Effects of Gallopamil in Severe Asthma

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Gallopamil on Bronchial Smooth Muscle Remodelling in Severe Asthma: a Double Blind Study.

Conditions
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Asthma

Intervention / Treatment
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* Drug: Methoxyverapamil (gallopamil)
* Drug: Placebo.


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>16 patients with a diagnosis of severe asthma under gallopamil treatment | Drug: Methoxyverapamil (gallopamil)<br>* 200 mg/day (1 tablet 100 mg morning and evening) for 12 months.<br>|
| Placebo Comparator: 2<br>16 patients with a diagnosis of severe asthma under placebo treatment | Drug: Placebo.<br>* 1 tablet morning and evening for 12 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchial smooth muscle remodelling assessed by optic microscopy. |  | Before and after 12 months treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gallopamil, airway remodelling, smooth muscle, Asthma