Single Dose of pGM169/GL67A in CF Patients

Phase 1

Completed

Conditions: Cystic Fibrosis

Interventions: Drug: pGM169/GL67A

Registration Number: NCT00789867

Lead Sponsor: Imperial College London

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

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:
1. Moderate/severe CF liver disease
2. Significant renal impairment
3. Significant coagulopathy
Receiving 2nd line immunosuppressant drugs such as methotrexate, cyclosporine, intravenous immunoglobulin preparations
Pregnant or breastfeeding

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
20ml pGM169/GL67A	pGM169/GL67A	Received a nebulized dose 20ml via an breath-actuated nebulizer
5ml pGM169/GL67A	pGM169/GL67A	Received a nebulized dose 5ml via an breath-actuated nebulizer
10ml pGM169/GL67A	pGM169/GL67A	Received a nebulized dose 10ml via an breath-actuated nebulizer

Primary Outcome Measures

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