ILD Research in Manchester
The North West ILD Unit in Manchester is involved in recruiting patients with IPF and other ILDs into local, national and international clinical trails and research.
We provide our patients with the opportunity to be involved in the current cutting edge clinical research trials and have been involved in all the large international multi-centre clinical trials in IPF, including interferon- gamma, bosentan, septrin, nintedanib and more recently pirfenidone.
You will get the opportunity to talk about trial involvement during your clinic consultation. If you would like to be involved please speak to your ILD Doctor.
Or Contact our research centres:
The Charles Blackley Ward:
Wythenshawe Hospital
Southmoor Road
Wythenshawe
Manchester
M23 9LT
0161 998 7070
or
The Medicines Evaluation Unit
The Langley Building
Southmoor Road
Wythenshawe
Manchester
M23 9QZ
0161 946 4050
http://www.meu.org.uk
We provide our patients with the opportunity to be involved in the current cutting edge clinical research trials and have been involved in all the large international multi-centre clinical trials in IPF, including interferon- gamma, bosentan, septrin, nintedanib and more recently pirfenidone.
You will get the opportunity to talk about trial involvement during your clinic consultation. If you would like to be involved please speak to your ILD Doctor.
Or Contact our research centres:
The Charles Blackley Ward:
Wythenshawe Hospital
Southmoor Road
Wythenshawe
Manchester
M23 9LT
0161 998 7070
or
The Medicines Evaluation Unit
The Langley Building
Southmoor Road
Wythenshawe
Manchester
M23 9QZ
0161 946 4050
http://www.meu.org.uk
Current trials
ATLAS AVALYN Phase 1a
24 week RCT of nebulised pirfenidone and then 48 weeks continuation.
50mg od vs 100mg bd
No placebo
FVC 50-90% (amendment in place for 40-50% once recruited first 20 and no AEs)
DLCO 30-90%
Visits 4 weekly
IPF diagnosis <5 years (probable UIP/Definite) – no central review
24 week RCT of nebulised pirfenidone and then 48 weeks continuation.
50mg od vs 100mg bd
No placebo
FVC 50-90% (amendment in place for 40-50% once recruited first 20 and no AEs)
DLCO 30-90%
Visits 4 weekly
IPF diagnosis <5 years (probable UIP/Definite) – no central review
GALAPAGOS
Phase 3 RCT 52 week study
2 doses of GLPG1690 (small molecule inhibitor of ATX)
200mg or 600mg once a day
Can have dose modifications within trial if get AEs
Can be on stable dose pirfenidone and nintedanib
Inclusions:
Age>40
IPF diagnosed within 5 years
Fibrosis>emphysema
FVC>45%
FEV/FVC>70
DLCO>30
Stable treatment for 4 weeks
Must be able to walk >150m on 6MWT
Exclusions:
HIV/Hepatitis
Malignancy within 5 years except basal cell treated; ca in situ cervix; prostate ca under surveillance
Prolonged QTc >450
Resp tract infection within 4 weeks
Acute exacerbation within 6 months
Long list of prohibited drugs that are metabolised by CYP2C8
Phase 3 RCT 52 week study
2 doses of GLPG1690 (small molecule inhibitor of ATX)
200mg or 600mg once a day
Can have dose modifications within trial if get AEs
Can be on stable dose pirfenidone and nintedanib
Inclusions:
Age>40
IPF diagnosed within 5 years
Fibrosis>emphysema
FVC>45%
FEV/FVC>70
DLCO>30
Stable treatment for 4 weeks
Must be able to walk >150m on 6MWT
Exclusions:
HIV/Hepatitis
Malignancy within 5 years except basal cell treated; ca in situ cervix; prostate ca under surveillance
Prolonged QTc >450
Resp tract infection within 4 weeks
Acute exacerbation within 6 months
Long list of prohibited drugs that are metabolised by CYP2C8
GALACTIC1
Phase 2b
TD139
Inhaled Galectin 3 inhibitor – dry powder inhaler
52 weeks
Three treatment arms:
TD139 10mg once a day by inhalation
TD139 3mg once a day by inhalation
Placebo
>40 years old
FVC>45%
DLCO 30-79%
Stable dose of antifibrotics for 12 weeks
Inclusions:
IPF diagnosed within 3 years
HRCT within 12months
Can continue pirfenidone and nintedanib
Exclusion:
FEV/FVC<70
Malignancy within 2 years except basal cell, prostate ca with androgen treatment
Phase 2b
TD139
Inhaled Galectin 3 inhibitor – dry powder inhaler
52 weeks
Three treatment arms:
TD139 10mg once a day by inhalation
TD139 3mg once a day by inhalation
Placebo
>40 years old
FVC>45%
DLCO 30-79%
Stable dose of antifibrotics for 12 weeks
Inclusions:
IPF diagnosed within 3 years
HRCT within 12months
Can continue pirfenidone and nintedanib
Exclusion:
FEV/FVC<70
Malignancy within 2 years except basal cell, prostate ca with androgen treatment
INDALO – MEU
Patient needs to ring MEU on 0800 655 6553 to register their interest
Phase 1 double blinded
10 week trial – only short trial
Placebo controlled
IDL-2965 multiple dosing once a day dosing (integrin antagonist selectively targeting fibroblast and epithelial integrins that are involved in activation of TGFbeta )
Is a substrate of CYP450 so need to avoid grapefruit and drugs that potentiate or inhibit CYP450
Assess safety and pharmacokinetics
CANNOT BE ON NINTEDANIB OR PIRFENIDONE
Patients will have a screening bronchoscopy
5 visits between day 1 and 26
Randomised to IDL-2965 vs placebo in 3:1 ratio
Inclusions:
>40 years old
IPF UIP or probable UIP
Must have a HRCT within 12months
IPF stable for 3 months ie no acute exacerbation or >10% decline in FVC
FVC>50%
DLCO>35%
Exclusions:
Ratio FEV/FVC<70
Emphysema>fibrosis
On antifibrotics
Antibiotics within 60 days
Resp tract illness in 14 days (not req antibiotics)
Smokers ecigs within 3 months
Safety is monitored with a monitoring committee throughout the study
Have to stay out of direct sunlight during study
Patient needs to ring MEU on 0800 655 6553 to register their interest
Phase 1 double blinded
10 week trial – only short trial
Placebo controlled
IDL-2965 multiple dosing once a day dosing (integrin antagonist selectively targeting fibroblast and epithelial integrins that are involved in activation of TGFbeta )
Is a substrate of CYP450 so need to avoid grapefruit and drugs that potentiate or inhibit CYP450
Assess safety and pharmacokinetics
CANNOT BE ON NINTEDANIB OR PIRFENIDONE
Patients will have a screening bronchoscopy
5 visits between day 1 and 26
Randomised to IDL-2965 vs placebo in 3:1 ratio
Inclusions:
>40 years old
IPF UIP or probable UIP
Must have a HRCT within 12months
IPF stable for 3 months ie no acute exacerbation or >10% decline in FVC
FVC>50%
DLCO>35%
Exclusions:
Ratio FEV/FVC<70
Emphysema>fibrosis
On antifibrotics
Antibiotics within 60 days
Resp tract illness in 14 days (not req antibiotics)
Smokers ecigs within 3 months
Safety is monitored with a monitoring committee throughout the study
Have to stay out of direct sunlight during study
INJUSTIS
Prospective biomarker study 2year observational
A diagnosis of Fibrotic Lung disease classified in 4 categories, RA-UIP, Asbestosis, Chronic HP and Unclassifiable as agreed by an ILD MDT consensus panel.
Up to 50 frequency matched IPF patients will be recruited as positive control group
Patients will receive usual standard of care throughout the study, however they will be asked to provide a blood sample, take daily spirometry readings for first 3 months (optional) and a few will be asked to undergo bronchoscopy as part of research (optional).
Once consented, the following test results, previously carried out as part of the participant’s usual NHS care, will be used for the purposes of this study:
For patients who have had a bronchoscopy as part of their standard of care, consent will be taken so that sample can be used for cell culture and biomarker discovery as part of this research.
Baseline Investigations:
3 Months Post Enrolment:
12 Months Post Enrolment:
24 Months Post Enrolment:
Both cohorts – case patients and positive controls will undertake the same investigations post consent, in order to directly compare outcomes.
Prospective biomarker study 2year observational
A diagnosis of Fibrotic Lung disease classified in 4 categories, RA-UIP, Asbestosis, Chronic HP and Unclassifiable as agreed by an ILD MDT consensus panel.
Up to 50 frequency matched IPF patients will be recruited as positive control group
Patients will receive usual standard of care throughout the study, however they will be asked to provide a blood sample, take daily spirometry readings for first 3 months (optional) and a few will be asked to undergo bronchoscopy as part of research (optional).
Once consented, the following test results, previously carried out as part of the participant’s usual NHS care, will be used for the purposes of this study:
- HRCT Findings
- Blood Results
- Spirometry and Lung Function Tests
- Leicester Cough Questionnaire
For patients who have had a bronchoscopy as part of their standard of care, consent will be taken so that sample can be used for cell culture and biomarker discovery as part of this research.
Baseline Investigations:
- Patients will be asked to give a blood sample of approximately 40ml. As part of this 40ml sample we will be aliquoting approximately 2ml to perform a full blood count for epigenomic studies. If the patient does not indicate that they consent to this genetic test then this 2ml will not be removed.
- Full lung function testing including departmental spirometry
- A 6 minute walk test will be performed
- Quality of Life Questionnaires administered (MRC Dyspnoea, IPARC, KBILD and EQ-5D-5L, Leicester Cough Questionnaire)
- Bronchoscopy (up to 3 months from baseline) – optional, if the patient consents and has not had it as part of their clinical care.
3 Months Post Enrolment:
- 40ml blood sample
- Departmental spirometry
- Quality of Life Questionnaires
12 Months Post Enrolment:
- 40ml blood sample
- Full lung function including departmental spirometry
- 6 minute walk test
- Quality of Life Questionnaires
24 Months Post Enrolment:
- 40ml blood sample
- Full lung function including departmental spirometry and 6 minute walk test
- Quality of Life Questionnaires
Both cohorts – case patients and positive controls will undertake the same investigations post consent, in order to directly compare outcomes.
Respivant: Nebulised Sodium Chromoglycate for Cough in IPF
Mast cell degranulation may have a role in cough but also IPF pathogenesis.
Increased mast cells and histamine in lungs of IPF patients
Animal and human studies show sodium chromoglycate reduced mast cell degranulation and in animal models fibrosis
So not only looking at cough as primary endpoint but also looking at disease modifying effects with FVC and HRCT etc
4 arms
80mg tds
40mg tds
20mg tds
Placebo
three times per day nebuliser therapy
6 months treatment: 12 weeks blinded and 12 weeks open label
After 3 months ALL with be on treatment
Patients will have 75% chance of being on active treatment and after 3 months ALL will be on treatment for 3 months
Trial closes May 2020 so 6 months to recruit
Inclusions:
Age 40-89 years
FVC>45%
DLCO>30%
On pirfenidone and nintedanib for at least 3 months stable dose
Cough for >8 weeks
Cough VAS> 40mm
At least 10 coughs per hour on cough monitor
Exclusions:
MI within 6 months and angina unstable 1 month
Acute exacerbations within 6 months of screening
Expect to have a transplant within 12 months
Long term oxygen greater than 4 litres to maintain resting sats of 88% at rest
Use of following drugs within 4 weeks of screening FOR COUGH MANAGEMENT:
Opiates; baclofen; gabapentin; pregabalin; thalidomide; amitryptilline; inhaled steroids/bronchodilators; ACE inhibitors; prednisolone
BUT CAN CONTINUE IF ON THEM FOR OTHER REASONS eg pain management; depression; asthma; breathlessness etc…
So if on these for cough patient will need to stop for 4 weeks before screening.
In phase 2 a study no real adverse events vs placebo noticed
Some GI symptoms but not sure if due to fact was also on antifibrotics
Maybe headache or diarrhoea
Patients will have to be shown how to use the nebuliser and will also have to wear a cough monitor.
Target is 5 patients.
Patients must be on stable dose – 3months of
Antifibrotics
Low dose pred <10 mg
Patients should be on stable dose 4weeks
PPI, H2 antihistamin
Muculytic
Vaccinations
Can start these treatments within the trial (but not antifibrotics)
Need to keep antifibrotic dose stable within trial if possible
If you have a respiratory tract infection need to wait 4 weeks before screening
Mast cell degranulation may have a role in cough but also IPF pathogenesis.
Increased mast cells and histamine in lungs of IPF patients
Animal and human studies show sodium chromoglycate reduced mast cell degranulation and in animal models fibrosis
So not only looking at cough as primary endpoint but also looking at disease modifying effects with FVC and HRCT etc
4 arms
80mg tds
40mg tds
20mg tds
Placebo
three times per day nebuliser therapy
6 months treatment: 12 weeks blinded and 12 weeks open label
After 3 months ALL with be on treatment
Patients will have 75% chance of being on active treatment and after 3 months ALL will be on treatment for 3 months
Trial closes May 2020 so 6 months to recruit
Inclusions:
Age 40-89 years
FVC>45%
DLCO>30%
On pirfenidone and nintedanib for at least 3 months stable dose
Cough for >8 weeks
Cough VAS> 40mm
At least 10 coughs per hour on cough monitor
Exclusions:
MI within 6 months and angina unstable 1 month
Acute exacerbations within 6 months of screening
Expect to have a transplant within 12 months
Long term oxygen greater than 4 litres to maintain resting sats of 88% at rest
Use of following drugs within 4 weeks of screening FOR COUGH MANAGEMENT:
Opiates; baclofen; gabapentin; pregabalin; thalidomide; amitryptilline; inhaled steroids/bronchodilators; ACE inhibitors; prednisolone
BUT CAN CONTINUE IF ON THEM FOR OTHER REASONS eg pain management; depression; asthma; breathlessness etc…
So if on these for cough patient will need to stop for 4 weeks before screening.
In phase 2 a study no real adverse events vs placebo noticed
Some GI symptoms but not sure if due to fact was also on antifibrotics
Maybe headache or diarrhoea
Patients will have to be shown how to use the nebuliser and will also have to wear a cough monitor.
Target is 5 patients.
Patients must be on stable dose – 3months of
Antifibrotics
Low dose pred <10 mg
Patients should be on stable dose 4weeks
PPI, H2 antihistamin
Muculytic
Vaccinations
Can start these treatments within the trial (but not antifibrotics)
Need to keep antifibrotic dose stable within trial if possible
If you have a respiratory tract infection need to wait 4 weeks before screening
TRAIL RAILD
RCT of Pirfenidone in Rheumatoid arthritis related ILD
12 month study
Placebo controlled
(Patient may be in study for 3 years ie last patient completing study)
Inclusions:
Age 18 through 85 years,
Probable or definite diagnosis of RA according to revised 2010 ACR/EULAR criteria, without evidence or suspicion of an alternative diagnosis that may contribute to their interstitial lung disease.
Diagnosis of ILD any UIP NSIP
- percent predicted FVC ≥ 40% at Screening
- percent predicted DLCO ≥30% and ≤80% at Screening
Stable dose (at least three months at the time of Screening) of corticosteroids or any cytotoxic, immunosuppressive or cytokinemodulating, or receptor- antagonist agent prescribed for rheumatoid arthritis, including but not limited to azathioprine, cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, tacrolimus, montelukast, tetrathiomolybdate, TNF-α inhibitors, rituximab, abatacept, tofacitintib, tociluzimab.
Exclusions:
Cigarette smoking within 3 months of Screening or unwilling to avoid tobacco products throughout the study
Concurrent presence of other interstitial lung disease, including but not limited to radiation, drug toxicity, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, human immunodeficiency virus (HIV), viral hepatitis, and cancer
Concurrent presence of other pleuropulmonary manifestations of RA, including but not limited to rheumatoid nodular disease of the lung, pleuritis/pleural thickening, and obliterative bronchiolitis
Post-bronchodilator FEV1/FVC < 0.7 at Screening
Presence of pleural effusion occupying more than 20% of the hemithorax on Screening HRCT
RCT of Pirfenidone in Rheumatoid arthritis related ILD
12 month study
Placebo controlled
(Patient may be in study for 3 years ie last patient completing study)
Inclusions:
Age 18 through 85 years,
Probable or definite diagnosis of RA according to revised 2010 ACR/EULAR criteria, without evidence or suspicion of an alternative diagnosis that may contribute to their interstitial lung disease.
Diagnosis of ILD any UIP NSIP
- percent predicted FVC ≥ 40% at Screening
- percent predicted DLCO ≥30% and ≤80% at Screening
Stable dose (at least three months at the time of Screening) of corticosteroids or any cytotoxic, immunosuppressive or cytokinemodulating, or receptor- antagonist agent prescribed for rheumatoid arthritis, including but not limited to azathioprine, cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, tacrolimus, montelukast, tetrathiomolybdate, TNF-α inhibitors, rituximab, abatacept, tofacitintib, tociluzimab.
Exclusions:
Cigarette smoking within 3 months of Screening or unwilling to avoid tobacco products throughout the study
Concurrent presence of other interstitial lung disease, including but not limited to radiation, drug toxicity, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, human immunodeficiency virus (HIV), viral hepatitis, and cancer
Concurrent presence of other pleuropulmonary manifestations of RA, including but not limited to rheumatoid nodular disease of the lung, pleuritis/pleural thickening, and obliterative bronchiolitis
Post-bronchodilator FEV1/FVC < 0.7 at Screening
Presence of pleural effusion occupying more than 20% of the hemithorax on Screening HRCT
TREVI CANAL – COUGH AND IPF
RCT Nalbuphine ER TABLETS for cough in IPF
Member of opioid antagonist agonist group
Phase 2 cross over – 2 x 3 week treatment and placebo (followed by 2 week washout)
NAL ER dose will be titrated from 27mg once a day to 54mg bd over 5 days and then maintain for 4 days and then increase to 108mg bd for one week and then 162mg bd over 6 days
Inclusions:
Definite or probable IPF
FVC>40%
DLCO>25%
Cough > 8 weeks
Cough VAS>4
Exclusions:
On LTOT
eGFR<44
resp tract infection within 4 weeks
OSA cPAP
Intolerance to opiates
Cannot drink alcohol during study
Cannot be on opiates or benzodiazepines within 2 weeks of study
Cardiac exclusions: MI within 3 months; angina >grade 2; prev VT
RCT Nalbuphine ER TABLETS for cough in IPF
Member of opioid antagonist agonist group
Phase 2 cross over – 2 x 3 week treatment and placebo (followed by 2 week washout)
NAL ER dose will be titrated from 27mg once a day to 54mg bd over 5 days and then maintain for 4 days and then increase to 108mg bd for one week and then 162mg bd over 6 days
Inclusions:
Definite or probable IPF
FVC>40%
DLCO>25%
Cough > 8 weeks
Cough VAS>4
Exclusions:
On LTOT
eGFR<44
resp tract infection within 4 weeks
OSA cPAP
Intolerance to opiates
Cannot drink alcohol during study
Cannot be on opiates or benzodiazepines within 2 weeks of study
Cardiac exclusions: MI within 3 months; angina >grade 2; prev VT
TRISTAN
Hypotheses: Quantitative CT and MRI measurements correlate with existing physiological measurements in ILD and provide diagnostic and prognostic information over and above existing measurements used in ILD.
The overarching aims of the current study are to evaluate and identify imaging measurements (IMs) which show promise for the detection and monitoring of patients with DI-ILD but also have potential for utilisation in the management of other types of ILD.
Primary aims of this study to compare imaging measurements with standard physiological measurements used in ILD and evaluate if early signs of resolution or progression can be detected using IMs.
The following groups will be studied:
Inflammatory ILD phenotypes:
*Incident defined as a new diagnosis of ILD as decided by MDT. Decline defined as significant deterioration in symptoms/physiology within the last 12 months and progressive changes on CT within 6 months.
We will aim to recruit a total of 85 patients, with a minimum of 15 participants per group.
lnclusions:
Overview of study design
Patients with any ILD process, except DIILD, will be stratified at baseline as having predominantly “Inflammatory” or predominantly “Fibrotic” disease.
Patients in the Inflammatory group will be reviewed and DIILD patients will be reviewed and imaged at baseline, 2 weeks, 6 weeks and 6 months irrespective of their phenotype (due to anticipated smaller patient numbers). A planned post hoc subset analysis will be conducted on these 2 patient groups. Figure 1 demonstrates an overview of study design.
Hypotheses: Quantitative CT and MRI measurements correlate with existing physiological measurements in ILD and provide diagnostic and prognostic information over and above existing measurements used in ILD.
The overarching aims of the current study are to evaluate and identify imaging measurements (IMs) which show promise for the detection and monitoring of patients with DI-ILD but also have potential for utilisation in the management of other types of ILD.
Primary aims of this study to compare imaging measurements with standard physiological measurements used in ILD and evaluate if early signs of resolution or progression can be detected using IMs.
The following groups will be studied:
- Suspected DI-ILD
Inflammatory ILD phenotypes:
- CTD-related ILD
- NSIP pattern ILD
- Acute or subacute hypersensitivity pneumonitis (HSP)Idiopathic Pulmonary Fibrosis
- predominantly fibrotic UIP pattern CTD-ILD e.g. rheumatoid arthritis associated ILD
- chronic hypersensitivity pneumonitis
*Incident defined as a new diagnosis of ILD as decided by MDT. Decline defined as significant deterioration in symptoms/physiology within the last 12 months and progressive changes on CT within 6 months.
We will aim to recruit a total of 85 patients, with a minimum of 15 participants per group.
lnclusions:
- Development of symptoms (e.g. cough, fever, dyspnoea, and hypoxia) and radiological abnormalities within the lungs on CT (e.g. diffuse lung changes, infiltrative opacification in the periphery of the lung or ground glass changes) suggestive of interstitial lung disease.
- Worsening of respiratory symptoms, decline in spirometry and progressive radiological changes noted on CT within 6 months of inclusion, in a patient know to have non drug induced ILD.
- Age 18 years or older
Overview of study design
Patients with any ILD process, except DIILD, will be stratified at baseline as having predominantly “Inflammatory” or predominantly “Fibrotic” disease.
Patients in the Inflammatory group will be reviewed and DIILD patients will be reviewed and imaged at baseline, 2 weeks, 6 weeks and 6 months irrespective of their phenotype (due to anticipated smaller patient numbers). A planned post hoc subset analysis will be conducted on these 2 patient groups. Figure 1 demonstrates an overview of study design.
Previous trials
RECITAL: RCT of cyclophosphomide vs Rituximab in CTD-ILDCI: Dr Toby Maher. Royal Brompton Hospital.
Now recruiting in:
Dr T. Maher. Royal Brompton Hospital, london.
Dr S. Fletcher. Southampton.
Dr N. Chaudhuri. Manchester.
Inclusion Criteria
· A diagnosis of Connective Tissue Disease (CTD), based on internationally accepted criteria, in one of the following categories22-25:
o Systemic sclerosis
o Idiopathic interstitial myopathy (including polymyositis/dermatomyositis)
o Mixed Connective Tissue Disease (MCTD)
· Severe and/or progressive Interstitial Lung Disease (ILD) associated with the underlying Connective Tissue Disease (CTD).
· Chest HRCT performed within 12 months of randomisation
· Intention of the caring physician to treat the ILD with intravenous Cyclophosphamide (with treatment indications including; deteriorating symptoms attributable to ILD, deteriorating lung function tests, worsening gas exchange or extent of ILD at first presentation) and where there is a reasonable expectation that immunosuppressive treatment will stabilize or improve CTD-ILD. In individuals with scleroderma it is anticipated that patients will fulfil the criteria for extensive disease defined by Goh et al19
· Written informed consent
Exclusion Criteria
· Age <18 or >80 years.
· Previous treatment with Rituximab and/or intravenous Cyclophosphamide
· Known hypersensitivity to Rituximab or Cyclophosphamide or their components
· Significant (in the opinion of the investigator) other organ co-morbidity including cardiac, hepatic or renal impairment
· Co-existent obstructive pulmonary disease (e.g. asthma, COPD, emphysema) with pre bronchodilator FEV1/FVC < 70%
· Patients at significant risk for infectious complications following immunosuppression
o Including HIV positive or other immunodeficiency syndromes (including hypogammaglobulineamia)
· Suspected or proven untreated tuberculosis
· Viral hepatitis
· Infection requiring antibiotic treatment in the preceding four weeks
RECITAL Study Version 6.1, 15th December 2014 Page 16 of 54
· Unexplained neurological symptoms (which may be suggestive of progressive mutifocal leukoencephalopathy; PML). Neurological symptoms arising as a consequence of the underlying CTD do not necessitate exclusion.
· Other investigational therapy (participation in research trial) received within 8 weeks of randomisation
· Immunosuppressive or CTD disease modifying therapy (other than corticosteroids) received within 2 weeks of randomisation
· Pregnant or breast feeding women, or women of child-bearing potential, not using a reliable contraceptive method for up to 12 months following IMP
· Unexplained haematuria, or previous bladder carcinoma
· CT scan > 12 months from randomisation
· Unable to provide informed written consent
Now recruiting in:
Dr T. Maher. Royal Brompton Hospital, london.
Dr S. Fletcher. Southampton.
Dr N. Chaudhuri. Manchester.
Inclusion Criteria
· A diagnosis of Connective Tissue Disease (CTD), based on internationally accepted criteria, in one of the following categories22-25:
o Systemic sclerosis
o Idiopathic interstitial myopathy (including polymyositis/dermatomyositis)
o Mixed Connective Tissue Disease (MCTD)
· Severe and/or progressive Interstitial Lung Disease (ILD) associated with the underlying Connective Tissue Disease (CTD).
· Chest HRCT performed within 12 months of randomisation
· Intention of the caring physician to treat the ILD with intravenous Cyclophosphamide (with treatment indications including; deteriorating symptoms attributable to ILD, deteriorating lung function tests, worsening gas exchange or extent of ILD at first presentation) and where there is a reasonable expectation that immunosuppressive treatment will stabilize or improve CTD-ILD. In individuals with scleroderma it is anticipated that patients will fulfil the criteria for extensive disease defined by Goh et al19
· Written informed consent
Exclusion Criteria
· Age <18 or >80 years.
· Previous treatment with Rituximab and/or intravenous Cyclophosphamide
· Known hypersensitivity to Rituximab or Cyclophosphamide or their components
· Significant (in the opinion of the investigator) other organ co-morbidity including cardiac, hepatic or renal impairment
· Co-existent obstructive pulmonary disease (e.g. asthma, COPD, emphysema) with pre bronchodilator FEV1/FVC < 70%
· Patients at significant risk for infectious complications following immunosuppression
o Including HIV positive or other immunodeficiency syndromes (including hypogammaglobulineamia)
· Suspected or proven untreated tuberculosis
· Viral hepatitis
· Infection requiring antibiotic treatment in the preceding four weeks
RECITAL Study Version 6.1, 15th December 2014 Page 16 of 54
· Unexplained neurological symptoms (which may be suggestive of progressive mutifocal leukoencephalopathy; PML). Neurological symptoms arising as a consequence of the underlying CTD do not necessitate exclusion.
· Other investigational therapy (participation in research trial) received within 8 weeks of randomisation
· Immunosuppressive or CTD disease modifying therapy (other than corticosteroids) received within 2 weeks of randomisation
· Pregnant or breast feeding women, or women of child-bearing potential, not using a reliable contraceptive method for up to 12 months following IMP
· Unexplained haematuria, or previous bladder carcinoma
· CT scan > 12 months from randomisation
· Unable to provide informed written consent
IPF-JES. Idiopathic Pulmonary Fibrosis Job Exposure Study.
A case-control study to investigate whether job exposures are an under-recognized cause of idiopathic pulmonary fibrosis (IPF) using an interview to collect information about previous jobs and a blood test to investigate genetic susceptibility. (clinicaltrials.gov NCT03211507)
website: ipfjes.org
Principle Investigator Organisation
Lisa Spencer Aintree University Hospitals NHS Foundation
Nazia Chaudhuri University Hospital of South Manchester
Gareth Walters Heart of England NHS Foundation Trust
Kim Harrison Morriston Hospita
Gauri Saini Nottingham University Hospitals NHS Trust
Michael Gibbons Royal Devon and Exeter NHS Foundation Trust
Huzaifa Adamali North Bristol NHS Trust
Carl Reynolds Imperial College Healthcare NHS Trust
Owen Dempsey Aberdeen Royal Infirmary
A case-control study to investigate whether job exposures are an under-recognized cause of idiopathic pulmonary fibrosis (IPF) using an interview to collect information about previous jobs and a blood test to investigate genetic susceptibility. (clinicaltrials.gov NCT03211507)
website: ipfjes.org
Principle Investigator Organisation
Lisa Spencer Aintree University Hospitals NHS Foundation
Nazia Chaudhuri University Hospital of South Manchester
Gareth Walters Heart of England NHS Foundation Trust
Kim Harrison Morriston Hospita
Gauri Saini Nottingham University Hospitals NHS Trust
Michael Gibbons Royal Devon and Exeter NHS Foundation Trust
Huzaifa Adamali North Bristol NHS Trust
Carl Reynolds Imperial College Healthcare NHS Trust
Owen Dempsey Aberdeen Royal Infirmary
Progressive ILD Clinical TrialRCT of Nintedanib vs Placebo for any progressive ILD (Not IPF) -
Currently recruiting in Manchester and other centres in the UK:
Manchester - Dr Rayid Abdulqawi/Nazia Chaudhuri
Stoke - Dr Helen Stone
Cardiff - Dr . Ben Hope Gill
Edinburgh - Dr Nik Hirani
Brompton - Dr Toby Maher
Leeds - Dr Paul Beirne
Inclusion criteria
1. Written Informed Consent consistent with ICH-GCP and local laws signed prior to entry into the study (and prior to any study procedure including shipment of HRCT to reviewer).
2. Male or female patients aged ≥ 18 years at Visit 1.
3. Patients with physician diagnosed ILD who fulfil at least one of the following criteria for PF-ILD within 24 months of screening visit (Visit 1) despite treatment with unapproved medications used in clinical practice to treat ILD, as assessed by the
investigator (refer to Exclusion Criteria):
a. Clinically significant decline in FVC % pred based on a relative decline of ≥10%
b. Marginal decline in FVC % pred based on a relative decline of ≥5-<10% combined with worsening of respiratory symptoms
c. Marginal decline in FVC % pred based on a relative decline of ≥5-<10% combined with increasing extent of fibrotic changes on chest imaging
d. Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging [Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus].
4. Fibrosing lung disease on HRCT, defined as reticular abnormality with traction bronchiectasis with or without honeycombing, with disease extent of >10%, performed within 12 months of Visit 1 as confirmed by central readers.
5. For patients with underlying CTD: stable CTD as defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.
6. DLCO corrected for Haemoglobin (Hb) [visit 1] ≥ 30% and <80% predicted of normal at Visit 2 (refer to Appendix 10.1).
7. FVC ≥ 45% predicted at Visit 2 (refer to Appendix 10.1)
Exclusion criteria
1. AST, ALT > 1.5 x ULN at Visit 1
2. Bilirubin > 1.5 x ULN at Visit 1
3. Creatinine clearance <30 mL/min calculated by Cockcroft–Gault formula at Visit 1 (refer to Appendix 10.2).
[Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown above. Visit 2 laboratory results will be available only after randomization. In case at Visit 2 the results do no longer satisfy the entry criteria, the Investigator has to decide whether it is justified that the patient remains on study drug. The justification for decision needs to be documented. Laboratory parameters that are found to be abnormal at Visit 1 are allowed to be re-tested (once) if it is thought to be a measurement error (i.e. there was no abnormal result of this test in the recent history of the patient and there is no related clinical sign) or the result of a temporary and reversible medical condition, once that condition is resolved].
4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
5. Previous treatment with nintedanib or pirfenidone.
6. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (Visit 1).
7. Use of any of the following medications for the treatment of ILD: azathioprine (AZA), cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and the combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide within 8 weeks of Visit 2, rituximab within 6 months of Visit 2. Note: Patients whose RA/CTD is managed by these medications should not be considered for participation in the current study unless change in RA/CTD medication is medically indicated (refer to Inclusion Criterion #5)
8. Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 Guidelines (P11-07084).
9. Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:
a. Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterization showing a cardiac index ≤ 2 l/min/m²
c. PAH requiring parenteral therapy with epoprostenol/treprostinil
10. Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at Visit 1).
11. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
12. Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)
13. Cardiovascular diseases, any of the following:
a. Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within
6 month of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
14. Bleeding risk, any of the following:
a. Known genetic predisposition to bleeding.
b. Patients who require
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy. [Note: Prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy) are not prohibited].
c. History of haemorrhagic central nervous system (CNS) event within 12 months of Visit 1.
d. Any of the following within 3 months of Visit 1:
i. Haemoptysis or haematuria
ii. Active gastro-intestinal (GI) bleeding or GI – ulcers
iii. Major injury or surgery (Investigators judgment).
e. Coagulation parameters: International normalized ratio (INR) >2, prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x ULN at Visit 1.
15. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1.
16. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
17. Patients with peanut allergy.
18. Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
19. Life expectancy for disease other than ILD < 2.5 years (Investigator assessment).
20. Planned major surgical procedures.
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
22. Women of childbearing potential* not willing or able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly as well as one barrier method for 28 days prior to and 3 months after nintedanib administration. A list of contraception methods meeting these criteria is provided in the patient information.
23. In the opinion of the Investigator, active alcohol or drug abuse.
24. Patients not able to understand or follow trial
Currently recruiting in Manchester and other centres in the UK:
Manchester - Dr Rayid Abdulqawi/Nazia Chaudhuri
Stoke - Dr Helen Stone
Cardiff - Dr . Ben Hope Gill
Edinburgh - Dr Nik Hirani
Brompton - Dr Toby Maher
Leeds - Dr Paul Beirne
Inclusion criteria
1. Written Informed Consent consistent with ICH-GCP and local laws signed prior to entry into the study (and prior to any study procedure including shipment of HRCT to reviewer).
2. Male or female patients aged ≥ 18 years at Visit 1.
3. Patients with physician diagnosed ILD who fulfil at least one of the following criteria for PF-ILD within 24 months of screening visit (Visit 1) despite treatment with unapproved medications used in clinical practice to treat ILD, as assessed by the
investigator (refer to Exclusion Criteria):
a. Clinically significant decline in FVC % pred based on a relative decline of ≥10%
b. Marginal decline in FVC % pred based on a relative decline of ≥5-<10% combined with worsening of respiratory symptoms
c. Marginal decline in FVC % pred based on a relative decline of ≥5-<10% combined with increasing extent of fibrotic changes on chest imaging
d. Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging [Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus].
4. Fibrosing lung disease on HRCT, defined as reticular abnormality with traction bronchiectasis with or without honeycombing, with disease extent of >10%, performed within 12 months of Visit 1 as confirmed by central readers.
5. For patients with underlying CTD: stable CTD as defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.
6. DLCO corrected for Haemoglobin (Hb) [visit 1] ≥ 30% and <80% predicted of normal at Visit 2 (refer to Appendix 10.1).
7. FVC ≥ 45% predicted at Visit 2 (refer to Appendix 10.1)
Exclusion criteria
1. AST, ALT > 1.5 x ULN at Visit 1
2. Bilirubin > 1.5 x ULN at Visit 1
3. Creatinine clearance <30 mL/min calculated by Cockcroft–Gault formula at Visit 1 (refer to Appendix 10.2).
[Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown above. Visit 2 laboratory results will be available only after randomization. In case at Visit 2 the results do no longer satisfy the entry criteria, the Investigator has to decide whether it is justified that the patient remains on study drug. The justification for decision needs to be documented. Laboratory parameters that are found to be abnormal at Visit 1 are allowed to be re-tested (once) if it is thought to be a measurement error (i.e. there was no abnormal result of this test in the recent history of the patient and there is no related clinical sign) or the result of a temporary and reversible medical condition, once that condition is resolved].
4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
5. Previous treatment with nintedanib or pirfenidone.
6. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (Visit 1).
7. Use of any of the following medications for the treatment of ILD: azathioprine (AZA), cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and the combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide within 8 weeks of Visit 2, rituximab within 6 months of Visit 2. Note: Patients whose RA/CTD is managed by these medications should not be considered for participation in the current study unless change in RA/CTD medication is medically indicated (refer to Inclusion Criterion #5)
8. Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 Guidelines (P11-07084).
9. Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:
a. Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterization showing a cardiac index ≤ 2 l/min/m²
c. PAH requiring parenteral therapy with epoprostenol/treprostinil
10. Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at Visit 1).
11. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
12. Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)
13. Cardiovascular diseases, any of the following:
a. Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within
6 month of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
14. Bleeding risk, any of the following:
a. Known genetic predisposition to bleeding.
b. Patients who require
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy. [Note: Prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy) are not prohibited].
c. History of haemorrhagic central nervous system (CNS) event within 12 months of Visit 1.
d. Any of the following within 3 months of Visit 1:
i. Haemoptysis or haematuria
ii. Active gastro-intestinal (GI) bleeding or GI – ulcers
iii. Major injury or surgery (Investigators judgment).
e. Coagulation parameters: International normalized ratio (INR) >2, prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x ULN at Visit 1.
15. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1.
16. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
17. Patients with peanut allergy.
18. Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
19. Life expectancy for disease other than ILD < 2.5 years (Investigator assessment).
20. Planned major surgical procedures.
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
22. Women of childbearing potential* not willing or able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly as well as one barrier method for 28 days prior to and 3 months after nintedanib administration. A list of contraception methods meeting these criteria is provided in the patient information.
23. In the opinion of the Investigator, active alcohol or drug abuse.
24. Patients not able to understand or follow trial
Unclassifiable ILD Clinical TrialRCT of Pirfenidone vs placebo for Unclassifiable ILD
now recruiting near you:
Dr Adamali - Southmead Hospital.
Dr S Bianchi - Northern General Hospital, Sheffield.
Dr N Chaudhuri - Wythenshawe Hospital, Manchester.
Dr S Fletcher - Southampton General Hospital.
Dr M. Gibbons - Royal Devon and Exeter Hospital.
Dr N Hirani - Royal Edinburgh Hospital.
Dr T. Maher - Royal Brompton, London.
Dr H. Pafrey - Papworth Hospital, Cambridge.
Dr Porter - UCLH.
Dr H. Stone - Royal Stoke University Hospital.
Dr D Thickett - Queen Elizabeth Hospital Birmingham.
Dr F. Woodhead - Glenfield Hospital, Leicester
Inclusion Criteria
Patients must meet the following criteria for trial entry:
1. Signed Informed Consent Form
2. Age 18–85 years
3. Able to comply with the trial protocol, according to the investigator’s judgment
4. Confirmed fibrosing ILD which, following MDT review, cannot be classified with either high or moderate confidence as a specific idiopathic interstitial pneumonia or other defined ILD (e.g. chronic hypersensitivity or connective tissue disease-ILD [CTD-ILD])
5. Progressive disease as considered by the investigator using the following definition:
a. Patient deterioration within the last 6 months, which is defined as:
i. A rate of decline in FVC >5% OR
ii. Significant symptomatic worsening not due to cardiac, pulmonary, vascular, or other causes.
6. Extent of fibrosis >10% on high-resolution computed tomography (HRCT; visual scoring) within the last 12 months
7. FVC 45% of predicted value
8. Diffusing capacity of the lung for carbon monoxide (DLco) 30% of predicted value
9. Forced expiratory volume in 1 second (FEV1)/FVC ratio 0.7
10. 6-minute walk distance (6MWD) 150 meters
11. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of <1% per year during the treatment period and for at least 58 days after the last dose of trial treatment:
a. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus)
b. Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives including those that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
c. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
a. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 118 days after the last dose of trial treatment. Men must refrain from donating sperm during this same period
b. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 118 d
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from trial entry:
1. Diagnosis with moderate or high confidence of nonspecific interstitial pneumonia (NSIP) and any ILD with an identifiable cause such as CTD-ILD, chronic hypersensitivity pneumonitis (cHP), or others
2. Diagnosis of idiopathic pulmonary fibrosis (IPF) independent of the confidence level
3. History of unstable angina or myocardial infarction during the previous 6 months
4. Pregnant or lactating, or intending to become pregnant during the trial
5. A positive urine pregnancy test, which was confirmed with a positive serum pregnancy test. Women with a confirmed pregnancy will be excluded from trial participation and must discontinue trial treatment
6. Treatment with high dose systemic corticosteroids (i.e., >15 mg/d of prednisolone or equivalent), or any immunosuppressant other than MMF, at any time at least 4 weeks prior to screening. Patients being treated with MMF should be on a stable dose that is expected to remain stable throughout the trial and was started at least 3 months prior to screening
7. Patients previously treated with pirfenidone or nintedanib
8. Patients treated with N-acetyl-cysteine (NAC) for fibrotic lung disease, at any time within the 4 weeks of the screening period
9. Drug treatment for any type of pulmonary hypertension (e.g. sildenafil, endothelin receptor antagonist [ERA], etc.)
10. Participation in a trial of an investigational medical product within the last 4 weeks
11. Significant co-existent emphysema (extent greater than extent of fibrosis on HRCT within the last 12 months)
12. Significant other organ co-morbidity including hepatic or renal impairment
13. Previous intolerance or allergy to the trial treatment
14. Pregnant patients, or women of child-bearing potential, not using a reliable contraceptive method
15. Unable to provide informed written consent
16. Predicted life expectancy <12 months or on an active transplant waiting list
17. Use of any tobacco product in the 12 weeks prior to the start of screening, or any unwillingness to abstain from their use through to the Follow-up Visit
18. Illicit drug or alcohol abuse within 12 months prior to screening, according to the investigator’s judgment
19. Planned major surgery during the trial
20. Hypersensitivity to the active substance or to any of the excipients of pirfenidone
21. History of angioedema
22. Concomitant use of fluvoxamine
23. Clinical evidence of any active infection which according to the investigator’s judgment may interfere with trial conduct, measurement of pulmonary function, or impact the course of the ILD
24. Any history of hepatic impairment, elevation of transaminase enzymes, or the confirmation of any of the following liver function test (LFT) criteria above the specified limits:
a. Total bilirubin above the upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 . ULN
c. Alkaline phosphatase >2.0 . ULN.
25. Creatinine clearance <30 mL/min, calculated using the Cockcroft-Gault formula
26. Any serious medical condition, clinically significant abnormality on an ECG at screening, or laboratory test results (hematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk to the patient following the administration of trial treatment
27. An ECG with a heart rate corrected QT interval (corrected using Fridericia’s formula [QTcF]) 500 ms at screening, or a family or personal history of long QT syndrome
now recruiting near you:
Dr Adamali - Southmead Hospital.
Dr S Bianchi - Northern General Hospital, Sheffield.
Dr N Chaudhuri - Wythenshawe Hospital, Manchester.
Dr S Fletcher - Southampton General Hospital.
Dr M. Gibbons - Royal Devon and Exeter Hospital.
Dr N Hirani - Royal Edinburgh Hospital.
Dr T. Maher - Royal Brompton, London.
Dr H. Pafrey - Papworth Hospital, Cambridge.
Dr Porter - UCLH.
Dr H. Stone - Royal Stoke University Hospital.
Dr D Thickett - Queen Elizabeth Hospital Birmingham.
Dr F. Woodhead - Glenfield Hospital, Leicester
Inclusion Criteria
Patients must meet the following criteria for trial entry:
1. Signed Informed Consent Form
2. Age 18–85 years
3. Able to comply with the trial protocol, according to the investigator’s judgment
4. Confirmed fibrosing ILD which, following MDT review, cannot be classified with either high or moderate confidence as a specific idiopathic interstitial pneumonia or other defined ILD (e.g. chronic hypersensitivity or connective tissue disease-ILD [CTD-ILD])
5. Progressive disease as considered by the investigator using the following definition:
a. Patient deterioration within the last 6 months, which is defined as:
i. A rate of decline in FVC >5% OR
ii. Significant symptomatic worsening not due to cardiac, pulmonary, vascular, or other causes.
6. Extent of fibrosis >10% on high-resolution computed tomography (HRCT; visual scoring) within the last 12 months
7. FVC 45% of predicted value
8. Diffusing capacity of the lung for carbon monoxide (DLco) 30% of predicted value
9. Forced expiratory volume in 1 second (FEV1)/FVC ratio 0.7
10. 6-minute walk distance (6MWD) 150 meters
11. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of <1% per year during the treatment period and for at least 58 days after the last dose of trial treatment:
a. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus)
b. Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives including those that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
c. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
a. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 118 days after the last dose of trial treatment. Men must refrain from donating sperm during this same period
b. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 118 d
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from trial entry:
1. Diagnosis with moderate or high confidence of nonspecific interstitial pneumonia (NSIP) and any ILD with an identifiable cause such as CTD-ILD, chronic hypersensitivity pneumonitis (cHP), or others
2. Diagnosis of idiopathic pulmonary fibrosis (IPF) independent of the confidence level
3. History of unstable angina or myocardial infarction during the previous 6 months
4. Pregnant or lactating, or intending to become pregnant during the trial
5. A positive urine pregnancy test, which was confirmed with a positive serum pregnancy test. Women with a confirmed pregnancy will be excluded from trial participation and must discontinue trial treatment
6. Treatment with high dose systemic corticosteroids (i.e., >15 mg/d of prednisolone or equivalent), or any immunosuppressant other than MMF, at any time at least 4 weeks prior to screening. Patients being treated with MMF should be on a stable dose that is expected to remain stable throughout the trial and was started at least 3 months prior to screening
7. Patients previously treated with pirfenidone or nintedanib
8. Patients treated with N-acetyl-cysteine (NAC) for fibrotic lung disease, at any time within the 4 weeks of the screening period
9. Drug treatment for any type of pulmonary hypertension (e.g. sildenafil, endothelin receptor antagonist [ERA], etc.)
10. Participation in a trial of an investigational medical product within the last 4 weeks
11. Significant co-existent emphysema (extent greater than extent of fibrosis on HRCT within the last 12 months)
12. Significant other organ co-morbidity including hepatic or renal impairment
13. Previous intolerance or allergy to the trial treatment
14. Pregnant patients, or women of child-bearing potential, not using a reliable contraceptive method
15. Unable to provide informed written consent
16. Predicted life expectancy <12 months or on an active transplant waiting list
17. Use of any tobacco product in the 12 weeks prior to the start of screening, or any unwillingness to abstain from their use through to the Follow-up Visit
18. Illicit drug or alcohol abuse within 12 months prior to screening, according to the investigator’s judgment
19. Planned major surgery during the trial
20. Hypersensitivity to the active substance or to any of the excipients of pirfenidone
21. History of angioedema
22. Concomitant use of fluvoxamine
23. Clinical evidence of any active infection which according to the investigator’s judgment may interfere with trial conduct, measurement of pulmonary function, or impact the course of the ILD
24. Any history of hepatic impairment, elevation of transaminase enzymes, or the confirmation of any of the following liver function test (LFT) criteria above the specified limits:
a. Total bilirubin above the upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 . ULN
c. Alkaline phosphatase >2.0 . ULN.
25. Creatinine clearance <30 mL/min, calculated using the Cockcroft-Gault formula
26. Any serious medical condition, clinically significant abnormality on an ECG at screening, or laboratory test results (hematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk to the patient following the administration of trial treatment
27. An ECG with a heart rate corrected QT interval (corrected using Fridericia’s formula [QTcF]) 500 ms at screening, or a family or personal history of long QT syndrome
BILD: Identifying disease susceptibility genes and auto-antibodies associated with the development and clinical characteristics of Interstitial Lung Disease (ILD) in patients with and without proven Connective Tissue Disease (CTDs).
