Open-label Study on Treatment of Primary Aldosteronism With Everolimus

NCT ID: NCT03174171

Last Updated: 2019-01-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-22
• Study Completion Date: 2018-06-25

Brief Summary

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

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.

Conditions

Primary Aldosteronism

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intervention

Everolimus 0.75 mg b.i.d. orally for 14 days.

Group Type: EXPERIMENTAL

Everolimus 0.75 mg

Intervention Type: DRUG

Everolimus 0.75 mg b.i.d. orally for 14 days.

Interventions

Everolimus 0.75 mg

Everolimus 0.75 mg b.i.d. orally for 14 days.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Basel, Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marc Y Donath, Prof.

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Basel, Switzerland

Locations

University Hospital Basel

Basel, Canton of Basel-City, Switzerland

Countries

Switzerland

Other Identifiers

EPA

Identifier Type: -

Identifier Source: org_study_id