final values): -39.51 · 90% CI -117.05 to 38.02
SecondaryChanges 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
Reported as:
Mean · score on a scale
Changes in the Dyspnea Borg Scale
score on a scaleRiociguatPlacebo
Changes in the Dyspnea Borg Scale0.50 (0.17 to 0.83)0.20 (-0.14 to 0.53)
Statistical analysis
  • Riociguat vs Placebo · Regression, Linear · p = 0.23 · Mean difference (final values): 0.31 · 90% CI -0.11 to 0.73
SecondaryFatigue 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
Reported as:
Mean · score on a scale
Fatigue Borg Scale
score on a scaleRiociguatPlacebo
Fatigue Borg Scale1.95 (1.53 to 2.37)2.03 (1.6 to 2.46)
Statistical analysis
  • Riociguat vs Placebo · ANCOVA · p = -0.80 · Mean difference (final values): -0.08 · 90% CI -0.62 to 0.46
SecondaryChanges 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
Reported as:
Mean · mmHg
Changes in Blood Pressure as the Main Pharmacodynamic (MAP)
mmHgRiociguatPlacebo
Changes in Blood Pressure as the Main Pharmacodynamic (MAP)-8.20 (-10.48 to -5.91)-1.24 (-3.58 to 1.10)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = <0.001 · Mean difference (final values): -6.96 · 90% CI -10.22 to -3.69
SecondaryTricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography

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

Time frame:
Baseline, 12 Weeks
Reported as:
Mean · m/s
Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography
m/sRiociguatPlacebo
Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography2.17 (2.04 to 2.30)2.31 (2.19 to 2.44)
Statistical analysis
  • Riociguat vs Placebo · ANCOVA · p = 0.15 · Mean difference (final values): -0.14 · 90% CI -0.31 to 0.02
SecondaryEnd-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
Reported as:
Mean · ml
End-systolic Volume Using Non-invasive Echocardiography
mlRiociguatPlacebo
End-systolic Volume Using Non-invasive Echocardiography46.40 (43.59 to 49.22)53.1 (50.33 to 55.88)
Statistical analysis
  • Riociguat vs Placebo · ANCOVA · p = 0.003 · Mean difference (final values): -6.70 · 90% CI -10.28 to -3.12
SecondaryEjection Fraction (Biplane) Using Non-invasive Echocardiography

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

Time frame:
Baseline, 12 weeks
Reported as:
Mean · percentage
Ejection Fraction (Biplane) Using Non-invasive Echocardiography
percentageRiociguatPlacebo
Ejection Fraction (Biplane) Using Non-invasive Echocardiography63.19 (62.01 to 64.37)59.67 (58.51 to 60.83)
Statistical analysis
  • Riociguat vs Placebo · ANCOVA · p = <0.001 · Mean difference (final values): 3.52 · 90% CI 2.00 to 5.04
SecondaryChanges 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
Reported as:
Mean · pg/mL
Changes in the Levels of Plasma NT-proBNP
pg/mLRiociguatPlacebo
Changes in the Levels of Plasma NT-proBNP54.67 (-477.91 to 587.2)-231.89 (-780.36 to 316.5)
Statistical analysis
  • Riociguat vs Placebo · Regression, Linear · p = 0.51 · Mean difference (final values): 286.56 · 90% CI -429.86 to 1002.99
SecondaryChanges in Albumin/Creatinine Ratio

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

Time frame:
Baseline,12 weeks
Reported as:
Mean · mg/g
Changes in Albumin/Creatinine Ratio
mg/gRiociguatPlacebo
Changes in Albumin/Creatinine Ratio-56.96 (-126.10 to 12.17)25.22 (-44.66 to 95.11)
Statistical analysis
  • Riociguat vs Placebo · Regression, Linear · p = 0.14 · Mean difference (final values): -82.18 · 90% CI -173.69 to 9.32
SecondaryMicroalbuminuria

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
Reported as:
Number · odds ratio
Microalbuminuria
odds ratioRiociguatPlacebo
Microalbuminuria0.96 (0.87 to 1.06)0.94 (0.85 to 1.04)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.78
SecondaryMacroalbuminuria

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
Reported as:
Number · odds ratio
Macroalbuminuria
odds ratioRiociguatPlacebo
Macroalbuminuria1.03 (0.81 to 1.31)0.84 (0.66 to 1.08)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.30
SecondaryChanges 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
Reported as:
Mean · ml/min/1.73 m²
Changes in Glomerular Filtration Rate
ml/min/1.73 m²RiociguatPlacebo
Changes in Glomerular Filtration Rate-4.13 (-7.11 to -1.14)0.79 (-2.29 to 3.87)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.06 · Mean difference (final values): -4.91 · 90% CI -9.21 to -0.62
SecondaryChronic 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
Reported as:
Number · odds ratio
Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk
odds ratioRiociguatPlacebo
Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk0.99 (0.90 to 1.08)0.95 (0.86 to 1.04)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.56
SecondaryChanges 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
Reported as:
Mean · g/dL
Changes in Hemoglobin
g/dLRiociguatPlacebo
Changes in Hemoglobin-0.21 (-0.40 to -0.01)0.04 (-0.16 to 0.24)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.15 · Mean difference (final values): -0.24 · 90% CI -0.52 to 0.03
SecondaryChanges 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
Reported as:
Mean · percentage
Changes in Reticulocyte Count
percentageRiociguatPlacebo
Changes in Reticulocyte Count0.32 (-0.54 to 1.19)-1.15 (-2.05 to -0.24)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.05 · Mean difference (final values): 1.47 · 90% CI 0.22 to 2.72
SecondaryChanges 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
Reported as:
Mean · (x10^9 cells/L)
Changes in White Blood Cell Count
(x10^9 cells/L)RiociguatPlacebo
Changes in White Blood Cell Count-0.28 (-0.83 to 0.26)-0.13 (-0.69 to 0.43)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.75 · Mean difference (final values): -0.15 · 90% CI -0.93 to 0.63
SecondaryChanges 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
Reported as:
Mean · U/L
Changes in Lactate Dehydrogenase (LDH)
U/LRiociguatPlacebo
Changes in Lactate Dehydrogenase (LDH)-43.30 (-67.49 to -19.10)-14.02 (-39.80 to 11.76)
Statistical analysis
  • Riociguat vs Placebo · Mixed Models Analysis · p = 0.17 · Mean difference (final values): -29.28 · 90% CI -64.63 to 6.08
SecondaryChanges in Fetal Hemoglobin

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

Time frame:
Baseline,12 weeks
Reported as:
Mean · Percentage
Changes in Fetal Hemoglobin
PercentageRiociguatPlacebo
Changes in Fetal Hemoglobin-1.91 (-3.05 to -0.78)-0.28 (-1.44 to 0.88)
Statistical analysis
  • Riociguat vs Placebo · Regression, Linear · p = 0.07 · Mean difference (final values): -1.64 · 90% CI -3.13 to -0.15

Adverse events

Collected over Adverse events were data collected from baseline through 7 days after discontinuation of treatment, up to 13 Weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Riociguat2/66 (3%)15/66 (22.7%)53/66 (80.3%)
Placebo2/64 (3.1%)20/64 (31.3%)45/64 (70.3%)
Most frequent serious events
Showing 10 of 14
Most frequent serious events
EventRiociguatPlacebo
VOCGeneral disorders11/6614/64
Mitral Valve DiseaseCardiac disorders0/661/64
Lung InfectionInfections and infestations0/661/64
Skin InfectionInfections and infestations0/661/64
Other - PyelonephritisRenal and urinary disorders0/661/64
Thrombotic Thrombocytopenic PurpuraBlood and lymphatic system disorders0/661/64
Other - DizzinessEndocrine disorders0/661/64
LethargyNervous system disorders0/661/64
Other - PapilledemaVascular disorders0/661/64
Cardiac ArrestCardiac disorders1/660/64
Most frequent other events
Showing 10 of 22
Most frequent other events
EventRiociguatPlacebo
VOCGeneral disorders23/6621/64
HeadacheNervous system disorders14/666/64
OtherMusculoskeletal and connective tissue disorders9/6610/64
DiarrheaGastrointestinal disorders9/668/64
Gastroesophageal Reflux DiseaseGastrointestinal disorders8/661/64
DizzinessNervous system disorders8/663/64
NauseaGastrointestinal disorders7/663/64
VomitingGastrointestinal disorders6/662/64
CoughRespiratory, thoracic and mediastinal disorders5/661/64
PalpitationsCardiac disorders5/662/64

Baseline characteristics

Age, Continuous
Age, Continuous(years)RiociguatPlaceboTotal
Mean41.0 ± 11.844.8 ± 12.342.9 ± 12.1
Sex: Female, Male
Sex: Female, Male(Participants)RiociguatPlaceboTotal
Female363672
Male302858
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)RiociguatPlaceboTotal
Hispanic or Latino202
Not Hispanic or Latino6361124
Unknown or Not Reported134
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)RiociguatPlaceboTotal
Race — Black or African American6364127
Race — Some Other Race202
Race — Unknown101
Clinical Sickle Cell Phenotype (as reported by site)
Clinical Sickle Cell Phenotype (as reported by site)(Participants)RiociguatPlaceboTotal
SCD, subtype not immediately available011
HbSS494897
HbSC131124
HbSbeta-zero-thalassemia314
HbSbeta-plus-thalassemia134
BMI
BMI(kg/m²)RiociguatPlaceboTotal
Mean29.2 ± 9.727.0 ± 6.228.1 ± 8.2
Systolic BP
Systolic BP(mmHg)RiociguatPlaceboTotal
Mean128.5 ± 17.8125.5 ± 15.6127.1 ± 16.7
Diastolic BP
Diastolic BP(mmHg)RiociguatPlaceboTotal
Mean76.7 ± 11.573.8 ± 11.275.3 ± 11.4

16 further baseline measures are reported on the registry.

08

Study locations

20 sites
  • UCSF Benioff Children's Hospital Oakland
    Oakland, California 94609, United States
  • Howard University
    Washington, District of Columbia 20060, United States
  • University of Miami
    Miami, Florida 33136, United States
  • Emory University School of Medicine
    Atlanta, Georgia 30329, United States
  • University of Illinois, Chicago
    Chicago, Illinois 60612, United States
  • Indiana University
    Indianapolis, Indiana 46202, United States
  • Tulane University
    New Orleans, Louisiana 70112, United States
  • Johns Hopkins University
    Baltimore, Maryland 21205, United States
  • Boston University Medical Center
    Boston, Massachusetts 02118, United States
  • Albert Einstein University/ Montefiore Medical Center
    Bronx, New York 10467, United States
  • New York Presbyterian Brooklyn Methodist Hospital
    Brooklyn, New York 11225, United States
  • UNC Comprehensive Sickle Cell Center
    Chapel Hill, North Carolina 27599-7305, United States
  • Duke University
    Durham, North Carolina 27710, United States
  • East Carolina University
    Greenville, North Carolina 27834, United States
  • Ohio State University
    Columbus, Ohio 43210, United States
  • UPMC Division of Hematology and Oncology
    Pittsburgh, Pennsylvania 15233, United States
  • Medical University of South Carolina
    Charleston, South Carolina 29425, United States
  • University of Tennessee Health Science Center
    Memphis, Tennessee 38163, United States
  • University of Texas Southwestern
    Dallas, Texas 75390, United States
  • Virginia Commonwealth University Medical Center
    Richmond, Virginia 23298, United States
09

References and documents

Publications

  • Azbell RCG, Desai PC. Treatment dilemmas: strategies for priapism, chronic leg ulcer disease, and pulmonary hypertension in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):411-417. doi: 10.1182/hematology.2021000275. PubMed 34889382 ↗

Study documents

  • Protocol and statistical analysis plan · Jan 7, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jul 19, 2023, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02633397
Lead sponsor
Mark Gladwin
Responsible party
Mark Gladwin (Chariman of the Department of Medicine, University of Pittsburgh) — Sponsor-investigator
First posted
Dec 17, 2015
Start date
Apr 11, 2017
Primary completion
May 4, 2022
Completion
May 4, 2022
Results posted
Jul 19, 2023
Last update
Jul 19, 2023

Study contacts

Mark Gladwin, MD
principal investigator · University of Pittsburgh

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Jul 2023. You cannot join it, but the record below documents what was studied.

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