Evaluating Alternative Medical Therapies in Primary Hyperparathyroidism

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.

Study Overview

• Status: Completed
• Conditions: Primary Hyperparathyroidism
• Intervention / Treatment: Drug: Placebo; Drug: Cinacalcet; Drug: amiloride; Drug: eplerenone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Anand Vaidya, MD MMSc, Brigham and Women's Hospital, Harvard Medical School

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): October 1, 2021
• Study Completion (Actual): October 2, 2021

Study Registration Dates

• First Submitted: August 14, 2015
• First Submitted That Met QC Criteria: August 14, 2015
• First Posted (Estimate): August 17, 2015

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Parathyroid Diseases; Hyperparathyroidism; Hyperparathyroidism, Primary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Channel Blockers; Hormone Antagonists; Calcium-Regulating Hormones and Agents; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Calcimimetic Agents; Acid Sensing Ion Channel Blockers; Epithelial Sodium Channel Blockers; Cinacalcet; Eplerenone; Amiloride
• Other Study ID Numbers: 107407

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be shared with interested investigators upon request 1 year after the study is completed. Investigators may request IPD by contacting the PI and proposing a data analysis plan