Effects of Gallopamil in Severe Asthma

NCT ID: NCT00896428

Last Updated: 2013-08-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-12-31
• Study Completion Date: 2012-11-30

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.

Conditions

Asthma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

1

16 patients with a diagnosis of severe asthma under gallopamil treatment

Group Type: EXPERIMENTAL

Methoxyverapamil (gallopamil)

Intervention Type: DRUG

200 mg/day (1 tablet 100 mg morning and evening) for 12 months.

2

16 patients with a diagnosis of severe asthma under placebo treatment

Group Type: PLACEBO_COMPARATOR

Placebo.

Intervention Type: DRUG

1 tablet morning and evening for 12 months

Interventions

Methoxyverapamil (gallopamil)

200 mg/day (1 tablet 100 mg morning and evening) for 12 months.

Intervention Type: DRUG

Placebo.

1 tablet morning and evening for 12 months

Intervention Type: DRUG

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

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

Sponsors

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patrick Berger, Professor

Role: PRINCIPAL_INVESTIGATOR

University Hospital Bordeaux, France

Locations

Hôpital Haut-Lévêque - Centre Hospitalier Universitaire de Bordeaux

Pessac, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 18056286 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25633090 (View on PubMed)

Other Identifiers

CHUBX2008/09

Identifier Type: -

Identifier Source: org_study_id