This protocol is part of the RCT DUPLICATE initiative, a project which is replicating 30+ randomized clinical trial designs using non-randomized healthcare data and comparing the results from the trials and non-randomized studies. The goal is to better understand when and how questions on drug effects can be validly answered with such data and used to inform regulatory, clinical or other decision-making.
This protocol focused on a phase 3 trial comparing different drugs administered via metered dose inhalers (MDI) for asthma. The trial evaluated whether one drug was better than another at preventing flare ups. We will replicate the trial design based on methods reported in the main trial publication.[2]
The objective of this protocol is to use real-world data to emulate the published randomized clinical trial (RCT): “Effects of Mometasone Furoate/Formoterol combination versus Mometasone Furoate alone in persistent asthmatics (NCT00383240)”. The purpose is to better understand what types of studies and characteristics of nonrandomized healthcare database studies that make replication of randomized clinical trials more likely. In this particular study, we will focus on the parallel comparison of budesonide/formoterol furoate versus formoterol to prevent asthma exacerbations. The original trial compares mometasone furoate/formoterol MDI vs formoterol MDI; however, this is a US based trial and the replication effort will be done using UK data wherein we do not have mometasone furoate/formoterol MDI marketed formulations as this drug combination is not approved in the UK. Hence, we are comparing budesonide/formoterol MDI combination vs formoterol MDI as mometasone and budesonide are similar inhaled corticosteroids and budesonide/formoterol MDI is approved in the UK and commonly used.
We are using CPRD data from the UK to replicate this trial for improved outcome assessment. The outcome will be measured as time-to-first exacerbation over 26-week treatment period of either of the study drugs. HES Admitted Patient Care data contains details of all admissions to, or attendances at English NHS healthcare providers and will be used to help with identification of outcome events, which is time-to-first asthma exacerbation over a 26-week treatment period. To reduce confounding bias, we will implement the new-user active comparator study design. We will further implement standard propensity score methods to reduce remaining residual imbalances when estimating the survival curves for each treatment group. Propensity scores will adjust for several investigator-specified variables to reduce the impact of confounding by indication. Investigator-specified variables will include a variety of comorbidities associated with COPD as well use of a range of different classes of medications.
Time-to-first Asthma Exacerbation Over the 26-week Treatment Period for the Comparison of MF/F Versus F [Time Frame: 26-week Treatment Period]. See attached files for formal CPRD definition.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Richard Wyss - Corresponding Applicant - Harvard Medical School
Sebastian Schneeweiss - Collaborator - Brigham & Women's Hospital
Shirley Wang - Collaborator - Harvard University
HES Admitted Patient Care