Macrolides for KCNJ5 - Mutated Aldosterone-Producing Adenoma (MAPA) (MAPA)

January 29, 2018 updated by: Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova

Macrolides for KCNJ5 - Mutated Aldosterone-Producing Adenoma (MAPA): A Study Of Personalized Diagnosis of Primary Aldosteronism With Implications For Treatment

This study evaluates if :

1 ) the plasma aldosterone concentration and blood pressure change in response to roxithromycin could be useful for the screening of PA patients carrying a KCNJ5-mutated APA; 2) the change of PAC in response to mutated KCNJ5 channel is truly occurring in KCNJ5-mutated APA.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Aldosterone-producing adenoma (APA) cause primary aldosteronism (PA), the main curable cause of endocrine hypertension, is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, the aim of the present study was to investigate if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA.

The investigators designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index (RASI) in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration (PAC) and other steroids, direct active renin concentration (DRC), serum K+, systolic and diastolic blood pressure.

The investigators expect to prove that: i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; ii) the acute changes of PAC, DRC, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations.

Study Type

Interventional

Enrollment (Anticipated)

342

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Padova, Italy
        • Department of Medicine - DIMED, University of Padova, Italy
        • Principal Investigator:
          • Gian Paolo Rossi, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 73 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • A signed and dated informed consent form
  • A diagnosis of hypertension defined either as:

Use of antihypertensive drug (s) Arterial hypertension: in untreated patients this must be confirmed by daytime ambulatory blood pressure monitoring (ABPM), or home blood pressure monitoring, with blood pressure higher or equal to 135 mmHg for systolic blood pressure and/or higher or equal to 85 mmHg for diastolic blood pressure.

Normal observation of ECG QT interval.

Exclusion Criteria:

  • History of allergy/intolerance to any macrolides;
  • Refusal of the patient to undergo dynamic testing;
  • Refusal of the patient to undergo AVS and/or contraindications to the general anesthesia that is required for laparoscopic adrenalectomy (for objective 2);
  • Suspicion of cortisol-aldosterone co-secreting adenoma
  • Pregnancy
  • Family history of sudden death
  • Family history of syncope
  • Family history of Long QT syndrome and or torsade de point
  • Congenital or drug-induced Long QT syndrome

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Clarithromycin
250 mg clarithromycin diluted in 250 ml saline will be administered as a slow infusion (45 min) in a peripheral vein during AVS. This dose of clarithromycin should yield peak plasma concentrations of 2.78 mcg/mL (on average)13, which are higher than the IC50 measured in vitro (0.53-1.29 mcg/mL).
Drug: Clarithromycin
Hypertensive patients will be exposed to a single oral dose of 150 mg of roxithromycin. A 150-mg oral dose of roxithromycin should yield peak plasma concentrations of 5-12 mcg/mL14, which are higher than the IC50 measured in vitro (0.18-0.53 mcg/mL).
Other Names:
  • roxithromycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Study 1: Change in Relative Aldosterone Secretion Index (RASI).
Time Frame: Baseline and after 45min clarithromycin infusion.
Within-patient change from baseline of the RASI in adrenal vein blood draining the gland with and without the APA.
Baseline and after 45min clarithromycin infusion.
Study 2: Change in plasma aldosterone concentration (PAC).
Time Frame: Baseline and after 60 and 120 minutes roxitromycin administration
Within-patient change from baseline of PAC in peripheral venous blood in patients undergoing screening for PA.
Baseline and after 60 and 120 minutes roxitromycin administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Padova

Collaborators

DMG Paris Descartes

Investigators

  • Principal Investigator: Gian Paolo Rossi, MD, University of Padova

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

March 1, 2018

Primary Completion (Anticipated)

January 1, 2019

Study Completion (Anticipated)

January 1, 2020

Study Registration Dates

First Submitted

December 27, 2017

First Submitted That Met QC Criteria

January 29, 2018

First Posted (Actual)

January 30, 2018

Study Record Updates

Last Update Posted (Actual)

January 30, 2018

Last Update Submitted That Met QC Criteria

January 29, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4283/AO/17

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

IPD Plan Description

The decision to share the data will be taken upon completion of the study and publication of the results.

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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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