Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With ADH1 (CALIBRATE)

CALIBRATE: A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With Autosomal Dominant Hypocalcemia Type 1 (ADH1)

The primary purpose of the study is to understand the effectiveness, safety, and tolerability of encaleret when compared to standard of care (SoC) treatment in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1).

Study Overview

• Status: Recruiting
• Conditions: Autosomal Dominant Hypocalcemia (ADH)
• Intervention / Treatment: Drug: Encaleret; Dietary supplement: Standard of Care

Detailed Description

ADH1 is a rare genetic form of hypoparathyroidism. ADH1 may be passed down from affected parents to their children.

The main portion of the study is divided into a Screening Period and 3 Periods followed by an optional Long-Term Extension (LTE). The estimated duration of this main portion of the study is approximately 12 months. The duration of the LTE is approximately 48 months.

Participants will enter an up-to-6-week Screening period and once confirmation of all Inclusion/Exclusion criteria transition into an up-to-15-week standard of care (SoC) optimization phase. The eligible participants will enter Period 1 after completing the SoC optimization phase.

Period 1 is the 4-week SoC Maintenance period of the study during which the SoC dose will only be adjusted to address potential safety concerns such as hypocalcemia or hypercalcemia.

After completion of Period 1, eligible participants will enter Period 2 and will be randomized to receive either encaleret or SoC treatment for 20 weeks. Both the investigator and participant will know whether the participant was randomized to the encaleret treatment arm or SoC treatment arm. During Period 2, encaleret or SoC will be adjusted based on blood calcium levels.

After completion of Period 2, participants will proceed to Period 3, the 4-week dose maintenance period.

Following completion of Period 3, participants from CLTX-305-302 may enter the LTE. Those who completed CLTX-305-201 (NCT04581629) are also eligible to continue in the LTE. Participants will receive encaleret treatment for approximately 48 months, or 72 months for participants who transitioned from CLTX-305-201, or until a participant has access to commercial encaleret, or the Sponsor decides to end the study, whichever occurs first.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Medical Information; Phone Number: 650.600.3610; Email: MedInfo@bridgebio.com

Study Locations

• Australia
  • New South Wales
    • Saint Leonards, New South Wales, Australia, 2065
      • Recruiting
      • Royal North Shore Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Recruiting
      • Royal Brisbane and Women's Hospital
• Canada
  • Ontario
    • Oakville, Ontario, Canada, L6M 1M1
      • Recruiting
      • Bone Research & Education Centre
• Czechia
  • Nové Město, Czechia, 128 08
    • Recruiting
    • Vseobecna Fakultni Nemocnice V Praze
• Denmark
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
• France
  • Le Kremlin-Bicêtre, France, 94270
    • Recruiting
    • CHU Bicêtre
  • Lyon, France, 69003
    • Recruiting
    • Hôpital Edouard Herriot - HCL
• Italy
  • Milano, Italy, 20132
    • Recruiting
    • IRCCS Ospedale San Raffaele
  • Roma, Italy, 00128
    • Recruiting
    • Fondazione Policlinico Universitario Campus Bio-medico
• Japan
  • Osaka, Japan, 565-0871
    • Recruiting
    • Osaka University Hospital
  • Tokyo, Japan, 113-8655
    • Recruiting
    • The University of Tokyo Hospital
• Netherlands
  • Rotterdam, Netherlands, 3015 AA
    • Recruiting
    • Eramus MC
• United States
  • California
    • Oakland, California, United States, 94609
      • Recruiting
      • UCSF Benioff Children's Hospital, Oakland
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University Health University Hospital
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • NIH
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic - Rochester
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Recruiting
      • Physicians East
      • Contact: M Warren, MD
  • Ohio
    • Columbus, Ohio, United States, 43203
      • Recruiting
      • Ohio State University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Houston Methodist Hospital

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

1. Participants must have a documented pathogenic or likely pathogenic activating variant, or variant of uncertain significance, of the calcium sensing receptor (CASR) gene associated with biochemical findings of hypoparathyroidism.
2. Participants must have a documented history of symptoms or signs of ADH1.
3. Participants 16 to <18 years old must have closed growth plates on hand radiograph.
4. Participants treated with thiazide diuretics must discontinue thiazides for at least 14 days prior to SoC Optimization Visit 1 through Week 24 (Period 3). When the thiazide is being used as an antihypertensive, alternative therapy will be prescribed by the Investigator as needed.
5. Participants treated with phosphate binders must discontinue the phosphate binders at least one day prior to the SoC Optimization Visit 1.
6. Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret.
7. Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret.
8. Participants must meet SoC Optimization criteria as defined in the protocol.

Key Exclusion Criteria:

1. History of hypocalcemic seizure within the past 3 months preceding Screening.
2. History of thyroid or parathyroid surgery.
3. History of renal transplantation.
4. Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive beta-human chorionic gonadotropin (β-hCG) laboratory test.
5. History of treatment with parathyroid hormone (PTH) 1-84 or 1-34 within the 2 months preceding Screening and requiring SoC doses exceeding >1.2× their pre-PTH treatment total daily doses or bone turnover markers, Collagen cross-linked C-telopeptide (CTx )and Procollagen type 1 N-propeptide (P1NP), > upper limit of normal for sex, age (men only) and menopausal status (women only).
6. Blood 25-OH Vitamin D level <25 nanograms (ng)/milliliter (mL).
7. Estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m^2 using chronic kidney disease-EPI creatinine equation refit without the race variable (chronic kidney disease-EPI creatinine equation refit without the race variable [CKD-EPIcr_R]) (for participants <18 years old the Bedside Schwartz equation should be used).
8. Participants with positive Hepatitis B surface antigen (HBsAg), Hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test at the Screening Visit. Participants who are in complete remission from Hepatitis C virus (HCV) as evidenced by sensitive assay ≥12 weeks after completion of HCV therapy may participate in the study.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Encaleret; Participants will receive encaleret at a dose as needed based on calcium levels.	Drug: Encaleret; Administered as film-coated tablet for oral use; Other Names: CLTX-305; Encaleret Sulfate
Other: Standard of Care (SoC); Participants will continue receiving calcium supplements and/or active Vitamin D (calcitriol, alfacalcidol, falecalcitriol, etc.)	Dietary supplement: Standard of Care; Calcium supplements and/or active Vitamin D (calcitriol, alfacalcidol, falecalcitriol, etc.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Responders who Achieve Both Albumin-Corrected Blood Calcium (cCa) and 24-hour Urinary Calcium (UCa) Within the Target Range	cCa within 8.3-10.7 mg/dL (2.1-2.7 millimoles per liter [mmol/L]); 24-hr UCa within the reference range (< 300 mg/day for men [7.5 mmol/day], < 250 mg/day for women [6.25 mmol/day])	Up to Week 24

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Intact Parathyroid Hormone (iPTH) Within or Greater than the Reference Range	Up to Week 24
Number of Participants who Achieve Blood Magnesium Within the Reference Range	Up to Week 24
Number of Participants who Achieve Blood Phosphate Within the Reference Range	Up to Week 24
Change From Baseline in Blood 1,25-(OH)2 Vitamin D	Baseline to Week 24
Change From Baseline in cCa	Baseline to Week 24
Change From Baseline in 24-hour UCa	Baseline to Week 24
Change From Baseline in iPTH	Baseline to Week 24
Change From Baseline in Blood Phosphate and Blood Magnesium	Baseline to Week 24
Change From Baseline in Urine Magnesium, Phosphate, Sodium, and Citrate Handling	Baseline to Week 24
Change From Baseline in QT Interval Corrected for Changes in the Heart Rate With Fridericia Formula (QTcF) as Assessed by Electrocardiogram (ECG)	Baseline to Week 24
Change from Baseline in 36-Item Short Form Health Survey (SF-36) Physical Component Score and Mental Component Score and Each of the Sub-Domains	Baseline to Week 24
Number of Participants in the Encaleret Arm Receiving Calcium and/or Vitamin D Supplements	Up to Week 24
Steady State Encaleret Trough Concentration (Ctrough)	Up to Week 24

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): January 6, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: December 12, 2022
• First Submitted That Met QC Criteria: January 9, 2023
• First Posted (Actual): January 11, 2023

Study Record Updates

• Last Update Posted (Estimated): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Musculoskeletal Diseases; Muscular Diseases; Metabolic Diseases; Hypocalcemia; Hypoparathyroidism; Hypercalciuria; Calcium Sensing Receptor; Autosomal Dominant Hypocalcemia Type 1 (ADH1); Musculoskeletal Abnormalities; Calcium Metabolism Disorders; Hypocalcemic Seizures; Nephrocalcinosis; Nephrolithiasis; Encaleret; Hypopara
• Additional Relevant MeSH Terms: Metabolic Diseases; Congenital Abnormalities; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Calcium Metabolism Disorders; Water-Electrolyte Imbalance; Hypocalcemia; Arthrogryposis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents; Micronutrients; Membrane Transport Modulators; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vasoconstrictor Agents; Calcium Channel Agonists; Vitamin D; Calcium; Calcitriol; Alfacalcidol; Hydroxycholecalciferols; 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3
• Other Study ID Numbers: CLTX-305-302

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