Clinical study to investigate the Efficacy and Safety of Encaleret Compared to Standard of Care treatment in patients with Autosomal Dominant Hypocalcemia Type 1 (ADH1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Calcilytix Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

2 Sep 2023 → ongoing

Decision date (initial)

2023-06-13

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Calcilytix Therapeutics, Inc

External identifiers

EU CT number

2022-501398-38-00

WHO UTN

U1111-1281-9668

ClinicalTrials.gov

NCT05680818

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacokinetic, Safety

To demonstrate the efficacy of encaleret compared to standard of care (SoC) treatment on albumin-corrected blood calcium (cCa) and 24-hr urinary calcium (UCa) excretion

Secondary objectives 7

1. 1. To compare the efficacy of encaleret and SoC treatments for the following: Effects on clinical laboratory assessments: intact parathyroid hormone (iPTH), albumin-corrected blood calcium, 24-hr urinary calcium excretion, blood phosphate, blood magnesium, 1,25-(OH)2 Vitamin D
2. 2. To compare the efficacy of encaleret and SoC treatments regarding effects on urine mineral and electrolyte biomarkers
3. 3. To compare the efficacy of encaleret and SoC treatments for the following: Effects on QT interval corrected for changes in the heart rate with Fridericia formula (QTcF) duration
4. 4. To compare the efficacy of encaleret and SoC treatments for the following: Effects on patient reported outcomes
5. 5. To compare the efficacy of encaleret and SoC treatments for the following: To compare safety and tolerability of encaleret and SoC treatments
6. 6. To compare the efficacy of encaleret and SoC treatments for the following: To assess the usage of calcium supplementation and/or active Vitamin D analogues while on encaleret treatment
7. 7. To compare the efficacy of encaleret and SoC treatments for the following: To evaluate the pharmacokinetics (PK) of encaleret in participants with ADH1

Conditions and MedDRA coding

Autosomal Dominant Hypocalcemia Type 1 (ADH1)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Danish Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Participant must be at least 18 years of age, at the time of signing the informed consent.
2. 2. 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.
3. 3. 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
4. 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. 5. Participants treated with phosphate binders must discontinue the phosphate binders (other than calcium salts) at least one day prior to SoC Optimization Visit 1.
6. 6. Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret.
7. 7. Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret.
8. 8. Participants must meet SoC Optimization criteria as defined in Section 5.4.1.
9. 9. Male participants with women of childbearing potential (WOCBP) partners must use acceptable contraceptive methods as defined in Section 7.7.2.
10. 10. 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..
11. 11. 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.
12. 12. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion criteria 17

1. 1. History of hypocalcemic seizure within the past 3 months preceding Screening.
2. 10. 12-lead resting ECG with clinically important abnormalities except for asymptomatic QTc prolongation clinically ascribed to hypocalcemia.
3. 11. 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.
4. 12. Male or female participants planning to conceive a child prior to the LTE.
5. 13. Hypersensitivity to any active substance or excipient of encaleret. See Section 7.2.1 for list of active ingredients and excipients.
6. 14. Any current disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism.
7. 15. Current treatment with cardiac glycosides (because hypercalcemia of any cause may predispose to digitalis toxicity).
8. 16. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency.
9. 2. History of thyroid or parathyroid surgery.
10. 3. 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.
11. 4. History of renal transplantation.
12. 5. Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive beta-human chorionic gonadotropin (β-hCG) laboratory test.
13. 6. 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).
14. 7. 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..
15. 8. 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.
16. 9. Estimated glomerular filtration rate <30 mL/minute/1.73 m2 using CKD-EPIcr_R. See Appendix C.
17. 17. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is the responder status of each participant. (...)

Secondary endpoints 18

1. 1. Key secondary endpoints are categorized into the following families: • Within -Patient Endpoint Family o iPTH status of each participant at each maintenance period. The positive result of this binary endpoint is defined as iPTH within or greater than the reference range at the completion of the maintenance period (Period 1 or 3)
2. 2. Between-Treat. Endp. Family ° Responder status of each particip. (...) ° iPTH status of each particip. The positive result of this binary endp. is defined as iPTH within or greater than the ref. range at the compl. of the maint. period (Period 3)
3. 3a. Additional secondary endpoints include: Observed cCa, 24-hr UCa, iPTH, blood phosphate, and blood magnesium values and changes from baseline over time
4. 3b. Additional secondary endpoints incl.: Responder status of each participant. (...)
5. 3c. Additional secondary endpoints incl.: Blood phosphate status of each participant over time. The positive result of this binary endpoint is defined as blood phosphate within the reference range
6. 3d. Additional secondary endpoints incl.: Blood magnesium status of each participant over time. The positive result of this binary endpoint is defined as blood magnesium within the reference range.
7. 3e. Additional secondary endpoints incl.: cCa and 24-hr UCa status of each participant. The positive result of this binary endpoint is defined as meeting both of the following criteria at the completion of the maintenance period (Period 1 or Period 3): (...)
8. 3e. (cont.) (...)
9. 3f. Additional secondary endpoint incl.: cCa and 24-hr UCa status without titration or supplemental calcium/vitamin D of each participant. The positive result of this binary endpoint is defined as meeting both of the following criteria at the completion of the maintenance period (Period 1 or Period 3): (...)
10. 3f. (cont.) −(...) and both of the following criteria during the maintenance period (Period 1 or Period 3: − no titration of encaleret or SoC − no oral calcium > 600 mg/day and/or active vitamin D for the participants randomized to encaleret arm
11. 3g. Additional secondary endpoint incl.: 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 to Week 24 (Period 3)
12. 4. Change from Baseline in urine magnesium, phosphate, sodium, and citrate handling to Week 24 (Period 3)
13. 5. Change from Baseline in QTcF as assessed by electrocardiogram (ECG) to Week 24 (Period 3)
14. 6. 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 to Week 24 (Period 3)
15. 7. Adverse events (AEs) and serious adverse events (SAEs), including frequency and severity.
16. 8. Changes from baseline for the following: o Vital signs o Physical examination o Renal ultrasound to evaluate nephrocalcinosis and nephrolithiasis o 12-lead ECG o Safety laboratory tests including chemistry, hematology, coagulation, and urinalysis
17. 9. Dose and frequency of calcium supplements and/or active Vitamin D analogue requirements for participants randomized to the encaleret treatment arm
18. 10. Determination of steady state encaleret trough concentration (Ctrough) during Periods 2 and 3

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Comparator 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Calcilytix Therapeutics Inc.

Sponsor organisation

Calcilytix Therapeutics Inc.

Address

1800 Owens Street Suite C1200

City

San Francisco

Postcode

94158-2381

Country

United States

Scientific contact point

Organisation

Calcilytix Therapeutics Inc.

Contact name

Medical Information Calcilytix Therapeutics, Inc., a BridgeBio Company

Public contact point

Organisation

Calcilytix Therapeutics Inc.

Contact name

Medical Information Calcilytix Therapeutics, Inc., a BridgeBio Company

Third parties 11

Locations

6 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 137 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications