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

Hyperaldosteronism Clinical Trial

— MAPA  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03414918
• Other study ID #: 4283/AO/17
• Status: Not yet recruiting
• Phase: N/A
• First received: December 27, 2017
• Last updated: January 29, 2018
• Start date: March 2018
• Est. completion date: January 2020

Study information

• Verified date: January 2018
• Source: University Hospital Padova
• Contact: Gian Paolo Rossi, MD
• Phone: +39-049-8212263
• Email: gianpaolo.rossi[@]unipd.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 342
• Est. completion date: January 2020
• Est. primary completion date: January 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Adenoma
• Hyperaldosteronism

Intervention

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).

Locations

Country	Name	City	State
Italy	Department of Medicine - DIMED, University of Padova, Italy	Padova

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Padova	DMG Paris Descartes

Country where clinical trial is conducted

Italy, 

References & Publications (5)

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. — View Citation

Choi M, Scholl UI, Yue P, Björklund 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, Åkerström 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. — View Citation

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. — View Citation

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. 2017 Sep 27. doi: 10.1097/HJH.0000000000001564. [Epub ahead of print] — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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