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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo + Cinacalcet | Placebo Comparator | Patients with primary hyperparathyroidism will receive placebo for 4 weeks followed by the addition of cinacalcet for 2 weeks |
|
| Amiloride + Cinacalcet | Active Comparator | Patients with primary hyperparathyroidism will receive amiloride for 4 weeks followed by the addition of cinacalcet for 2 weeks |
|
| Eplerenone + Cinacalcet | Experimental | Patients with primary hyperparathyroidism will receive eplerenone for 4 weeks followed by the addition of cinacalcet for 2 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| eplerenone | Drug | eplerenone, titrated up to a maximum of 50mg BID |
| |
| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Anand Vaidya, MD MMSc | Brigham and Women's Hospital, Harvard Medical School | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
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
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Following enrollment (n=69), participants underwent medication washout to eliminate interference with renin-angiotensin-aldosterone system measurements. ACE inhibitors, ARBs, ENaC inhibitors, and MR antagonists were stopped for 2 weeks and BP controlled with alternative agents, if needed. During washout, 28 participants were withdrawn, thus the number of participants at the time of randomization to monotherapy was 41. 36 of 41 completed 4wks and began the cinacalcet open-label phase.
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| ID | Title | Description |
|---|---|---|
| FG000 | Eplerenone | Patients with primary hyperparathyroidism will receive maximally-tolerated, double-blinded, eplerenone monotherapy for 4 weeks, followed by an open-label extension wherein maximally-tolerated cinacalcet therapy will be added to eplerenone for 2 weeks. |
| FG001 | Amiloride | Patients with primary hyperparathyroidism will receive maximally-tolerated, double-blinded, amiloride monotherapy for 4 weeks, , followed by an open-label extension wherein maximally-tolerated cinacalcet therapy will be added to amiloride for 2 weeks. |
| FG002 | Placebo | Patients with primary hyperparathyroidism will receive maximally-tolerated, double-blinded, placebo monotherapy for 4 weeks, followed by an open-label extension wherein maximally-tolerated cinacalcet therapy will be added to placebo for 2 weeks. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomization to Monotherapy for 4 Weeks |
|
| |||||||||||||||||||||
| Open-label Addition of Cinacalcet |
|
Patient with primary hyperparathyroidism
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| ID | Title | Description |
|---|---|---|
| BG000 | Eplerenone | Patients with primary hyperparathyroidism will receive maximally-tolerated eplerenone for 4 weeks |
| BG001 | Amiloride | Patients with primary hyperparathyroidism will receive maximally-tolerated amiloride for 4 weeks |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Parathyroid Hormone Levels | Change in circulating PTH levels before and after 4 weeks of double-blinded intervention when compared to placebo | Number of participants who completed the 4 week double-blinded monotherapy intervention | Posted | Median | Inter-Quartile Range | pg/mL | 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) |
|
Over the course of the entire study, including the 4 week randomization to monotherapy (eplerenone vs amiloride vs placebo) and the 2 week open-label addition of cinacalcet (6 weeks in total).
same as clinicaltrials.gov
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Eplerenone | Patients with primary hyperparathyroidism will receive maximally-tolerated eplerenone for 4 weeks |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| low egfr | Renal and urinary disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Anand Vaidya | Brigham and Women's Hospital | 16177325666 | anandvaidya@bwh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 2, 2021 | Apr 6, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 31, 2015 | Apr 6, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D049950 | Hyperparathyroidism, Primary |
| ID | Term |
|---|---|
| D006961 | Hyperparathyroidism |
| D010279 | Parathyroid Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000077545 | Eplerenone |
| D000584 | Amiloride |
| D000069449 | Cinacalcet |
| ID | Term |
|---|---|
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 |
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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.
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| amiloride |
| Drug |
amiloride, titrated up to a maximum of 10mg BID |
|
| Placebo | Drug |
|
| Cinacalcet | Drug | Cinacalcet, as add-on therapy in addition to eplerenone/amiloride/placebo, titrated up to a maximum of 30mg BID |
|
| Physician Decision |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| BG002 | Placebo | Patients with primary hyperparathyroidism will receive placebo for 4 weeks |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Parathyroid hormone | Mean | Standard Deviation | pg/mL |
|
| Serum calcium | Mean | Standard Deviation | mg/dL |
|
| OG002 | Placebo | Patients with primary hyperparathyroidism will receive placebo monotherapy for 4 weeks |
|
|
|
| Secondary | Change in Calcium Levels | Change in serum calcium levels before and after intervention when compared to placebo | patients with primary hyperparathyroidism receiving double-blinded monotherapy for 4 weeks | Posted | Median | Inter-Quartile Range | mg/dL | 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) |
|
|
|
|
| 0 |
| 14 |
| 0 |
| 14 |
| 1 |
| 14 |
| EG001 | Amiloride | Patients with primary hyperparathyroidism will receive maximally-tolerated amiloride for 4 weeks | 0 | 14 | 0 | 14 | 1 | 14 |
| EG002 | Placebo | Patients with primary hyperparathyroidism will receive placebo for 4 weeks | 0 | 13 | 0 | 13 | 1 | 13 |
| EG003 | Eplerenone + Cinacalcet | Open-label cinacalcet added for 2 weeks | 0 | 12 | 0 | 12 | 2 | 12 |
| EG004 | Amiloride + Cinacalcet | Open-label cinacalcet added for 2 weeks | 0 | 12 | 0 | 12 | 2 | 12 |
| EG005 | Placebo + Cinacalcet | Open-label cinacalcet added for 2 weeks | 0 | 12 | 0 | 12 | 2 | 12 |
| hyperkalemia | General disorders | Systematic Assessment |
|
| hypocalcemia | Endocrine disorders | Systematic Assessment | low serum calcium |
|
| low blood pressure | Cardiac disorders | Systematic Assessment | blood pressure below target range |
|
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| Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| ANOVA |
| 0.21 |
| Median Difference (Net) |
| 0.1 |
| 2-Sided |
| Superiority |
| ANOVA comparing the change in serum calcium over 4 weeks between eplerenone monotherapy and amiloride monotherapy | ANOVA | 0.12 | Median Difference (Net) | 0.1 | 2-Sided | Superiority |