Repeated Application of Gene Therapy in CF Patients

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
University of Edinburgh
University of Oxford
Royal Brompton & Harefield NHS Foundation Trust
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01621867
First received: June 14, 2012
Last updated: September 20, 2013
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Cystic Fibrosis
Drug: pGM169/GL67A
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomised, Double-blind, Placebo-controlled Phase 2B Clinical Trial of Repeated Application of Gene Therapy in Patients With Cystic Fibrosis

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • Relative change in percent predicted FEV1 after 12 doses of gene product [ Time Frame: 12-months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • EFFICACY [ Time Frame: 12-months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    Transgene mRNA expression in nasal and lower airway brushing samples; potential difference measurements in nose and bronchi.


Estimated Enrollment: 130
Study Start Date: May 2012
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: pGM169/GL67A (CFTR Gene/Lipid Vector) 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)
Placebo Comparator: Placebo Drug: Placebo
5ml Nebulised non-active placebo; 2ml nasal administration of non-active placebo (nasal subgroup)

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.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01621867

Locations
United Kingdom
Royal Hospital for Sick Children
Edinburgh, United Kingdom, EH9 1LF
Western General Hospital
Edinburgh, United Kingdom, EH4 2XU
Royal Brompton Hospital
London, United Kingdom, SW3 6NP
Sponsors and Collaborators
Imperial College London
University of Edinburgh
University of Oxford
Royal Brompton & Harefield NHS Foundation Trust
Investigators
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 Oxford University
Principal Investigator: Deborah Gill, PhD Oxford University
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
  More Information

Additional Information:
Publications:
Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT01621867     History of Changes
Other Study ID Numbers: ICL/CRO-1881, 2011-004761-33
Study First Received: June 14, 2012
Last Updated: September 20, 2013
Health Authority: UNITED KINGDOM: DATA MONITORING AND ETHICS COMMITTEE (DMEC)

Keywords provided by Imperial College London:
Cystic fibrosis
Gene therapy
CFTR gene
Gene expression
Non-viral
Multi dose

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on September 16, 2014