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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Riociguat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat<br>Treatment Arm | Drug: Riociguat<br>* Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks<br>* Other names: Adempas;|
| Placebo Comparator: Placebo<br>Placebo Arm | Drug: Placebo<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SCD, Sickle Cell Disease, Riociguat, Adempas