Effect of a Proposed Cav1.3 Inhibitor in Primary Aldosteronism

NCT ID: NCT05686993

Last Updated: 2024-07-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-04-24
• Study Completion Date: 2023-09-06

Brief Summary

The goal of this pilot, open-label prospective study is to evaluate if the effect of calcium channel blockade on plasma aldosterone levels in people with primary aldosteronism (PA) is due primarily to Cav1.3 blockade.

This will be tested by treating participants who have PA with both cinnarizine (Cav1.3 blocker) and nifedipine (Cav1.2 blocker) and evaluating effect on aldosterone levels and blood pressure over a two week course of treatment.

Detailed Description

Medical treatment for Primary Aldosteronism (PA) is currently limited to mineralocorticoid receptor antagonists (MRA), the most widely available of which is spironolactone. This can cause numerous adverse effects, especially in men, due to interference with androgen and progesterone signalling. Hence, alternative drug targets are needed, one potential of which is Cav1.3.

The CACNA1D mutation in PA affects the calcium channel Cav1.3. Cav1.3 inhibition may offer targeted treatment for patients with mutations in CACNA1D. Cav1.3 has been a candidate for novel inhibitors of aldosterone production,4 for which the case is enhanced if CACNA1D-mutations underlie the above-described phenotype of PA (asymmetric disease leading to failure to achieve cure with adrenalectomy).

The calcium-channel blocker, cinnarizine, typically used for vertigo and nausea, has been identified to fit the recently described crystal structure of Cav1.3. This raises the possibility of using this drug to assess the effect of Cav1.3 inhibition in PA. This may lead to further studies involving randomisation and placebo to determine if Cav1.3 inhibition is an important method by which aldosterone levels can be lowered in people with PA.

This study seeks to explore whether the effect of calcium channel blockade on aldosterone levels in people with PA is due to Cav1.3 blockade, by comparing cinnarizine (proposed Cav1.3 inhibitor) to a conventional calcium channel blocker nifedipine (Cav1.2 inhibitor). Cinnarizine is not a likely prospect for long-term treatment of PA, because of its potential additional actions as well as Cav1.3 blockade, but using it in this setting, for a short period of time, allows exploration of a property of this existing drug (Cav1.3 inhibition). Outcomes could form the basis of further exploration of this mechanism for future PA treatments.

Conditions

Primary Aldosteronism; Endocrine Hypertension

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cinnarizine and nifedipine

Drug 1 for 2 weeks, 2 weeks of washout, then Drug 2 for 2 weeks Drug 1 and 2, in no specified order, Cinnarizine 30 mg oral TDS and Nifedipine 60 mg oral daily

Group Type: EXPERIMENTAL

Cinnarizine

Intervention Type: DRUG

Cinnarizine oral 30mg TDS

NIFEdipine ER

Intervention Type: DRUG

Nifedipine oral 60mg daily extended release

Interventions

Cinnarizine

Cinnarizine oral 30mg TDS

Intervention Type: DRUG

NIFEdipine ER

Nifedipine oral 60mg daily extended release

Intervention Type: DRUG

Other Intervention Names

Stugeron, Stunarone, Cinarin; Adalat, Adipine, Coracten, Fortipine, Nifedipress

Eligibility Criteria

Inclusion Criteria

• Confirmed PA, as demonstrated by a positive screening test and internationally endorsed confirmatory test (saline suppression test, captopril challenge test)
• Adults > 18 years of age
• Able and willing to give informed consent

Exclusion Criteria

• Uncontrolled hypertension requiring use of MRA
• Unwilling or unable to give consent
• Below age 18 or above age 90 years
• Allergy to cinnarizine or nifedipine or their excipients
• Existing use of cinnarizine or nifedipine for an alternative indication
• Breastfeeding or pregnant women
• Diagnosis of Parkinson's disease
• Severe hepatic or renal insufficiency
• Concurrent use of sedating central nervous system (CNS) depressants or rifampicin
• Porphyria
• Cardiogenic shock, clinically significant aortic stenosis, unstable angina, within one month of a myocardial infarction
• Previous gastro-intestinal or oesophageal obstruction or ileostomy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Queen Mary University of London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Morris Brown, MD FRCP

Role: PRINCIPAL_INVESTIGATOR

Queen Mary University of London

Locations

St Bartholomew's Hospital

London, , United Kingdom

Countries

United Kingdom

References

Ng E, Lee YN, Taylor A, Shaheen F, Azizan E, Drake WM, Brown MJ. Evaluation of Aldosterone Suppression by Cinnarizine, a Putative Cav1.3 Inhibitor. J Clin Endocrinol Metab. 2025 Sep 16;110(10):2752-2761. doi: 10.1210/clinem/dgaf081.

Reference Type: DERIVED

PMID: 40052842 (View on PubMed)

Other Identifiers

154739

Identifier Type: -

Identifier Source: org_study_id