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Interest of Gentamicin-induced Readthrough in Cystic Fibrosis Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00376428
Recruitment Status : Terminated
First Posted : September 14, 2006
Last Update Posted : February 25, 2015
Sponsor:
Information provided by:
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE September 13, 2006
First Posted Date  ICMJE September 14, 2006
Last Update Posted Date February 25, 2015
Study Start Date  ICMJE January 2003
Primary Completion Date Not Provided
Current Primary Outcome Measures  ICMJE
 (submitted: September 13, 2006)
CFTR-dependant chlorate secretion
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 13, 2006)
  • CFTR expression in nasal cells
  • Clinical beneficial effects
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Interest of Gentamicin-induced Readthrough in Cystic Fibrosis Patients
Official Title  ICMJE Application of Functional Electrophysiological Tests to Evaluate Pharmacological Treatments in Patients With Cystic Fibrosis
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE Drug: Gentamicin
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Enrollment  ICMJE
 (submitted: September 13, 2006)
20
Original Enrollment  ICMJE Same as current
Study Completion Date  ICMJE June 2005
Primary Completion Date Not Provided
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00376428
Other Study ID Numbers  ICMJE 02-03-10
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Aleksander Edelman, PhD Institut National de la Santé Et de la Recherche Médicale, France
Principal Investigator: Isabelle Sermet, MD; PhD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date September 2006

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