Single Dose Clinical Trial (2009-2011)

The aim of the Pilot study was to assess the safety of a single dose of the Wave 1 product. Over 30 patients took part in the study and received one dose of the gene therapy. Patients were treated with different quantities of the gene therapy formulation to assess the optimal dose going forward to the multi-dose clinical trial.

The gene therapy was administered in a filtered cubicle through a nebuliser and some patients also received a small dose in the nose from a nasal spray. A 20ml dose took around 1½ hours to administer.

Each patient had any symptoms recorded and had physical examinations, oxygen saturation levels, spirometry, CT scans and numerous blood and sputum tests. A subgroup of patients were kept in hospital for overnight monitoring after dosing. Although the primary purpose of the study was not to check for efficacy, the clinicians also took some measurements to see if the single dose had any effect (at a molecular level, not for clinical benefit).

Patients on the pilot study underwent the following tests at study visits (some of the patients did not undergo all of these procedures):

Medical history and clinical examination
Blood and urine samples taken
Spirometry
Lung function tests
Nasal Potential Difference analysis
Bronchoscopies
Nasal brushings
Sputum analysis
Completion of diary card
Lung clearance index (LCI)
Airway mucosal blood flow
Gas transfer tests

Some patients experienced a mild flu-like reaction to the dose with a temporarily raised temperature and drop in FEV1 (which were noticed more by clinical measurements than the patients themselves) along with other mild symptoms. The response in the patients who had a lower dose was less than in those who had a higher dose. The symptoms were short lived and mostly gone in one or two days.

One of the areas of work the Consortium had undertaken was to refine the plasmid DNA (the correct version of the gene) to remove elements which are believed to cause this flu-like reaction, which was also seen in a previous lung trial. The changes made in the plasmid were successful in reducing these flu-like reactions in animal models. However in the CF patients, there is likely to be another important component, namely the amount of gloopy, fatty substance (the gene transfer agent) being delivered to the lungs.

The pilot study used a new and highly efficient nebuliser, which deposits about 75% more of the gene into the airways than occurred in the first trial. Both the Consortium and the CF Trust's Scientific Advisory Committee think it likely that we are now being over-efficient and the lungs are simply responding to the large volume of this material. Once the amount delivered is reduced, the expectation is that the symptoms will reduce or disappear.

The pilot study is now complete and is awaiting full publication. Results were presented at the 2011 North American Cystic Fibrosis Conference.