Calcium Channel Blockade in Primary Aldosteronism
Phase: PHASE2
Conditions: Primary Aldosteronism, Primary Aldosteronism Due to Adrenal Hyperplasia (Bilateral)
Sponsor: Brigham and Women's Hospital

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Title: Calcium Channel Blockade in Primary Aldosteronism 
 
Detailed Protocol 
 
NCT04179019 
 
Date of IRB Approval & Document Version: 1/9/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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I. 
BACKGROUND AND SIGNIFICANCE 
 
Primary aldosteronism is the most common cause of secondary hypertension, with studies 
reporting prevalence rates of ~10% in the general hypertensive population and ~20% among 
patients with resistant 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 >70% 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 even higher 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. 
 
In recent years, several mutations in cellular membrane ion channels and pumps have been found 
to cause primary aldosteronism. Nearly all APAs that cause primary aldosteronism harbor an 
underlying driver mutation in one or more of the following genes: KCNJ5 (inward-rectifying 
potassium channel), ATP1A1 (Na+/K+ ATPase), ATP2B3 (Ca2+ ATPase), CACNA1D (L-type 
voltage-dependent Ca2+ channel), CACNA1H (T-type voltage-dependent Ca2+ channel), or 
CLCN2 (chloride channel). The unifying mechanism of all these gene alterations is that the 
underlying pathology induces increased calcium ion influx into adrenal zona glomerulosa cells 
which induces excess aldosterone production.   
 
Moreover, 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 
mutations 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 and hence decrease aldosterone production. 
Calcium channel blockade would also represent a more upstream therapy than mineralocorticoid 
receptor antagonists, which block aldosterone’s action at its receptor rather than lower its 
production. 
 
Calcium channel blockers such as amlodipine are a class of medications that have been used in 
the treatment of essential hypertension for years and are safe with minimal risks. We hypothesize 
that amlodipine can lower autonomous aldosterone production in primary aldosteronism patients 
with IHA, a population that is more likely to harbor a mutation in the L-type voltage-gated calcium 
channel and a population in whom medical therapy is usually the only treatment option. 
 
 
 
Preliminary Data to Support the Proposed Study 
 
 
II. 
SPECIFIC AIMS 
 

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The hypothesis for this pilot study is that the calcium-channel blocker amlodipine can 
specifically decrease aldosterone production in patients with idiopathic bilateral 
hyperaldosteronism. 
 
• Primary Outcome:  Change in 24-hour urinary aldosterone excretion rate and plasma 
aldosterone in response to maximal amlodipine therapy. 
 
•  Secondary Outcomes: Acute change in plasma aldosterone in response to amlodipine therapy.  
 
 
III. 
SUBJECT SELECTION 
 
Sample Size:  
 
Up to 15 participants with confirmed or presumed IHA will be recruited. Some patients with IHA 
will have this diagnosis confirmed via adrenal venous sampling. Many patients have not 
undergone adrenal venous sampling but have a preumptive diagnosis of IHA because they have 
no adrenal abnormalities on imaging and/or are already being treated with mineralocorticoid 
receptor antagonists. 
 
Participants will be included if they are aged 18-80 years, have a confirmed diagnosis of primary 
aldosteronism, a suppressed plasma renin activity (<1.0 ng/mL/h), and confirmed or presumed 
IHA. Participants taking a calcium-channel blocker will be included if they are willing to undergo 
a washout protocol (described below). Participants taking mineralocorticoid receptor antagonists 
will be included if their plasma renin activity is <1.0 ng/mL/h; if it is not, they may still be included 
if they are able to lower the dose of this medication such that their renin activity falls below 1.0 
ng/mL/h. 
 
Participants will be excluded if they have discrete or large bilateral adrenal adenomas on cross-
sectional imaging (done as a part of standard clinical care) to avoid including participants who 
may have APAs, which predominantly have KCNJ5 mutations rather than CACNA1D calcium 
channel mutations. Participants with anemia, leukopenia, or thrombocytopenia (based on our 
acceptable ranges) or a blood pressure greater than 180/100 mmHg, will be excluded. Pregnant 
or breastfeeding women will also be excluded. 
 
 
IV. 
SUBJECT ENROLLMENT 
 
The study will take place at Brigham and Women’s Hospital (BWH). Our research team has 
extensive experience and an established infrastructure for recruiting individuals with IHA. 
Participants will be recruited from 2 sources.  
 
1. Center for Adrenal Disorders at BWH: The PI sees primary aldosteronism patients in the 
clinic. In addition, participants undergoing adrenal venous sampling for primary 
aldosteronism will be contacted if they have IHA. Patients with IHA will be contacted 
regarding interest in participation by the PI’s research team with a letter.  
 
2. Partners Research Patient Data Registry (RPDR): The Brigham & Women’s Hospital 
and Partners affiliates i.e. Massachusetts General Hospital, Faulkner Hospital, Newton 
Wellesley, etc. have a shared database to identify potentially eligible patients that can be 
used for clinical research studies. We will search for patients with primary aldosteronism 

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in the RPDR and with IRB committee approval, conduct targeted chart reviews to assess 
which patients likely meet inclusion criteria for this study. Once we have identified 
potentially eligible patients, they will be invited to participate via the Mass General 
Brigham Patient Gateway secure online portal or we will identify their primary care 
physician, or endocrinologist, or other internist with close ties to the patient in our 
system, and request permission to contact their potentially eligible patient with our IRB 
approved letter (co-signed by the PI and physician) including information regarding the 
study. The letter is used to ask permission to send their patients a co-signed letter 
inviting them to learn more about and potentially participate in our study. In the letter, 
participants will be notified that we will be calling within about 2 weeks after receipt of the 
letter. Our phone number will be provided so individuals may contact us with questions 
or to opt out of receiving further information about the study. Interested patients will be 
invited for a screening visit to formally assess eligibility.  
 
V. 
STUDY PROCEDURES 
 
The study will take place in the outpatient clinical research centers of the BWH.  There will be one 
screening visit, and 3 study visits.  The duration of the entire study is 2-10 weeks (see protocol 
schema). 
 
 
 
 
Screening visit (Visit 1): Participants will meet with a study staff member (licensed physician or 
nurse practitioner or physician assistant) to review the study protocol, risks, and benefits.  They 
will have received the consent form ahead of this visit and it will be reviewed in detail and 
signed prior to proceeding. The screening visit will entail a brief review of the patient’s medical 
history, a physical examination, blood pressure measurements, an EKG will be perfomed, and 
phlebotomy to assess eligibility. Women between the ages of 18-50 will have a pregnancy test 
that must be negative. 
 
Blood pressure medication washout and optimization period: Many participants may already be 
treated with a calcium-channel blocker per standard of care. To assess the effect of amlodipine 
on aldosterone production, these participants will washout their prescribed calcium-channel 
blocker for 4-8 weeks and will have their blood pressure managed with other anti-hypertensive 
agents in the interim. After stopping their calcium-channel blocker, participants will be provided 
with a home blood pressure machine and taught how to measure their blood pressure at home 
and how to report daily readings to study staff.  The target blood pressure for this washout 
period, and throughout the entire study protocol, will be 120-150/60-90 mmHg. The upper limit 
of this blood pressure range exceeds the normal range because many patients with primary 
aldosteronism have chronically elevated and poorly controlled blood pressure; although study 
staff will make every effort to maintain their blood pressure in a normal range (<130/80 mmHg), 
CCB Drug 
Washout 
(if needed)
VISIT 2:  
Acute CCB Effect on 
Aldosterone Production
Objective - Can CCB acutely lower 
autonomous aldosterone secretion in PA?
VISIT 1:
SCREENING
Acute CCB 
Dose x1
Testing at 
T=0, 2, 4, 6 
hours
CCB 
therapy
x 2 weeks
Acute CCB 
Dose x1
Testing at 
T=0, 2, 4, 6 
hours
VISIT 3:  
Chronic CCB Effect on 
Aldosterone Production
Objective - Can CCB sustain reductions in 
autonomous aldosterone secretion in PA?

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this goal may not be achievable in this short study. If home blood pressure exceeds 130/80 
mmHg, participants will be prescribed doxazosin (in 2 mg daily increments up to 8 mg daily) 
and/or hydralazine (in 25 mg daily increments up to 25 mg three times daily) in efforts to keep 
blood pressure in the target range. These medications will be used to substitute calcium-
channel blockers since they do not interfere with the renin-angiotensin-aldosterone system and 
are the recommended medications by the international Endocrine Society guidelines. 
 
In addition to blood pressure monitoring during this washout period, serum potassium will be 
monitored to ensure it remains in a target range of 3.5-4.5 mEq/L. Most patients with primary 
aldosteronism are hypokalemic and already taking daily potassium supplements. Study staff 
may increase the dose of potassium supplementation (using potassium chloride in 20 mEq 
supplements) to keep serum potassium in the target range. Serum potassium will be checked at 
2-4 weeks, and if not in range, again at 4-8 weeks. 
 
Participants already taking a mineralocorticoid receptor antagonist (such as spironolactone or 
eplerenone) will be included and studied as long as their renin activity remains suppressed 
(<1.0 ng/mL/h). Participants who have a renin activity greater than or equal to 1.0 ng/mL/h while 
on mineralocorticoid receptor antagonists may still participate if their dose can be safely 
decreased such that renin activity decreases to <1.0 ng/mL/h. If needed, renin will be measured 
at 2-4 weeks, and if not in range, again at 4-8 weeks. 
 
This washout and optimization period will range from 4-8 weeks to provide sufficient time for 
optimization of washout, blood pressure, potassium, and renin levels.  Participants who are 
unable to tolerate a washout or maintain blood pressure or potassium in the target range, will be 
withdrawn from the study. 
 
Study Visit 2-Dexamethasone Suppression Test/Cosyntropin stimulation test: After completing 
the washout period, participants will be scheduled to undergo a dexamethasone suppression 
test and cosyntropin stimulation test. This will be conducted prior to the high sodium diet given 
before visit 3.  
 
The dexamethasone suppression test is often used in the clinical setting to measure whether 
there is excess cortisol secretion. Dexamethasone (1mg) is a synthetic adrenal steroid and is 
taken the night before the cosyntropin stimulation test between 11pm and 12am. When the 
participant arrives to the CCI the following morning between 8-9am, initial biochemical testing 
will include ACTH and cortisol levels. These hormone values will demonstrate how well cortisol 
can be suppressed.  
 
The cosyntropin stimulation test will measure how well cortisol can be stimulated. A cosyntropin 
stimulation test is a common procedure that is performed routinely in the ambulatory setting at 
BWH in the primary care, endocrine, and oncology clinics. It involves the measurement of 
adrenal hormones before, and one hour after, the administration of cosyntropin (an analogue of 
the peptide ACTH: “ACTH 1-24”). Participants will arrive to the CCI at 8-9am in the morning and 
will have an IV placed in the arm. A baseline blood measurement will be analyzed for cortisol, 
aldosterone, plasma renin activity, direct renin concentration, ACTH, and basic metabolic 
chemistries. The standard dose of cosyntropin (250 mcg) will then be administered by IV bolus 
and blood work for cortisol and aldosterone measured again 60mins later. This will conclude the 
visit which is expected to last ~2hours.   
 
Study Visits 3 and 4: Following screening and washout/optimization, there will be two study visits 
separated by 2 weeks (see Schema Figure). Critical determinants of aldosterone production 

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include body posture, dietary sodium intake, serum potassium, and blood pressure. Thus, this 
protocol ensures that all 4 of these confounders are controlled to ensure that outcome measures 
are reliable and reproducible. 
 
Study Visit 3: The objective for study visit 3 is to establish the magnitude of autonomous 
aldosterone production at baseline and evaluate the acute impact of amlodipine on aldosterone 
production.  
 
To ensure rigor and reproducibility, all aldosterone (and other measurements) will be conducted 
under conditions where diet and posture are controlled. Five days before study visit 3, participants 
will be provided with sodium supplements (in the form of 3 broth packets approximating 3,000 mg 
of sodium daily) to consume daily. The average daily sodium consumption in the United States is 
3.8-4.5 grams daily, and thus this sodium intake will ensure that all participants are consuming a 
typical U.S. sodium diet and for research purposes, ensure that the 24 hour urinary sodium 
excretion at study visit 3 is >200 mmol Na+/24h. This sodium loading is a standard of care clinical 
practice referred to as an “oral sodium suppression test” and the internationally recommended 
test to diagnose primary aldosteronism by the Endocrine Society. 
 
After consuming this sodium diet, participants will arrive at the BWH Clinical Research Center at 
8AM, after having collected their urine for 24 hours. An EKG will be performed if the participant 
had a remote screening visit. Participants will remain in an upright seated position for a total of 
seven hours. After one hour of seated rest, baseline blood measures will be obtained, and a single 
dose of amlodipine 10 mg will be administered. In order to reflect amlodipine pharmacodynamics, 
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). This serial blood testing may be 
performed via repeated venipuncture, or by placing an intravenous line to draw, whichever is 
preferable to the participant. Blood tests will include serum aldosterone, plasma renin activity, 
basic metabolic panel, adrenocorticotropic hormone, cortisol, and other hybrid adrenal steroids. 
Extra plasma and serum will be saved for future use and DNA will be extracted from peripheral 
leukocytes for genetic analyses of aldosterone-related genes. The 24h urine will be analyzed for 
aldosterone excretion rate, cortisol, sodium, potassium, and creatinine.  
 
During the study visit, participants will be able to drink water and after a 4-hour period be able to 
eat a light snack. After the study is completed, participants will be able to eat and encouraged to 
bring food with them for this. 
 
Treatment phase: Following completion of Visit 3, 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  3. 
 
Study Visit 4: The objective for study visit 4 is to establish the magnitude of autonomous 
aldosterone production after 2 weeks of amlodipine treatment. 
 
Participants will again complete 5 days of sodium supplements and arrive to the BWH Clinical 
Research Center at 8AM, bringing with them a 24-hour urine collection. Participants will be 
instructed to not take their daily amlodipine dose prior to arriving, they will take it as a part of the 
study visit. They will repeat the exact same study protocol completed at Visit 3. Participants will 

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remain in an upright seated position for a total of seven hours. After the first hour of seated rest, 
baseline blood measures will be obtained and a single dose of amlodipine (the dose will be the 
same dose they took for the preceding 2 weeks) will be administered. Blood and urinary 
measurements will again be performed exactly as they were at visit 3. 
 
 
VI. 
BIOSTATISTICAL ANALYSIS 
 
The analytic plan for this pilot study is to compare the change in plasma aldosterone (Aldo) and 
the change in 24h urinary aldosterone excretion rate (AER). The primary analytic plan will be to 
evaluate Aldo and AER between visit 2 and 3. Wilcoxon signed rank, or paired T-test statistics, 
will be used for univariate statistical analyses to assess significant differences between the paired 
measurements of Aldo and AER. Adjustment for potential confounders (age, sex, 
race/ethnicity, BMI, BP) will be considered using generalized linear mixed random effects models 
(SAS 9.4). Secondary analyses to assess the acute change in plasma aldosterone after a single 
dose of amlodipine will be conducted using the same methodological approach. 
 
Sample size calculations are based on an expected Aldo of 5 ng/dL, with up to a S.D. of 4-5 
ng/dL. It is thus estimated that 7-10 participants are needed in this paired design to reject the null 
hypothesis that ΔAldo does not significantly change with amlodipine therapy with 80% power. 
Similarly, for an expected AER of 7 mcg/24h, with a S.D. of 5-6 mcg/24h, it is estimated that 
6-8 participants are needed in this paired design to reject the null hypothesis that ΔAER does not 
significantly change with amlodipine therapy with 80% power.  
 
We aim to enroll 15 participants to provide sufficient sample size and power to detect differences 
even if 2-5 participants (up to 33%) are non-responders to amlodipine. As this is a pilot study, any 
information regarding the influence of amlodipine on aldosterone production may be useful in 
designing future studies. 
 
 
VII. 
RISKS AND DISCOMFORTS 
 
Sodium supplementation  
The sodium intake is not intrinsically harmful, and in fact contains a similar amount of sodium to 
the diet consumed by the average American. This sodium intake is also the standard of care, 
and international guideline recommended approach, to assess aldosterone production in 
patients with primary aldosteronism. Possible side effects include a rise in blood pressure or 
drop in serum potassium which study staff will be monitoring closely and will be able to titrate 
medications to prevent or treat. 
 
Risk of Washout Period/Risk of Stopping Regular Blood Pressure Medications 
During the washout/optimization period, there is a risk that the participants’ blood pressure may 
rise despite initiation of an alternative antihypertensive agent. Risks of high blood pressure 
include headache and in rare and extreme circumstances stroke, heart attack, and death. Home 
blood pressure will be closely monitored, and study staff will actively titrate alternative 
antihypertensive agent(s) to ensure blood pressure remains well-controlled. This is a commonly 
performed procedure in clinical practice and routine. 
 
Calcium channel blocker treatment (amlodipine) 

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Amlodipine is a commonly prescribed medication that has been used to treat essential 
hypertension for years. The most common side effect is swelling in the legs and ankles (which 
usually takes 1-2 weeks or longer to manifest). It can also cause low blood pressure particularly 
at a high dose, but this is unlikely in the current study. Other rare side effects include fluid in the 
lungs in heart failure patients, palpitations, fatigue, skin rash, and stomach upset. 
 
Hydralazine  
Hydralazine has been used for many years in the treatment of essential hypertension. It is an 
international guideline recommended medication for treatment in primary aldosteronism when 
diagnostic testing is conducted. Side effects include low blood pressure, fast heart rate, 
stomach upset, and headache. Rare side effects include an autoimmune lupus-like syndrome, 
liver damage, and decreased white blood cell count. It should not be used in patients with 
coronary artery disease. 
 
Doxazosin 
Doxazosin has been approved for the treatment of essential hypertension for many years. It is 
an international guideline recommended medication for treatment in primary aldosteronism 
when diagnostic testing is conducted. Side effects include low blood pressure, leg swelling, 
nausea, dizziness, and headache. Rare side effects include liver inflammation and angioedema 
(swelling of the lips and tongue).  
 
ACTH infusion 
Cosyntropin is a synthetic derivative of naturally occurring adrenocorticotrophic hormone 
(ACTH), specifically the first 24 of the 39 amino acids of the hormone. Very rarely, patients with 
a history of asthma or other forms of allergy may be predisposed to hypersensitivity reaction or 
anaphylaxis during Cosyntropin administration; bradycardia, tachycardia, hypertension, 
peripheral edema, and rash have also been reported with cosyntropin. A physician or nurse will 
be present for the test. This cosyntropin stimulation test is a common ambulatory test that is 
performed in the clinical setting.  
 
Dexamethasone 
Dexamethasone is a synthetic glucocorticoid. Very rarely dexamethasone may cause 
anaphylactic reactions in those with hypersensitivity to dexamethasone; infection; slow wound 
healing; diaphoresis; nausea; headache; and mood changes. Most of these reactions are cause 
from chronic use, not the one-time administration as in our study.  
 
 
Blood Draws/Phlebotomy 
Some may experience a mild sting or painful feeling at the site of needle or intravenous catheter 
insertion. Although uncommon, it can also lead to a blood clot or infection. Standard sterile 
precautions will be taken to minimize these risks.   
 
Pregnancy/Fetus 
Women cannot take part in this study if they are pregnant or breastfeeding. Women between 
the age of 18-50 years will be required to have a negative pregnancy test prior to taking part in 
the study. Women who are postmenopausal and amenorrheic for one year or who have had a 
surgical sterilization procedure are exempt from submitting to a pregnancy test. Women will be 
counseled about using abstinence or contraception during participation in this study to avoid 
exposure to potentially teratogenic medications. 
 
Genetic Information 

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Genetic information about this study does not have medical or treatment implications at this 
time. However, information about participation in a genetic study may influence insurance 
and/or employers. These risks are minimized by not sharing information about participation and 
by using de-identified study codes. We will not place genetic information in the medical record. 
All results and samples will be coded and the key to the code kept in a separate locked file.  
 
In order to allow researchers to share test results, the National Institutes of Health (NIH) and 
other central repositories have developed special data (information) banks that analyze data 
and collect the results of whole genome studies. These banks may also analyze and store DNA 
samples, as well. These central banks will store genetic information and samples and give them 
to other researchers to do more studies. Although it is impossible to predict how genetic 
information will be used in the future, there are many safeguards in place to ensure that all 
genetic information is protected and de-identified.  
 
Unknown Risks 
There may be other risks or side effects that are not known at this time.   
 
 
VIII. 
POTENTIAL BENEFITS 
 
Although patients are not expected to directly benefit from the trial, their participation will 
contribute to medical research. Because of the close monitoring, supervision, and pro-active 
blood pressure and potassium therapies, participants will likely see an improvement in their 
primary aldosteronism therapy goals, even though this is not the primary objective of the study.  
 
IX. 
REMUNERATION 
 
Patients will receive monetary compensation for participating in the study and parking and/or 
transportation costs will also be covered. Participants will receive $100 for completing study visit  
3 and $100 for completing study visit  4. Parking at BWH lots will be covered.  For participants 
who need transportation, reimbursement for public transportation and/or livery services (i.e. 
Uber, Lyft, taxi, etc) will be strongly considered on a case-by-case basis based on feasibility and 
location. 
 
X. 
MONITORING AND QUALITY ASSURANCE 
 
The Principal Investigator will be responsible for reviewing the safety and/or efficacy data and 
determining whether the research should be altered or stopped.   
 
Safety data will be reviewed on every case studied in the PI’s monthly research group meeting.  
The PI’s research group, the Cardiovascular Endocrinology Research Group (CERG), meets 
once a month on a Tuesday.  The CERG includes more than 5 patient-oriented clinical 
investigators who are all endocrinologists with detailed knowledge of human research protocols, 
safety monitoring, and managing hypertension.  At each CERG meeting, each PI presents 
recruitment status, adverse events/safety issues, minor deviations, and other pertinent study-
related issues to the group of PI’s. Research coordinators also attend this meeting.  Discussion 
of issues and a plan are formulated for each adverse event. The PI will be responsible for 
executing any plans agreed upon during these meetings. 
 
 
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