Evaluating Alternative Medical Therapies in Primary Hyperparathyroidism

Study Overview
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Brief Summary
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This study will evaluate whether blocking the mineralocorticoid receptor, alone, or in combination with the calcimimetic cinacalcet, can lower parathyroid hormone and calcium levels in primary hyperparathyroidism.

Detailed Description
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To conduct a double-blinded, placebo-controlled, randomized intervention study to investigate whether mineralocorticoid receptor (MR) antagonism, alone or in combination with cinacalcet, is an effective therapy for primary hyperparathyroidism (P-HPTH). Hypothesis: MR antagonism, as a monotherapy or in combination with a calcimimetic, is a mechanism to lower parathyroid hormone (PTH) in primary hyperparathyroidism (P-HPTH). Study Design: Sixty subjects with P-HPTH will be enrolled to randomly receive eplerenone (a potassium-sparing diuretic that directly blocks the MR), amiloride (a potassium-sparing diuretic that does not directly block the MR), or placebo for 4 weeks. Thereafter, all subjects will receive cinacalcet therapy (a calcimimetic that lowers PTH) in addition to their randomized intervention for an additional 2 weeks. Anticipated Results: In this proof-of-concept study, eplerenone therapy will lower PTH, serum calcium, and markers of bone resorption in P-HPTH, when compared to placebo. The PTH response to amiloride will resemble that of placebo, suggesting that the eplerenone mediated reductions in PTH are specific to interactions with the MR. Combination therapy with eplerenone + cinacalcet will result in additive or synergistic reductions in PTH, when compared to placebo + cinacalcet or placebo + amiloride. Implications: MR antagonism (alone or in combination with cinacalcet) may be a mechanism to lower PTH and calcium in P-HPTH, thereby identifying a new potential option in the limited medical therapies for P-HPTH.

Official Title
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Evaluating Alternative Medical Therapies in Primary Hyperparathyroidism

Conditions
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Primary Hyperparathyroidism

Intervention / Treatment
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* Drug: eplerenone
* Drug: amiloride
* Drug: Placebo
* Drug: Cinacalcet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: physician diagnosis of active P-HPTH (Serum calcium > upper limit of reference range and serum PTH > ULRR; or Serum Calcium > ULRR AND serum PTH > 30 pg/mL; or Serum Calcium within 0.2 mg/dL of the ULRR and PTH>ULRR). negative pregnancy test in women aged 18-45 Exclusion Criteria: estimated glomerular filtration rate < 60mL/min/1,73m2 serum potassium > 5.0 mmol/L age <18 or >80 years diabetes that is not well controlled (HbA1c>8%)\ liver failure heart failure history of myocardial infarction or stroke active use of lithium active chronic inflammatory conditions (such as inflammatory bowel disease, rheumatoid arthritis, sarcoidosis) initiation within 3 months of bisphosphonates or cinacalcet need for imminent parathyroidectomy (within the next 6-8 weeks) as determined by their endocrinologist or surgeon absolute serum calcium >13.0 mg/dL positive pregnancy test on any of the study visits for women ages 18-45.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 3-parallel-armed double-blinded randomized controlled trial wherein monotherapy of eplerenone or amiloride or placebo administered for 4 weeks. After weeks, an open-label extension addition of cinacalcet to all 3 arms conducted for 2 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + Cinacalcet<br>Patients with primary hyperparathyroidism will receive placebo for 4 weeks followed by the addition of cinacalcet for 2 weeks | Drug: Placebo<br> <br> Drug: Cinacalcet<br>* Cinacalcet, as add-on therapy in addition to eplerenone/amiloride/placebo, titrated up to a maximum of 30mg BID<br>|
| Active Comparator: Amiloride + Cinacalcet<br>Patients with primary hyperparathyroidism will receive amiloride for 4 weeks followed by the addition of cinacalcet for 2 weeks | Drug: amiloride<br>* amiloride, titrated up to a maximum of 10mg BID<br>Drug: Cinacalcet<br>* Cinacalcet, as add-on therapy in addition to eplerenone/amiloride/placebo, titrated up to a maximum of 30mg BID<br>|
| Experimental: Eplerenone + Cinacalcet<br>Patients with primary hyperparathyroidism will receive eplerenone for 4 weeks followed by the addition of cinacalcet for 2 weeks | Drug: eplerenone<br>* eplerenone, titrated up to a maximum of 50mg BID<br>Drug: Cinacalcet<br>* Cinacalcet, as add-on therapy in addition to eplerenone/amiloride/placebo, titrated up to a maximum of 30mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Parathyroid Hormone Levels | Change in circulating PTH levels before and after 4 weeks of double-blinded intervention when compared to placebo | Change in circulating PTH levels before and after 4 weeks of double-blinded monotherapy intervention when compared to placebo (PTH at 4 weeks minus PTH at baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Calcium Levels | Change in serum calcium levels before and after intervention when compared to placebo | Change in serum calcium levels before and after 4 weeks of double-blinded monotherapy intervention when compared to placebo (calcium at 4 weeks minus calcium at baseline) |