Effects of Gallopamil in Severe Asthma

Phase 2

Completed

• Conditions: Asthma
• Interventions: Drug: Methoxyverapamil (gallopamil); Drug: Placebo.

• Registration Number: NCT00896428
• Lead Sponsor: University Hospital, Bordeaux

Brief Summary

Severe asthma is a difficult to treat disease, characterized by bronchial remodelling, which is an abnormal repair process that contributes to the development of poorly reversible airway narrowing. Such remodelling is now considered as one of the main prognostic factors. Gallopamil-sensitive calcium influx plays a key role in this remodelling process in vitro. The objective of this study is to compare the effects of gallopamil versus placebo on the bronchial smooth muscle remodelling in severe asthmatic patients.

Detailed Description

Bronchial remodelling mainly involves an increased mass of bronchial smooth muscle (BSM), which is related with an increase proliferation of smooth muscle cells. Recently, using BSM cells obtained from severe asthmatics, we have demonstrated that such an increase proliferation was induced by an activation cascade (Trian, J Exp Med, 2007). It first started with a gallopamil-sensitive calcium influx which induced the activation of calcium-calmodulin kinase IV (CamK-IV). CamK-IV then enhanced mitochondrial biogenesis through the subsequent activation of various transcription factors including PGC-1α, NRF-1 and mt-TFA. BSM cell proliferation was mainly mitochondria-dependent in vitro in severe asthma whereas that of controls was virtually mitochondria-independent. However, in vivo effects of gallopamil remain to be investigated. We will thus enrol 32 severe asthmatic patients in a phase 2 randomized double blind study against placebo and evaluate the effect of gallopamil on BSM remodelling. Since inflammation also activates mitochondrial biogenesis in BSM cells, we will initially optimized asthma treatment for 3 months by both controlling co morbidities and decreasing bronchial inflammation using exhaled NO and eosinophil count within the induced sputum. We will then perform fiberoptic fibroscopy before and after 12 month treatment with gallopamil.

Study Timeline

• Study First Submitted: 2009-05-07
• Study First Submitted QC: 2009-05-08
• Study First Posted: 2009-05-11
• Study Start: 2009-12
• Primary Completion: 2012-07
• Study Completion: 2012-11
• Status Verified: 2013-08
• Last Update Submitted: 2013-08-13
• Last Update Posted: 2013-08-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 31

Inclusion Criteria

• Male or female aged more than 18 years
• Written informed consent
• Diagnosis of severe asthma according to ATS criteria

Exclusion Criteria

• Smoker or former smoker
• Chronic viral infections (hepatitis, HIV)
• Aspergillosis
• Pregnancy
• Breastfeeding
• Contraindications to gallopamil or bronchoscopy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	Methoxyverapamil (gallopamil)	16 patients with a diagnosis of severe asthma under gallopamil treatment
2	Placebo.	16 patients with a diagnosis of severe asthma under placebo treatment

Primary Outcome Measures

Name	Time	Method
Bronchial smooth muscle remodelling assessed by optic microscopy.	Before and after 12 months treatment.

Secondary Outcome Measures

Name	Time	Method
Bronchial smooth muscle remodelling assessed by electron microscopy	Before and after 12 months treatment.
Bronchial smooth muscle mitochondrial number and activity assessed in vitro	Before and after 12 months treatment.
Bronchial thickness assessed by 3D analysis of computed tomography	Before and after 12 months treatment.
Asthma control using asthma control questionnaire, inflammation monitoring, number of hospitalizations, number of emergency visits, number of unplanned medical visits.	Once per month for 12 months.

Trial Locations

Locations (1)

Hôpital Haut-Lévêque - Centre Hospitalier Universitaire de Bordeaux; 🇫🇷 Pessac, France