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)
- Trial ID
- 2022-501398-38-00
- Protocol
- CLTX-305-302
- Sponsor
- Calcilytix Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the efficacy of **encaleret** compared to standard of care (SoC) treatment in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1). The focus is on evaluating changes in albumin-corrected blood calcium (cCa) and 24-hour urinary calcium (UCa) excretion. This is clinically relevant as it addresses the management of calcium homeostasis in ADH1, a condition characterized by low blood calcium levels, which can lead to various complications if not properly managed.
Secondary objectives include comparing the efficacy of encaleret and SoC treatments on several parameters:
- Effects on clinical laboratory assessments, including intact parathyroid hormone (iPTH), blood phosphate, blood magnesium, and 1,25-(OH)2 Vitamin D levels.
- Effects on urine mineral and electrolyte biomarkers.
- Effects on the QT interval corrected for heart rate changes using the Fridericia formula (QTcF).
- Patient-reported outcomes.
- Safety and tolerability of the treatments.
- Usage of calcium supplementation and/or active Vitamin D analogues during encaleret treatment.
- Pharmacokinetics of encaleret in participants with ADH1.
Participants
The clinical trial investigating the efficacy of encaleret in comparison to standard of care treatment for **Autosomal Dominant Hypocalcemia Type 1 (ADH1)** involves a total of 26 participants. The study population includes both male and female subjects, with an age range starting from 18 years and above. Participants were selected based on specific genetic and biochemical criteria, including a documented pathogenic or likely pathogenic activating variant of the CASR gene associated with hypoparathyroidism. The trial does not involve a vulnerable population. Lifestyle considerations include the discontinuation of certain medications such as thiazide diuretics, phosphate binders, magnesium or potassium supplements, and potassium-sparing diuretics prior to the administration of encaleret. The study ensures that female participants of childbearing potential adhere to effective contraceptive measures, while postmenopausal females and those not of childbearing potential are exempt from such requirements. The selection criteria ensure that participants have a documented history of symptoms or signs of ADH1, ensuring a targeted and relevant study cohort.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **encaleret** compared to standard of care in participants with **Autosomal Dominant Hypocalcemia Type 1 (ADH1)**. This is a Phase 3, randomized, open-label study. The trial will involve a series of study visits over an estimated duration until May 31, 2029. Participants will be randomly assigned to receive either encaleret or standard of care, with the primary objective being to assess the impact on albumin-corrected blood calcium and 24-hour urinary calcium excretion.
The trial will commence with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic analysis of the CASR gene, and documented history of ADH1 symptoms. Participants must be at least 18 years old and capable of providing informed consent. Females of childbearing potential must use effective contraception. The study will exclude those unable to meet these criteria or those currently on certain medications unless willing to discontinue them prior to the study.
Following the screening, participants will undergo a series of follow-up visits, including SoC Optimization visits and maintenance periods, to monitor their response to treatment. The primary endpoint is the responder status, defined by specific calcium levels in blood and urine at the end of the maintenance period. Secondary endpoints include changes in parathyroid hormone levels, blood phosphate, and magnesium status, as well as quality of life assessments.
The expected length of participant involvement is up to 54 weeks, with conditions for early termination including non-compliance with the protocol or adverse events. Participants will conclude their involvement with an end-of-study visit, where final assessments will be conducted to evaluate the overall impact of the treatment. The trial aims to provide comprehensive data on the safety and efficacy of encaleret in managing ADH1, contributing to the understanding and potential treatment options for this rare condition.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Encaleret sulfate**, marketed under the name Encaleret GEN1 and Encaleret tablets (GEN2). This medication is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose is 324 mg, with a total maximum dose of 530 g over a treatment period of 54 weeks. Encaleret sulfate is classified as a chemical product and is designated as an orphan drug for the treatment of Autosomal Dominant Hypocalcemia Type 1 (ADH1).
Non-experimental treatments in the study include **Calcium acetate anhydrous**, which is administered as a film-coated tablet for oral use. The maximum daily dose is 6650 mg, with a total maximum dose of 10773 g over the treatment period. This chemical entity serves as a comparator in the trial.
**Colecalciferol** is another comparator treatment, provided in the form of a hard capsule for oral administration. The maximum daily dose is 4000 IU, with a total maximum dose of 3240000 IU over the 54-week period. This chemical entity is used to compare its effects against the experimental treatment.
**Alfacalcidol** is administered as a soft capsule, with a maximum daily dose of 4 µg and a total maximum dose of 6568 µg. This chemical product is also used as a comparator in the study, administered orally over the same treatment period.
**Calcitriol** is provided in a soft capsule form, with a maximum daily dose of 4 µg and a total maximum dose of 6480 µg. This chemical entity is administered orally and serves as a comparator treatment in the trial.
Lastly, **Calcium carbonate** is administered as a chewable tablet, with a maximum daily dose of 2000 mg and a total maximum dose of 3284 g. This chemical entity is used as a comparator in the study, administered orally over the 54-week treatment period.
All treatments are monitored for participant compliance, and dosing schedules are adhered to as per the study protocol. The trial aims to evaluate the efficacy and safety of Encaleret compared to standard-of-care treatments in participants with ADH1, focusing on albumin-corrected blood calcium and 24-hour urinary calcium excretion.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary efficacy endpoint is the responder status of each participant, defined by achieving both albumin-corrected blood calcium (**cCa**) levels within 8.3-10.7 mg/dL (2.1-2.7 mmol/L) and 24-hour urinary calcium (**UCa**) excretion within the reference range (<300 mg/day for men [7.5 mmol/day], <250 mg/day for women [6.25 mmol/day]) at the completion of the maintenance period (Period 1 or Period 3).
Secondary endpoints include several key measures: the status of intact parathyroid hormone (**iPTH**) at each maintenance period, with a positive result defined as iPTH within or greater than the reference range. Additional secondary endpoints involve observed changes in cCa, 24-hr UCa, iPTH, blood phosphate, and blood magnesium values from baseline over time. The trial will also assess the responder status over time, defined by meeting the cCa and UCa criteria, and the status of blood phosphate and magnesium within their respective reference ranges. Furthermore, changes from baseline in the 36-Item Short Form Health Survey (SF-36) physical and mental component scores, as well as changes in urine magnesium, phosphate, sodium, and citrate handling, will be evaluated to Week 24 (Period 3).
Data collection will occur at specified timepoints, including the completion of the maintenance periods and Week 24, using validated laboratory tests and patient-reported outcomes. The analysis will focus on determining the efficacy of Encaleret compared to the standard of care in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be at least 18 years of age, at the time of signing the informed consent.
- Participants must have a documented pathogenic or likely pathogenic activating variant, or variant of uncertain significance, of the CASR gene associated with biochemical findings of hypoparathyroidism either present at Screening or a documented history of both: (...). Note: A genetic analysis report for CASR will be acceptable. In the absence of any documentation for the CASR variant, participants must be willing to undergo CASR variant analysis. Participants who have undergone an allogeneic bone marrow transplant must provide CASR variant analysis report performed prior to the bone marrow transplant Participants who have received a packed red blood cell transfusion must wait 2 weeks following the transfusion before undergoing CASR variant analysis, and participants who have received a whole blood transfusion must wait 4 weeks following the transfusion before undergoing CASR variant analysis.
- Participants must have a documented history of symptoms or signs of ADH1. Symptoms of ADH1 include agitation, anxiety, back pain, brain fog, bronchospasm, blepharospasm, cardiac failure, cognitive impairment, difficulty focusing/concentration, esophageal spasm, facial spasm, headaches, hypoesthesia (including facial and oral), irritability, laryngospasm, muscle cramping, muscle fatigue, muscle spasms, muscle tightness, muscle twitching, musculoskeletal pain, musculoskeletal stiffness, myalgia, nephrolithiasis, nervousness, paresthesia (including oral), polydipsia, polyuria, seizure, tetany, throat tightness, or tremor. Signs of ADH1 include basal ganglia or other cerebral calcification, Chvostek sign, hypercalciuria, nephrocalcinosis, papilledema, premature cataracts, prolonged QT interval on ECG, pseudotumor cerebri, or Trousseau sign
- 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.
- Participants treated with phosphate binders must discontinue the phosphate binders (other than calcium salts) at least one day prior to SoC Optimization Visit 1.
- 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 Section 5.4.1.
- Male participants with women of childbearing potential (WOCBP) partners must use acceptable contraceptive methods as defined in Section 7.7.2.
- Postmenopausal females and females not of childbearing potential may participate in this study without use of contraception: a) Females are considered postmenopausal if they have had 12 months of natural (spontaneous) amenorrhea without an alternative medical cause and must be confirmed with plasma FSH. b) Females are considered not of childbearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) or hysterectomy. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment, shall she be considered not of childbearing potential..
- Females of childbearing potential, defined as all females physiologically capable of becoming pregnant, must use highly effective methods of contraception starting at Screening and for 3 months following the last dose of encaleret. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria
- History of hypocalcemic seizure within the past 3 months preceding Screening.
- 12-lead resting ECG with clinically important abnormalities except for asymptomatic QTc prolongation clinically ascribed to hypocalcemia.
- Participants with positive Hepatitis B surface antigen (HBbsAg), 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. See Section 7.2.1 for list of active ingredients and excipients.
- Any current disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism.
- Current treatment with cardiac glycosides (because hypercalcemia of any cause may predispose to digitalis toxicity).
- Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency.
- History of thyroid or parathyroid surgery.
- History of the following within 5 years of screening: cancer except thyroid cancer, basal cell skin cancer or squamous cell skin cancer, patients with skeletal malignancies or bone metastases or irradiation (radiotherapy) to the skeleton.
- History of renal transplantation.
- 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 doses 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 If participant has a blood 25-OH Vitamin D level <25 ng/mL at the Screening Visit, they will be prescribed cholecalciferol or ergocalciferol supplementation per the Investigator. Once the 25-OH Vitamin D level is ≥ 25 ng/mL, the participant will be eligible to proceed with SoC Optimization (if still within Screening window of up to 84 days total) or re-screen for the study.
- Estimated glomerular filtration rate <30 mL/minute/1.73 m2 using CKD-EPIcr_R. See Appendix C.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Ended | 30 Jul 2023 | 6 |
 Czechia | Not Recruiting | 30 Jul 2023 | 3 |
 Denmark | Not Recruiting | 30 Jul 2023 | 5 |
 France | Not Recruiting | 30 Jul 2023 | 8 |
 Italy | Not Recruiting | 30 Jul 2023 | 9 |
 The Netherlands | Not Recruiting | 30 Jul 2023 | — |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
COLECALCIFEROL | Comparator | — | ORAL USE | 4000 | 54 | SUB06794MIG |
CALCIUM CARBONATE | Comparator | — | ORAL | 2000 | 54 | SUB13166MIG |
Encaleret tabletsGEN2 | Test | FILM-COATED TABLET | ORAL USE | 0 | 1 | PRD10841312 |
Encaleret GEN1 | Test | FILM-COATED TABLET | ORAL USE | 0 | 1 | PRD10262176 |
Encaleret GEN1 | Test | FILM-COATED TABLET | ORAL USE | 0 | 1 | PRD10262178 |
Encaleret GEN1 | Test | FILM-COATED TABLET | ORAL USE | 0 | 1 | PRD9472801 |
ALFACALCIDOL | Comparator | — | ORAL | 4 | 54 | SUB05312MIG |
CALCITRIOL | Comparator | — | ORAL USE | 4 | 54 | SUB06047MIG |
CALCIUM ACETATE ANHYDROUS | Comparator | — | ORAL USE | 6650 | 54 | SUB89444 |
Encaleret GEN1 | Test | FILM-COATED TABLET | ORAL USE | 0 | 1 | PRD10262179 |