Macrolides for KCNJ5 - Mutated Aldosterone-Producing Adenoma (MAPA) (MAPA)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03414918|
Recruitment Status : Not yet recruiting
First Posted : January 30, 2018
Last Update Posted : January 30, 2018
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|
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 (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)|
|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|
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).
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
- 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.
- 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.
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
|Contact: Gian Paolo Rossi, MDemail@example.com|
|Department of Medicine - DIMED, University of Padova, Italy||Not yet recruiting|
|Principal Investigator: Gian Paolo Rossi, MD|
|Principal Investigator:||Gian Paolo Rossi, MD||University of Padova|