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Repeated Application of Gene Therapy in CF Patients

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ClinicalTrials.gov Identifier: NCT01621867
Recruitment Status : Completed
First Posted : June 18, 2012
Last Update Posted : October 22, 2015
University of Edinburgh
University of Oxford
Royal Brompton & Harefield NHS Foundation Trust
Information provided by (Responsible Party):
Imperial College London

Tracking Information
First Submitted Date  ICMJE June 14, 2012
First Posted Date  ICMJE June 18, 2012
Last Update Posted Date October 22, 2015
Study Start Date  ICMJE May 2012
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 14, 2012)
Relative change in percent predicted FEV1 after 12 doses of gene product [ Time Frame: 12-months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 14, 2012)
  • EFFICACY [ Time Frame: 12-months ]
    Relative change in other spirometric measures; lung clearance index; chest CT scan; Quality of Life Questionnaires; exercise capacity; activity monitoring; serum calprotectin; sputum culture; sputum weight, cell counts and inflammatory markers; frequency of antibiotics for increased chest symptoms
  • SAFETY [ Time Frame: 12-months ]
    The above efficacy measures; clinical examination; transcutaneous oxygen saturation; serum inflammatory markers (CRP, white blood cell count,cytokines); renal and hepatic function; gas transfer; immune response markers (anti-nuclear and double-stranded DNA antibodies, CFTR-specific T cell responses); endobronchial histology (subgroup only)
  • GENE EXPRESSION(subgroups only) [ Time Frame: 12-months ]
    Transgene mRNA expression in nasal and lower airway brushing samples; potential difference measurements in nose and bronchi.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Repeated Application of Gene Therapy in CF Patients
Official Title  ICMJE A Randomised, Double-blind, Placebo-controlled Phase 2B Clinical Trial of Repeated Application of Gene Therapy in Patients With Cystic Fibrosis
Brief Summary Cystic fibrosis is a genetic condition where epithelial cells, including from the respiratory tract, have an abnormal function of a surface protein, the cystic fibrosis transmembrane conductance regulator (CFTR) protein resulting from abnormal gene expression. The trial will assess the clinical efficacy, safety & tolerability and gene expression following repeated nebulised doses of a gene product coding for a normal CFTR protein, with the primary outcome of the trial assessing lung function.
Detailed Description

Cystic fibrosis (CF), a common, genetically inherited disease, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene encodes the CFTR protein, which is expressed on the apical surface of epithelial cells, and which has many functions, the most important of which is thought to be ion transport. Abnormal ion transport leads to thick secretions in the airways, infection, inflammation and eventually irreversible lung damage. There is currently no treatment that halts the natural progression of the disease; all available successful therapies merely slow the rate of decline in clinical condition.

To date, no viral gene transfer agents retain efficacy upon repeated administration. Our study will assess the safety and efficacy of a lipid-mediated vector harbouring a normal CFTR gene in repeated nebulised administrations. We have completed a single dose safety study which evaluated the safety and gene expression of a single dose of pGM169/GL67A administered to the nose and lung of individuals with cystic fibrosis.

This trial is will randomise 130-patients to receive either a gene product (pGM169/GL67A)encoding for CFTR or placebo in a double-blinded fashion. All subjects will receive 12 doses of nebulised gene therapy at intervals of 4 weeks over a 48 week period. After dose 12 there will be 2 formal follow up visits, at 14 and 28 days post-dose. In addition, patients will be followed up long-term.

Subgroups of patients will be enrolled for gene expression measurement in both nose (at least n=20) and lower airway via bronchoscopy (at least n=20).

The primary outcome of the trial is to evaluate the relative change in predicted Forced Expiratory Volume in 1-second (FEV1) after 12-doses. Secondary outcome measures will assess the efficacy of the gene product (by assessment of patients' physiological function, serological indices, radiological appearances of the lungs and self-reported assessment of quality of life), on the degree of gene expression and on the product safely.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE
  • Drug: pGM169/GL67A
    5ml Gene Product/Lipid Vector pGM169/GL67A nebulised; 2ml nasal application of pGM169/GL67A in addition to 5ml nebulised gene product (Nasal Subgroup)
  • Drug: Placebo
    5ml Nebulised non-active placebo; 2ml nasal administration of non-active placebo (nasal subgroup)
Study Arms  ICMJE
  • Active Comparator: pGM169/GL67A (CFTR Gene/Lipid Vector)
    Intervention: Drug: pGM169/GL67A
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 14, 2012)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2014
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Cystic fibrosis confirmed by sweat testing or genetic analysis
  2. Males and females aged 12 years and above
  3. Forced expiratory volume in the 1st second (FEV1) between 50 & 90% predicted inclusive (Stanojevic reference equations).
  4. Clinical stability at screening defined by:

    1. Not on any additional antibiotics (excluding routine, long-term treatments) for the previous 2 weeks
    2. No increase in symptoms such as change in sputum production/colour, increased wheeze or breathlessness over the previous 2 weeks
    3. No change in regular respiratory treatments over the previous 4 weeks
    4. If any of these apply, entry into the study can be deferred
  5. Prepared to take effective contraceptive precautions for the duration of their participation in the study and for 3 months thereafter (as stated in GTAC guidelines)
  6. 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 (nebulised doses only)
  7. Written informed consent obtained
  8. Permission to inform their general practitioner of participation in study

Exclusion Criteria:

  1. Infection with Burkholderia cepacia complex organisms, MRSA or M. abscessus
  2. Significant nasal pathology including polyps, clinically-significant rhinosinusitis, or recurrent severe epistaxis (nose bleeds) (nasal cohort only)
  3. Chloride secretory response on nasal PD of > 5 mV (nasal cohort only; will only be known after first measurement)
  4. Acute upper respiratory tract infection within the last 2 weeks (entry can be deferred)
  5. Previous spontaneous pneumothorax without pleurodesis (bronchoscopic subgroup only)
  6. Recurrent severe haemoptysis (bronchoscopic subgroup only)
  7. Current smoker
  8. Significant comorbidity including:

    1. Moderate/severe CF liver disease (varices or significant, sustained elevation of transaminases: ALT/ AST>100 IU/l)
    2. Significant renal impairment (serum creatinine > 150 mmol/l)
    3. Significant coagulopathy (bronchoscopic group only)
  9. Receiving 2nd line immunosuppressant drugs such as methotrexate, cyclosporine, intravenous immunoglobulin preparations
  10. Pregnant or breastfeeding
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01621867
Other Study ID Numbers  ICMJE ICL/CRO-1881
2011-004761-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Imperial College London
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Imperial College London
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • University of Edinburgh
  • University of Oxford
  • Royal Brompton & Harefield NHS Foundation Trust
Investigators  ICMJE
Study Director: Eric Alton, MD, FMedSci Imperial College London
Principal Investigator: Jane Davies, MD Imperial College London
Principal Investigator: Uta Griesenbach, PhD Imperial College London
Principal Investigator: Steve Hyde, MA, DPhil University of Oxford
Principal Investigator: Deborah Gill, PhD University of Oxford
Principal Investigator: Chris Boyd, PhD Edinburgh University
Principal Investigator: David Porteous, FMedSci Edinburgh University
Principal Investigator: Alastair Innes, PhD Edinburgh University
Principal Investigator: Steve Cunningham, PhD Edinburgh University
PRS Account Imperial College London
Verification Date November 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP