A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
研究概览
简要总结
The primary purpose of this study is to evaluate the safety, tolerability and effectiveness of encaleret in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be able to understand and sign a written informed consent or assent form, which must be obtained prior to initiation of study procedures.
- •Postmenopausal women are allowed to participate in this study
- •Body mass index (BMI) ≥ 18.5 to < 39 kilograms (kg)/square meter (m^2)
- •Have an activating mutation of the Calcium-sensing receptor (CASR) gene
- •Participants being treated with thiazide diuretics may be enrolled if they are willing and able to discontinue thiazides
- •Participants being treated with strong Cytochrome P3A4 (CYP3A4) inhibitors should ideally, if clinically appropriate, discontinue these medications during the screening period
- •Participants being treated with magnesium or potassium citrate supplements should discontinue such treatment starting on Day -1 during Period 1 and Period 2 and may be asked to discontinue treatment during Period 3
排除标准
- •History of treatment with parathyroid hormone (PTH) 1-84 or 1-34 within the previous 3 months
- •History of hypocalcemic seizure within the past 3 months
- •Blood 25-OH Vitamin D level < 25 nanograms (ng)/milliliter (mL)
- •Participants with hemoglobin (Hgb) < 13 grams (g)/deciliter (dL) for men and < 12 g/dL for women
- •Estimated glomerular filtration rate (eGFR) < 25 mL/minute/1.73 m^2 using Chronic Kidney Disease Epidemiology Collaboration (for participants <18 years old the Schwartz equation will be calculated)
- •12-lead resting electrocardiogram (ECG) with clinically significant abnormalities
- •Participants with positive hepatitis B surface antigen (HBsAg), hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test results at the Screening Visit
- •Pregnant or nursing (lactating) women
- •History of drug or alcohol dependency within 12 months preceding the Screening Visit
- •History of thyroid or parathyroid surgery
- •Current participation in other investigational drug studies
- •Unwillingness to refrain from blood donation within 12 weeks prior to Screening Visit from the start of the study enrollment through one year after the last dose of the study drug
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Cohort 1: Ascending + Steady-State Dose
Period 1: Participants will receive an ascending dose of encaleret once daily for the first 3 days. Participants will then receive an individualized dose of encaleret twice daily for 2 days.
Period 2: Participants will receive encaleret twice daily for 5 days at a single dose level based on responses from Period 1.
Period 3: After completion of Period 2, participants will be eligible to receive encaleret for an additional 24 weeks.
Long-Term Extension (LTE): At the end of the study, participants will also have an option to receive encaleret for up to an additional 2 years.
干预措施: Encaleret (Drug)
Cohort 2: Steady-State Dose
Participants will directly be enrolled into Period 2, and receive encaleret twice daily at a dose based on data and responses from Cohort 1 Period 1.
Period 2: Participants will receive encaleret twice daily for 5 days.
Period 3: After completion of Period 2, participants will be eligible to receive encaleret for an additional 24 weeks.
LTE: At the end of the study, participants will also have an option to receive encaleret for up to an additional 2 years.
干预措施: Encaleret (Drug)
结局指标
主要结局
Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: Day 1 up to 16 months
Adverse events (AEs) were defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. Treatment-emergence was defined as any AE(s) regardless of relationship to investigational medicinal product (IMP), that had an onset or worsened in severity on or after the first dose of IMP.
Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa)
时间窗: Baseline, Week 24
Period 3: Rate of Urinary Calcium Excretion
时间窗: Week 24
次要结局
- Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood(15 minutes pre-dose on Day 5 of Periods 1 and 2 (Periods were 5 days))
- Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret(Periods 1 and 2: Day 5 (Periods were 5 days))
- Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret(Periods 1 and 2: Day 5, Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret(Periods 1 and 2: Day 5; Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa)(Period 2: Baseline, Day 5 (Period was 5 days), Period 3: Baseline, Week 24 (Period was 24 weeks))
- Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion(Period 3: Week 24, 15 minutes pre-dose (Period was 24 weeks))
- Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion(Periods 1 and 2: Day 5; Period 3, Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR)(Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose) (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D(Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations(Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations(Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations(Periods 1 and 2: Day 5 (0-24 hours post-dose), Period 3: Week 24: (0-24 hours post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations(Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for periods 1 and 2; 24 weeks for period 3))
- Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations(Periods 1 and 2: Day 5 (0-4h post-dose), Period 3: Week 24 (0-4h post dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx)(Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))
- Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP)(Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3))