Post-Surgical Hypoparathyroidism Clinical Trial
Official title:
Phase 2 Study of the PTH-Independent Effects of Encaleret on Mineral Homeostasis in Subjects With Post-Surgical Hypoparathyroidism (PSH)
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.
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 ;