Calcium Channel Blockade in Primary Aldosteronism
Condition: Primary Aldosteronism; Primary Aldosteronism Due to Adrenal Hyperplasia (Bilateral)
MeSH terms: Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Hyperaldosteronism; Hyperplasia
Study type: Interventional
Phase: Phase 2

Summary: 
      Primary aldosteronism is a common cause of hypertension. Recent evidence suggests that many
      patients with bilateral idiopathic hyperaldosteronism harbor gain-of-function somatic
      mutations in zona glomerulosa calcium channels that results in aldosterone production. This
      finding raises the possibility that calcium channel antagonists may be a targeted therapy to
      reduce aldosterone production in patients who harbor these mutations.
    

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.
    

Intervention name(s): Amlodipine
Intervention type(s): Drug
Intervention description(s): Amlodipine (10mg daily, as tolerated by blood pressure parameters) for 2 weeks
Intervention MeSH terms: Amlodipine
Intervention model: Single Group Assignment
Intervention model description: Open-label, single group, pilot intervention to evaluate physiologic changes in hormonal parameters.
Masking: None (Open Label)
Primary purpose: Treatment