Calcium Channel Blockade in Primary Aldosteronism

Phase 2

Completed

Conditions: Primary Aldosteronism Due to Adrenal Hyperplasia (Bilateral)
Primary Aldosteronism

Interventions: Drug: Amlodipine

Registration Number: NCT04179019

Lead Sponsor: Brigham and Women's Hospital

Brief Summary: This pilot study explore whether the calcium channel blocker amlodipine can lower aldosterone levels in people with primary aldosteronism.

Detailed Description: BACKGROUND:

Primary aldosteronism is a common cause of hypertension. The cause of primary aldosteronism can be a unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) whereby there is diffuse production of ectopic and non-physiologic aldosterone in the adrenal cortex. IHA likely contributes to the majority of all primary aldosteronism. Whereas surgical cure is the preferred therapy for APA, lifelong mineralocorticoid receptor antagonists (MRAs), such as spironolactone or eplerenone, are used to treat IHA. Treatment is important as patients with primary aldosteronism have an elevated risk of adverse cardiovascular and renal outcomes compared to patients with essential hypertension. It was long thought that curative surgery and lifelong medical therapy were equivalent treatment options, but more recent studies suggest that MRAs may not ameliorate the adverse cardiovascular and renovascular effects of primary aldosteronism to the same extent as surgery. For one, MRAs do not lower aldosterone levels, in fact, aldosterone levels are often increased with MRA therapy. Therefore, for IHA patients with primary aldosteronism in whom surgery is not an option, efforts to improve and optimize medical therapy are important.

Recent evidence in surgically removed adrenal glands from patients with primary aldosteronism and IHA has shown that even though IHA adrenal glands do not harbor adrenal tumors, they do harbor foci of ectopic aldosterone production and these foci are enriched for somatic mutations (gain of function) in CACNA1D, thereby suggesting that calcium channel mutations are predominant in the pathogenesis of IHA. This represents an intriguing target for medical therapy as blockade of this channel could lower intracellular calcium influx and hence decrease aldosterone production. Calcium channel blockade could also represent a more upstream therapy than mineralocorticoid receptor antagonists, which block the action of aldosterone at its receptor rather than lower its production.

This study is a pilot study to test the hypothesis that calcium channel blockade may lower autonomous aldosterone production in primary aldosteronism patients with IHA.

PROTOCOL:

Participants taking calcium channel blockers will be required to stop these medications for 2-4 weeks prior to initiation of the study. During this time, blood pressure will be managed with doxazosin and/or hydralazine to target an ideal range of \<130/80 mmHg, but practically ranges of 120-150/60-90 mmHg will be allowed. Serum potassium will be treated with supplemental potassium chloride to target a range of 3.5-4.5 mEq/L prior to initiation of the study. Participants already on a mineralocorticoid receptor blocker must have a plasma renin activity of \<1.0 ng/mL/h to participate, or be able to reduce or stop the dose of this medication for the duration of the study.

Study Visit 1: Participants will be provided sodium supplements (3g/daily) to take for five days prior to study visit 1. On the fifth day, a 24h urine collection will be obtained to measure urinary sodium and aldosterone and participants will arrive at the Clinical Research Center for testing. After one hour of seated rest, baseline blood measures will be obtained, and a single dose of amlodipine 10 mg will be administered. Blood measurements will be repeated every 2 hours to assess the serial change in outcome measures (t=2,4,and 6 hours after the amlodipine dose). Upon completion of the visit, participants will be prescribed amlodipine 10mg daily for 2 weeks.

Treatment phase: Following completion of Visit 1, participants will be prescribed amlodipine 10mg daily for 2 weeks. Home blood pressure monitoring will continue to ensure blood pressure remains in the target range of 120-150/80-90 mmHg. If blood pressure falls below this range with amlodipine, doxazosin and/or hydralazine doses may be reduced or stopped. If blood pressure remains low even after stopping doxazosin and hydralazine, the dose of amlodipine may be lowered to 5mg daily. Potassium chloride supplements may be titrated based on the values obtained at Study visit 1.

Study Visit 2: Participants will be provided sodium supplements (3g/daily) to take for five days prior to study visit 2. On the fifth day, a 24h urine collection will be obtained to measure urinary sodium and aldosterone and participants will arrive at the Clinical Research Center for testing. After one hour of seated rest, baseline blood measures will be obtained, and a single dose of amlodipine 10 mg will be administered. Blood measurements will be repeated every 2 hours to assess the serial change in outcome measures (t=2,4,and 6 hours after the amlodipine dose). Upon completion of the visit, the study will have concluded and participants will return to their usual care.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Confirmed diagnosis of primary aldosteronism
Idiopathic bilateral hyperaldosteronism subtype based on adrenal venous sampling
Primary aldosteronism treated with medical therapy (not surgery)
Plasma renin activity <1.0 ng/mL/h

Exclusion Criteria

large or discrete adrenal adenoma on cross-sectional imaging
inability to stop calcium channel blocker and transition to alternative medication
inability to stop mineralocorticoid receptor antagonist and transition to alternative medication if plasma renin activity > 1.0 ng/mL/h
Anemia
leukopenia
thrombocytopenia
pregnant
breastfeeding

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Amlodipine	Amlodipine	Amlodipine (dose 10 mg, once daily)

Primary Outcome Measures

Name	Time	Method
Change in 24-hour Urinary Aldosterone Excretion Rate	Baseline and 2 weeks of amlodipine therapy	Change in 24h urinary aldosterone excretion rate in response to maximal amlodipine therapy
Change in Plasma Aldosterone Concentration	Baseline and 2 weeks of amlodipine therapy	Change in plasma aldosterone concentration in response to maximal amlodipine therapy

Secondary Outcome Measures

Name	Time	Method
Acute Change in Plasma Aldosterone Concentration	Baseline plasma aldosterone concentration before amlodipine therapy and 6 hours post-amlodipine dose, compared to baseline plasma aldosterone after 2 weeks of amlodipine therapy and 6 hours post-amlodipine therapy.	Change in plasma aldosterone concentration after a single dose of amlodipine, before and after 2 weeks of amlodipine therapy