Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 in Autosomal Dominant Hypocalcemia Type 1 (ADH1)

Hypoparathyroidism Clinical Trial

Official title:

A Phase IIb, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX Hypocalcemia Type l (ADHl).

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04465227
• Other study ID #: 200122
• Secondary ID: 20-D-0122
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 15, 2020
• Est. completion date: September 30, 2021

Study information

• Verified date: July 1, 2020
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Karen A Pozo, R.N.
• Phone: (301) 827-1138
• Email: karen.pozo[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

The Calcium-Sensing Receptor (CaSR) detects the amount of calcium in the blood and urine. Parathyroid hormone (PTH) helps keep blood calcium levels normal. When PTH and calcium blood levels are low, this is called hypoparathyroidism. People with changes in the CaSR have a type of hypoparathyroidism called ADH1. ADH1 is treated with calcium supplements and vitamin D. But these do not always work, and can cause problems like kidney stones. Researchers want to see if the drug CLTX-305 is a better treatment option.

Objective:

To see if CLTX-305 is safe and works in people with ADH1.

Eligibility:

People ages 16 and older with ADH1

Design:

Participants will be screened with:

Medical history

Physical exam

Kidney ultrasound: Participants will lie on a table while a wand is moved over their back.

Bone density test: Participants will lie on a table while an X-ray machine moves around them.

Blood, urine, and heart tests

The study is split into 3 periods. Participants may take part in some or all periods.

In Periods 1 and 2, participants will take CLTX-305 by mouth once or twice daily for up to 5 days. Participants will stay at the NIH for 7 days and 6 nights.

In Period 3, participants will take CLTX-305 at home for 24 weeks. They will have 3 inpatient visits that last 1 2 days each.

Screening tests will be repeated during the study. Blood and urine will be collected often.

Participants dose of calcium and vitamin D may be changed. They may be asked to stop taking other medicines or change the dose.

Description:

Study Description:

This will be a single-site, open-label, dose-ranging study to evaluate the safety, tolerability and efficacy of CLTX-305 to maintain normalized albumin-corrected blood calcium (cCa) in subjects with hypocalcemia due to ADH1. The study consists of 2 cohorts and 3 periods.

Primary Objectives:

• Periods 1 and 2: Evaluate the safety and tolerability of single and multiple doses of CLTX-305 in subjects with ADH1

• Period 3: Evaluate the efficacy of CLTX-305 in subjects with ADH1 after 24 weeks of dosing

Secondary Objectives:

• Periods 1 and 2:

--Evaluate the effect of CLTX-305 to increase serum PTH levels after both single and multiple doses across a dose range in subjects with ADH1

• Periods 1, 2, and 3:

• Evaluate the pharmacodynamic (PD) effects of CLTX-305 on blood calcium concentrations

• Evaluate the PD effects of CLTX-305 on associated measures of calcium homeostasis including 1,25-(OH)2 vitamin D levels and urinary calcium excretion

• Evaluate the PK of both single and multiple ascending doses of CLTX-305 in subjects with ADH1.

• Period 3:

• Evaluate the safety and tolerability of CLTX-305 in subjects with ADH1 after 24 weeks of dosing

Primary Endpoints:

• Periods 1 and 2: Adverse events (AEs), clinical safety laboratory tests, vital signs, and electrocardiograms (ECGs)

• Period 3: Albumin-corrected blood calcium concentrations (cCa) after treatment with CLTX-305 for up to 24 weeks.

Secondary Endpoints:

• Periods 1 and 2: iPTH blood concentrations profiles (24-hours) over time after single and multiple doses of CLTX-305

• Period 3: AEs, clinical safety laboratory tests, vital signs, and ECGs

• Periods 1, 2, and 3:

• Pharmacodynamic endpoints measured over time up to 24 weeks (final visit):

• Blood calcium - Absolute levels and change from baseline in cCa

• Urinary calcium clearance (fractional excretion and 24-hour total excretion)

• Serum levels of 1,25-(OH)2 Vitamin D

• Blood samples for magnesium, phosphate, creatinine

• Urine samples for pH, magnesium, phosphate, sodium, potassium, creatinine, cAMP, citrate

• Bone resorption markers collagen cross-linked C-telopeptide (CTx)

• Bone formation markers blood procollagen type 1 N-propeptide (P1NP)

• PK parameters: maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), apparent terminal half-life (t1/2), area under the concentration-time curve (AUC) from time 0 to the last measurable time point (AUC(0-t)), AUC from time 0 to 24 hours (AUC(0-24)), AUC extrapolated to infinity (AUC(0-inf)) following single-doses.

• Determination of the steady state PK parameters: Cmax, trough concentration (Ctrough), and AUC over the dosing interval AUC(0-tau)

Study Population:

Up to 20 male or female subjects (16 to enter the treatment phase) with Autosomal Dominant Hypocalcemia Type 1(ADH1)

Phase: Phase 2b

Description of Sites/Facilities Enrolling Participants:

National Institutes of Health (NIH) Clinical Center (CC)

Description of Study Intervention:

CLTX-305 is an oral tablet containing the active ingredient encaleret provided in 10, 30 and 60 mg doses.

Study Duration:

Estimated time from when the study opens to enrollment until completion of data analyses is approximately 24 months.

Participant Duration:

Total duration of study participation, including Periods 1, 2, and 3, will be approximately 12 months for each subject, including up to 60 days between the screening visit and study drug initiation.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: September 30, 2021
• Est. primary completion date: September 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

• INCLUSION CRITERIA:

Subjects must meet the following criteria for inclusion during screening:

1. Be able to understand and sign a written informed consent or assent form, which must be obtained prior to initiation of study procedures.

2. Age greater than or equal to 16 years

3. Postmenopausal women are allowed to participate in this study:

a. Women are considered postmenopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to start of the study. 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.

4. Body mass index (BMI) greater than or equal to 18.5 to < 39 kg/m2

5. Have an activating mutation of the CaSR gene

6. Subjects being treated with thiazide diuretics may be enrolled if they are willing and able to discontinue thiazides for at least 5 half-lives prior to initiation of CLTX-305 and during the study treatment period. When the thiazide is being used as an antihypertensive, alternative therapy will be offered.

7. Subjects being treated with strong CYP3A4 inhibitors (including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) should ideally, if clinically appropriate, discontinue these medications during the screening period for at least 5 half-lives prior to initiation of CLTX-305. Subjects who must remain on strong CYP3A4 inhibitors may still enroll if they are able to remain on their medications at stable doses throughout the trial.

EXCLUSION CRITERIA:

Subjects who meet any of the following criteria during Screening will not be eligible to participate in the study:

1. History of treatment with PTH 1-84 or 1-34 within the previous 3 months

2. History of hypocalcemic seizure within the past 3 months

3. Blood 25-OH vitamin D level < 25 ng/mL

a. If subject has a blood 25-OH vitamin D level < 25 ng/mL at the screening visit, they will be prescribed cholecalciferol or ergocalciferol supplementation. Once the 25-OH vitamin D level is > 25 ng/mL, the subject will be eligible to continue to the treatment phase of the study.

4. Abnormal laboratory values which in the opinion of the investigator, would make the subject not suitable for participation in the study

5. Estimated glomerular filtration rate (eGFR) < 45 mL/minute/1.73 m2 using CKD-EPI (for subjects < 18 years old the Schwartz equation will be calculated)

6. 12-lead resting electrocardiogram (ECG) with clinically significant abnormalities

7. Subjects with positive hepatitis B surface antigen (HbsAg), Hepatitis C antibody, Hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test results at the Screening Visit

8. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test

9. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months following the discontinuation of study treatment. Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

• Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.

• Combination of the following (a+b or a+c, or b+c):

• Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

10. Sexually active males unless they use a condom during intercourse while taking the CLTX-305 (study drug) and for 3 months after the last dose of the study drug and should not father a child during active participation in the study starting with the first CLTX-305 dose in Period 1, Period 2 (for Cohort 2) until the end of Period 3. A condom is required to be used also by vasectomized men in order to prevent delivery of the study drug via seminal fluid.

11. Hypersensitivity to any active substance or excipient of CLTX-305

12. History of drug or alcohol dependency within 12 months preceding the Screening Visit

13. History of thyroid or parathyroid surgery

14. Current participation in other investigational drug studies

Related Conditions & MeSH terms

• Hypocalcemia
• Hypoparathyroidism

Intervention

Drug:
• CLTX-305
Oral administration, once or twice a day.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Dental and Craniofacial Research (NIDCR)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety, Tolerability, Efficacy	Periods 1 and 2: Evaluate the safety and tolerability of single and multiple doses of CLTX-305 in subjects with ADH1 Period 3: Evaluate the efficacy of CLTX-305 in subjects with ADH1 after 24 weeks of dosing.	1 year
Secondary	Effect of CLTX-305 to increase PTH levels	Periods 1 and 2:-Evaluate the effect of CLTX- 305 to increase serum PTH levels after both single and multiple doses across a dose range in subjects with ADH1Periods 1, 2, and 3:-Evaluate the pharmacodynamic (PD) effects of CLTX-305 on blood calcium concentrations-Evaluate the PD effects of CLTX-305 on associated measures of calcium homeostasis including 1,25-(OH)2 vitamin D levels and urinary calcium excretion-Evaluate the PK of both single and multiple ascending doses of CLTX-305 in subjects with ADH1.Period 3:-Evaluate the safety and tolerability of CLTX-305 in subjects with ADH1 after 24 weeks of dosing.	One year

External Links

•   NIH Clinical Center Detailed Web Page