Open-label Study on Treatment of Primary Aldosteronism With Everolimus

The overall objective is to evaluate everolimus as an aldosterone-lowering drug in the treatment of primary hyperaldosteronism.

Study Overview

• Status: Completed
• Conditions: Primary Aldosteronism
• Intervention / Treatment: Drug: Everolimus 0.75 mg

Detailed Description

The purpose of this study is to evaluate everolimus as an aldosterone-lowering drug in treatment of primary aldosteronism.

Primary aldosteronism is defined as a group of disorders in which aldosterone production is inappropriately high and relatively autonomous from regulation by the renin-angiotensin-aldosterone system. It often presents with increased blood pressure and constitutes the most common cause of endocrine hypertension. It is associated with an increased risk of cardiovascular complications, structural and functional renal abnormalities and metabolic syndrome. The goal of primary aldosteronism treatment is to prevent mortality and morbidity associated with hypertension, hypokalemia and direct aldosterone-associated organ damage.

Treatment depends on the underlying cause of primary aldosteronism. In general, patients with aldosterone-producing adenoma and unilateral adrenal hyperplasia are recommended to have adrenalectomy while patients with bilateral adrenal hyperplasia and those not willing to obtain surgery are offered targeted treatment with mineralocorticoid receptor antagonists. However, the use of mineralocorticoid receptor antagonist is related to side effects that include breast tenderness, gynecomastia, sexual dysfunction and menstrual irregularities.

The primary purpose of this proof-of-concept study is to evaluate whether inhibition of adrenocortical mammilian target of rapamycin (mTOR) signalling with everolimus decreases circulating aldosterone levels. The study also aims to determine whether potential changes in aldosterone levels result solely from a direct effect of everolimus on the adrenal gland or could be caused by changes in aldosterone metabolism and/or levels of canonical regulators of adrenal function (ACTH, AngII). The secondary purpose of this study is to test whether everolimus treatment ameliorates hypertension, improves cardiac function and to better understand molecular mechanisms leading to the development of primary aldosteronism.

Participants will receive Everolimus 0.75mg b.i.d. orally for a duration of 14 days. Blood pressure measurements, haemodynamic measurements, blood tests, 24h urine collection and saline Infusion tests will be conducted in order to compare changes in blood pressure, cardiac and kidney function, aldosterone and steroid hormone metabolite levels, activity of the renin-angiotensin-aldosterone system before and after treatment.

In patients undergoing adrenalectomy, adrenocortical cells will be isolated and primary adrenocortical cell cultures will be established from excised adrenal glands. Cultured cells will be treated with mTOR inhibitors and their proliferation and steroidogenic potential will be assessed. Cells treated with mTOR inhibitors will be subjected to transcriptomic, proteomic and phosphoproteomic analyses that will allow identification of mTOR signaling effectors in the adrenal cortex and to better understand molecular mechanisms leading to the development of primary aldosteronism.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Basel Stadt
    • Basel, Basel Stadt, Switzerland, 4031
      • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with primary aldosteronism
• Age ≥ 18 years
• Office blood pressure <160/90 mmHg on antihypertensive therapy
• For subjects with reproductive potential, willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study

Exclusion Criteria:

• Signs of current infection
• Neutropenia (leukocyte count < 1.5 × 109/L or absolute neutrophil count (ANC) < 0.5 × 109/L)
• Anemia (hemoglobin < 11 g/dL for males, < 10 g/dL for females)
• Clinically significant kidney or liver disease (creatinine > 1.5 mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2 × ULN, alkaline phosphatase > 2 × ULN, total bilirubin > 1.5 × ULN)
• Current immunosuppressive treatment or documented immunodeficiency
• Uncontrolled congestive heart failure
• Currently pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Everolimus 0.75 mg b.i.d. orally for 14 days.	Drug: Everolimus 0.75 mg; Everolimus 0.75 mg b.i.d. orally for 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aldosterone level	Change in aldosterone level after saline infusion test after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure values	Change in mean systolic and diastolic blood pressure during standardized office and home blood pressure measurement after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days
Kidney function	Change in albumin in 24 hour-urine after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days
Steroid hormones in serum	Change in steroid hormones in serum in 24h-urine after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days
Level of plasma renin activity	Change in Renin-angiotensin-aldosterone System after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days
Level of Potassium	Change in potassium level and need of potassium substitution after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days
Steroid hormone metabolites in urine	Change in steroid hormone metabolites in 24h-urine after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days
Level of plasma ACTH	Change in the Renin-angiotensin-aldosterone system after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days
Level of plasma angiotensin II (ATII)	Change in the Renin-angiotensin-aldosterone system after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).	28 days

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Marc Y Donath, Prof., University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2017
• Primary Completion (Actual): June 25, 2018
• Study Completion (Actual): June 25, 2018

Study Registration Dates

• First Submitted: May 24, 2017
• First Submitted That Met QC Criteria: May 30, 2017
• First Posted (Actual): June 2, 2017

Study Record Updates

• Last Update Posted (Actual): January 9, 2019
• Last Update Submitted That Met QC Criteria: January 8, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Everolimus, mTor inhibitor
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Hyperaldosteronism; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: EPA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No