Evaluating Alternative Medical Therapies 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.

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.