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Open-label Study on Treatment of Primary Aldosteronism With Everolimus

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ClinicalTrials.gov Identifier: NCT03174171
Recruitment Status : Completed
First Posted : June 2, 2017
Last Update Posted : January 9, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

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

Condition or disease Intervention/treatment Phase
Primary Aldosteronism Drug: Everolimus 0.75 mg Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label Study on Treatment of Primary Aldosteronism With Everolimus
Actual Study Start Date : May 22, 2017
Actual Primary Completion Date : June 25, 2018
Actual Study Completion Date : June 25, 2018


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.




Primary Outcome Measures :
  1. Aldosterone level [ Time Frame: 28 days ]
    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).


Secondary Outcome Measures :
  1. Blood pressure values [ Time Frame: 28 days ]
    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).

  2. Kidney function [ Time Frame: 28 days ]
    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).

  3. Steroid hormones in serum [ Time Frame: 28 days ]
    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).

  4. Level of plasma renin activity [ Time Frame: 28 days ]
    Change in Renin-angiotensin-aldosterone System after the treatment period (Day 15) and after the washout period (Day 28) compared to baseline (Day 0).

  5. Level of Potassium [ Time Frame: 28 days ]
    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).

  6. Steroid hormone metabolites in urine [ Time Frame: 28 days ]
    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).

  7. Level of plasma ACTH [ Time Frame: 28 days ]
    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).

  8. Level of plasma angiotensin II (ATII) [ Time Frame: 28 days ]
    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).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03174171


Locations
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Switzerland
University Hospital Basel
Basel, Basel Stadt, Switzerland, 4031
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Investigators
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Principal Investigator: Marc Y Donath, Prof. University Hospital, Basel, Switzerland

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Responsible Party: University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT03174171     History of Changes
Other Study ID Numbers: EPA
First Posted: June 2, 2017    Key Record Dates
Last Update Posted: January 9, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by University Hospital, Basel, Switzerland:
Everolimus, mTor inhibitor

Additional relevant MeSH terms:
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Hyperaldosteronism
Adrenocortical Hyperfunction
Adrenal Gland Diseases
Endocrine System Diseases
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents