Cystic FibrosisPhase 2NCT01621867
Repeated Application of Gene Therapy in CF Patients
A Phase 2 study testing pGM169/GL67A in people with Cystic Fibrosis, run by Imperial College London at 3 sites in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Cystic Fibrosis
- What is being tested?
- pGM169/GL67A
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 130 participants
- Where
- 3 sitesUnited Kingdom
- Study dates
- May 2012to May 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Cystic fibrosis confirmed by sweat testing or genetic analysis
- Males and females aged 12 years and above
- Forced expiratory volume in the 1st second (FEV1) between 50 \& 90% predicted inclusive (Stanojevic reference equations).
- Clinical stability at screening defined by:
- Not on any additional antibiotics (excluding routine, long-term treatments) for the previous 2 weeks
- No increase in symptoms such as change in sputum production/colour, increased wheeze or breathlessness over the previous 2 weeks
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- No change in regular respiratory treatments over the previous 4 weeks
- If any of these apply, entry into the study can be deferred
- 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)
- 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)
- Written informed consent obtained
- Permission to inform their general practitioner of participation in study
Who cannot join
- Infection with Burkholderia cepacia complex organisms, MRSA or M. abscessus
- Significant nasal pathology including polyps, clinically-significant rhinosinusitis, or recurrent severe epistaxis (nose bleeds) (nasal cohort only)
- Chloride secretory response on nasal PD of > 5 mV (nasal cohort only; will only be known after first measurement)
- Acute upper respiratory tract infection within the last 2 weeks (entry can be deferred)
- Previous spontaneous pneumothorax without pleurodesis (bronchoscopic subgroup only)
- Recurrent severe haemoptysis (bronchoscopic subgroup only)
Show all 13Show fewer
- Current smoker
- Significant comorbidity including:
- Moderate/severe CF liver disease (varices or significant, sustained elevation of transaminases: ALT/ AST>100 IU/l)
- Significant renal impairment (serum creatinine > 150 mmol/l)
- Significant coagulopathy (bronchoscopic group only)
- Receiving 2nd line immunosuppressant drugs such as methotrexate, cyclosporine, intravenous immunoglobulin preparations
- Pregnant or breastfeeding
Trial locations and contacts
3 sites in 1 country.
United Kingdom3 sites
Western General Hospital
Edinburgh, EH4 2XU
Royal Hospital for Sick Children
Edinburgh, EH9 1LF
Royal Brompton Hospital
London, SW3 6NP
About this study
Official title: A Randomised, Double-blind, Placebo-controlled Phase 2B Clinical Trial of Repeated Application of Gene Therapy in Patients With Cystic Fibrosis
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.
Read the 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.
- Conditions
- Cystic Fibrosis
- Being tested
- pGM169/GL67A, Placebo
- Keywords
- Cystic fibrosis, Gene therapy, CFTR gene, Gene expression, Non-viral, Multi dose
- Medical subject headings
- Cystic Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
pGM169/GL67ADrug
5ml Gene Product/Lipid Vector pGM169/GL67A nebulised; 2ml nasal application of pGM169/GL67A in addition to 5ml nebulised gene product (Nasal Subgroup)
PlaceboDrug
5ml Nebulised non-active placebo; 2ml nasal administration of non-active placebo (nasal subgroup)
| Study group | Role | What they receive |
|---|---|---|
| pGM169/GL67A (CFTR Gene/Lipid Vector) | Active comparator | Not described Receives: Drug: pGM169/GL67A |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Relative change in percent predicted FEV1 after 12 doses of gene product
Measured: 12-months
Secondary outcomes (3)
EFFICACY
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
Measured: 12-months
SAFETY
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)
Measured: 12-months
GENE EXPRESSION(subgroups only)
Transgene mRNA expression in nasal and lower airway brushing samples; potential difference measurements in nose and bronchi.
Measured: 12-months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2012 (estimated)
- Study startMay 2012
- Primary completionMay 2014
- Study completionMay 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 130 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- University of Edinburgh, University of Oxford, Royal Brompton & Harefield NHS Foundation Trust
- Responsible party
- Sponsor
- Investigators
- Eric Alton, MD, FMedSci, Study director, Imperial College LondonJane Davies, MD, Principal investigator, Imperial College LondonUta Griesenbach, PhD, Principal investigator, Imperial College LondonSteve Hyde, MA, DPhil, Principal investigator, University of OxfordDeborah Gill, PhD, Principal investigator, University of OxfordChris Boyd, PhD, Principal investigator, Edinburgh UniversityDavid Porteous, FMedSci, Principal investigator, Edinburgh UniversityAlastair Innes, PhD, Principal investigator, Edinburgh University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01621867
- Sponsor's protocol ID
- ICL/CRO-1881
- Other IDs
- 2011-004761-33
- Status last verified
- Nov 2012
- First submitted
- 14 Jun 2012
- Last updated
- 22 Oct 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 10459902Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27.
PubMed 31215818Alton EWFW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, Carvelli P, Chan M, Cheng SH, Collie DDS, Cunningham S, Davidson HE, Davies G, Davies JC, Davies LA, Dewar MH, Doherty A, Donovan J, Dwyer NS, Elgmati HI, Featherstone RF, Gavino J, Gea-Sorli S, Geddes DM, Gibson JSR, Gill DR, Greening AP, Griesenbach U, Hansell DM, Harman K, Higgins TE, Hodges SL, Hyde SC, Hyndman L, Innes JA, Jacob J, Jones N, Keogh BF, Limberis MP, Lloyd-Evans P, Maclean AW, Manvell MC, McCormick D, McGovern M, McLachlan G, Meng C, Montero MA, Milligan H, Moyce LJ, Murray GD, Nicholson AG, Osadolor T, Parra-Leiton J, Porteous DJ, Pringle IA, Punch EK, Pytel KM, Quittner AL, Rivellini G, Saunders CJ, Scheule RK, Sheard S, Simmonds NJ, Smith K, Smith SN, Soussi N, Soussi S, Spearing EJ, Stevenson BJ, Sumner-Jones SG, Turkkila M, Ureta RP, Waller MD, Wasowicz MY, Wilson JM, Wolstenholme-Hogg P; UK Cystic Fibrosis Gene Therapy Consortium. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015 Sep;3(9):684-691. doi: 10.1016/S2213-2600(15)00245-3. Epub 2015 Jul 3.
PubMed 26149841
Study at a glance
From the registry record, last updated by the sponsor on 22 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised, Double-blind, Placebo-controlled Phase 2B Clinical Trial of Repeated Application of Gene Therapy in Patients With Cystic Fibrosis
- ClinicalTrials.gov ID
- NCT01621867
- Acronym / sponsor ID
- ICL/CRO-1881
- Conditions
- Cystic Fibrosis
- Keywords
- Cystic fibrosis, Gene therapy, CFTR gene, Gene expression, Non-viral, Multi dose
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 130 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- University of Edinburgh, University of Oxford, Royal Brompton & Harefield NHS Foundation Trust
- Study start
- May 2012
- Primary completion
- May 2014 (actual)
- Study completion
- May 2014 (actual)
- First posted
- 18 Jun 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| pGM169/GL67A (CFTR Gene/Lipid Vector) | Active comparator | Drug: pGM169/GL67A |
| Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (12 listed)
- Cystic fibrosis confirmed by sweat testing or genetic analysis
- Males and females aged 12 years and above
- Forced expiratory volume in the 1st second (FEV1) between 50 \& 90% predicted inclusive (Stanojevic reference equations).
- Clinical stability at screening defined by:
- 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)
Key exclusion criteria (13 listed)
- Infection with Burkholderia cepacia complex organisms, MRSA or M. abscessus
- Significant nasal pathology including polyps, clinically-significant rhinosinusitis, or recurrent severe epistaxis (nose bleeds) (nasal cohort only)
- Chloride secretory response on nasal PD of > 5 mV (nasal cohort only; will only be known after first measurement)
- Acute upper respiratory tract infection within the last 2 weeks (entry can be deferred)
- Previous spontaneous pneumothorax without pleurodesis (bronchoscopic subgroup only)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| pGM169/GL67A5ml Gene Product/Lipid Vector pGM169/GL67A nebulised; 2ml nasal application of pGM169/GL67A in addition to 5ml nebulised gene product (Nasal Subgroup) | Drug | pGM169/GL67A (CFTR Gene/Lipid Vector) |
| Placebo5ml Nebulised non-active placebo; 2ml nasal administration of non-active placebo (nasal subgroup) | Drug | Placebo |
Primary outcome
Relative change in percent predicted FEV1 after 12 doses of gene product
Time frame: 12-months
3 secondary outcomes
EFFICACY
Time frame: 12-months
SAFETY
Time frame: 12-months
GENE EXPRESSION(subgroups only)
Time frame: 12-months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Oct 2015.
- Results publication: PubMed 10459902Alton 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.
- Derived from this study: PubMed 31215818Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27.
- Derived from this study: PubMed 26149841Alton EWFW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, Carvelli P, Chan M, Cheng SH, Collie DDS, Cunningham S, Davidson HE, Davies G, Davies JC, Davies LA, Dewar MH, Doherty A, Donovan J, Dwyer NS, Elgmati HI, Featherstone RF, Gavino J, Gea-Sorli S, Geddes DM, Gibson JSR, Gill DR, Greening AP, Griesenbach U, Hansell DM, Harman K, Higgins TE, Hodges SL, Hyde SC, Hyndman L, Innes JA, Jacob J, Jones N, Keogh BF, Limberis MP, Lloyd-Evans P, Maclean AW, Manvell MC, McCormick D, McGovern M, McLachlan G, Meng C, Montero MA, Milligan H, Moyce LJ, Murray GD, Nicholson AG, Osadolor T, Parra-Leiton J, Porteous DJ, Pringle IA, Punch EK, Pytel KM, Quittner AL, Rivellini G, Saunders CJ, Scheule RK, Sheard S, Simmonds NJ, Smith K, Smith SN, Soussi N, Soussi S, Spearing EJ, Stevenson BJ, Sumner-Jones SG, Turkkila M, Ureta RP, Waller MD, Wasowicz MY, Wilson JM, Wolstenholme-Hogg P; UK Cystic Fibrosis Gene Therapy Consortium. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015 Sep;3(9):684-691. doi: 10.1016/S2213-2600(15)00245-3. Epub 2015 Jul 3.
- The UK Cystic Fibrosis Gene Therapy ConsortiumLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Eric Alton, MD, FMedSci study director
Imperial College London
Jane Davies, MD principal investigator
Imperial College London
Uta Griesenbach, PhD principal investigator
Imperial College London
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing pGM169/GL67A in people with Cystic Fibrosis, run by Imperial College London at 3 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Relative change in percent predicted FEV1 after 12 doses of gene product (time frame: 12-months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01621867, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2015.