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

Sponsor

Calcilytix Therapeutics, Inc., a BridgeBio company (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05680818

Collaborator

(none)

Enrollment

Location

Arms

71.3

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A global, multi-center, 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)

Condition or Disease	Intervention/Treatment	Phase
Autosomal Dominant Hypocalcemia (ADH)	Drug: Encaleret Dietary Supplement: Calcium supplements and active Vitamin D (calcitriol, alfacalcidol, falecalcitriol, etc.)	Phase 3

Detailed Description

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.

This is a multi-center, randomized, open-label, two-arm, three-period Phase 3 study with a Long-Term Extension (LTE) evaluating the efficacy and safety of encaleret in participants with ADH1. The study will be conducted in adolescents and adults (≥16 years). Approximately 45 eligible ADH1 participants who are naïve to encaleret will enroll in this study.

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-4-week Screening period and once confirmation of all Inclusion/Exclusion criteria transition into an up-to-15-week standard of care (SoC) optimization phase in which each participant's SoC treatment regimen will be assessed and optimized by Investigators in relation to the presence/absence and control of hypocalcemia-related symptoms and the observed blood and 24-hr urine calcium values. 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 be randomized 2:1 to the encaleret treatment arm or the SoC treatment arm and will enter Period 2, a 20-week dose titration period. 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 titrated/adjusted as needed in an effort to achieve target blood calcium levels while minimizing urine calcium excretion.

After completion of Period 2, participants will proceed to Period 3, the 4-week dose maintenance period. During Period 3, encaleret or SoC doses should remain stable. Doses will only be titrated/adjusted to address potential safety concerns including management of hypocalcemia or hypercalcemia.

Following completion of Period 3, participants may enter a Long-Term Extension 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Jan 6, 2023

Anticipated Primary Completion Date :

Dec 15, 2023

Anticipated Study Completion Date :

Dec 15, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Encaleret Participants will undergo encaleret dosing titration as needed in order to achieve the optimal encaleret dose to reach acceptable calcium levels.	Drug: Encaleret Encaleret is a drug product supplied as a film-coated tablet intended for oral administration Other Names: CLTX-305 Encaleret Sulfate
Other: Standard of Care (SoC) Participants randomized to SoC treatment will continue calcium supplements and active Vitamin D (calcitriol or alfacalcidol)	Dietary Supplement: Calcium supplements and active Vitamin D (calcitriol, alfacalcidol, falecalcitriol, etc.) Standard of Care

Arm

Intervention/Treatment

Experimental: Encaleret

Participants will undergo encaleret dosing titration as needed in order to achieve the optimal encaleret dose to reach acceptable calcium levels.

Drug: Encaleret

Encaleret is a drug product supplied as a film-coated tablet intended for oral administration

Other Names:

CLTX-305

Encaleret Sulfate

Other: Standard of Care (SoC)

Participants randomized to SoC treatment will continue calcium supplements and active Vitamin D (calcitriol or alfacalcidol)

Dietary Supplement: Calcium supplements and active Vitamin D (calcitriol, alfacalcidol, falecalcitriol, etc.)

Standard of Care

Outcome Measures

Primary Outcome Measures

Efficacy - Primary Endpoint [Period 3 length is 4 weeks]
The proportion of participants who meet both of the following criteria for ≥50% of available Period 3 visits: 1) cCa within 8.3-10.7 mg/dL and 2) 24-hr UCa within the reference range (<300 mg/day for men, <250 mg/day for women) or ≥50% decrease from Baseline

Secondary Outcome Measures

To compare the efficacy of encaleret and SoC treatments on intact PTH (iPTH) [Period 3 length is 4 weeks]
Proportion of participants with iPTH within or greater than the reference range post-dose at Period 3, Week 24
To compare the efficacy of encaleret and SoC treatments on blood phosphate [Period 3 length is 4 weeks]
Proportion of participants with blood phosphate within the reference range when averaged across Period 3
To compare the efficacy of encaleret and SoC treatments on blood magnesium [Period 3 length is 4 weeks]
Proportion of participants with blood magnesium within the reference range when averaged across Period 3
To compare the efficacy of encaleret and SoC treatments on 1,25-(OH)2 Vitamin D [Period 1 thru Period 3 length approximately 30 weeks]
Change from Baseline in blood 1,25-(OH)2 Vitamin D to Period 3, Week 24
To compare the efficacy of encaleret and SoC treatments on urine biomarkers [Period 1 thru Period 3 length approximately 30 weeks]
Change from Baseline in urine magnesium, phosphate, creatinine, sodium, and citrate handling to Period 3, Week 24
To compare the efficacy of encaleret and SoC treatments on QTcF duration [Period 1 thru Period 3 length approximately 30 weeks]
Change from Baseline in QTcF as assessed by ECG to Period 3, Week 24
To compare the efficacy of encaleret and SoC treatments on patient reported outcomes [Period 1 thru Period 3 length approximately 30 weeks]
Change from Baseline in the The Short Form-36 Health Survey (SF-36) to Period 3, Week 24. This consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Screening thru Period 3 length approximately 49 weeks]
AEs and SAEs, including frequency and severity while enrolled in study
To assess the usage of calcium supplementation and/or active Vitamin D analogues while on encaleret treatment [Period 2 thru Period 3 length is 24 weeks]
Dose and frequency of calcium supplements and/or active Vitamin D analogue requirements for participants randomized to the encaleret treatment arm
To evaluate the PK of encaleret in participants with ADH1 [Period 2 thru Period 3 length is 24 weeks]
Determination of steady state encaleret trough concentration (Ctrough) during Periods 2 and 3

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participant must be at least 16 years of age, at the time of signing the informed consent or assent.
Participants must have a documented pathogenic activating variant, or variant of uncertain significance, of the 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 Period 3 Week 24. 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
Male participants must use a highly effective contraceptive method (eg, condoms with spermicidal gel or foam) during vaginal intercourse and should not father a child nor donate sperm while taking encaleret and for 3 months after the last dose of encaleret. Condoms are not required if the participant is vasectomized or if the participant's partner is not a female of childbearing potential.
Postmenopausal females and females not of childbearing potential may participate in this study without use of contraception
Females of childbearing potential, defined as all females physiologically capable of becoming pregnant, must use two highly effective methods of contraception starting at Screening and for 3 months following the last dose of encaleret.
Capable of giving signed informed consent or assent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

Exclusion Criteria:

cCa and 24-hr UCa both within the respective reference ranges (cCa = 8.6-10.5 mg/dL in participants 16 to <18 years or 8.5-10.5 mg/dL in participants ≥ 18 years and 24-hr UCa <250 mg/day for women and <300 mg/day for men) at Screening Visit.
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, CTx and P1NP, > upper limit of normal for sex, age (men only) and menopausal status (women only).
Received any investigational medicinal product other than encaleret within 30 days or 5 half-lives, whichever is longer, prior to the first day on study, or are in follow-up for another interventional clinical study during Screening. If the half-life of an investigational medicinal product is unknown, then 30 days prior to Screening.
Blood 25-OH Vitamin D level <25 ng/mL
Estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2 using CKD-EPI creatinine equation refit without the race variable (CKD-EPIcr_R) (for participants <18 years old the Bedside Schwartz equation should be used).
12-lead resting ECG with clinically important abnormalities except for asymptomatic QT interval corrected (QTc) prolongation clinically ascribed to hypocalcemia.
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
Male or female participants planning to conceive a child prior to the LTE
Hypersensitivity to any active substance or excipient of encaleret.
Presence or history of any disease or condition (eg, drug or alcohol dependency) that, in the view of the Investigator, would affect the participant's safety or places the participant at high risk of poor treatment compliance or of not completing the study.