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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02633397
Recruitment Status : Completed
First Posted : December 17, 2015
Last Update Posted : July 13, 2022
Information provided by (Responsible Party):
Mark Gladwin, University of Pittsburgh

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).

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Riociguat Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 97 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase II Randomized, Double-Blind, Placebo-Controlled Multi-Center Study to Assess the Safety, Tolerability, and Efficacy of Riociguat in Patients With Sickle Cell Diseases
Actual Study Start Date : April 11, 2017
Actual Primary Completion Date : May 4, 2022
Actual Study Completion Date : May 4, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Riociguat

Arm Intervention/treatment
Experimental: Riociguat
Treatment Arm
Drug: 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
Other Name: Adempas

Placebo Comparator: Placebo
Placebo Arm
Drug: 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

Primary Outcome Measures :
  1. Overall incidence of treatment emergent severe adverse events (SAE) [ Time Frame: Baseline to Week 12 ]

Secondary Outcome Measures :
  1. Frequency of SAE due to sickle cell related painful crisis [ Time Frame: Baseline to Week 12 ]
  2. Overall incidences of treatment-emergent adverse events (AEs) [ Time Frame: Baseline to Week 12 ]
  3. Changes in pain intensity using numerical pain score [ Time Frame: Baseline to Week 12 ]
  4. Changes in functional exercise capacity by assessing 6 minute walk distance test [ Time Frame: Baseline to Week 12 ]
  5. Changes in blood pressure as the main pharmacodynamic variable [ Time Frame: Baseline to Week 12 ]
  6. Changes in the levels of plasma NT-proBNP [ Time Frame: Baseline to Week 12 ]
  7. Changes in the Modified Borg Dyspnoea Scale [ Time Frame: Baseline to Week 12 ]
  8. Changes in laboratory measures [ Time Frame: Baseline to Week 12 ]
  9. Incidences of sickle cell related clinical complications [ Time Frame: Baseline to Week 12 ]
  10. Changes in tricuspid regurgitant velocity using non-invasive echocardiography [ Time Frame: Baseline to Week 12 ]
  11. Changes in pain intensity using the Brief Pain Inventory [ Time Frame: Baseline to Week 12 ]
  12. Changes in pain intensity using electronic daily pain diary piloted at selected sites [ Time Frame: Baseline to Week 12 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   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:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02633397

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Sponsors and Collaborators
Mark Gladwin
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Principal Investigator: Mark Gladwin, MD University of Pittsburgh
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Mark Gladwin, Chariman of the Department of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02633397    
Other Study ID Numbers: PRO15110016
First Posted: December 17, 2015    Key Record Dates
Last Update Posted: July 13, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mark Gladwin, University of Pittsburgh:
Sickle Cell Disease
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Enzyme Activators
Molecular Mechanisms of Pharmacological Action