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  string(699) "Idiopathic pulmonary fibrosis (IPF) is a devastating condition which causes scarring of the lungs and affects around 3 million people worldwide. Disease trajectory is variable, with some patients progressing much quicker than others. Identifying early predictors of progression may enable relevant therapies to be offered at an early stage. Physiological biomarkers such as lung function (FVC, DLCO) and total distance walked in 6 minutes (6MWD) are non-invasive measurements. We therefore hope to collate data from clinical trial placebo arms to explore whether short term change in these measurements may be able to predict clinical outcomes. This will help better inform healthcare professionals."
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  string(26) "PI is funded by NIHR grant"
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      string(234) "NCT00391443 - Effects of Bosentan on Morbidity and Mortality in Patients With Idiopathic Pulmonary Fibrosis - a Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Group Sequential, Phase III Study"
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      string(209) "NCT00071461 - A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Bosentan in Patients With Idiopathic Pulmonary Fibrosis, Open Label Extension"
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  string(1616) "Prospero protocol: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=164935
Background: Idiopathic Pulmonary Fibrosis (IPF) is a devastating lung condition of unknown origin, characterised by variable and unpredictable disease behaviour. A number of studies evaluating the role of physiological biomarkers in predicting progression have been published.
Objectives: We aim to conduct a systematic review and meta-analysis of individual patient data of treatment naive IPF patients (placebo arm) to assess whether baseline and/or short term change in physiological biomarkers can accurately predict important clinical outcomes such as disease progression and mortality.
Study Design: Individual patient data from randomised interventional clinical trial placebo arms will be analysed, and a two-step meta-analysis performed.
Participants: Adult patients with untreated IPF evaluated in interventional clinical trials (placebo arms only).
Main outcome measures: Mortality and disease progression (defined as relative decline in forced vital capacity of at least 10%, or death, at 12 months)
Statistical analysis: Individual patient data will be sought and a two-step meta-analysis performed adjusted for a priori confounders including age, sex and smoking status. Hazard ratios for baseline and three month change of physiological parameters in predicting mortality will be calculated. Disease progression will be standardised as 10% relative decline in FVC or death within 12 months of baseline, and odds ratios for predicting disease progression calculated." ["project_brief_bg"]=> string(1043) "Idiopathic pulmonary fibrosis (IPF) is a devastating lung condition of unknown origin characterised by progressive and irreversible interstitial fibrosis. Although median survival is 3 years, IPF is manifest by variable and unpredictable disease trajectory amongst individual patients. Advances in the management of IPF are hampered by the absence of validated prognostic measures, especially biomarkers that change over short time periods. Physiological biomarkers (such as but not limited to forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO) and six minute walk distance (6MWD)) may be suitable as early predictive markers of disease behaviour enabling stratification of therapy and personalised medicine.
We aim to conduct a systematic review and meta-analysis of individual patient data of treatment naive IPF patients (placebo arm) to assess whether baseline and/or short term change in physiological biomarkers can accurately predict important clinical outcomes such as disease progression and mortality." ["project_specific_aims"]=> string(202) "Research question - Do baseline values or 3-month change in physiological (FVC, DLCO, 6MWD) biomarkers predict disease progression and mortality in untreated patients with idiopathic pulmonary fibrosis?" ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(0) { } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(459) "Types of study to be included
Inclusion: Placebo arms of randomised interventional clinical trials in adult (aged>18) patients with IPF.
Exclusion: Non-interventional studies, conference abstracts, letters, commentaries, correspondence, case reports, expert opinions, editorials, other non-original systematic reviews, retrospective studies and animal studies. Studies investigating non-IPF Interstitial Lung Diseases. Studies with sample size n" ["project_main_outcome_measure"]=> string(825) "Participants/population
Adult patients aged > 18 with untreated idiopathic pulmonary fibrosis diagnosed according to contemporaneous consensus guidelines.
Intervention(s), exposure(s)
Physiological biomarkers (Forced Vital Capacity, Gas transfer and 6-minute walk test) at the following time points:
1) Baseline
2) Change over 3 months.
Comparator(s)/control
Age, Gender, Smoking
Context
Main outcome(s)
Overall mortality.
Timing and effect measures
All time periods.
Additional outcome(s)
1) Absolute or relative percentage change from baseline in FVC at 12 months
2) Disease progression at 12 months defined as:
a. >10% relative decline in FVC
b. Death
Timing and effect measures
12 months." ["project_main_predictor_indep"]=> string(87) "Baseline FVC, DLCO and 6 min walk distance
Change in 3 month of above parameters" ["project_other_variables_interest"]=> string(642) "- Patient pseudoID
- Age at consent
- Height (cm)
- Ethnicity
- Gender (M or F)
- Smoking (ever or never)
- Follow up time (days)
- Dead or alive at end
- Time to death (days)
- Baseline FVC (L)
- Baseline FVC (% predicted)
- 3 month FVC (L)
- 3 month FVC (% predicted)
- 12 month FVC (L)
- 12 month FVC (% predicted)
- Baseline DLCO (% predicted)
- Baseline DLCO (ml/min/mmHg)" ["project_stat_analysis_plan"]=> string(1141) "A narrative synthesis of the findings from the included studies will be presented according to the review question, with summary tables inclusive of study and participant characteristics. Derivation and validation cohorts from the same study will be treated as two individual cohorts.
Correlation of physiological performance over 3 months and twelve months from baseline will be assessed in a repeated measures design, relevant time-point meta-analysis. Individual patient data will be sought and a two-step meta-analysis performed adjusted for a priori confounders including age, sex and smoking status.
Hazard ratios for baseline and three month change of physiological parameters in predicting mortality will be calculated. Disease progression will be standardised as 10% relative decline in FVC or death within 12 months of baseline, and odds ratios for predicting disease progression calculated. Data will be graphically displayed using forest plots.
Heterogeneity will be assessed by Cochran's Q and I using random effects. Synthesis criteria exclude sample sizes that are not conducive to random effect models (n" ["project_timeline"]=> string(143) "Start date - 1st Feb 2020
Analysis completion date - 1st Dec 2020
Manuscript drafted/results reported back to Yoda - 1st Feb 2021" ["project_dissemination_plan"]=> string(529) "All data will be anonymised and grouped for presentation and publication. The results from this study will be publicised at regional and national conferences as well as being submitted for publication in open access peer-reviewed journals in accordance with UK Research Council policies. No participants will be identified in any publications that arise from this research.
Conferences work to be submitted to include: British Thoracic Society Winter Meeting, European Respiratory Society Congress
Journals - Thorax" ["project_bibliography"]=> string(1212) "

1. Navaratnam V, Fleming KM, West J, et al. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax 2011;66(6):462-7. doi: 10.1136/thx.2010.148031
2. Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174(7):810-6. doi: 10.1164/rccm.200602-163OC [published Online First: 2006/07/01]
3. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018;378(19):1811-23. doi: 10.1056/NEJMra1705751 [published Online First: 2018/05/10]
4. Navaratnam V, Hubbard RB. The Mortality Burden of Idiopathic Pulmonary Fibrosis in the United Kingdom. Am J Respir Crit Care Med 2019 doi: 10.1164/rccm.201902-0467LE [published Online First: 2019/04/12]
5. Martinez FJ, Collard HR, Pardo A, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers 2017;3:17074. doi: 10.1038/nrdp.2017.74 [published Online First: 2017/10/21]
6. Ley B, Collard HR, King TE, Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2011;183(4):431-40. doi: 10.1164/rccm.201006-0894CI [published Online First: 2010/10/12]

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2020-4215

Research Proposal

Project Title: A systematic review and individual patient data meta-analysis of physiological biomarkers in idiopathic pulmonary fibrosis

Scientific Abstract: Prospero protocol: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=164935
Background: Idiopathic Pulmonary Fibrosis (IPF) is a devastating lung condition of unknown origin, characterised by variable and unpredictable disease behaviour. A number of studies evaluating the role of physiological biomarkers in predicting progression have been published.
Objectives: We aim to conduct a systematic review and meta-analysis of individual patient data of treatment naive IPF patients (placebo arm) to assess whether baseline and/or short term change in physiological biomarkers can accurately predict important clinical outcomes such as disease progression and mortality.
Study Design: Individual patient data from randomised interventional clinical trial placebo arms will be analysed, and a two-step meta-analysis performed.
Participants: Adult patients with untreated IPF evaluated in interventional clinical trials (placebo arms only).
Main outcome measures: Mortality and disease progression (defined as relative decline in forced vital capacity of at least 10%, or death, at 12 months)
Statistical analysis: Individual patient data will be sought and a two-step meta-analysis performed adjusted for a priori confounders including age, sex and smoking status. Hazard ratios for baseline and three month change of physiological parameters in predicting mortality will be calculated. Disease progression will be standardised as 10% relative decline in FVC or death within 12 months of baseline, and odds ratios for predicting disease progression calculated.

Brief Project Background and Statement of Project Significance: Idiopathic pulmonary fibrosis (IPF) is a devastating lung condition of unknown origin characterised by progressive and irreversible interstitial fibrosis. Although median survival is 3 years, IPF is manifest by variable and unpredictable disease trajectory amongst individual patients. Advances in the management of IPF are hampered by the absence of validated prognostic measures, especially biomarkers that change over short time periods. Physiological biomarkers (such as but not limited to forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO) and six minute walk distance (6MWD)) may be suitable as early predictive markers of disease behaviour enabling stratification of therapy and personalised medicine.
We aim to conduct a systematic review and meta-analysis of individual patient data of treatment naive IPF patients (placebo arm) to assess whether baseline and/or short term change in physiological biomarkers can accurately predict important clinical outcomes such as disease progression and mortality.

Specific Aims of the Project: Research question - Do baseline values or 3-month change in physiological (FVC, DLCO, 6MWD) biomarkers predict disease progression and mortality in untreated patients with idiopathic pulmonary fibrosis?

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.:

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Types of study to be included
Inclusion: Placebo arms of randomised interventional clinical trials in adult (aged>18) patients with IPF.
Exclusion: Non-interventional studies, conference abstracts, letters, commentaries, correspondence, case reports, expert opinions, editorials, other non-original systematic reviews, retrospective studies and animal studies. Studies investigating non-IPF Interstitial Lung Diseases. Studies with sample size n

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Participants/population
Adult patients aged > 18 with untreated idiopathic pulmonary fibrosis diagnosed according to contemporaneous consensus guidelines.
Intervention(s), exposure(s)
Physiological biomarkers (Forced Vital Capacity, Gas transfer and 6-minute walk test) at the following time points:
1) Baseline
2) Change over 3 months.
Comparator(s)/control
Age, Gender, Smoking
Context
Main outcome(s)
Overall mortality.
Timing and effect measures
All time periods.
Additional outcome(s)
1) Absolute or relative percentage change from baseline in FVC at 12 months
2) Disease progression at 12 months defined as:
a. >10% relative decline in FVC
b. Death
Timing and effect measures
12 months.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Baseline FVC, DLCO and 6 min walk distance
Change in 3 month of above parameters

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: - Patient pseudoID
- Age at consent
- Height (cm)
- Ethnicity
- Gender (M or F)
- Smoking (ever or never)
- Follow up time (days)
- Dead or alive at end
- Time to death (days)
- Baseline FVC (L)
- Baseline FVC (% predicted)
- 3 month FVC (L)
- 3 month FVC (% predicted)
- 12 month FVC (L)
- 12 month FVC (% predicted)
- Baseline DLCO (% predicted)
- Baseline DLCO (ml/min/mmHg)

Statistical Analysis Plan: A narrative synthesis of the findings from the included studies will be presented according to the review question, with summary tables inclusive of study and participant characteristics. Derivation and validation cohorts from the same study will be treated as two individual cohorts.
Correlation of physiological performance over 3 months and twelve months from baseline will be assessed in a repeated measures design, relevant time-point meta-analysis. Individual patient data will be sought and a two-step meta-analysis performed adjusted for a priori confounders including age, sex and smoking status.
Hazard ratios for baseline and three month change of physiological parameters in predicting mortality will be calculated. Disease progression will be standardised as 10% relative decline in FVC or death within 12 months of baseline, and odds ratios for predicting disease progression calculated. Data will be graphically displayed using forest plots.
Heterogeneity will be assessed by Cochran's Q and I using random effects. Synthesis criteria exclude sample sizes that are not conducive to random effect models (n

Narrative Summary: Idiopathic pulmonary fibrosis (IPF) is a devastating condition which causes scarring of the lungs and affects around 3 million people worldwide. Disease trajectory is variable, with some patients progressing much quicker than others. Identifying early predictors of progression may enable relevant therapies to be offered at an early stage. Physiological biomarkers such as lung function (FVC, DLCO) and total distance walked in 6 minutes (6MWD) are non-invasive measurements. We therefore hope to collate data from clinical trial placebo arms to explore whether short term change in these measurements may be able to predict clinical outcomes. This will help better inform healthcare professionals.

Project Timeline: Start date - 1st Feb 2020
Analysis completion date - 1st Dec 2020
Manuscript drafted/results reported back to Yoda - 1st Feb 2021

Dissemination Plan: All data will be anonymised and grouped for presentation and publication. The results from this study will be publicised at regional and national conferences as well as being submitted for publication in open access peer-reviewed journals in accordance with UK Research Council policies. No participants will be identified in any publications that arise from this research.
Conferences work to be submitted to include: British Thoracic Society Winter Meeting, European Respiratory Society Congress
Journals - Thorax

Bibliography:

1. Navaratnam V, Fleming KM, West J, et al. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax 2011;66(6):462-7. doi: 10.1136/thx.2010.148031
2. Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174(7):810-6. doi: 10.1164/rccm.200602-163OC [published Online First: 2006/07/01]
3. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018;378(19):1811-23. doi: 10.1056/NEJMra1705751 [published Online First: 2018/05/10]
4. Navaratnam V, Hubbard RB. The Mortality Burden of Idiopathic Pulmonary Fibrosis in the United Kingdom. Am J Respir Crit Care Med 2019 doi: 10.1164/rccm.201902-0467LE [published Online First: 2019/04/12]
5. Martinez FJ, Collard HR, Pardo A, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers 2017;3:17074. doi: 10.1038/nrdp.2017.74 [published Online First: 2017/10/21]
6. Ley B, Collard HR, King TE, Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2011;183(4):431-40. doi: 10.1164/rccm.201006-0894CI [published Online First: 2010/10/12]