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

Autosomal Dominant Hypocalcemia (ADH) Clinical Trial

— CALIBRATE  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05680818
• Other study ID #: CLTX-305-302
• Status: Recruiting
• Phase: Phase 3
• Start date: January 6, 2023
• Est. completion date: September 2028

Study information

• Verified date: January 2024
• Source: Calcilytix Therapeutics, Inc., a BridgeBio company
• Contact: Medical Information
• Phone: 650.600.3610
• Email: MedInfo[@]bridgebio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: September 2028
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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 (ß-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.

Related Conditions & MeSH terms

• Arthrogryposis
• Autosomal Dominant Hypocalcemia (ADH)
• Hypocalcemia

Intervention

Drug:
• Encaleret
Administered as film-coated tablet for oral use

Dietary Supplement:
• Standard of Care
Calcium supplements and/or active Vitamin D (calcitriol, alfacalcidol, falecalcitriol, etc.)

Locations

Country	Name	City	State
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal North Shore Hospital	Saint Leonards	New South Wales
Canada	Bone Research & Education Centre	Oakville	Ontario
Czechia	Vseobecna fakultni nemocnice v Praze	Nové Mesto
Denmark	Aarhus University Hospital	Aarhus
France	CHU Bicetre	Le Kremlin-Bicêtre
France	Hôpital Edouard Herriot - HCL	Lyon
Italy	IRCCS Ospedale San Raffaele	Milano
Italy	Fondazione Policlinico Universitario Campus Bio-Medico	Roma
Japan	Osaka University Hospital	Osaka
Japan	The University of Tokyo Hospital	Tokyo
Netherlands	Eramus MC	Rotterdam
United States	Children's Hospital Colorado	Aurora	Colorado
United States	NIH	Bethesda	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Physicians East	Greenville	North Carolina
United States	Houston Methodist Hospital	Houston	Texas
United States	Indiana University Health University Hospital	Indianapolis	Indiana
United States	UCSF Benioff Children's Hospital, Oakland	Oakland	California
United States	Mayo Clinic - Rochester	Rochester	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Calcilytix Therapeutics, Inc., a BridgeBio company

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Czechia,  Denmark,  France,  Italy,  Japan,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of Participants With Intact Parathyroid Hormone (iPTH) Within or Greater than the Reference Range		Up to Week 24
Secondary	Number of Participants who Achieve Blood Magnesium Within the Reference Range		Up to Week 24
Secondary	Number of Participants who Achieve Blood Phosphate Within the Reference Range		Up to Week 24
Secondary	Change From Baseline in Blood 1,25-(OH)2 Vitamin D		Baseline to Week 24
Secondary	Change From Baseline in cCa		Baseline to Week 24
Secondary	Change From Baseline in 24-hour UCa		Baseline to Week 24
Secondary	Change From Baseline in iPTH		Baseline to Week 24
Secondary	Change From Baseline in Blood Phosphate and Blood Magnesium		Baseline to Week 24
Secondary	Change From Baseline in Urine Magnesium, Phosphate, Sodium, and Citrate Handling		Baseline to Week 24
Secondary	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
Secondary	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
Secondary	Number of Participants in the Encaleret Arm Receiving Calcium and/or Vitamin D Supplements		Up to Week 24
Secondary	Steady State Encaleret Trough Concentration (Ctrough)		Up to Week 24