Clinical trial NCT03683069
Conditions: Hypertension Genetics Hypertension
Sponsor: Brigham and Women's Hospital
Start date: 2019-01-15; Completion date: 2024-01-31
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Salt sensitivity of blood pressure is a substantial risk factor for cardiovascular morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension and salt sensitive blood pressure. Key homeostatic mechanisms that regulate renal sodium reabsorption are: first, hormonal, e.g., renin-angiotensin-aldosterone system and second, vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to hypertension and salt sensitive blood pressure. The investigators recently documented that striatin plays a novel role in the development of salt sensitive blood pressure. However, the mechanisms that lead to striatin-mediated salt sensitive blood pressure are not clear; defining these mechanisms is the overall goal of this proposal.

Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to the mechanism of action of steroids. In a large study of well characterized subjects from the International Hypertensive Pathotype (HyperPATH) cohort, the investigators documented that hypertensive and normotensive humans who are striatin risk allele carriers have salt sensitive blood pressure.

The investigators then developed a striatin heterozygous knockout mouse as a tool to identify potential mechanisms for the salt sensitive blood pressure. The investigators documented that these mice also have salt sensitive blood pressure with higher blood pressure levels and inappropriately increased aldosterone levels on a liberal salt diet.

Detailed description:
HYPOTHESIS:

Hypertensive striatin risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine).

PROTOCOL:

1. The screened, eligible hypertensives will enter a two to three-week single blind placebo washout phase. Pill count will be used to determine compliance. Those with blood pressure between 145-170/90-109 mmHg and pill count between 80-100% after two to three-weeks will enter the randomized phase and counseled regarding salt intake.
2. The first step: subjects will be fed a 10 mEq Na+, 100 mEq K+ calculated diet for 6 days. The meals will be provided by the CCI Dietary Core. On the 7th day, the subjects will come to the CCI Ambulatory Clinical Center. After remaining supine for 60-90 minutes, the subjects will have blood samples obtained for future analyses and their blood pressure measured using an automatic recording sphygmomanometer (Space Labs, Snoqualmie, WA). Readings will be obtained every 2 minutes for 20 minutes with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and sodium as a check on balance and stored for future analyses.
3. The second step: Subjects will be counseled regarding liberal salt dietary intake. Subjects will be given high salt broth packets, calcium tablets (as calcium bicarbonate), and potassium tablets (as potassium bicarbonate) to supplement their diet to ensure similar intakes in all subjects \[Na+ (200 mEq), potassium (K+, 100 mEq) and calcium (800 mg)\]. This or a greater level of Na+ intake was consumed by 60-70% of subjects before entering the HyperPATH protocol. On the morning of the 6th day the subject will begin a 24-hour blood pressure recording, using a blood pressure machine provided by study staff. After completion of this diet for 6 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center and after remaining supine for 60-90 mins will have blood samples obtained for future analyses, and their BP measured using an automatic recording sphygmomanometer (Space Labs, Snoqualmie, WA). Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses. The BP data from 2) and 3) will allow us to calculate Salt Sensitivity of Blood Pressure (SSBP), an approach performed successfully more than 500 times in the HyperPATH cohort.
4. The hypertensive striatin risk carrier subjects will be randomized, double blinded to one of two primary treatment groups and titrated to effect every four weeks, as was previously reported (1, 2), eplerenone 50, 100 and 200 mg daily or amlodipine 2.5, 5 and 10 mg daily. Study duration will be sixteen weeks.
5. Participants will be randomized in blocks of four to 1 of 2 study drugs (amlodipine and eplerenone). The drug class assignment will remain the same throughout the study for each subject. The PI or Co-PI will notify The Brigham and Womens Hospital Investigational Drug Pharmacy Service to escalate or maintain current dose on each of the two visits. The Brigham and Womens Hospital Investigational Drug Pharmacy Service will be responsible for the randomization schema, recording of study drug assignment, and dispensing of prescriptions. All others (PI, Co-PI, research staff, subject) will be blinded as to drug assignment.
6. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored by study staff weekly as a safety check with the information provided to the study staff by email or phone. The blood pressure results from the 7 days prior to the next visit will be averaged, with the highest and lowest values discarded. This average blood pressure value will be used to determine if the drug dose will be titrated after the next visit If the subject has reached goal blood pressure (less than or equal to140/90 mmHg), then the subject is maintained on his/her current dose. If not, the subject's dose is up titrated as per protocol. A member of the research team will contact the subject if the blood pressure data are not received within 24-hr of the designated time. If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24 hours apart, or the subject develops cardiovascular symptoms, the subject will be terminated from the study and re-started on medications used before the washout period. The subject's physician will be contacted.
7. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly during the study. This will be obtained at the time of their monthly visit unless a dose increase is made at the time of the visit. Then, the Serum K+ will be obtain one week later. If Serum K+ is greater than 5.5 milliMolar (mM) on two consecutive occasions 24 hours apart, the subject will be terminated from the study. If unexpected adverse event is noted The Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so as to break code and identify agent.
8. At the end of four weeks since randomization and the subjects have completed the first dose of the agent, the subject will be counseled regarding a 24-hour dietary intake of sodium (200 mEq), potassium (100 mEq) and calcium (800 mg). Subjects will receive supplementary high salt broth packets to ensure that they are reaching the target Na+ intake. After completion of this diet for 6 days, the subject returns to Center for Clinical Investigation - Ambulatory Clinical Center and after remaining supine for 60-90 minutes again will have blood samples obtained for future analyses and their blood pressure measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 minutes for 20 minutes with the highest and lowest values discarded and the rest averaged. This measurement will be used to assess the blood pressure response to a single dose of each agent. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and sodium as a check on balance and stored for future analyses.
9. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored by study staff weekly as a safety check with the information provided to the study staff by email or phone. The blood pressure results from the 7 days prior to the next visit will be averaged, with the highest and lowest values discarded. This average blood pressure value will be used to determine if the drug dose will be titrated after the next visit If the subject has reached goal blood pressure (less than or equal to140/90 mmHg), then the subject is maintained on his/her current dose. If not, the subject's dose is up titrated as per protocol. A member of the research team will contact the subject if the blood pressure data are not received within 24-hr of the designated time. If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24 hours apart, or the subject develops cardiovascular symptoms, the subject will be terminated from the study and re-started on medications used before the washout period. The subject's physician will be contacted.
10. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly during the study. This will be obtained at the time of their monthly visit unless a dose increase is made at the time of the visit. Then, the Serum K+ will be obtain one week later. If Serum K+ is greater than 5.5 mM on two consecutive occasions 24 hours apart, the subject will be terminated from the study. If unexpected adverse event is noted The Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so as to break code and identify agent.
11. At the end of eight weeks since randomization and the subjects have completed the second dose of the agent, the subject will be counseled regarding a 24-hour dietary intake of sodium (200 mEq), potassium (100 mEq) and calcium (800 mg). Subjects will receive supplementary high salt broth packets to ensure that they are reaching the target Na+ intake. After completion of this diet for 6 days, the subject returns to Center for Clinical Investigation - Ambulatory Clinical Center and after remaining supine for 60-90 minutes again will have blood samples obtained for future analyses and will have their blood pressure measured using an automatic recording sphygmomanometer. Readings will be obtained every 2 minutes for 20 minutes with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and sodium as a check on balance and stored for future analyses.
12. Home seated, morning cuff blood pressure and pulse will be obtained daily and monitored by study staff weekly as a safety check with the information provided to the study staff by email or phone. A member of the research team will contact the subject if the blood pressure data are not received within 24-hr of the designated time. If the cuff blood pressure is greater than 170/109 mmHg on two consecutive occasions 24 hours apart, or the subject develops cardiovascular symptoms, the subject will be terminated from the study and re-started on medications used before the washout period. The subject's physician will be contacted.
13. Because eplerenone may increase Serum K+ levels, we will monitor its level monthly during the study. This will be obtained at the time of their monthly visit unless a dose increase is made at the time of the visit. Then, the Serum K+ will be obtain one week later. If Serum K+ is greater than 5.5 mM on two consecutive occasions 24 hours apart, the subject will be terminated from the study. If unexpected adverse event is noted The Brigham and Women's Hospital Investigational Drug Pharmacy Service will be notified so as to break code and identify agent.
14. At the end of the study, twelve weeks after randomization, subjects will be counseled regarding liberal salt dietary intake. Subjects will be given high salt broth packets, calcium tablets (as calcium bicarbonate), and potassium tablets (as potassium bicarbonate) to supplement their diet to ensure similar intakes in all subjects \[Na+ (200 mEq), potassium (K+, 100 mEq) and calcium (800 mg)\]. This or a greater level of Na+ intake was consumed by 60-70% of subjects before entering the HyperPATH protocol. On the morning of the 6th day the subject will begin a 24-hour blood pressure recording, using a blood pressure machine provided by study staff. After completion of this diet for 6 days, the subject will come to the Center for Clinical Investigation (CCI) Ambulatory Clinical Center and after remaining supine for 60-90 mins will have blood samples obtained for future analyses, and their BP measured using an automatic recording sphygmomanometer (Space Labs, Snoqualmie, WA). Readings will be obtained every 2 mins for 20 mins with the highest and lowest values discarded and the rest averaged. From the morning of the 6th to the morning of the 7th day, a 24-hr. urine will be collected for creatinine and Na+ as a check on balance and stored for future analyses.
15. The subject then will have completed the study and will be re-started on medications used before the washout period. The subject's physician will be contacted.

Arms: arm 1: antihypertensive eplerenone arm 2: antihypertensive amlodipine
Interventions: intervention 1: Eplerenone vs Amlodipine
Intervention descriptions: intervention 1: We posit that decreases in striatin activity/levels increases aldosterone secretion resulting in hypertension and salt sensitive blood pressure. Thus, our mechanistic clinical study will assess whether hypertensive striatin risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine). To test this hypothesis, we will perform a randomized, double-blind, active controlled study in hypertensive carriers of the striatin risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic blood pressure with a secondary outcome of salt sensitive blood pressure. Therefore, this mechanistic trial will provide support for using a genetic marker that identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine.

Protocol documents:
Prot_000.pdf: 
 
PROTOCOL 
 
Official title:  
MR Antagonist – Eplerenone vs Amolidipine and STRIATIN 
 
Document number:  
NCT03683069 
 
Date:   
 
 
12/14/2024  
 


Flow Chart – Study Design (FIG 1) 
 
Subjects in the RPDR cohort were recruited to the study using Patient Gateway to 
specifically invite their participation. After documenting that the subject had the correct 
striatin genotype, current antihypertensive medications were discontinued. To assess the 
salt sensitivity of their blood pressure (SSBP) six - seven days of a restricted salt diet 
(Visit 1) was provided with blood pressure (BP) measured seated, daily in the morning 
at home and in the office at the end of the diet study. Then, the diet was changed to a 
liberal salt intake (Visit 2), and the BP studies were repeated. At the conclusion of the 
SSBP study, the subjects were randomized to the eplerenone or amlodipine arms and 
resumed a normal diet. After 3 weeks of the normal salt diet, the diet was changed to a 
liberal salt intake. Subjects continued to measure home BPs and returned to the clinic on 
the 7th day to have office BPs measured (Visit 3). If the last two home BPs were < 140/90 
mmHg, goal BP was achieved, and the subjects were maintained on the present dose. If 
goal BPs were not achieved, then the doses were increased. The whole process is 
repeated for a second month (Visit 4); if goal BP is not achieved, a third dose increase is 
instituted, and the process is repeated for a third month (Visit 5). A 24-hour ambulatory 
BP was obtained at the time of randomization and at Visit 5 on all subjects when they 
were on a liberal salt diet.                                                                                                                          
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIG 1. 
Visit 1
Visit 2
Visit 4
Visit 5
Washout anti-
hypertensives
Weeks
-4
Dose titration if BP > 140/90 mmHg
Liberal Na+ Diet (1-14 days)
Restricted Na+ Diet (6-10 days)
24-hour BP monitoring
-2
-1
0
4
8
12
E P L E R E N O N E
A M L O D I P I N E
Visit 3
Visit 4
Visit 5
Visit 3
Study drug 
randomization


Participant Flow – Consort Diagram (FIG 2) 
 
There were 2786 individuals invited to participate in the study, of which 400 met the 
screening and genotype criteria. Of these, 67 were randomized to a treatment arm. Two 
subjects dropped out before receiving any medications. Thus, of the 65 enrolled, 33 were 
in the eplerenone limb and 32 in the amlodipine limb. All but one completed the entire 
study after randomization.  
 
 
 
 
 
FIG 2. 
Assessed for genotype eligibility: 400
Qualified for study and agreed to enroll: 80
Excluded following first screen: 280
• 256 did not have correct genotype
• 23 had correct genotype but
• 8 voluntarily withdrew participation
• 11 lost to follow-up
• 4 excluded for newly-identified 
health conditions
• 1 had inconclusive genotyping results but 
withdrew participation
Excluded before randomization: 13
• 7 discontinued by study staff
• 2 elevated BP during washout 
phase
• 5 did not meet 140/90 mmHg BP 
threshold after liberal salt diet
• 6 voluntarily withdrew participation
Assessed for eligibility at second in-person screen: 120
Excluded following second screen: 40
• 27 did not meet eligibility criteria
• 6 voluntarily withdrew participation
• 7 lost to follow-up
Completed final study visit: 32
Completed final study visit: 33
Excluded after randomization: 2 
• 1 discontinued by study staff 
due to non-compliance
• 1 voluntarily withdrew 
participation
Did not proceed to genotyping step: 2386
Either did not meet eligibility criteria, 
voluntarily withdrew participation, or lost to 
follow-up
Filled out pre-screening questionnaire: 2786
Randomized to amlodipine and began study drug: 32
Randomized to eplerenone and began study drug: 35

SAP_001.pdf: 
STATISTICAL PLAN
Official title:
MR Antagonist – Eplerenone vs Amolidipine and STRIATIN
Document number:
Date:
NCT03683069
12/14/2024


single
SNP
(rs254 923)
or
diplotype
Table 2: Anticipated proportions of
subjects reaching goal BP at each
Maximum dose rank
Amlodipine
0.10
0.30
0.35
0.25
Eplerenone
(n=45)
0.30
0.40
0.20
0.10
ded alpha
end of s udy (mmHg)
ndard deviati
(mmHg)
(n=45)
e (n=45)
9.0
17.0
10.0
0.97
11.0
16.0
9.0
0.75
Statistical Plan and Power Calculations
After screening, 105 subjects will be randomized to amlodipine or eplerenone, using
random block sizes in this double-blind study, with at least 45 on each arm expected to
have complete data for analysis as previously described. For the first independent
approach, subjects will be on a liberal salt diet and come to the clinic between 8-9 AM
after fasting overnight before randomization and at the end of the trial. We will measure
their BP using a 24-hour ambulatory BP monitoring system at each point. From previous
studies in general hypertensive populations, our initial and final doses of eplerenone vs
amlodipine have produced similar 24-hr and daytime ambulatory systolic BP reductions
(delta final doses 12-14 mm Hg). However,
we anticipate that in hypertensive Striatin
Table 1: Scenarios providing sufficient power and a 5% 2-
(rs888083/rs6744560)
0
risk allele carriers,
si
Baseline
t
BP minus BP
sta
Within-group 
on
Power
the mean change in daytime automated        Amlodipine
eplerenon          of the changes
systolic BP from baseline to end of study            9.0                  15.0                       10.0                    0.81.
treated with eplerenone will be greater, while            9.0                  16.0                       10.0                     0.91
with amlodipine it will be less, because of the
10.0
15.0
9.0
0.75
specific
mechanism
(increased
ALDO)
10.0
16.0
10.0
0.81
causing the HTN. We assume the relative
11.0
17.0                         9
0.89
delta systolic BP will be ~16 in response to
eplerenone and ~10 in response to amlodipine. The within-group standard deviation for
the change in automated mean daytime systolic BP is expected to be 8-10 mmHg as
previously reported. As shown in Table 1, with a 0.05 significance level, we will have
>80% power with 45 in each group, and sufficient power for more conservative effect
sizes as well.
For this analysis, we will use the mean daytime ambulatory systolic BP as our dependent
variable adjusted for sex, race, body mass index, and age.
For the second independent approach, we will compare the groups regarding the
maximum dose needed to achieve goal BP (≤140/90 mmHg) determined by the home BP
averaged for the last two days of the liberal salt diet at the end of each month as previously
described58,61-68. For the anticipated effect size, we
used the rank of the drug dose to equate eplerenone
and amlodipine dosing, with rankings of 1, 2, and 3 for
successive ranked dose
the ordered maximum dose for each drug, and a
ranking of four for the failure to reach BP goal by the
end of the study. The anticipated percentage of
1
2
3
4
subjects in each group with each ranking is shown in
Table 2. Power to compare the arms will be >90%.
(n=45)
Data will be inspected and plotted to check
distributional assumptions, e.g., 24-hour urine Na+
excretion >160 mEq on the liberal salt diet and <30
mEq on the restricted salt diet, and veracity of outliers,
if any.


The primary analytical approach will be a Kaplan-Meier survival analysis with Cox
regression. Thus, this ordinal logistic regression or “survival” curve analyses will be used,
predicting the ordered maximum dose category, assuming a proportional odds model.
The odds ratio and 95% confidence interval for eplerenone relative to amlodipine will be
reported, representing the relative cumulative odds of needing a higher (or lower)
maximum dose to achieve goal BP. Body mass index, sex, race, and age will be potential
covariates.
Secondary analysis will be the same as used above in our primary analyses except
performed for each sex separately and only in response to eplerenone. However, it is
unlikely that we will have sufficient power to achieve a 0.025 significance level, but a
positive trend may warrant the performance of a larger, focused future clinical trial.
Exploratory analysis will include the difference in systolic home BP calculated at
baseline and at the end of the first dose for each subject to provide an indication of BP
sensitivity to each drug. Effect sizes will be reported to improve the design of a future
confirmatory study. In addition, we will analyze with adjustments (separately in each sex):
24-hr ambulatory mean systolic SSBP; 24-hr ambulatory mean systolic BP on the liberal
Na+ diet; 24-hr mean diastolic BP on the liberal Na+ diet; serum and urine ALDO (also
adjusted for serum K+ and cortisol); and ALDO/PRA ratio.