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

NCT03414918 | Unknown

• 1 other identifier: 4283/AO/17
• Study Type: interventional
• Target: 342
• Locations: 1 country
• Sites: 1

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.

Conditions

Hyperaldosteronism

Keywords

Macrolides, KCNJ5 potassium channel, aldosteronism

Outcome Measures

Primary Outcomes (2)

• Study 1: Change in Relative Aldosterone Secretion Index (RASI).

  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).

  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

Study Arms (1)

Clarithromycin

EXPERIMENTAL

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

Interventions

Clarithromycin DRUG

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).

Also known as: roxithromycin

Clarithromycin

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital Padova: lead
• DMG Paris Descartes: collaborator

Study Sites (1)

Department of Medicine - DIMED, University of Padova, Italy

Padua, Italy

Location

Related Publications (5)

• Rossi GP, Belfiore A, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Montemurro D, Palumbo G, Rizzoni D, Rossi E, Semplicini A, Agabiti-Rosei E, Pessina AC, Mantero F; PAPY Study Investigators. Prospective evaluation of the saline infusion test for excluding primary aldosteronism due to aldosterone-producing adenoma. J Hypertens. 2007 Jul;25(7):1433-42. doi: 10.1097/HJH.0b013e328126856e.

  PMID: 17563566 BACKGROUND

• Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011 Feb 11;331(6018):768-72. doi: 10.1126/science.1198785.

  PMID: 21311022 BACKGROUND

• Scholl UI, Abriola L, Zhang C, Reimer EN, Plummer M, Kazmierczak BI, Zhang J, Hoyer D, Merkel JS, Wang W, Lifton RP. Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma. J Clin Invest. 2017 Jun 30;127(7):2739-2750. doi: 10.1172/JCI91733. Epub 2017 Jun 12.

  PMID: 28604387 BACKGROUND

• Caroccia B, Prisco S, Seccia TM, Piazza M, Maiolino G, Rossi GP. Macrolides Blunt Aldosterone Biosynthesis: A Proof-of-Concept Study in KCNJ5 Mutated Adenoma Cells Ex Vivo. Hypertension. 2017 Dec;70(6):1238-1242. doi: 10.1161/HYPERTENSIONAHA.117.10226. Epub 2017 Oct 9.

  PMID: 28993452 BACKGROUND

• Rossitto G, Battistel M, Barbiero G, Bisogni V, Maiolino G, Diego M, Seccia TM, Rossi GP. The subtyping of primary aldosteronism by adrenal vein sampling: sequential blood sampling causes factitious lateralization. J Hypertens. 2018 Feb;36(2):335-343. doi: 10.1097/HJH.0000000000001564.

  PMID: 28957852 BACKGROUND

MeSH Terms

Conditions

Hyperaldosteronism

Interventions

Clarithromycin; Roxithromycin

Condition Hierarchy (Ancestors)

Adrenocortical Hyperfunction; Adrenal Gland Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Gian Paolo Rossi, MD

  University of Padova

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gian Paolo Rossi, MD

CONTACT

+39-049-8212263; gianpaolo.rossi@unipd.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Arterial Hypertension Unit - DIMED

Model Details: 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.

Study Record Dates

• First Submitted: December 27, 2017
• First Posted: January 30, 2018
• Study Start: March 1, 2018
• Primary Completion: January 1, 2019
• Study Completion: January 1, 2020
• Last Updated: January 30, 2018

Record last verified: 2018-01

Locations

IT (1)