Antihypertensive Pharmacological Therapy With Mineralocorticoid Receptor Antagonists in Obese Hypertensive Patients

Phase 4

• Conditions: Obesity; Hypertension
• Interventions: Drug: Eplerenone (-based therapy) arm; Drug: Valsartan (-based therapy) arm

• Registration Number: NCT03476616
• Lead Sponsor: Hippocration General Hospital

Brief Summary

Obesity is a complex metabolic state at which many pathophysiological pathways seem to interfere, like imbalance of autonomic nervous system, as well as renin-angiotensin-aldosterone system (RAAS) activation. Latest studies have shown that the increase of peripheral fat in obese patients, alongside with the increase of P-450 aromatase leads to hyper-aldosteronism, which results to increased sodium intake and rise of blood pressure. The present study aims to investigate the potential superiority of an aldosterone antagonist based therapy (eplerenone) over the renin-angiotensin antagonists (ARBs) (valsartan) based therapy in hypertensive obese patients regarding reduction of blood pressure (office, home and ambulatory) over a 24-week period.

Detailed Description

The present study plans to enroll obese patients (BMI= 30-40 kg/m2) of 30-75 years of age, with untreated or never-treated essential hypertension to either eplerenone-based or valsartan-based therapy Patients visiting hypertension center(s), eligible to participate in the study and meeting study's inclusion criteria, will at first thoroughly be informed of study's protocol rationale, including scheduled follow-up visits. There will be a period of 2-4 weeks, at which medical history will be taken, as well as somatometrics, including height, weight, BMI and waist circumference. Moreover, a thorough clinical examination will take place, including office blood pressure, ECG, heart-echo, renal ultrasound, blood and urine ultrasound. All women of gestational age should have pregnancy test.

At randomization visit, patients still meeting inclusion/exclusion criteria will be randomized (1:1) to either eplerenone (E) 25mg bd or valsartan (V) 160mg od for 8 weeks. At 8, 16 and 24 weeks, patients at both arms will be evaluated with ambulatory BP measurements primary, as well as home and office BP measurements. At week 8, patients with controlled hypertension (mean ambulatory blood pressure measurement (ABPM) \<130/80mmHg), will continue in monotherapy with eplerenone or valsartan and patients with uncontrolled hypertension (mean 24-h ambulatory≥130/80mmHg) will continue with the addition of calcium-channel blocker, amlodipine (C) 5 mg od. At week 16, patients achieving BP control will continue in either monotherapy (E), (V) or dual therapy (E+C), (V+C). However, in patients not achieving blood pressure target, a third drug, thiazide-like-diuretic will be added \[indapamide (D) 1.25 mg od\]. All groups at both arms will be finally evaluated at 24 weeks.

Study Timeline

• Study First Submitted: 2018-03-19
• Study First Submitted QC: 2018-03-19
• Study First Posted: 2018-03-26
• Status Verified: 2018-08
• Last Update Submitted: 2018-08-02
• Last Update Posted: 2018-08-03
• Study Start: 2018-09-01
• Primary Completion: 2020-09-01
• Study Completion: 2020-09-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 330

Inclusion Criteria

1. 30-75 years of age
2. Written consent
3. Untreated or never-treated arterial hypertension with office systolic blood pressure of 140-180 mmHg and/or diastolic blood pressure of 90-120 mmHg, confirmed by 24-hour ambulatory blood pressure measurements of mean ambulatory systolic blood pressure over 130 mmHg and/or mean ambulatory diastolic blood pressure over 80 mmHg
4. Obesity, confirmed estimated by Body Mass Index (BMI) of 30-40 kg/m2

Exclusion Criteria

1. Age <30 or >75

2. Inability to give informed consent

3. Participation in a clinical study involving an investigational drug or device within 4 weeks of screening

4. Secondary hypertension

5. Recent (<6 months) cardiovascular event requiring hospitalization (eg. myocardial infarction or stroke)

6. Type 1 diabetes

7. Chronic kidney disease assessed by Estimated Glomerular Filtration Rate (eGFR) <45 mL/min

8. Bilateral renal arteries stenosis

9. Addison's disease

10. Hemodynamically significant valvular heart disease

11. Plasma potassium outside of normal range on two successive measurements during screening

12. Pregnancy, planning to conceive or women of childbearing potential, that is, not using effective contraception

13. Scheduled surgery or cardiovascular surgery over the next 6 months

14. Absolute contra-indication to study drugs (eg. asthma) or previous intolerance of trial therapy

15. History of sustained atrial fibrillation

16. Requirement for study drug for reason other than to treat hypertension, (eg, β-blockers for angina or aldosterone antagonists for heart failure)

17. Neoplasm under treatment (radiotherapy / chemotherapy / immunotherapy)

18. Any concomitant condition that, in the opinion of the investigator, may adversely affect the safety and/or efficacy of the study drug or

19. severely limit that patients' life-span or ability to complete the study (eg, alcohol or drug abuse, disabling or terminal illness, mental

20. disorders)

21. Contemporary systemic disease with life expectancy shorter than the end of the study

22. Treatment with any of the following medications:

    • Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation
    • Chronic stable use, or unstable use of NSAIDs (other than low dose aspirin) is prohibited. Chronic use is defined as >3 consecutive or non-consecutive days of treatment per week. In addition, intermittent use of NSAIDs is strongly discouraged throughout the study and NSAIDs if required, must not be used for more than a total of 2 days. For those requiring analgesics during the study, paracetamol is recommended.
    • The use of short-acting nitrates (eg, sublingual nitroglycerin) is permitted.
    • The use of sympathomimetic decongestants is permitted, however, not within 1 day prior to any study visit/BP assessment
    • The use of theophylline is permitted but the dose must be stable for at least 4 weeks prior to screening and throughout the study;
    • The use of phosphodiesterase type V inhibitors is permitted; however, study participants must refrain from taking these medications for at least 1 day prior to screening or any subsequent study visits
    • The use of α-blockers is not permitted, with the exception of alfuzosin and tamsulosin for prostatic symptoms

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Eplerenone (-based therapy) arm	Eplerenone (-based therapy) arm	Obese pts with hypertension, starting treatment with eplerenone 25mg twice daily (BD). ABPM wil be scheduled at wks 8, 16 and 24. At wk 8 if mean ABPM \< 130/80mm Hg will continue to monotherapy with eplerenone. If not controlled (mean ABPM \> 130/80mm Hg) at wk8, amlodipine 5mg OD will be added. At wk 16 if mean ABPM \< 130/80mm Hg will continue to monotherapy with eplerenone, or dual therapy with eplerenone and amlodipine. If not controlled (mean ABPM \> 130/80mm Hg) at wk16, indapamide 1,5mg OD will be added. All patients will be followed up for 24 weeks.
Valsartan (-based therapy) arm	Valsartan (-based therapy) arm	Obese pts with hypertension, starting treatment with valsartan 160mg once daily (OD). ABPM wil be scheduled at wks 8, 16 and 24. At wk 8 if mean ABPM \< 130/80mm Hg will continue to monotherapy with valsartan. If not controlled (mean ABPM \> 130/80mm Hg) at wk8, amlodipine 5mg OD will be added. At wk 16 if mean ABPM \< 130/80mm Hg will continue to monotherapy with valsartan, or dual therapy with valsartan and amlodipine. If not controlled (mean ABPM \> 130/80mm Hg) at wk16, indapamide 1,5mg OD will be added. All patients will be followed up for 24 weeks.

Primary Outcome Measures

Name	Time	Method
Difference in change of ABPM from baseline, in the eplerenone arm versus the valsartan arm as monotherapy at 8 weeks, as combined dual treatment with amlodipine at 16 weeks and as combined triple treatment with amlodipine and indapamide at 24 weeks.	8, 16 and 24 weeks	Ambulatory blood pressure measurements (metric unit: mmHg) at baseline and 8,16 and 24 weeks and evaluation of the difference of mean ambulatory systolic and diastolic blood pressure measurements between baseline and each time frame in all participants

Secondary Outcome Measures

Name	Time	Method
Difference in change of office BP from baseline, in the eplerenone arm versus the valsartan arm as monotherapy at 8 weeks, as combined dual treatment with amlodipine at 16 weeks and as combined triple treatment with amlodipine and indapamide at 24 weeks.	8, 16 and 24 weeks	Office blood pressure measurements (metric unit: mmHg) at baseline and 8,16 and 24 weeks and evaluation of the difference of office systolic and diastolic blood pressure measurements between baseline and each time frame in all participants

Trial Locations

Locations (1)

Hypertension Unit, First Cardiology Clinic, Hippocration General Hospital, University of Athens, Athens, Greece; 🇬🇷 Athens, Greece