Safety, Tolerability, and Efficacy of Encaleret in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1
Phase 2
Completed
- Conditions
- Autosomal Dominant Hypocalcemia (ADH)Autosomal Dominant Hypocalcemia Type 1 (ADH1)
- Interventions
- Registration Number
- NCT04581629
- Lead Sponsor
- Calcilytix Therapeutics, Inc., a BridgeBio company
- Brief Summary
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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 13
Inclusion Criteria
- 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
Key
Exclusion Criteria
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1: Ascending + Steady-State Dose Encaleret 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. Cohort 2: Steady-State Dose Encaleret 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.
- Primary Outcome Measures
Name Time Method Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs) 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) Baseline, Week 24 Period 3: Rate of Urinary Calcium Excretion Week 24
- Secondary Outcome Measures
Name Time Method 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) Blood samples were taken for analysis of iPTH concentrations. iPTH concentrations were analyzed via an electrochemiluminescence immunoassay.
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) Data values presented are for the change from baseline for the average values at the specified timepoints/visits.
Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion Period 3: Week 24, 15 minutes pre-dose (Period was 24 weeks) Fractional Excretion of Calcium was derived as (Urine Calcium at the interval considered \* Serum Creatinine at the end of the interval considered)/(Serum Calcium at the end of the interval considered \* Urine Creatinine at the interval considered) and is presented as percentage.
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) eGFR was calculated using Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) formula (mL/min/1.73m\^2) = 141 x min (SCr/K, 1)\^α x max(SCR /K,1)-1.209 x 0.993Age x 1.018 \[if female\] x 1.159 \[if Black\], where SCr is the serum creatinine (mg/dL), K = 0.7 for female and 0.9 for males, α is -0.329 for female and -0.411 for males.
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) Blood samples were taken for analysis of bone resorption markers (CTx).
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) Blood samples were taken for analysis of bone formation markers (P1NP).
Trial Locations
- Locations (1)
National Institutes of Health (NIH) Clinical Center
🇺🇸Bethesda, Maryland, United States