Encaleret for Hypocalcemia
(CALIBRATE Trial)
Recruiting in Palo Alto (17 mi)
+29 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: Calcilytix Therapeutics, Inc., a BridgeBio company
Must not be taking: Thiazides, Phosphate binders
Disqualifiers: Hypocalcemic seizure, Thyroid surgery, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing a new medication called encaleret for people with a rare genetic condition known as ADH1. ADH1 causes low calcium levels, and current treatments may not be effective or safe enough. Encaleret aims to help by balancing calcium levels in the blood.
Will I have to stop taking my current medications?
Yes, you may need to stop taking certain medications. If you are on thiazide diuretics, phosphate binders, magnesium or potassium supplements, or potassium-sparing diuretics, you will need to discontinue them before starting the trial. There are specific timeframes for stopping these medications, such as at least 14 days for thiazides and at least one day for phosphate binders.
What data supports the effectiveness of the drug Encaleret for treating hypocalcemia?
Research on similar drugs like cinacalcet, which also targets the calcium sensing receptor, shows that it effectively lowers calcium levels in conditions with high calcium, suggesting that Encaleret might work similarly for hypocalcemia by adjusting calcium levels.
12345Is Encaleret safe for treating hypocalcemia?
The safety data for Encaleret specifically is not available in the provided research articles. However, similar treatments like cinacalcet and etelcalcetide, used for related conditions, have shown that hypocalcemia (low calcium levels) is a common side effect, but they are generally considered safe with careful monitoring.
678910Eligibility Criteria
This trial is for people with a genetic variant causing hypoparathyroidism (ADH1), aged 16-18 with closed growth plates, not on certain diuretics or supplements, and meeting specific treatment criteria. Excluded are those recently on PTH treatments, had seizures or thyroid surgery, pregnant/nursing women, low Vitamin D levels, certain viral infections, or severely reduced kidney function.Inclusion Criteria
I am 16-17 years old and my growth plates are closed.
I have shown symptoms or signs of ADH1.
Participants must meet SoC Optimization criteria as defined in the protocol
+5 more
Exclusion Criteria
Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive beta-human chorionic gonadotropin (β-hCG) laboratory test
I have had surgery on my thyroid or parathyroid.
My kidney function is low, with an eGFR below 30 mL/min/1.73 m^2.
+5 more
Participant Groups
The study aims to compare the effectiveness and safety of encaleret against standard care in treating ADH1. Participants will receive either encaleret or the usual treatment without knowing which one they're getting to measure differences in health outcomes.
2Treatment groups
Experimental Treatment
Group I: Standard of Care (SoC)Experimental Treatment1 Intervention
Participants will continue receiving calcium supplements and/or active Vitamin D (calcitriol, alfacalcidol, falecalcitriol, etc.)
Group II: EncaleretExperimental Treatment1 Intervention
Participants will receive encaleret at a dose as needed based on calcium levels.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Boston Children's HospitalBoston, MA
Columbia University Irving Medical CenterNew York, NY
The Children's Hospital of PhiladelphiaPhiladelphia, PA
University of Chicago - Medical CenterChicago, IL
More Trial Locations
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Who Is Running the Clinical Trial?
Calcilytix Therapeutics, Inc., a BridgeBio companyLead Sponsor
References
The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies. [2022]Cinacalcet, a positive allosteric modulator of the calcium sensing receptor (CaSR) reduces parathyroid hormone (PTH) secretion by increasing the sensitivity of the CaSR on parathyroid cells. We conducted a systematic review and meta-analysis on the safety and efficacy of cinacalcet in Primary Hyperparathyroidism (PHPT). MEDLINE, Embase, BIOSIS, and the Cochrane Library were searched for published articles (from database inception to Sept 2020). All double-blind RCTs and cohort studies that reported data on the efficacy and safety of cinacalcet therapy in individuals ≥ 18 with PHPT were included. Random effect meta-analysis was performed to estimate the efficacy of cinacalcet in lowering serum calcium and PTH levels compared with placebo. 4 RCTs (177 participants) and 17 cohort studies (763 participants) were eligible for final analysis. Pooled results from the RCTs suggest that, when compared to placebo and administered for up to 28 weeks, cinacalcet normalizes serum calcium (≤ 10.3 mg/dl) in patients with PHPT [RR 20 (95% CI 6.04 - 68.52, I2 = 0%, pheterogeneity < 0·00001)]. Serum PTH levels decreased significantly after 2 weeks and up to 28 weeks after treatment with cinacalcet. In the pooled analysis of the 17 cohort studies, serum calcium levels normalized in 76% (95% CI 66% to 86%; I2 = 92%, pheterogeneity < 0·00001) of patients regardless of the duration of treatment. In most studies, PTH levels decreased by 13% to 55%. No RCT reported on BMD as a primary or secondary outcome, and no improvement in BMD was noted in the 2 non-randomized studies that reported densitometric findings. No significant difference in urinary calcium was noted with cinacalcet therapy in either the RCTs or non-randomized studies. There was no significant difference in overall adverse events (AE) (RD 0.01, 95% CI -0.07 to 0.26) compared to placebo noted in the RCTs. In the non-randomized studies, pooled weighted AE rate was 45% (95% CI 32 to 59%). Risk of bias was low in 2/4 RCTs and 6/17cohort studies; risk was intermediate in 2/4 RCTs and 8/17 cohort studies, and risk was high in 3/17 cohort studies. In PHPT, cinacalcet lowers serum calcium and PTH with greater effects on calcium than on PTH in the short term. In the doses reported, the drug is safe with tolerable side effects. These findings can help inform targeted medical therapy of PHPT in those for whom lowering the serum calcium is indicated and for whom parathyroidectomy is not an option.
Intravenous pamidronate in the treatment of severe idiopathic infantile hypercalcemia. [2018]Idiopathic infantile hypercalcemia (IIH) is a rare disorder caused by CYP24A1 loss-of-function mutation, resulting in impaired degradation of 1,25-dihydroxyvitamin D3. Pamidronate, an intravenously administered bisphosphonate, which is a potent inhibitor of bone resorption, has been reported only once for treatment IIH. We present a case of a previously healthy 5-month-old boy with IIH, where calcemia peaked to 5 mmol/L. Treatment with methylprednisone and furosemide had only minor effects; therefore, 2 intravenous infusions of pamidronate (0.6 mg/kg per dose) corrected the serum calcium level to 2.95 mmol/L. Furthermore, CYP24A1 homozygous mutation p.R396W (c.1186c>t) was identified in this patient, confirming the clinical diagnosis of IIH. In conclusion, IIH has a favorable outcome once properly detected and appropriately treated. Pamidronate has a beneficial effect in those patients with IIH where glucocorticoids and furosemide fail to meet the expectations.
A novel case of neonatal severe hyperparathyroidism successfully treated with a type II calcimimetic drug. [2021]We report a boy with hypercalcemia due to neonatal severe hyperparathyroidism (NSHPT) caused by a compound heterozygous mutation in the calcium sensing receptor (CaSR) managed successfully on a type II calcimimetic drug. The hypercalcemia was temporarily treated by hyperhydration, bisphosphonate and calcium depleted milk. At 29 days of age cinacalcet was introduced. The starting dose was 0.5 mg/kg/day and was subsequently titrated to the point of efficacy (5.2 mg/kg/day) when a persuasive reduction in parathyroid hormone and calcium concentrations was observed. We propose a trial of type II calcimimetics in newborns with NSHPT irrespective of the genetic mutation and advocate that residual functionality of the CaSR predict the drug efficacy.
Early initiation of cinacalcet for the treatment of secondary hyperparathyroidism in hemodialysis patients: a three-year clinical experience. [2018]Despite the availability of standard therapy (vitamin D sterols and phosphate binders) for the treatment of secondary hyperparathyroidism (SHPT) in hemodialyzed (HD) patients, a significant percentage of patients still fail to achieve targets recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation for parathyroid hormone (PTH), calcium, and phosphorus. The calcimimetic cinacalcet (CN) has been shown to be an effective treatment for SHPT, significantly reducing serum PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product levels, thus increasing the proportion of patients achieving the K/DOQI targets for bone mineral parameters. The aim of this study was to evaluate if early treatment with CN had beneficial effects in HD patients with mild-to-moderate SHPT in whom conventional treatments had failed to achieve NKF-K/DOQI targets for PTH, serum-corrected calcium, and phosphorus while minimizing the risk of paradoxical hypercalcemia and/or hyperphosphatemia. Clinical practice data were collected monthly, starting from 6 months prior to, and up to 36 months after, the start of CN therapy. CN was started at a dose of 30 mg daily or every other day, and titrated thereafter to achieve intact PTH (iPTH) 300 pg/mL (570 ± 295 pg/mL) and/or serum-corrected calcium >9.5 mg/dL. CN induced significant decreases in iPTH, calcium, and calcium-phosphorus product with respect to baseline levels. The percentage of patients within K/DOQI target levels at baseline, 12, 24, and 36 months was 0, 81.2, 83.3, and 86.2% for iPTH; 34.4, 65.6, 86.6, and 89.6% for serum-corrected calcium; 40.6, 56.2, 69.6, and 72.4% for phosphorus; and 37.5, 62.5, 80, and 82.7% for calcium-phosphorus product. The mean dose of CN at the end of the observation period was 38 mg/day. The mean dose of concomitant medication (calcitriol, Al-containing phosphate binders, and sevelamer) decreased from baseline to 36 months. Early treatment with CN in HD patients with SHPT increases the proportion of patients achieving and maintaining K/DOQI targets with a low dose of CN (38 mg/day). These results suggest that the metabolic control obtained with low-dose CN administered early in the course of SHPT can be maintained or increased over time.
Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. [2018]To evaluate the hypocalcemic effect and safety of three different doses of the bisphosphonate ibandronate in tumor-associated hypercalcemia, and to identify factors predicting response.
Dyselectrolytemias after single dose of pamidronate administration. [2018]Bisphosphonate such as pamidronate initially described for the treatment of neoplastic hypercalcemia, currently is being used off label to treat sever hypercalcemia of any etiology. Multiple dyselectrolytemias are a potential adverse effect of this drug, and are considered infrequent. We describe a case of transient electrolyte abnormalities after single dose of 60 mg intravenous pamidronate.
Inhibition of parathyroid hormone secretion and parathyroid hormone-independent diminution of tubular calcium reabsorption by WR-2721, a unique hypocalcemic agent. [2018]Hypocalcemia has been observed in patients receiving WR-2721 [S-,2-(3-aminopropylamino)-, ethylphosphorothioic acid]. WR-2721 is a compound that, after being dephosphorylated, provides protection of normal tissues against radio- and chemotherapy. The hypocalcemic response was accompanied by a decrease in the plasma level of parathyroid hormone (PTH) and by hypomagnesemia. Our present studies in rats on the mechanism of the hypocalcemic effect of WR-2721 indicate that: (a) The phosphorylated and dephosphorylated form of WR-2721 induced an equal dose-dependent decrement in plasma calcium. (b) In intact rats a maximal hypocalcemic dose of WR-2721 reduced urinary cyclic AMP excretion from 70.5 +/- 6.3 to 38.2 +/- 3.1 pmol/ml glomerular filtration rate (GFR), a level comparable to that observed (35.9 +/- 5.2 pmol/ml GFR) in thyroparathyroidectomized (TPTX) rats. (c) WR-2721 given to TPTX rats did not significantly interfere with the calcemic effect of bovine PTH 1-34 infused at 2.5 IU/h. Likewise, the drug did not impair the PTH actions on the renal Ca and inorganic phosphate (Pi) handling, and on the urine cyclic AMP excretion. (d) In TPTX rats made normocalcemic by low Pi diet, the hypocalcemic effect of WR-2721 was only about 25% of that observed in intact animals. However, it was associated with increased urine Ca per milliliter GFR, indicating a PTH-independent inhibitory effect on tubular Ca reabsorption. (e) In WR-2721-treated intact rats, prevention of hypomagnesemia by infusing magnesium chloride did not reduce hypocalcemia. In conclusion, the hypocalcemic effect of WR-2721 is not dependent upon the presence of a phosphate group in the molecule and is not causally related to hypomagnesemia. WR-2721 appears to be a unique hypocalcemic pharmacologic agent with strong inhibitory activity on PTH secretion and additional PTH-independent action on renal Ca reabsorption.
Parathyroid Apoplexy Following Cinacalcet Treatment in Primary Hyperparathyroidism. [2020]Cinacalcet, a calcimimetic drug, is considered a safe and valid option for the treatment of hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. Hypocalcemia and gastrointestinal adverse reactions are the main side effects reported in patients treated with cinacalcet. We present here the case of an 80-years-old patient with primary hyperparathyroidism treated with cinacalcet for 17 months who developed a severe and symptomatic episode of hypocalcemia requiring hospitalization 1 month after reaching a daily dose of 180 mg. Follow-up laboratory and imaging exams showed remission of primary hyperparathyroidism and disappearance of the parathyroid adenoma, suggesting a possible association between cinacalcet therapy and parathyroid infarction resulting in normalization of the elevated serum parathyroid hormone levels and severe hypocalcemia. No known cases of iatrogenic parathyroid apoplexy have thus far been described. We report here the first case of parathyroid apoplexy associated with the administration of cinacalcet in a patient with primary hyperparathyroidism. Parathyroid apoplexy features heterogeneous clinical manifestations ranging from relatively asymptomatic to potentially life-threatening cases. The occurrence of this complication should be carefully considered in patients with primary hyperparathyroidism in therapy with cinacalcet.
[Long-term efficacy and safety of etelcalcetide in hemodialysis patients with severe secondary hyperparathyroidism]. [2021]Introduction: Etelcalcetide has proven effective and well tolerated in the treatment of secondary hyperparathyroidism (IPS) in patients on hemodialysis (HD). Since long-term studies are scarce, we assessed the efficacy and safety of etelcalcetide in the treatment of severe IPS in a group of HD patients over a 12-month period. Patients and Methods: We selected 24 HD patients with PTH levels > 500 pg/mL (range 502-2148 pg/mL), despite following a therapy with cinacalcet and/or vitamin D analogues. The initial dosage of etelcalcetide was 7.5 mg/week, then it was adjusted based on the trend of the levels of the total albumin-corrected serum calcium (CaALb_c) and PTH. Treatment was temporarily suspended if CaALb_c levels were <7.5 mg/dL or if hypocalcemia was symptomatic. CaALb_c, phosphorus, PTH and total alkaline phosphatase (t-ALP) were measured monthly. The main endpoint was the decrease in PTH levels >30% compared to baseline values. Results: At F-U, the reduction in PTH levels was > 30% in 83% of our patients. PTH levels decreased from 1169 ± 438 to 452±241 pg/mL at F-U (P <0.001). The percentage of reduction in PTH levels at F-U was -56 ± 25%. CaALb_c and phosphate levels decreased from 9.8 ± 0.4 mg/dL to 9.0 ± 0.6 mg/dL (P <0.001), and from 6.1 ± 1.3 mg/dL to 4.9 ± 1.3 mg/dL (P <0.01), respectively. The main side effect was hypocalcaemia, but never so severe as to require the interruption of treatment. Hypocalcemia was more pronounced in patients with higher basal levels of PTH and t-ALP. During the study, the percentage of patients treated with calcium carbonate increased from 33% to 54% and that of patients treated with paricalcitol from 33% to 79%. At F-U the average weekly dosage of etelcalcetide was 21.0 ± 9.5 mg (range 7.5-37.5 mg/week). Conclusions: The treatment of severe IPS with etelcalcetide has been proved effective and safe in the long term. Hypocalcaemia, the most frequent side effect, was more evident in patients with the most severe forms of IPS and was probably due to a reduction in bone turnover rather than to the direct effect of etelcalcetide.
Phase 1, single-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of etelcalcetide in pediatric patients with secondary hyperparathyroidism receiving hemodialysis. [2021]Data on the safety, efficacy of etelcalcetide in children with secondary hyperparathyroidism (sHPT) are limited.