Safety, Tolerability, and Efficacy of Encaleret in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1

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

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).

Study Overview

• Status: Completed
• Conditions: Autosomal Dominant Hypocalcemia (ADH); Autosomal Dominant Hypocalcemia Type 1 (ADH1)
• Intervention / Treatment: Drug: Encaleret

Detailed Description

Autosomal dominant hypocalcemia Type 1 is a rare familial genetic form of hypoparathyroidism. Autosomal Dominant Hypocalcemia (ADH) Type 1 is typically passed down from affected parents to their children.

This is a Phase 2b open label, dose finding study to evaluate the safety and tolerability of CLTX-305 (encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1 as well as the effects of CLTX-305 (encaleret) on blood calcium concentration.

The estimated duration of this study is 41 months. This study plans to evaluate multiple doses of the investigational drug CLTX-305 (encaleret), in addition to safety and efficacy. CLTX-305 is administered orally.

The study is divided into 3 Periods followed by a Long-Term Extension (LTE):

Periods 1: Up to 8 study participants will be admitted to the NIH Clinical Center for 7 days, where they will be administered different doses of CLTX-305 (encaleret) for up to 5 days.

Period 2: Participants from Period 1, and up to 10 new study participants will be admitted to the NIH Clinical Center for 7 days, where they will be administered different doses of CLTX-305 (encaleret) for up to 5 days.

Period 3: 24 weeks during which eligible study participants who completed Period 2 will take CLTX-305 (encaleret) at home.

LTE: Up to 25 months during which eligible study participants who completed Period 3 will take CLTX-305 (encaleret) at home.

Study participants may:

• Participate in Period 1
• Participate in Period 2
• Participate in both Period 1 and Period 2
• Participate in Period 3 after completing Period 2
• Participate in LTE after completing Period 3

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health (NIH) Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Encaleret; Tablets administered orally; Other Names: CLTX-305
Experimental: 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.	Drug: Encaleret; Tablets administered orally; Other Names: CLTX-305

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	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.	Day 1 up to 16 months
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

Outcome Measure	Measure Description	Time Frame
Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood	Blood samples were taken for analysis of iPTH concentrations. iPTH concentrations were analyzed via an electrochemiluminescence immunoassay.	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)	Data values presented are for the change from baseline for the average values at the specified timepoints/visits.	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	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.	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)	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 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)	Blood samples were taken for analysis of bone resorption markers (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)	Blood samples were taken for analysis of bone formation markers (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)

Collaborators and Investigators

• Sponsor: Calcilytix Therapeutics, Inc., a BridgeBio company
• Investigators: Study Director: Calcilytix Medical Director, Calcilytix Therapeutics, Inc., a BridgeBio company

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2020
• Primary Completion (Actual): September 7, 2023
• Study Completion (Actual): September 7, 2023

Study Registration Dates

• First Submitted: September 16, 2020
• First Submitted That Met QC Criteria: October 8, 2020
• First Posted (Actual): October 9, 2020

Study Record Updates

• Last Update Posted (Estimated): November 19, 2024
• Last Update Submitted That Met QC Criteria: October 28, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Muscular Diseases; Joint Diseases; Metabolic Diseases; Musculoskeletal Abnormalities; Congenital Abnormalities; Water-Electrolyte Imbalance; Calcium Metabolism Disorders; Arthrogryposis; Hypocalcemia
• Other Study ID Numbers: CLTX-305-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No