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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 130
- 试验地点
- 20
- 主要终点
- Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Riociguat
Treatment Arm
干预措施: Riociguat (Drug)
Placebo
Placebo Arm
干预措施: Placebo (Drug)
结局指标
主要结局
Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)
时间窗: 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.
次要结局
- Frequency of SAE Due to Sickle Cell Related Painful Crisis(Baseline through 7 days after discontinuation of treatment, up to 13 Weeks)
- Overall Incidences of Treatment-emergent Adverse Events (AEs)(Baseline to Week 12)
- Incidences of Sickle Cell Related Clinical Complications(Baseline to Week 12)
- Pain Intensity Using the Brief Pain Inventory(Baseline, 12 weeks)
- 6-minute Walk Distance(Baseline, 12 weeks)
- Changes in the Dyspnea Borg Scale(Baseline,12 Weeks)
- Fatigue Borg Scale(Baseline,12 weeks)
- Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography(Baseline, 12 Weeks)
- Ejection Fraction (Biplane) Using Non-invasive Echocardiography(Baseline, 12 weeks)
- Microalbuminuria(Baseline,12 weeks)
- Changes in Reticulocyte Count(Baseline, 4 weeks, 8 weeks,12 weeks)
- Changes in Lactate Dehydrogenase (LDH)(Baseline, 4 weeks, 8 weeks,12 weeks)
- Changes in Blood Pressure as the Main Pharmacodynamic (MAP)(Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks)
- Changes in Hemoglobin(Baseline, 4 weeks, 8 weeks,12 weeks)
- Changes in White Blood Cell Count(Baseline, 4 weeks, 8 weeks,12 weeks)
- Changes in Fetal Hemoglobin(Baseline,12 weeks)
- End-systolic Volume Using Non-invasive Echocardiography(Baseline,12 weeks)
- Macroalbuminuria(Baseline,12 weeks)
- Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk(Baseline,12 weeks)
- Changes in the Levels of Plasma NT-proBNP(Baseline,12 weeks)
- Changes in Albumin/Creatinine Ratio(Baseline,12 weeks)
- Changes in Glomerular Filtration Rate(Baseline, 4 weeks, 8 weeks, 12 weeks)
研究者
Mark Gladwin
Chariman of the Department of Medicine
University of Pittsburgh