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Center for Global Research Data

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

Lead Investigator: Fasihul Khan, University of Nottingham
Title of Proposal Research: A systematic review and individual patient data meta-analysis of physiological biomarkers in idiopathic pulmonary fibrosis
Vivli Data Request: 5207
Funding Source: PI is funded by NIHR grant
Conflicts of Interest: RGJ reports grants from GlaxoSmithKline, UK Medical Research Council, Biogen, Galecto, MedImmune; as well as personal fees from Boehringer Ingelheim, Galapagos, GlaxoSmithKline, Heptares, MedImmune, Roche and Pulmatrix; served as consultant for NuMedii and Pliant; a trustee for charities Action for Pulmonary Fibrosis and the British Thoracic Society
None of these will impact data analysis and publication.

Summary of the Proposed Research:

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.

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 standardized 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 I² using random effects. Synthesis criteria exclude sample sizes that are not conducive to random effect models (n<30). Where heterogeneity is high, sensitivity analyses will be performed using inverse variance heterogeneity models.

Data from individual platforms will be combined using a two-step approach. In the first step, data will be analyzed using the Vivli secure research environment and summary estimates calculated. Summary estimates/coefficients will thereafter be downloaded and imported into STATA alongside summary estimates from other studies/platforms, and a meta-analysis performed, taking into account individual study weighting.

 

Requested Studies:

A 12 Month, Double Blind, Randomized, Placebo-controlled Trial Evaluating the Effect of BIBF 1120 Administered at Oral Doses of 50 mg qd, 50 mg Bid, 100 mg Bid and 150 mg Bid on Forced Vital Capacity Decline During One Year, in Patients With Idiopathic Pulmonary Fibrosis, With Optional Active Treatment Extension Until Last Patient Out
Sponsor: Boehringer Ingelheim
Study ID: NCT00514683
Sponsor ID: 1199.30

A 52 Weeks, Double Blind, Randomized, Placebo-controlled Trial Evaluating the Effect of Oral BIBF 1120, 150 mg Twice Daily, on Annual Forced Vital Capacity Decline, in Patients With Idiopathic Pulmonary Fibrosis (IPF)
Sponsor: Boehringer Ingelheim
Study ID: NCT01335477
Sponsor ID: 1199.34

A 52 Weeks, Double Blind, Randomized, Placebo-controlled Trial Evaluating the Effect of Oral BIBF 1120, 150 mg Twice Daily, on Annual Forced Vital Capacity Decline, in Patients With Idiopathic Pulmonary Fibrosis (IPF)
Sponsor: Boehringer Ingelheim
Study ID: NCT01335464
Sponsor ID: 1199.32

A Double-blind, Randomized, Placebo-controlled, Multicenter, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Macitentan in Patients With Idiopathic Pulmonary Fibrosis
Sponsor: Johnson & Johnson
Study ID: NCT00903331
Sponsor ID: AC-055B201

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.
Sponsor: Johnson & Johnson
Study ID: NCT00391443
Sponsor ID: AC-052-321

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
Sponsor: Johnson & Johnson
Study ID: NCT00071461
Sponsor ID: AC-052-320

AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF)
Sponsor: BioLINCC (a data-sharing platform funded by the National Institutes of Health)
Study ID: NCT00957242
Sponsor ID: Pro00017156

Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in IPF
Sponsor: BioLINCC (a data-sharing platform funded by the National Institutes of Health)
Study ID: NCT00650091
Sponsor ID: Pro00020066

A Randomized, Double-Blind, Placebo Controlled, Phase 3, Three-Arm Study of the Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis
Sponsor: Roche
Study ID: NCT00287716
Sponsor ID: PIPF-004

A Randomized, Double-Blind, Placebo Controlled, Phase 3 Study of the Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis
Sponsor: Roche
Study ID: NCT00287729
Sponsor ID: PIPF-006

A Randomized, Double-Blind, Placebo Controlled, Phase 3 Study of the Efficacy and Safety of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis (ASCEND Trial)
Sponsor: Roche
Study ID: NCT01366209
Sponsor ID: PIPF-016

Public disclosure:

Khan FA, Stewart I, Saini G, Robinson KA, Jenkins RG. A systematic review of blood biomarkers with individual participant data meta-analysis of matrix-metalloproteinase-7 in IPF. Eur Respir J. 2021 Sep 29:2101612. doi: 10.1183/13993003.01612-2021 PMID: 34588192.