- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00376428
Interest of Gentamicin-induced Readthrough in Cystic Fibrosis Patients
Application of Functional Electrophysiological Tests to Evaluate Pharmacological Treatments in Patients With Cystic Fibrosis
Study Overview
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
Enrollment
Phase
- Phase 2
Contacts and Locations
Study Locations
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Paris, France, 75015
- Necker-Enfants malades
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
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CFTR-dependant chlorate secretion
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Secondary Outcome Measures
Outcome Measure |
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CFTR expression in nasal cells
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Clinical beneficial effects
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Collaborators and Investigators
Investigators
- 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
Study record dates
Study Major Dates
Study Start
Study Completion
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Respiratory Tract Diseases
- Lung Diseases
- Infant, Newborn, Diseases
- Genetic Diseases, Inborn
- Pancreatic Diseases
- Fibrosis
- Cystic Fibrosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Anti-Bacterial Agents
- Protein Synthesis Inhibitors
- Gentamicins
Other Study ID Numbers
- 02-03-10
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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