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Interest of Gentamicin-Induced Readthrough in Cystic Fibrosis Patients

This study has been terminated.
Sponsor:
Information provided by:
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT00376428
First received: September 13, 2006
Last updated: NA
Last verified: September 2006
History: No changes posted

September 13, 2006
September 13, 2006
January 2003
Not Provided
CFTR-dependant chlorate secretion
Same as current
No Changes Posted
  • CFTR expression in nasal cells
  • Clinical beneficial effects
Same as current
Not Provided
Not Provided
 
Interest of Gentamicin-Induced Readthrough in Cystic Fibrosis Patients
Application of Functional Electrophysiological Tests to Evaluate Pharmacological Treatments in Patients With Cystic Fibrosis

Suppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated chloride transport in nasal and sweat gland epithelium.

Background: This study was conducted to determine whether intravenous gentamicin can suppress stop codons in cystic fibrosis (CF) patients and, if so, whether it has any clinical benefits.

Methods: We first used a dual gene reporter system to determine the gentamicin-induced readthrough level of the most frequent CFTR stop mutations in the French population. We next investigated readthrough efficiency in response to 10 mg/kg once daily intravenous gentamicin perfusions in patients with stop mutations and in a control group of patients without stop mutations. Respiratory function, sweat chloride concentration, nasal potential difference (NPD) and CFTR expression in nasal epithelial cells were measured at baseline and after 15 days of treatment.

Results: After in vitro gentamicin incubation, the readthrough efficiency for the Y122X mutation was at least five times higher than that for G542X, R1162X, and W1282X. In six of the nine patients with the Y122X mutation, CFTR immunodetection showed protein expression at the membrane of the nasal ciliated cells and the CFTR-dependent chloride secretion in their NPD measurements increased significantly. Respiratory status also improved in these patients, irrespective of the gentamicin sensitivity of the germs present in the sputum. Mean sweat chloride concentration decreased significantly and normalized in two patients. These measurements did not change in the Y122X patients with no protein expression, in patients with the other stop mutations investigated in vitro (n=4) and those without stop mutations (n=5).

Conclusion: Suppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated chloride transport in nasal and sweat gland epithelium.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Cystic Fibrosis
Drug: Gentamicin
Not Provided
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
20
June 2005
Not Provided

Inclusion Criteria:

  • cystic fibrosis with CFTR codon stop mutations

Exclusion Criteria:

  • Rhinitis
  • nasal polyposis
  • passive or active smoking
  • modification of basal treatments within the previous month
  • treatments with aminoglycosides within three previous months
Both
Not Provided
No
Contact information is only displayed when the study is recruiting subjects
France
 
NCT00376428
02-03-10
Not Provided
Not Provided
Assistance Publique - Hôpitaux de Paris
Not Provided
Study Director: Aleksander Edelman, PhD Institut National de la Santé Et de la Recherche Médicale, France
Principal Investigator: Isabelle Sermet, MD; PhD AP-HP
Assistance Publique - Hôpitaux de Paris
September 2006

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP