Safety, Tolerability, and Efficacy of CLTX-305 in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1

• ClinicalTrials.gov Identifier: NCT04581629
• Recruitment Status: Active, not recruiting
• First Posted: October 9, 2020
• Last Update Posted: February 8, 2023
• Sponsor: Calcilytix Therapeutics, Inc., a BridgeBio company
• Information provided by (Responsible Party): Calcilytix Therapeutics, Inc., a BridgeBio company

Study Description

Brief Summary:

A Phase 2b open label, dose finding study to evaluate the Safety, Tolerability and Efficacy of CLTX-305 (encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1

Condition or disease	Intervention/treatment	Phase
Autosomal Dominant Hypocalcemia (ADH)	Drug: CLTX-305	Phase 2

Detailed Description:

Autosomal dominant hypocalcemia Type 1 is a rare familial genetic form of hypoparathyroidism. Autosomal Dominant Hypocalcemia (ADH) Type 1 is typically passed down from affected parents to their children.

This is a Phase 2b open label, dose finding study to evaluate the safety and tolerability of CLTX-305 (encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1 as well as the effects of CLTX-305 (encaleret) on blood calcium concentration.

The estimated duration of this study is 41 months. This study plans to evaluate multiple doses of the investigational drug CLTX-305 (encaleret), in addition to safety and efficacy. CLTX-305 is administered orally.

The study is divided into 3 Periods followed by a Long-Term Extension (LTE):

Periods 1: Up to 8 study participants will be admitted to the NIH Clinical Center for 7 days, where they will be administered different doses of CLTX-305 (encaleret) for up to 5 days.

Period 2: Participants from Period 1, and up to 10 new study participants will be admitted to the NIH Clinical Center for 7 days, where they will be administered different doses of CLTX-305 (encaleret) for up to 5 days.

Period 3: 24 weeks during which eligible study participants who completed Period 2 will take CLTX-305 (encaleret) at home.

LTE: Up to 25 months during which eligible study participants who completed Period 3 will take CLTX-305 (encaleret) at home.

Study participants may:

• Participate in Period 1
• Participate in Period 2
• Participate in both Period 1 and Period 2
• Participate in Period 3 after completing Period 2
• Participate in LTE after completing Period 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1
• Actual Study Start Date: September 15, 2020
• Estimated Primary Completion Date: January 2024
• Estimated Study Completion Date: January 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: CLTX-305; CLTX-305 (encaleret) dose finding study to determine safety, tolerability and dose response during three (3) periods and a long term extension of this study with dose levels at QD and BID; up to 41 months of active treatment per participant	Drug: CLTX-305; Period 1: Once daily, followed by twice daily of CLTX-305 for 5 days; Period 2: Twice daily doses of CLTX-305 for 5 days; Period 3: Individualized dose titration of CLTX-305 for up to 24 weeks; LTE: Individualized dose titration of CLTX-305 for up to 25 months; Other Name: Encaleret

Outcome Measures

Primary Outcome Measures :

1. Number of Participants with Adverse Events (AEs) [ Time Frame: Up to 3 years ]
   An Adverse Event (AE) is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study are reported as adverse events.
2. Change From baseline in albumin-corrected blood calcium concentrations (cCa) after treatment with CLTX-305 [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
3. Change from baseline in 24-hour urinary calcium excretion after treatment with CLTX-305 (encaleret) [ Time Frame: Period 3; 24 weeks (pre-dose and out to 24 hours post dose) - Period 3 length is 24 weeks ]

Secondary Outcome Measures :

1. Change From baseline in albumin-corrected blood calcium concentrations (cCa) after treatment with CLTX-305 [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
2. Change from baseline in intact PTH blood concentration profile after treatment with CLTX-305 [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
3. Change from baseline in intact PTH blood concentration profile after treatment with CLTX-305 [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
4. Change from baseline in intact PTH blood concentration profile after treatment with CLTX-305 [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
5. Change from baseline in urinary calcium clearance fractional excretion [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
6. Change from baseline in urinary calcium clearance fractional excretion [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
7. Change from baseline in renal function eGFR [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
8. Change from baseline in renal function eGFR [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
9. Change from baseline in Serum levels of 1,25-(OH)2 Vitamin D [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
10. Change from baseline in Serum levels of 1,25-(OH)2 Vitamin D [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
11. Change from baseline in blood magnesium levels [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
12. Change from baseline in blood magnesium levels [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
13. Change from baseline in blood magnesium levels [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
14. Change from baseline in blood phosphate levels [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
15. Change from baseline in blood phosphate levels [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
16. Change from baseline in blood phosphate levels [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
17. Change from baseline in blood creatinine levels [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
18. Change from baseline in blood creatinine levels [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
19. Change from baseline in blood creatinine levels [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
20. Change from baseline in urinary content of pH [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
21. Change from baseline in urinary content of pH [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
22. Change from baseline in urinary content of pH [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
23. Change from baseline in urinary content of magnesium [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
24. Change from baseline in urinary content of magnesium [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
25. Change from baseline in urinary content of magnesium [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
26. Change from baseline in urinary content of phosphate [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
27. Change from baseline in urinary content of phosphate [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
28. Change from baseline in urinary content of phosphate [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
29. Change from baseline in urinary content of sodium [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
30. Change from baseline in urinary content of sodium [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
31. Change from baseline in urinary content of sodium [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
32. Change from baseline in urinary content of potassium [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
33. Change from baseline in urinary content of potassium [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
34. Change from baseline in urinary content of potassium [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
35. Change from baseline in urinary content of creatinine [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
36. Change from baseline in urinary content of creatinine [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
37. Change from baseline in urinary content of creatinine [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
38. Change from baseline in urinary content of cAMP [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
39. Change from baseline in urinary content of cAMP [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
40. Change from baseline in urinary content of cAMP [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
41. Change from baseline in urinary content of citrate [ Time Frame: Periods 1 and 2, days 1, 2, 3 and 5; up to 17 hours post-dose - Periods 1 and 2 lengths are 7 days each ]
42. Change from baseline in urinary content of citrate [ Time Frame: Period 3; 24 weeks (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
43. Change from baseline in urinary content of citrate [ Time Frame: LTE; Approximately 2 years (approximately 4 hours post dose) - LTE length is approximately 2 years ]
44. Change from baseline in bone marker - blood collagen cross-linked C-telopeptide (CTx) [ Time Frame: Periods 1, 2, 3 and LTE; Approximately 3 years - Periods 1 and 2 lengths are 7 days each, Period 3 length is 24 weeks. LTE length is approximately 2 years. ]
45. Change from baseline in bone marker - blood procollagen type 1 N-propeptide (P1NP) [ Time Frame: Periods 1, 2, 3 and LTE; Approximately 3 years - Periods 1 and 2 lengths are 7 days each, Period 3 length is 24 weeks. LTE length is approximately 2 years. ]
46. Maximum Observed Plasma Concentration (Cmax) of CLTX-305 [ Time Frame: Period 1; Day 1, 2, 4, and 5 (pre-dose and out to 13 hours post dose) - Period 1 length is 7 days ]
47. Maximum Observed Plasma Concentration (Cmax) of CLTX-305 [ Time Frame: Period 2; Day 1, 2, 4, and 5 (pre-dose and out to 13 hours post dose) - Period 2 length is 7 days ]
48. Maximum Observed Plasma Concentration (Cmax) of CLTX-305 [ Time Frame: Period 3; week 24 (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
49. Area Under the Plasma Concentration Versus Time Curve (AUC) of CLTX-305 [ Time Frame: Period 1; Day 1, 2, 4, and 5 (pre-dose and out to 13 hours post dose) - Period 1 length is 7 days ]
50. Area Under the Plasma Concentration Versus Time Curve (AUC) of CLTX-305 [ Time Frame: Period 2; Day 1, 2, 4, and 5 (pre-dose and out to 13 hours post dose) - Period 2 length is 7 days ]
51. Area Under the Plasma Concentration Versus Time Curve (AUC) of CLTX-305 [ Time Frame: Period 3; week 24 (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]
52. Apparent Terminal Plasma Half-Life (t1/2) of CLTX-305 [ Time Frame: Period 3; week 24 (pre-dose and out to 13 hours post dose) - Period 3 length is 24 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Be able to understand and sign a written informed consent or assent form, which must be obtained prior to initiation of study procedures.
• Age ≥ 16 years
• Postmenopausal women are allowed to participate in this study
• Body mass index (BMI) ≥ 18.5 to < 39 kg/m2
• Have an activating mutation of the CASR gene
• Participants being treated with thiazide diuretics may be enrolled if they are willing and able to discontinue thiazides
• Participants being treated with strong CYP3A4 inhibitors should ideally, if clinically appropriate, discontinue these medications during the screening period
• Participants being treated with magnesium or potassium citrate supplements should discontinue such treatment starting on Day -1 during Period 1 and Period 2 and may be asked to discontinue treatment during Period 3

Exclusion Criteria:

• History of treatment with PTH 1-84 or 1-34 within the previous 3 months
• History of hypocalcemic seizure within the past 3 months
• Blood 25-OH Vitamin D level < 25 ng/mL
• Participants with hemoglobin (Hgb) < 13 g/dL for men and < 12 g/dL for women
• Estimated glomerular filtration rate (eGFR) < 25 mL/minute/1.73 m2 using CKD-EPI (for participants <18 years old the Schwartz equation will be calculated)
• 12-lead resting electrocardiogram (ECG) with clinically significant abnormalities
• Participants with positive hepatitis B surface antigen (HBsAg), hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test results at the Screening Visit
• Pregnant or nursing (lactating) women
• History of drug or alcohol dependency within 12 months preceding the Screening Visit
• History of thyroid or parathyroid surgery
• Current participation in other investigational drug studies
• Unwillingness to refrain from blood donation within 12 weeks prior to Screening Visit from the start of the study enrollment through one year after the last dose of the study drug

Contacts and Locations

Locations

United States, Maryland

National Institute of Health

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

Calcilytix Therapeutics, Inc., a BridgeBio company

More Information

• Responsible Party: Calcilytix Therapeutics, Inc., a BridgeBio company
• ClinicalTrials.gov Identifier: NCT04581629
• Other Study ID Numbers: CLTX-305-201
• First Posted: October 9, 2020
• Last Update Posted: February 8, 2023
• Last Verified: February 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Arthrogryposis; Hypocalcemia; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Congenital Abnormalities; Calcium Metabolism Disorders; Metabolic Diseases; Water-Electrolyte Imbalance