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

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ClinicalTrials.gov Identifier: NCT03414918
Recruitment Status : Not yet recruiting
First Posted : January 30, 2018
Last Update Posted : January 30, 2018
Sponsor:
Collaborator:
DMG Paris Descartes
Information provided by (Responsible Party):
Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Hyperaldosteronism Drug: Clarithromycin Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 342 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

Study 1: We will enroll consecutive hypertensive patients with PA, who need to undergo adrenal vein sampling (AVS) before being referred for adrenalectomy, according to current guidelines12.

Study 2: Regardless of the results of study 1, we will recruit consecutive referred hypertensive patients undergoing screening for secondary hypertension. This is because to prove unambiguously the role of macrolides in the screening of mutated APA we must enroll a population of patients with and without PA and with/without the different gene mutations so far identified in APA.

Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Macrolides for KCNJ5 - Mutated Aldosterone-Producing Adenoma (MAPA): A Study Of Personalized Diagnosis of Primary Aldosteronism With Implications For Treatment
Estimated Study Start Date : March 2018
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2020


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 Name: roxithromycin




Primary Outcome Measures :
  1. 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.

  2. 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.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

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): NCT03414918


Contacts
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Contact: Gian Paolo Rossi, MD +39-049-8212263 gianpaolo.rossi@unipd.it

Locations
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Italy
Department of Medicine - DIMED, University of Padova, Italy Not yet recruiting
Padova, Italy
Principal Investigator: Gian Paolo Rossi, MD         
Sponsors and Collaborators
University Hospital Padova
DMG Paris Descartes
Investigators
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Principal Investigator: Gian Paolo Rossi, MD University of Padova

Publications:

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Responsible Party: Gian Paolo Rossi, MD, FAHA, FACC, Director of Arterial Hypertension Unit - DIMED, University Hospital Padova
ClinicalTrials.gov Identifier: NCT03414918     History of Changes
Other Study ID Numbers: 4283/AO/17
First Posted: January 30, 2018    Key Record Dates
Last Update Posted: January 30, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: The decision to share the data will be taken upon completion of the study and publication of the results.

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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.: Yes
Keywords provided by Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova:
Macrolides, KCNJ5 potassium channel, aldosteronism
Additional relevant MeSH terms:
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Adenoma
Hyperaldosteronism
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adrenocortical Hyperfunction
Adrenal Gland Diseases
Endocrine System Diseases
Clarithromycin
Roxithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors