Real-world Effectiveness of Combination Therapy in Asthma

Study Overview
=================
Brief Summary
-----------------
This study will evaluate and compare the effectiveness of asthma management in patients with evidence of persistent asthma following a switch in asthma therapy to combination inhaled glucocorticosteroid (ICS) / long-acting bronchodilator (LABA) therapy as either: fixed-combination fluticasone propionate / salmeterol (FP/SAL; Seretide®) via pressurised metered-dose inhaler (pMDI) or dry-powder inhaler (DPI) plus as-needed (prn) reliever therapy (salbutamol as DPI, BAI or pMDI), or fixed-combination budesonide / formoterol (BUD/FOR; Symbicort®) via DPI plus prn reliever therapy (salbutamol as DPI, BAI or pMDI or bricanyl as DPI). The final analysis plan will define exact comparators and age groups to be studied after reviewing baseline data.

Detailed Description
-----------------
Current asthma guidelines in the UK are underpinned by evidence derived from randomised controlled trials (RCTs). Although RCT data are considered the gold standard, patients recruited to asthma RCTs are estimated to represent less than 10% of the UK's asthma population. The poor representation of the asthma population is due to a number of factors, such as tightly-controlled inclusion criteria for RCTs. There is, therefore, a need for more representative RCTs and real-life observational studies to inform existing guidelines and help optimise asthma outcomes. The fixed combination asthma inhalers FP/SAL (as pMDI and DPI) and BUD/FOR (as DPI) are indicated for use in asthma when adequate asthma control is not achieved with low / medium dose ICS therapy and prn reliever therapy (a short-acting beta-agonist [SABA]). Fixed combination inhalers are also indicated in patients already adequately controlled on separate ICS/LABA therapy. However, emerging trends in asthma prescribing indicate increasing use of add-on therapies (particularly in the form of combination inhalers) in the early stages of asthma therapy, even as first-line therapy. The British Thoracic Society (BTS) Scottish Intercollegiate Guidelines Network (SIGN) guidelines on the management of asthma advise that there is no difference in efficacy between ICS/LABA therapy given as separate or combined inhalers. However, they do note that, once a patients is on stable therapy, combination inhalers have the advantage of guaranteeing that patients do not take their LABA without their ICS. In practice, there is significant pressure (supported by asthma guidelines) to use the least expensive, effective inhaled therapies available. While the effect of increased use of combination therapies in terms of patient benefits remains uncertain, the impact on treatment costs for the United Kingdom's (UK's) National Health Service (NHS) is unequivocal and, to date, there are limited data available as to the absolute and relative effectiveness of the ICS/LABA combination therapies currently licensed. There are a number of inhaler delivery devices available for use in asthma management. Whatever therapy is prescribed, optimal treatment response requires effective drug delivery within the airways; selecting the most appropriate delivery device for an asthma patient, therefore, plays an important role in optimising their asthma control. According to the recent BTS/SIGN guidelines, there is currently no evidence of a clinical difference in the effectiveness of therapy delivery via pMDI ± spacer compared with DPI in either adults or children, and more recent DPIs are rated as effective as older DPIs. Effective use of DPIs and pMDI requires entirely different inhalation techniques and there is some debate as to whether patients prescribed different device types for their reliever and preventer medication (requiring different techniques for each) may have poorer disease control than those prescribed the same device type for both preventer and reliever. Combining aerosols (e.g. pMDI preventer plus BAI reliever) is not considered to cause a problem in this respect. The aim of this study is to compare the absolute and relative effectiveness of currently licensed ICS/LABA combinations - FP/SAL and BUD/FOR (and their available delivery devices) - in children and adults with asthma whose therapy was changed or increased. Consideration will also be given to the effect of reliever therapy inhaler and the effect of consistency of device used (i.e. same or different devices for preventer and inhaler therapies) on asthma control outcomes. Also to be evaluated are the associated impact of inhaler technique review, recorded inhaler handling problems and use of a spacer in conjunction with a pMDI in terms of achieving asthma control outcomes.

Official Title
-----------------
A Retrospective Evaluation of the Effectiveness of Fixed-dose Combination Inhaled Corticosteroid /. Long-acting Beta Agonist (ICS/LABA) Therapy in the Management of Asthma in a Representative UK Primary Care Population

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Fluticasone / formoterol metered dose inhaler
* Drug: Fluticasone / salmeterol dry powder inhaler
* Drug: Budesonide / formoterol dry powder inhaler
* Drug: Fluticasone / salmeterol dry powder inhaler
* Drug: Fluticasone / salmeterol metred dose inhaler
* Drug: BUD/FOR dry powder inhaler


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged: 4-80 years: Paediatric cohort (aged 4-11 years); Adult cohort (aged 12-69 years); Elderly cohort (aged 70-80 years. Evidence of asthma: i.e. a diagnostic code of asthma or ≥2 prescriptions for asthma at different points in time during the prior year, including one ICS prescription. Be on current asthma therapy: i.e. ≥1 asthma prescriptions in the prior year, and at least 1 other asthma prescription during the same period. Have at least one year of up-to-standard (UTS) baseline data (prior to the IPD) and at least one year of UTS outcome data (following the IPD). Exclusion Criteria: Diagnostic read code for chronic respiratory disease (including COPD) at any time On maintenance oral steroid therapy at baseline Any patients receiving a combination inhaler in addition to their separate ICS inhaler in the baseline year.

Ages Eligible for Study
-----------------
Minimum Age: 4 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| IPDA FP/SAL DPI<br>Patients who were on inhaled corticosteroid therapy during the baseline year (any ICS therapy) who, at an index prescription date, initiated combination therapy as FP/SAL DPI at ≥twice the equivalent BDP-equivalent dose | Drug: Fluticasone / salmeterol dry powder inhaler<br>* Prescribed at ≥twice BDP-equivalent dose as baseline ICS<br>* Other names: Seretide DPI;|
| IPDA FP/SAL MDI<br>Patients who were on inhaled corticosteroid therapy during the baseline year (any ICS therapy) who, at an index prescription date, initiated combination therapy as FP/SAL MDI at ≥twice the equivalent BDP-equivalent dose | Drug: Fluticasone / salmeterol metred dose inhaler<br>* Prescribed at ≥twice BDP-equivalent dose as baseline ICS<br>* Other names: Seretide MDI;|
| IPDI FP/SAL DPI<br>Patients who were on inhaled corticosteroid therapy during the baseline year (any ICS therapy) who, at an index prescription date, initiated combination therapy as FP/SAL DPI at equivalent BDP-equivalent dose | Drug: Fluticasone / salmeterol dry powder inhaler<br>* Prescribed at the same BDP-equivalent dose as baseline ICS<br>* Other names: Seretide DPI;|
| IPDI BUD/FOR DPI<br>Patients who were on inhaled corticosteroid therapy during the baseline year (any ICS therapy) who, at an index prescription date, initiated combination therapy as BUD/FOR DPI at equivalent BDP-equivalent dose | Drug: Budesonide / formoterol dry powder inhaler<br>* Prescribed at the same BDP-equivalent dose as baseline ICS<br>* Other names: Symbicort DPI;|
| IPDI FP/SAL MDI<br>Patients who were on inhaled corticosteroid therapy during the baseline year (any ICS therapy) who, at an index prescription date, initiated combination therapy as FP/SAL MDI at equivalent BDP-equivalent dose | Drug: Fluticasone / formoterol metered dose inhaler<br>* Prescribed at the same BDP-equivalent dose as baseline ICS<br>* Other names: Seretide MDI;|
| IPDA BUD/FOR DPI<br>Patients who were on inhaled corticosteroid therapy during the baseline year (any ICS therapy) who, at an index prescription date, initiated combination therapy as BUD/FOR DPI at ≥twice the equivalent BDP-equivalent dose | Drug: BUD/FOR dry powder inhaler<br>* Prescribed at ≥twice BDP-equivalent dose as baseline ICS<br>* Other names: Symbicort DPI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite proxy for asthma control | No recorded hospital attendance for asthma, including admission, Accident & Emergency (A&E) attendance, out-of-hours attendance, or Out-Patient Department (OPD) attendance, AND No prescriptions for oral steroids, AND No GP consultations, hospital admissions or A&E attendance for lower respiratory tract infections (LRTI) requiring antibiotics. | One-year outcome period | 
| Exacerbations (total and rate ratio) | Unscheduled hospital admissions / A&E attendance for asthma, AND/OR Use of oral steroids. | One-year outcome period | 
| GOAL Total Control (proxy measure to replicate total control as measured in the GOAL RCT in a real world patient population | No day-time symptoms; No night-time symptoms; No exacerbations; No treatment-related adverse events PEF ≥80% predicted = normal No SABA use | 6 months (sensitivity analysis at 8 weeks) | 
| GOAL exacerbations | Absence of: Documented episodes of hospitalisations AND/OR Exacerbation treatment - oral steroids or antibiotics for asthma over one year | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance with ICS/LABA combination therapy | Percentage compliance calculated based on prescription refills | One year outcome period | 
| Compliance with ICS as part of ICS/LABA combination therapy | Percentage compliance calculated based on prescription refill | One-year outcome period | 
| Treatment success | Success of the therapeutic regimen, defined as the absence of: Exacerbation, and Increased dose of ICS, and Change in ICS/LABA, and Change in delivery device, and Use of additional therapy as defined by: oral steroids, theophylline, leukotreine receptor antagonists (LTRAs). | One-year outcome period | 
| SABA dosage | Categorised average SABA dosage during outcome year: 0mcg, >0-100mcg, >100-200mcg, >200-400mcg, >400-800mcg, >800mcg. | One-year outcome period | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Primary care, Asthma management, Combined therapy, Real-world, Effectiveness, Control, Exacerbations