Clinical trial NCT02633397: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Disease
Keywords: SCD
Sickle Cell Disease
Riociguat
Adempas
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2015-12-17
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)
timeFrame: Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
Secondary outcomes:
measure: Frequency of SAE Due to Sickle Cell Related Painful Crisis
timeFrame: Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
measure: Overall Incidences of Treatment-emergent Adverse Events (AEs)
timeFrame: Baseline to Week 12
measure: Incidences of Sickle Cell Related Clinical Complications
timeFrame: Baseline to Week 12
measure: Pain Intensity Using the Brief Pain Inventory
timeFrame: Baseline, 12 weeks
measure: 6-minute Walk Distance
timeFrame: Baseline, 12 weeks
measure: Changes in the Dyspnea Borg Scale
timeFrame: Baseline,12 Weeks
measure: Fatigue Borg Scale
timeFrame: Baseline,12 weeks
measure: Changes in Blood Pressure as the Main Pharmacodynamic (MAP)
timeFrame: Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks
measure: Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography
timeFrame: Baseline, 12 Weeks
measure: End-systolic Volume Using Non-invasive Echocardiography
timeFrame: Baseline,12 weeks
measure: Ejection Fraction (Biplane) Using Non-invasive Echocardiography
timeFrame: Baseline, 12 weeks
measure: Changes in the Levels of Plasma NT-proBNP
timeFrame: Baseline,12 weeks
measure: Changes in Albumin/Creatinine Ratio
timeFrame: Baseline,12 weeks
measure: Microalbuminuria
timeFrame: Baseline,12 weeks
measure: Macroalbuminuria
timeFrame: Baseline,12 weeks
measure: Changes in Glomerular Filtration Rate
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks
measure: Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk
timeFrame: Baseline,12 weeks
measure: Changes in Hemoglobin
timeFrame: Baseline, 4 weeks, 8 weeks,12 weeks
measure: Changes in Reticulocyte Count
timeFrame: Baseline, 4 weeks, 8 weeks,12 weeks
measure: Changes in White Blood Cell Count
timeFrame: Baseline, 4 weeks, 8 weeks,12 weeks
measure: Changes in Lactate Dehydrogenase (LDH)
timeFrame: Baseline, 4 weeks, 8 weeks,12 weeks
measure: Changes in Fetal Hemoglobin
timeFrame: Baseline,12 weeks
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: University of Illinois, Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Bronx
country: United States
facility: Albert Einstein University/ Montefiore Medical Center
state: New York
city: Brooklyn
country: United States
facility: New York Presbyterian Brooklyn Methodist Hospital
state: New York
city: Chapel Hill
country: United States
facility: UNC Comprehensive Sickle Cell Center
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Division of Hematology and Oncology
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: University of Tennessee Health Science Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
Study officials:
affiliation: University of Pittsburgh
name: Mark Gladwin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.