MR Antagonist and STRIATIN

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).

RATIONALE

Striatin deficient versus wild-type mice have salt sensitive blood pressure and inappropriately increased aldosterone levels on a liberal salt diet. In observational studies, the investigators documented that in humans, striatin risk allele carriers also have salt sensitive blood pressure. Since aldosterone increases sodium retention, excess aldosterone levels could be one mechanism for their salt sensitive blood pressure. The goal of this project is to document that a genetic marker identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade - personalized, precision medicine. The investigators will perform a novel two-limb, proof-of-principle, randomized, double-blind, active controlled study contrasting a mineralocorticoid receptor antagonist versus a calcium channel blocker in hypertensive striatin risk allele carriers. Our primary outcome will be systolic blood pressure assessed on a liberal salt diet with our secondary outcome being salt sensitive blood pressure.

PRELIMINARY RESULTS:

The investigators recently reported that in two large cohorts from HyperPATH, the striatin risk allele carriers have increased blood pressure on a liberal salt diet and salt sensitive blood pressure. The link between striatin risk allele and salt sensitive blood pressure was seen in ALL participant groups - hypertensives, Caucasians, Africans, males, females, old and young. The investigators then created a striatin deficient mouse. It also had salt sensitive blood pressure. Furthermore, compared to wild-type mice, the striatin deficient mice had increased aldosterone levels on a liberal salt diet. An inappropriate aldosterone level for the level of sodium intake is a well-known and important mediator of salt sensitive blood pressure and hypertension. Thus, if human striatin risk allele carriers have dysregulated aldosterone production, this genetic biomarker could identify subjects at increased risk for aldosterone-mediated salt sensitive blood pressure and hypertension.

SUBJECT POPULATION:

It is estimated that most of the striatin rs2540923 risk allele carriers will come from our HyperPATH cohort. Because there are no racial, age or ethnic differences in the salt sensitive blood pressure responses observed, an equal number of females and males and the same proportion of Africans as in the HyperPATH cohort will be studied. Additional subjects will be recruited from the BWH and Partners Healthcare's Research Patient Data Registry and the Partners Biobank. We will use the MGB patient gateway to contact subjects who consented to the Research Opportunities Direct to You (RODY) program, which allows researchers to contact subjects directly. We will first use the Research Patient Data Registry to obtain an identified data set of patients who consented to the RODY program. We will then send a recruitment email to those subjects via the patient gateway. We will also use Partners Biobank to contact potential study subjects with the striatin rs888083 allele and rs6744560 allele, as the rs888083 allele and the 6744560 have been genotyped in Partners Biobank. Partners Biobank staff will send a re-contact letter, co-signed by the Biobank PI and our PI, and an opt-out card to patients. Patients who consent to participate in the Partners Biobank provide consent to be re-contacted by the Biobank in the future for additional information/samples, and/or to be asked if they would be interested in joining other research studies. The Biobank will also provide us with an identified data set that includes patient MRNs, names, phone numbers and mailing addresses for all re-contacted patients. Ten business days after the Biobank sends the recontact letters to patients, we will call each patient on the list (who did not send us the opt-out card) to ask whether they would like to participate in our study. As an example of the richness of these sources, Research Patient Data Registry contains over 90,000 hypertensive patients, ages 18-65 years with 13.5 % of African descent and 52.8 % women. Partners Biobank contains over 14,000 hypertensive subjects between the ages of 18-65. We will recruit approximately 105 individuals to have 45 individuals in each drug group for analyses, so we aim to enroll approximately 1000 individuals who will be consented into the study. This assumes that we will have 90% individuals ineligible due to status as a non striatin risk allele carrier, and of those who are allele carriers will have 10-15% non-completers. Based on our previous studies we estimated that approximately 10% of hypertensives will be carriers of the rs2540923 risk allele. We have DNA, history, screening laboratory tests, and physical examinations on 4000 individuals in HyperPATH. Approximately 60% have hypertension and 10% carry the risk allele, i.e., approximately 250 individuals. We estimate from our previous use of this cohort that we will be able to recruit 75-80 individuals during the 4 years of this project. Thus, we will need to recruit 25-30 new subjects over four years, i.e., 6-8 per year. The research Patient Data Registry is the source from which we have the most success. Approximately 20% of those to whom we send requests to participate in the study enter the electronic screening phase. Approximately 50% of these subjects enter the clinic screening phase and about 25% of them are enrolled in a study that is comparable or more time consuming than the one proposed in this project. Thus, we will need to invite each month approximately 200 of the 90,000 hypertensives in the Research Patient Data Registry to participate in our study. All subjects will be genotyped at rs2540923, and the risk allele carriers will be entered into the protocol and randomized blindly into one or the other treatment arms.

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 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 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.

ANTICIPATED RESULTS:

Based on our Preliminary Results, the investigators anticipate that: 1) in response to the first dose of each agent, the risk allele carriers will have significantly greater BP reductions with eplerenone than with amlodipine; 2) a significantly lower dose of eplerenone will be required to achieve goal BP than with amlodipine; and 3) greater reduction in SSBP will occur with eplerenone than with amlodipine. If proven, these results will support: a) proof of principle that an activated MR, likely secondary to increased ALDO, is contributing to the HTN in STRN risk allele carriers, a conclusion inferred from HET-KO studies described in our Preliminary Results; b) that genotype can be used to predict therapeutic response in HTN -a positive application of pharmacogenetics to a complex, common condition; and c) provide specific information necessary to appropriately statically power and design a definitive clinical trial. The investigators also will draw on data obtained from the studies performed in AIMS 2 and 3 in designing this new trial. The investigators anticipate that this new treatment trial will contrast not only BP and SSBP responses to specific treatments in carriers versus non-carriers (a control group) of the STRN risk allele, but also will assess the human relevance of the likely mechanisms linking STRN to SSBP, as will be suggested by the data generated in the mechanistic studies (AIMS 2 and 3 of this project). For example, if AIM 3 shows that STRN deficiency results in decreased RBF response to a liberal salt intake, then in addition to measuring the response of BP and SSBP to specific therapy, the investigators will measure the treatment's effect on RBF.

ALTERNATIVE RESULTS AND POTENTIAL PITFALLS:

First, a negative outcome may not be a true treatment failure, but secondary to: 1) the length of treatment being too short; 2) an ALDO mediated effect not blocked by eplerenone; or 3) an ALDO mediated effect whose mechanism is made worse by blocking the MR. These possibilities, in part will be addressed in AIM 2 where the investigators are determining the mechanism(s) underlying the STRN/ALDO interaction. Second, a positive outcome could indicate that an activated MR is a proximate mediator of the increased liberal salt BP and SSBP associated with STRN's risk allele carriers. However, since the investigators did not include a control group (non-risk allele carriers), a future study would need to be performed as outlined in the Anticipated Results above. Third, the STRN risk allele carriers do have increased liberal salt BP and SSBP but the primary mechanism is dysfunction in the renal vasculature. This possibility will be addressed in AIM 3. Fourth, the study's length could lead to a false positive, i.e. the length is not long enough to see an initial difference disappearing with longer therapeutic exposure. However, the investigators believe the trial length is appropriate because: 1) most clinical trials using these agents achieve stable BP responses during this time interval; 2) with eplerenone treatment, BP nadirs after three months with no significant changes even if therapy is extended to a year. Finally, the study is too complicated. The investigators will have too many dropouts. The investigators have completed this and even more complicated studies in more than 1000 subjects and achieved the completion rate assumed for this study.

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