Effect of a Proposed Cav1.3 Inhibitor in Primary Aldosteronism

Sponsor

Queen Mary University of London (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05686993

Collaborator

(none)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Aldosteronism Endocrine Hypertension	Drug: Cinnarizine Drug: NIFEdipine ER	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Intervention Model Description:

Treatment with cinnarizine for 2 weeks, then 2 weeks of drug washout, and then 2 weeks of treatment with nifedipineTreatment with cinnarizine for 2 weeks, then 2 weeks of drug washout, and then 2 weeks of treatment with nifedipine

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effect of a Proposed Cav1.3 Inhibitor in Primary Aldosteronism - a Pilot Study

Anticipated Study Start Date :

Mar 6, 2023

Anticipated Primary Completion Date :

Oct 6, 2023

Anticipated Study Completion Date :

Dec 6, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cinnarizine and nifedipine Cinnarizine 30 mg oral TDS for 2 weeks, 2 weeks of washout, then Nifedipine 60 mg oral daily for 2 weeks	Drug: Cinnarizine Cinnarizine oral 30mg TDS Other Names: Stugeron, Stunarone, Cinarin Drug: NIFEdipine ER Nifedipine oral 60mg daily extended release Other Names: Adalat, Adipine, Coracten, Fortipine, Nifedipress

Arm

Intervention/Treatment

Experimental: Cinnarizine and nifedipine

Cinnarizine 30 mg oral TDS for 2 weeks, 2 weeks of washout, then Nifedipine 60 mg oral daily for 2 weeks

Drug: Cinnarizine

Cinnarizine oral 30mg TDS

Other Names:

Stugeron, Stunarone, Cinarin

Drug: NIFEdipine ER

Nifedipine oral 60mg daily extended release

Other Names:

Adalat, Adipine, Coracten, Fortipine, Nifedipress

Outcome Measures

Primary Outcome Measures

Aldosterone change [6 weeks]
Evaluate whether the effect of calcium channel blockade on plasma aldosterone levels is due primarily to Cav1.3 blockade in individuals with PA and clinical features suggesting an increased likelihood of a CACNA1D mutation.

Secondary Outcome Measures

Blood pressure change [6 weeks]
Evaluate whether the use of a proposed Cav1.3 inhibitor affects blood pressure in individuals with PA, evaluating both systolic blood pressure and diastolic blood pressure.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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