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Drug & research development » Clinical trials » NCT01621867

Repeated Application of Gene Therapy in CF Patients

Official title: A Randomised, Double-blind, Placebo-controlled Phase 2B Clinical Trial of Repeated Application of Gene Therapy in Patients With Cystic Fibrosis

Clinical Trials gov number: NCT01621867

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Purpose: To assess the clinical efficacy, safety and 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.

Phase: 2B

Type: Interventional

Study sponsor: Imperial College London

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

Intervention
Genetic, pGM169/GL67A

Geographical Location
United Kingdom

Number of Participants
101-1000 (≥12 years)

Primary Endpoint

Relative change in percent predicted FEV1 after 12 doses of gene product [Time frame: 12 months]

Secondary Endpoint

•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

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  • Allocation: Randomized
  • Endpoint Classification: Safety/Efficacy Study
  • Intervention Model: Single Group Assignment
  • Masking: Double Blind (Subject, Investigator)
  • Primary Purpose: Treatment

Links:

https://www.ncbi.nlm.nih.gov/pubmed/10459902?dopt=Abstract

Reference:

Alton EW1, 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.

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