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

• ClinicalTrials.gov Identifier: NCT02633397
• Recruitment Status: Completed
• First Posted: December 17, 2015
• Last Update Posted: July 13, 2022
• Sponsor: Mark Gladwin
• Information provided by (Responsible Party): Mark Gladwin, University of Pittsburgh

Tracking Information

• First Submitted Date: December 7, 2015
• First Posted Date: December 17, 2015
• Last Update Posted Date: July 13, 2022
• Actual Study Start Date: April 11, 2017
• Actual Primary Completion Date: May 4, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 10, 2018): Overall incidence of treatment emergent severe adverse events (SAE) [ Time Frame: Baseline to Week 12 ]
• Original Primary Outcome Measures (submitted: December 14, 2015): Overall incidence of treatment emergent SAE [ Time Frame: Baseline to Week 12 ]

Current Secondary Outcome Measures (submitted: May 10, 2018)

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

Original Secondary Outcome Measures (submitted: December 14, 2015)

• Frequency of SAE due to sickle cell related painful crisis [ Time Frame: Baseline to Week 12 ]
• Overall incidences of treatment-emergent AEs [ Time Frame: Baseline to Week 12 ]
• Changes in pain intensity using numerical pain score [ Time Frame: Baseline to Week 12 ]
• Changes in functional exercise capacity by assessing 6 minute walk distance test [ Time Frame: Baseline to Week 12 ]
• Changes in blood pressure as the main pharmacodynamic variable [ Time Frame: Baseline to Week 12 ]
• Changes in the levels of plasma NT-proBNP [ Time Frame: Baseline to Week 12 ]
• Changes in the Modified Borg Dyspnoea Scale [ Time Frame: Baseline to Week 12 ]
• Changes in laboratory measures [ Time Frame: Baseline to Week 12 ]
• Incidences of Sickle Cell related clinical complications [ Time Frame: Baseline to Week 12 ]
• Changes in tricuspid regurgitant velocity using an invasive transthoracic echocardiography [ Time Frame: Baseline to Week 12 ]
• Changes in pain intensity using the Brief Pain Inventory [ Time Frame: Baseline to Week 12 ]
• Changes in pain intensity using electronic daily pain diary piloted at selected sites [ Time Frame: Baseline to Week 12 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Multi-Center Study of Riociguat in Patients With Sickle Cell Diseases
• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Sickle Cell Disease

Intervention

• 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
• 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

Study Arms

• Experimental: Riociguat
  Treatment Arm
  Intervention: Drug: Riociguat
• Placebo Comparator: Placebo
  Placebo Arm
  Intervention: Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 11, 2022): 97
• Original Estimated Enrollment (submitted: December 14, 2015): 100
• Actual Study Completion Date: May 4, 2022
• Actual Primary Completion Date: May 4, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02633397
• Other Study ID Numbers: PRO15110016
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Mark Gladwin, University of Pittsburgh
• Original Responsible Party: Gregory J. Kato, MD, University of Pittsburgh, Professor of Medicine
• Current Study Sponsor: Mark Gladwin
• Original Study Sponsor: Gregory J. Kato, MD
• Collaborators: Not Provided

Investigators

• Principal Investigator: Mark Gladwin, MD; University of Pittsburgh

• PRS Account: University of Pittsburgh
• Verification Date: July 2022