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

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

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).

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Riociguat; Drug: Placebo

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
• Enrollment (Actual): 130
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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
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 Names: Adempas

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline through 7 days after discontinuation of treatment, up to 13 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
Overall Incidences of Treatment-emergent Adverse Events (AEs)	Proportion of participants that experienced treatment-emergent AEs	Baseline to Week 12
Incidences of Sickle Cell Related Clinical Complications	Incidence of Vaso-occlusive Crisis (VOC) between baseline and week 12	Baseline to Week 12
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.	Baseline, 12 weeks
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.	Baseline, 12 weeks
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.	Baseline,12 Weeks
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.	Baseline,12 weeks
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.	Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks
Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography	Mean TRV at 12 weeks assessed using ANCOVA, adjusting for baseline.	Baseline, 12 Weeks
End-systolic Volume Using Non-invasive Echocardiography	Mean end-systolic volume (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.	Baseline,12 weeks
Ejection Fraction (Biplane) Using Non-invasive Echocardiography	Mean ejection fraction (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.	Baseline, 12 weeks
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.	Baseline,12 weeks
Changes in Albumin/Creatinine Ratio	Albumin/Creatinine Ratio (ACR) mean change from baseline to 12 weeks using linear regression model.	Baseline,12 weeks
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	Baseline,12 weeks
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.	Baseline,12 weeks
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.	Baseline, 4 weeks, 8 weeks, 12 weeks
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	Baseline,12 weeks
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.	Baseline, 4 weeks, 8 weeks,12 weeks
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.	Baseline, 4 weeks, 8 weeks,12 weeks
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.	Baseline, 4 weeks, 8 weeks,12 weeks
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.	Baseline, 4 weeks, 8 weeks,12 weeks
Changes in Fetal Hemoglobin	Mean change in fetal hemoglobin from baseline to 12 weeks using a linear mixed model	Baseline,12 weeks

Collaborators and Investigators

• Sponsor: Mark Gladwin
• Investigators: Principal Investigator: Mark Gladwin, MD, University of Pittsburgh

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2017
• Primary Completion (Actual): May 4, 2022
• Study Completion (Actual): May 4, 2022

Study Registration Dates

• First Submitted: December 7, 2015
• First Submitted That Met QC Criteria: December 14, 2015
• First Posted (Estimated): December 17, 2015

Study Record Updates

• Last Update Posted (Actual): July 19, 2023
• Last Update Submitted That Met QC Criteria: July 17, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; SCD; Adempas; Riociguat
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: PRO15110016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No