Single Dose of pGM169/GL67A in CF Patients

Study Overview
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Brief Summary
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The study objectives are to assess safety, tolerability and gene expression after a single dose of non-viral CFTR gene therapy (pGM169/GL67A) administered to the nose and lungs of patients with cystic fibrosis.

Detailed Description
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The trial is designed as single administration to nose and lung. Initially, in Part A, 3 patients will be dosed individually one week apart with 10 ml (26.5mg pDNA) via nebuliser and a nasal dose equivalent to 10% of this (based on relative surface area calculations: conducting airways approximate 540 cm2; nasal epithelium from both nostrils approximately 40 cm2). Based on our previous study, we do not expect any side effects of the nasal dose, but we are taking this opportunity, as this group will not be undergoing bronchoscopic efficacy measures, to assess gene transfer to the nasal epithelium. A further group of 3 patients will then be treated in exactly the same way with 20 ml nebulised and a 2 ml nasal dose. Subsequently, patients will receive doses of 2 ml (nasal) and 20 ml (nebulised). These patients will undergo more intensive monitoring for gene expression both before and after administration. In Part B of the protocol, we will test combinations of delivery conditions and dose in an attempt to identify the maximal tolerated dose. We may also use Ibuprofen or Prednisolone in standard clinical doses around the dosing period to reduce the inflammatory response. Delivery conditions include: standard nebulisation (each 5 ml over 25 minutes as in Part A), slow (each 5 ml over 75-150 minutes) and divided (standard rate delivery with a period of up to 6 hours between aliquots). With these conditions we will test the following doses until a tolerable dose is reached: 20 ml (no standard delivery as sufficient data already available from Part A); 10 ml; 5 ml; 2.5 ml. Each dosing strategy will initially be performed in a cohort of 3 patients although numbers may need to be increased to 6 if data are inconclusive. Once a satisfactory Single dose of pGM169/GL67A in CF patients; cro851 Version 10; 16.08.2010 10 dose and nebulisation strategy has been identified, the numbers receiving this will be increased to 6. The maximum number of patients recruited to this arm of the study will be 30. Part B will also allow either these subjects or others to receive a 2 ml nasal dose with both pre and post-measurements of nasal PD.

Official Title
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Evaluation of Safety and Gene Expression With a Single Dose of pGM169/GL67A Administered to the Nose and Lung of Individuals With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: pGM169/GL67A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cystic fibrosis confirmed by sweat testing or genetic analysis Males and females aged 16 years and above Forced expiratory volume in the 1st second (FEV1) > 60% predicted values Clinical stability at entry Prepared to take effective contraceptive precautions for the duration of their participation in the study and for 3 months thereafter If taking regular rhDNase (pulmozyme) is willing, and considered able by independent medical carers, to withhold treatment for 24 hours before and 24 hours after the gene therapy dose Written informed consent obtained Permission to inform GP of participation in study Exclusion Criteria: Infection with Burkholderia cepacia complex organisms or MRSA Significant nasal pathology including polyps, clinically-significant rhinosinusitis, or recurrent severe epistaxis (nose bleeds) Acute upper respiratory tract infection within the last 2 weeks Previous spontaneous pneumothorax without pleurodesis Recurrent severe haemoptysis Current smoker Significant comorbidity including: Moderate/severe CF liver disease Significant renal impairment Significant coagulopathy Receiving 2nd line immunosuppressant drugs such as methotrexate, cyclosporine, intravenous immunoglobulin preparations Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 20ml pGM169/GL67A<br>Received a nebulized dose 20ml via an breath-actuated nebulizer | Drug: pGM169/GL67A<br>* Received a nebulized dose via an breath-actuated nebulizer<br>* Other names: 5ml pGM169/GL67A, 10ml pGM169/GL67A and 20ml pGM169/GL67A;|
| Experimental: 10ml pGM169/GL67A<br>Received a nebulized dose 10ml via an breath-actuated nebulizer | Drug: pGM169/GL67A<br>* Received a nebulized dose via an breath-actuated nebulizer<br>* Other names: 5ml pGM169/GL67A, 10ml pGM169/GL67A and 20ml pGM169/GL67A;|
| Experimental: 5ml pGM169/GL67A<br>Received a nebulized dose 5ml via an breath-actuated nebulizer | Drug: pGM169/GL67A<br>* Received a nebulized dose via an breath-actuated nebulizer<br>* Other names: 5ml pGM169/GL67A, 10ml pGM169/GL67A and 20ml pGM169/GL67A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Maximum Temperature |  | 6-8h | 
| Blood Leukocytes | Blood leukocytes measure | 8h | 
| Blood Neutrophils | Blood neutrophils measures | 8h | 
| FEV1 Relative % Drop | FEV1 relative % drop measure | 8h | 
| FVC Relative % Drop | FVC relative % drop measure | 6h | 
| Lung Clearance Index - LCI | Lung clearance index measure is a measure of abnormal ventilation distribution derived from the multiple breath inert gas washout technique. | 8h | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Single dose, Pilot, Safety, Gene expression, Tolerability, CFTR gene, Cystic fibrosis, Non-viral