Primary Hyperparathyroidism
Conditions
Brief summary
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
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.
Interventions
DRUGeplerenone
eplerenone, titrated up to a maximum of 50mg BID
DRUGamiloride
amiloride, titrated up to a maximum of 10mg BID
DRUGPlacebo
DRUGCinacalcet
Cinacalcet, as add-on therapy in addition to eplerenone/amiloride/placebo, titrated up to a maximum of 30mg BID
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Parathyroid Hormone Levels | 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) | Change in circulating PTH levels before and after 4 weeks of double-blinded intervention when compared to placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Calcium Levels | 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) | Change in serum calcium levels before and after intervention when compared to placebo |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Eplerenone Patients with primary hyperparathyroidism will receive maximally-tolerated eplerenone for 4 weeks | 14 |
| Amiloride Patients with primary hyperparathyroidism will receive maximally-tolerated amiloride for 4 weeks | 14 |
| Placebo Patients with primary hyperparathyroidism will receive placebo for 4 weeks | 13 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Addition of Cinacalcet | Adverse Event | 2 | 2 | 2 |
| Open-label Addition of Cinacalcet | Withdrawal by Subject | 2 | 0 | 1 |
| Randomization to Monotherapy for 4 Weeks | Adverse Event | 1 | 1 | 1 |
| Randomization to Monotherapy for 4 Weeks | Lost to Follow-up | 1 | 0 | 0 |
| Randomization to Monotherapy for 4 Weeks | Physician Decision | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Eplerenone | Amiloride |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 10 Participants | 7 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 3 Participants | 7 Participants | 9 Participants |
| Age, Continuous | 65 years STANDARD_DEVIATION 9 | 69 years STANDARD_DEVIATION 10 | 65 years STANDARD_DEVIATION 7 | 61 years STANDARD_DEVIATION 9 |
| Parathyroid hormone | 74 pg/mL STANDARD_DEVIATION 39 | 66 pg/mL STANDARD_DEVIATION 26 | 65 pg/mL STANDARD_DEVIATION 17 | 89 pg/mL STANDARD_DEVIATION 56 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 31 Participants | 12 Participants | 12 Participants | 7 Participants |
| Region of Enrollment United States | 41 participants | 13 participants | 14 participants | 14 participants |
| Serum calcium | 10.5 mg/dL STANDARD_DEVIATION 0.5 | 10.4 mg/dL STANDARD_DEVIATION 0.6 | 10.4 mg/dL STANDARD_DEVIATION 0.5 | 10.5 mg/dL STANDARD_DEVIATION 0.5 |
| Sex: Female, Male Female | 34 Participants | 11 Participants | 12 Participants | 11 Participants |
| Sex: Female, Male Male | 7 Participants | 2 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 13 | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 1 / 14 | 1 / 14 | 1 / 13 | 2 / 12 | 2 / 12 | 2 / 12 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 13 | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Change in Parathyroid Hormone Levels
Change in circulating PTH levels before and after 4 weeks of double-blinded intervention when compared to placebo
Time frame: 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)
Population: Number of participants who completed the 4 week double-blinded monotherapy intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Change in Parathyroid Hormone Levels | 4.0 pg/mL |
| Amiloride | Change in Parathyroid Hormone Levels | -3.7 pg/mL |
| Placebo | Change in Parathyroid Hormone Levels | 0.8 pg/mL |
Comparison: ANOVA comparing the change in PTH over 4 weeks between eplerenone monotherapy and placebop-value: 0.84ANOVA
Comparison: ANOVA comparing the change in PTH over 4 weeks between amiloride monotherapy and placebop-value: 0.54ANOVA
Comparison: ANOVA comparing the change in PTH over 4 weeks between eplerenone monotherapy and amiloride monotherapyp-value: 0.58ANOVA
Secondary
Change in Calcium Levels
Change in serum calcium levels before and after intervention when compared to placebo
Time frame: 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)
Population: patients with primary hyperparathyroidism receiving double-blinded monotherapy for 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eplerenone | Change in Calcium Levels | 0.1 mg/dL |
| Amiloride | Change in Calcium Levels | 0.0 mg/dL |
| Placebo | Change in Calcium Levels | 0.1 mg/dL |
Comparison: ANOVA comparing the change in serum calcium over 4 weeks between eplerenone monotherapy and placebop-value: 0.82ANOVA
Comparison: ANOVA comparing the change in serum calcium over 4 weeks between amiloride monotherapy and placebop-value: 0.21ANOVA
Comparison: ANOVA comparing the change in serum calcium over 4 weeks between eplerenone monotherapy and amiloride monotherapyp-value: 0.12ANOVA