Statistical Analysis Plan

Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version V1.4 Date 14 July 2017 Decline In lung-function Among Patients with chronic obstructive Lung disease On maintenance therapy (DIAPLO) An observational study evaluating the benefits of early intervention with maintenance therapies to prevent or slow down rapid lung function decline in patients who are at high risk at the time of COPD diagnosis in the combined Optimum Patient Care Research Database and Clinical Practice Research Datalink databases TITLE PAGE Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 TABLE OF CONTENTS PAGE TITLE PAGE ........................................................................................................... 1 TABLE OF CONTENTS ......................................................................................... 2 LIST OF ABBREVIATIONS .................................................................................. 5 RESPONSIBLE PARTIES ...................................................................................... 6 PROTOCOL SYNOPSIS DIAPLO STUDY ........................................................... 7 AMENDMENT HISTORY ................................................................................... 12 MILESTONES ....................................................................................................... 13 1. BACKGROUND AND RATIONALE .................................................................. 14 1.1 Background ............................................................................................................ 14 1.2 Rationale ................................................................................................................ 17 2. OBJECTIVES AND HYPOTHESES .................................................................... 18 2.1 First Objective & Hypothesis ................................................................................. 18 2.2 Second Objective & Hypothesis ............................................................................ 18 2.3 Third Objective & Hypothesis ............................................................................... 18 2.4 Fourth Objective & Hypothesis ............................................................................. 18 3. METHODOLOGY ................................................................................................ 19 3.1 Study Design – General Aspects ............................................................................ 19 3.1.1 Objective 1: Validation of Zafari prediction model ............................................... 19 3.1.2 Objective 2: Characterisation of patients at high risk of rapid lung function decline .................................................................................................................... 20 3.1.3 Objective 3: Comparison of observed FEV1 decline under maintenance therapy with predicted decline under minimal therapy .......................................... 20 3.1.4 Objective 4: Effectiveness of triple therapy on lung function decline ................... 20 3.1.5 Data Source(s) ........................................................................................................ 20 3.2 Study Population .................................................................................................... 21 3.3 Inclusion Criteria ................................................................................................... 21 3.3.1 Overall inclusion criteria ........................................................................................ 21 3.3.2 Additional inclusion criteria objective 1 ................................................................ 22 3.3.3 Additional inclusion criteria objective 3 ................................................................ 22 3.3.4 Additional inclusion criteria objective 4 ................................................................ 22 3.4 Exclusion Criteria .................................................................................................. 22 4. VARIABLES AND EPIDEMIOLOGICAL MEASUREMENTS ........................ 23 2 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 4.1 Predictors of Zafari model ..................................................................................... 23 4.2 Therapy exposure ................................................................................................... 23 4.2.1 Period of minimal inhalation therapy..................................................................... 23 4.2.2 Period of maintenance inhalation therapy .............................................................. 23 4.2.3 Period of triple therapy .......................................................................................... 24 4.2.4 Period of poor adherence to maintenance inhalation therapy ................................ 24 4.3 High risk of rapid FEV1 decline ............................................................................. 24 4.4 Outcomes ............................................................................................................... 25 4.4.1 Primary end-point objective 4: Rate of FEV1 decline............................................ 25 4.4.2 Secondary endpoints objective 4: Matched comparison of patients on triple therapy with patients on minimal therapy .............................................................. 25 4.4.2.1 Time to first COPD exacerbation / Exacerbation rate ........................................... 25 4.4.2.2 Time to first hospitalisation for COPD .................................................................. 25 4.4.2.3 Treatment success .................................................................................................. 26 4.5 Other Variables and Covariates ............................................................................. 26 4.5.1 Baseline characteristics .......................................................................................... 26 4.5.2 Comorbidities ......................................................................................................... 26 4.5.3 Clinical characteristics ........................................................................................... 27 5. STATISTICAL ANALYSIS PLAN ...................................................................... 28 5.1 Statistical Methods – General Aspects................................................................... 28 5.1.1 First objective(s): Validation of Zafari prediction model ..................................... 29 5.1.1.1 Validation of predicted FEV1 values during follow up under minimal therapy .................................................................................................................... 29 5.1.2 Second objective: Characterisation of patients at high risk of rapid lung function decline ...................................................................................................... 29 5.1.3 Third Objective: Comparison of individual observed lung function decline under maintenance therapy with predicted rate under minimal therapy ................ 29 5.1.4 Fourth Objective: effectiveness of triple therapy on lung function decline and secondary COPD outcomes ............................................................................. 30 5.1.4.1 Matching ................................................................................................................ 30 5.1.4.2 Outcome analyses objective 4 ................................................................................ 32 5.2 Bias ........................................................................................................................ 33 5.2.1 Methods to Minimize Bias ..................................................................................... 33 5.2.2 Strengths and Limitations ...................................................................................... 33 5.3 Sample Size and Power Calculations ..................................................................... 34 5.4 Communication Plan .............................................................................................. 34 5.4.1 Publication Plan ..................................................................................................... 34 6. LIST OF REFERENCES ....................................................................................... 35 7. APPENDICES ....................................................................................................... 37 7.1 Diagnostic Read codes for COPD .......................................................................... 37 3 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 7.2 Read codes for exclusion of patients with overlapping asthma ............................. 39 7.3 Read codes other chronic respiratory conditions ................................................... 44 7.4 Zafari prediction model .......................................................................................... 54 7.5 MRC Dyspnoea Scale ............................................................................................ 56 7.6 Co-morbidities Read codes .................................................................................... 57 7.6.1 Diagnosis of Asthma .............................................................................................. 57 7.6.2

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