Study of the PTH-independent Effects of Encaleret on Mineral Homeostasis in Subjects With Postsurgical Hypoparathyroidism (PSH)
- Registration Number
- NCT05735015
- Lead Sponsor
- National Institute of Dental and Craniofacial Research (NIDCR)
- Brief Summary
Background:
Parathyroid glands in the neck make a hormone that keeps blood calcium levels stable. Sometimes these glands are damaged or removed during neck surgery. This can lead to a condition called postsurgical hypoparathyroidism (PSH). People with PSH have low levels of calcium in their blood. Calcium and vitamin D pills can help them keep their blood calcium levels steady. But this can increase calcium in the urine and result in kidney problems. New treatments for PSH are needed.
Objective:
To test a drug (encaleret) in people with PSH.
Eligibility:
People aged 18 or older who have PSH.
Design:
Participants will be in the study for 6 months. They will have a screening visit and a treatment visit.
Screening will take up to 2 days. Participants will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have an ultrasound of their kidneys; they will lie on a table for 15 to 30 minutes while a wand is moved over their back.
Treatment will require participants to stay in the clinic for 7 days and 6 nights. They will take the study drug (encaleret) by mouth twice a day for 5 days. They will have a small, flexible tube inserted into a vein; this will remain in place during the visit. Blood samples will be taken through the tube 4 to 9 times each day. Participants urine will be collected.
Participants will have follow-up blood tests 1 week after leaving the clinic. They will have 3 follow-up phone calls.
- Detailed Description
Study Description:
This will be a single-site, proof-of-principle, open-label study to explore the PTH-independent effects of encaleret on calcium homeostasis in participants with low or undetectable PTH levels as a result of neck surgery (PSH).
Objectives:
Primary Objective:
-Evaluate the PTH-independent effects of encaleret on renal calcium handling in participants with PSH.
Secondary Objectives:
-Evaluate the ability of encaleret to normalize blood calcium while maintaining a normal urinary calcium in participants with PSH.
Tertiary/Exploratory Objectives:
* Evaluate the ability of encaleret to increase serum iPTH levels in participants with PSH.
* Evaluate the effect of encaleret on 1-alpha hydroxylase action by measuring 1,25-(OH)2 Vitamin D levels.
* Explore the dynamic effect of encaleret on blood and urinary calcium, iPTH, cAMP, 1,25-(OH)2 Vitamin D, and urinary citrate.
* Evaluate the effect of encaleret on bone turnover in participants with PSH.
* Evaluate the effect of encaleret on phosphate, magnesium, and FGF23 levels.
* Explore the effects of encaleret on 24-hour urine markers that impact stone formation
* Examine the PK of encaleret in participants with PSH and explore PK-PD interactions.
* Explore the effect of encaleret on bone and mineral homeostasis in the following sub-groups, as defined:
* Permanent hypoparathyroidism (Cohort 1)
* Recent hypoparathyroidism (Cohort 2)
* "PTH-Clamp" cohort
* "Aparathyroid" cohort
* Hyperthyroid cohort
* Normothyroid cohort
* Thyroid cancer cohort
Primary Endpoint:
-Percent change in Fractional Excretion of Calcium (FECa) from baseline (Day -1) to the final day of treatment (Day 6 or the last measurement while on encaleret). FECa calculated using fasting blood levels and spot urine collection.
Secondary Endpoints:
-Proportion of participants who achieve a concomitant normal or elevated fasting blood calcium (albumin-corrected calcium\>8.5 mg/dL) and a normal 24-hour urinary calcium level (\<250 mg/24 hours for women, \<300 mg/24 hours for men) on encaleret at any point between day 1 and day 5.
Tertiary/Exploratory Endpoints:
* Percent change in Fractional Excretion of Calcium (FECa) from baseline (Screening visit) to the final day of treatment (Day 6 or the last measurement while on encaleret). FECa calculated using fasting blood levels and spot urine collection.
* Change in blood iPTH comparing average baseline iPTH to average peak iPTH on encaleret. The average baseline iPTH will include all baseline iPTH levels from the screening visit, Day -1, and pre-dose on Day 1. The average peak iPTH will average the peak iPTH levels on every day the patient is on encaleret (days 1 to 5). An increase in iPTH will be considered clinically significant if there is an increase both by 50% AND by more than 10 pg/dL.
* Change in 1,25-(OH)2 Vitamin D on encaleret comparing the maximal level prior to receiving calcitriol (On Days 3- 5) to baseline (Average of Day 1 Pre-dose levels). Increase will be considered significant if there is an increase of more than 50%. Participants who receive calcitriol prior to Day 3 will be excluded.
Pharmacodynamic endpoints measured over 5 days of encaleret therapy:
* Blood iPTH - Absolute levels and change from baseline
* Albumin-corrected blood calcium - Absolute levels and change from baseline
* Ionized Calcium - Absolute levels and change from baseline
* Urinary calcium clearance (fractional excretion and 24-hour total excretion) - Absolute levels and change from baseline
* Serum levels of 1,25-(OH)2 Vitamin D - Absolute levels and change from baseline
* Blood intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) - Absolute levels and change from baseline
* Urine cAMP and citrate - Absolute levels and change from baseline
* Blood bone resorption marker, collagen crosslinked C-telopeptide (CTx) - Absolute levels and change from baseline
* Blood bone formation marker, blood procollagen type 1 N-propeptide (P1NP) - Absolute levels and change from baseline
* PK parameters such as maximum plasma concentration Cmax), time to maximum plasma concentration (tmax), apparent terminal half-life (t 1/2)
* Change in components of urine including: supersaturation, sodium, potassium, calcium, magnesium, chloride, phosphorus, sulfate, citrate excretion, oxalate, pH, uric acid, creatinine, osmolality, ammonium, urea nitrogen, protein catabolic rate
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 30
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment encaleret All participants given 5 days of encaleret twice daily
- Primary Outcome Measures
Name Time Method Effect of encaleret on Fractional Excretion of Calcium 6 days Evaluate the ability of encaleret to decrease Fractional Excretion of Calcium comparing baseline (day -1) to the last day on encaleret.
- Secondary Outcome Measures
Name Time Method Effect of encaleret on achieving concomitant normal fasting blood calcium and a normal 24-hour urinary calcium level 6 days Evaluate the ability of encaleret to normalize blood calcium and urinary calcium.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States