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

Phase 2

Completed

Conditions: Sickle Cell Disease

Interventions: Drug: Placebo
Drug: Riociguat

Registration Number: NCT02633397

Lead Sponsor: Mark Gladwin

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 130

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo Arm
Riociguat	Riociguat	Treatment Arm

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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.
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.
Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography	Baseline, 12 Weeks	Mean TRV 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.
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
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 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 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.
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 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 Fetal Hemoglobin	Baseline,12 weeks	Mean change in fetal hemoglobin from baseline to 12 weeks using a linear mixed model
End-systolic Volume Using Non-invasive Echocardiography	Baseline,12 weeks	Mean end-systolic volume (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.
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.
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 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.
Changes in Albumin/Creatinine Ratio	Baseline,12 weeks	Albumin/Creatinine Ratio (ACR) mean change from baseline to 12 weeks using linear regression model.
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.

Trial Locations

Locations (20): Ohio State University
🇺🇸
Columbus, Ohio, United States
New York Presbyterian Brooklyn Methodist Hospital
🇺🇸
Brooklyn, New York, United States
UPMC Division of Hematology and Oncology
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Texas Southwestern
🇺🇸
Dallas, Texas, United States
University of Tennessee Health Science Center
🇺🇸
Memphis, Tennessee, United States
Emory University School of Medicine
🇺🇸
Atlanta, Georgia, United States
Albert Einstein University/ Montefiore Medical Center
🇺🇸
Bronx, New York, United States
University of Illinois, Chicago
🇺🇸
Chicago, Illinois, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸
Oakland, California, United States
Tulane University
🇺🇸
New Orleans, Louisiana, United States
Indiana University
🇺🇸
Indianapolis, Indiana, United States
Duke University
🇺🇸
Durham, North Carolina, United States
Virginia Commonwealth University Medical Center
🇺🇸
Richmond, Virginia, United States
University of Miami
🇺🇸
Miami, Florida, United States
Boston University Medical Center
🇺🇸
Boston, Massachusetts, United States
UNC Comprehensive Sickle Cell Center
🇺🇸
Chapel Hill, North Carolina, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Howard University
🇺🇸
Washington, District of Columbia, United States