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

Study Overview
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Brief Summary
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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 ADH1.

Detailed Description
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Autosomal Dominant Hypocalcemia Type 1 is a rare genetic form of hypoparathyroidism. Autosomal Dominant Hypocalcemia (ADH) Type 1 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. The estimated duration of this main portion of the study is approximately 12 months. The duration of the long-term extension 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 may enter a Long-Term Extension (LTE) and receive encaleret treatment for approximately 48 months, or until a participant has access to commercial encaleret, or the Sponsor decides to end the study, whichever occurs first.

Official Title
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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)

Conditions
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Autosomal Dominant Hypocalcemia (ADH)

Intervention / Treatment
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* Drug: Encaleret
* Dietary Supplement: Standard of Care


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants must have a documented pathogenic activating variant, or variant of uncertain significance, of the calcium sensing receptor (CASR) gene associated with biochemical findings of hypoparathyroidism. Participants must have a documented history of symptoms or signs of ADH1. Participants 16 to <18 years old must have closed growth plates on hand radiograph. Participants treated with thiazide diuretics must discontinue thiazides for at least 14 days prior to Screening through Week 24 (Period 3). When the thiazide is being used as an antihypertensive, alternative therapy will be prescribed by the Investigator as needed. Participants treated with phosphate binders must discontinue the phosphate binders at least one day prior to the Screening Visit. Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret. Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret. Participants must meet SoC Optimization criteria as defined in the protocol. Key Exclusion Criteria: History of hypocalcemic seizure within the past 3 months preceding Screening. History of thyroid or parathyroid surgery. Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive beta-human chorionic gonadotropin (β-hCG) laboratory test. History of treatment with PTH 1-84 or 1-34 within the 2 months preceding Screening and requiring SoC 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). Blood 25-OH Vitamin D level <25 ng/mL. Estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2 using 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). 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autosomal Dominant Hypocalcemia Type 1 (ADH1), Hypocalcemia, Musculoskeletal Diseases, Muscular Diseases, Musculoskeletal Abnormalities, Calcium Metabolism Disorders, Metabolic Diseases, Hypoparathyroidism, Hypocalcemic Seizures, Hypercalciuria, Nephrocalcinosis, Nephrolithiasis, Calcium Sensing Receptor, Encaleret, Hypopara