Clinical trial NCT00896428: Effects of Gallopamil in Severe Asthma
Official title: Effects of Gallopamil on Bronchial Smooth Muscle Remodelling in Severe Asthma: a Double Blind Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: Asthma
gallopamil
airway remodelling
smooth muscle
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
First posted: 2009-05-11
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Bronchial smooth muscle remodelling assessed by optic microscopy.
timeFrame: Before and after 12 months treatment.
Secondary outcomes:
measure: Bronchial smooth muscle remodelling assessed by electron microscopy
timeFrame: Before and after 12 months treatment.
measure: Bronchial smooth muscle mitochondrial number and activity assessed in vitro
timeFrame: Before and after 12 months treatment.
measure: Bronchial thickness assessed by 3D analysis of computed tomography
timeFrame: Before and after 12 months treatment.
measure: Asthma control using asthma control questionnaire, inflammation monitoring, number of hospitalizations, number of emergency visits, number of unplanned medical visits.
timeFrame: Once per month for 12 months.
Other outcomes:
Locations:
city: Pessac
country: France
facility: Hôpital Haut-Lévêque - Centre Hospitalier Universitaire de Bordeaux
Study officials:
affiliation: University Hospital Bordeaux, France
name: Patrick Berger, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, Berger P. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med. 2007 Dec 24;204(13):3173-81. doi: 10.1084/jem.20070956. Epub 2007 Dec 3.
citation: Girodet PO, Dournes G, Thumerel M, Begueret H, Dos Santos P, Ozier A, Dupin I, Trian T, Montaudon M, Laurent F, Marthan R, Berger P. Calcium channel blocker reduces airway remodeling in severe asthma. A proof-of-concept study. Am J Respir Crit Care Med. 2015 Apr 15;191(8):876-83. doi: 10.1164/rccm.201410-1874OC.