Clinical trial NCT00789867: Single Dose of pGM169/GL67A in CF Patients
Official title: Evaluation of Safety and Gene Expression With a Single Dose of pGM169/GL67A Administered to the Nose and Lung of Individuals With Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cystic Fibrosis
Keywords: Single dose
Pilot
Safety
Gene expression
Tolerability
CFTR gene
Cystic fibrosis
Non-viral
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Royal Brompton & Harefield NHS Foundation Trust
name: University of Oxford
name: University of Edinburgh
name: Cystic Fibrosis Trust
name: University of Pennsylvania
First posted: 2008-11-13
Enrollment: 35
Sex: ALL
Minimum age (years): 16
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Body Maximum Temperature
timeFrame: 6-8h
measure: Blood Leukocytes
timeFrame: 8h
measure: Blood Neutrophils
timeFrame: 8h
measure: FEV1 Relative % Drop
timeFrame: 8h
measure: FVC Relative % Drop
timeFrame: 6h
measure: Lung Clearance Index - LCI
timeFrame: 8h
Secondary outcomes:
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
affiliation: Imperial College London
name: Eric Alton
role: STUDY_DIRECTOR
affiliation: Imperial College London
name: Jane C Davies
role: PRINCIPAL_INVESTIGATOR
affiliation: Imperial College London
name: Uta Griesenbach
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Oxford
name: Steve Hyde
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Oxford
name: Deborah Gill
role: PRINCIPAL_INVESTIGATOR
affiliation: Edinburgh University
name: David Porteous
role: PRINCIPAL_INVESTIGATOR
affiliation: Edinburgh University
name: Chris Boyd
role: PRINCIPAL_INVESTIGATOR
affiliation: Edinburgh University
name: Alastair Innes
role: PRINCIPAL_INVESTIGATOR
References:
citation: Alton EW, Stern M, Farley R, Jaffe A, Chadwick SL, Phillips J, Davies J, Smith SN, Browning J, Davies MG, Hodson ME, Durham SR, Li D, Jeffery PK, Scallan M, Balfour R, Eastman SJ, Cheng SH, Smith AE, Meeker D, Geddes DM. Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet. 1999 Mar 20;353(9157):947-54. doi: 10.1016/s0140-6736(98)06532-5.
citation: Alton EW, Boyd AC, Porteous DJ, Davies G, Davies JC, Griesenbach U, Higgins TE, Gill DR, Hyde SC, Innes JA; UK Cystic Fibrosis Gene Therapy Consortium *. A Phase I/IIa Safety and Efficacy Study of Nebulized Liposome-mediated Gene Therapy for Cystic Fibrosis Supports a Multidose Trial. Am J Respir Crit Care Med. 2015 Dec 1;192(11):1389-92. doi: 10.1164/rccm.201506-1193LE. No abstract available.