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

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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

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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 Allergic or non-allergic rhinitis diagnosis ...... 62 7.6.3 Allergic rhinitis drugs Prodcodes for CPRD ...... 63 7.6.4 Allergic rhinitis drugs Readcode for OPCRD...... 77 7.6.5 Eczema diagnosis ...... 88 7.6.6 Nasal polyps ...... 92 7.6.7 Chronic sinusitis diagnosis and treatment procedures ...... 92 7.6.8 Gastro-oesophageal reflux ...... 98 7.6.9 Diabetes Mellitus ...... 100 7.6.10 Osteoporosis diagnosis ...... 112 7.6.11 Hypertension ...... 114 7.6.12 Ischaemic heart disease ...... 116 7.6.13 Heart Failure ...... 121 7.6.14 Depression ...... 123 7.6.15 Anxiety ...... 126 7.6.16 Obstructive Sleep Apnea ...... 131 7.6.17 Sleep disorders ...... 132 7.6.18 Chronic Kidney disease ...... 134

4 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 LIST OF ABBREVIATIONS

Abbreviation or Explanation special term COPD Chronic Obstructive Pulmonary Disease CPRD Clinical Practice Research Datalink

FEV1 Forced Expiratory Volume in one second FVC Forced Vital Capacity HES Hospital Episode Statistics ICS Inhaled Corticosteroids ID Index Date LABA Long-Acting Beta Agonist LAMA Long-Acting Muscarinic Antagonist MPR Medication Possession Ratio OPCRD Optimum Patient Care Research Database OPRI Observational and Pragmatic Research Institute SABA Short-Acting Beta Agonist SAMA Short-Acting Muscarinic Antagonist RMSE Root mean squared error

5 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 RESPONSIBLE PARTIES

Name Professional Title Role in Study Affiliation Email Address Claudia Cabrera, MPH Epidemiology Lead Researcher AZ [email protected] PhD

Paul Dorinsky, MD Global Clinical Lead Researcher PEARL [email protected] David Price Professor Chief Scientist University of [email protected] Aberdeen Observational and Pragmatic Research Institute Pte Ltd (OPRI) Sen Yang, MD Vice president OPRI Senior Medical OPRI [email protected] affiliates and project Lead co-ordinator Chris Price Commercial Director Contracting OPRI [email protected]

Marjan Kerkhof, MD, PhD Senior Researcher, Researcher OPRI [email protected] Epidemiologist Marcus Ngantcha. Msc Statistician Statistician OPRI [email protected]

6 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 PROTOCOL SYNOPSIS DIAPLO STUDY

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

Background/Rationale: Chronic obstructive pulmonary disease (COPD) is a progressive disease characterised by non- reversible airflow limitation. A few clinical trials demonstrated modest effects of maintenance inhalation therapy on reduction of lung function decline in patients with COPD.1,2 To date, there is a lack of evidence on the effect of triple therapy (ICS/LABA/LAMA) on lung function decline, although several RCTs have found adding a LAMA to ICS/LABA to improve lung function.3-6 As lung function data are captured in electronic health records in the UK, there is a unique opportunity to study the benefits of early intervention with maintenance therapies to prevent or slow down rapid lung function decline in patients who are at high risk and most likely to benefit from preventive therapies at the time of COPD diagnosis.

Objectives and Hypotheses: The hypothesis of this study is that early treatment with maintenance therapy, particularly triple therapy, will prevent or slow down rapid lung function loss in patients diagnosed with mild or moderate COPD (FEV1 %predicted ≥50%) who are at high risk of rapid lung function decline. Four sub-studies will be performed with the following objectives: 1. In later objectives, the Zafari model – a prediction model for lung function decline under minimal therapy- will be used to identify patients at high risk of rapid FEV1 decline. Thus, our first objective concerns the validation of this model: To study whether the observed FEV1 decline during minimal inhalation therapy in patients diagnosed with mild or moderate COPD corresponds with the rate of decline predicted by the model of Zafari et al.7 2. To characterise patients at high risk of rapid FEV1 decline at the time they were identified when diagnosed with mild or moderate COPD and at the time of initiation of maintenance therapy (LAMA, LABA and/or ICS) and to compare these characteristics with those of patients not being at high risk of rapid FEV1 decline. 3. To compare observed FEV1 values recorded during maintenance therapy with predicted values for minimal inhalation therapy within patients identified as being at high risk of rapid lung function decline by the prediction model. 4. To study the effectiveness of triple therapy on slowing down the rate of FEV1 decline in patients who were identified as being at high risk of rapid FEV1 decline by comparing the rate of FEV1 decline in patients during triple therapy with that of similar patients during minimal therapy or poor adherence to maintenance therapy.

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Methods: Study design: Patients who are newly diagnosed with mild or moderate COPD and have a positive history of tobacco smoking will be identified at the time of their first FEV1 recording, that is within 3 months prior to and 12 months after their COPD diagnosis. This point will be called Index Date 1 (ID1). Patients will be followed from ID1 until the date at which maintenance therapy is introduced, which will be called Index date 2 (ID2). All FEV1 values recorded under minimal therapy (no therapy, or short-acting bronchodilators only) during this period between ID1 and ID2 will be used for analyses in patients. The recorded FEV1 values will be compared with the individual’s predicted values at that time as calculated from the model published by Zafari et al.

If the observed FEV1 values during minimal inhalation therapy are found to correspond well with the predicted values, the Zafari model will be used to identify patients at high risk of rapid FEV1 decline, defined as a probability of ≥80% of ≥40 ml/year decline in FEV1 over the next 11 years. These patients will be selected for the subsequent analyses.

For objective 2, the patients will be characterised at the date of identification (ID1=date of first FEV1 recording at or around time of first diagnosis of mild to moderate COPD) and at the date of initiation of maintenance therapy (ID2).

For objective 3, FEV1 values recorded during maintenance therapy (after ID2) will be compared with predicted values for minimal therapy within patients at high risk of rapid lung function decline at the time of COPD diagnosis. Analyses will be performed for patients with first maintenance therapy being a single inhaler, dual therapy and triple therapy separately.

For objective 4, patients who are initiated on triple therapy will be matched to similar patients from a combined group of patients on minimal therapy or patients who are persistently non-adherent to maintenance therapy (Medication Possession Ratio for maintenance therapies < 40% in 3 consecutive years prior to index date (ID3)). The mean observed rates of FEV1 decline after index date will be compared between these two study arms.

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Data Source(s): A combined dataset of patients with COPD using data extracted from OPCRD and CPRD will be used for analyses. A subpopulation of patients from CPRD with linkage to Hospital Episode Statistics (HES) available will be selected to study the association between therapy and the secondary outcome of COPD-related hospital admission. Interim analyses will be delivered based on OPCRD data only for objectives 1 and 2. Study Population: The study population will consist of patients with COPD who are registered at general practices providing data to OPCRD and CPRD across England, Scotland, Wales, and Northern Ireland

Overall inclusion Criteria: 1. A diagnostic Read code for COPD as from 1 January 2005 (date of first diagnostic Read code is ID0) 1 2. Valid spirometry recorded in period between 3 months before and 12 months after ID0 (date of spirometry is ID1) 3. Evidence of obstruction, defined as FEV1/FVC<0.7 and mild or moderate COPD, i.e. i.e. FEV1 % predicted ≥50 and ≤ 90% at ID1 4. Age ≥35 years at ID0 5. ≥1 year of medical records prior to ID1 for baseline characterisation 6. A positive history of tobacco smoking at the time of first COPD diagnosis (ID0) at any recording of smoking status prior to ID0 or at first recording after ID0 7. Recorded height at adult age (≥21 years) and weight within 5 years of ID1

Additional inclusion criteria objective 1

1. Follow-up period covering ≥1 spirometry records after ID1 2. Minimal inhalation therapy during follow-up period after ID1, defined as no inhalation therapy or only short-acting bronchodilator prescriptions

Additional inclusion criteria objective 3

1. Identified as being at high risk of rapid FEV1 decline at ID1, defined as ≥80% probability of ≥40ml FEV1 decline per year over 11 years, using prediction model 2. Initiation of maintenance inhalation therapy at any time during follow-up after ID1. Date of initiation is index date 2 (ID2) 3. Follow-up period covering ≥1 spirometry records after ID2

Additional inclusion criteria objective 4

1. Identified as being at high risk of rapid FEV1 decline at ID1, defined as ≥80% probability of ≥40ml FEV1 decline per year over 11 years, using prediction model 2. Period of treatment at any time during follow-up after ID1 (definitions at paragraph 4.2) with: a. Triple therapy b. Control therapy:

1 Time period following QOF indicator for spirometry confirmed COPD diagnosis

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i. Minimal inhalation therapy for ≥ 1 year OR ii. Poor adherence to maintenance inhalation therapy for ≥3 consecutive years, defined as a Medication Possession Ratio (MPR) <40% Date of triple therapy initiation or matched control date is index date 3 (ID3) 3. ≥2 follow-up spirometry records during treatment period after ID3

Exclusion criteria

1. Active asthma after date of first COPD diagnosis (ID0), defined as ≥1 diagnostic Read code for asthma or ≥1 asthma monitoring or review Read code recorded 2. Diagnostic Read code for Asthma-COPD overlap syndrome as first COPD diagnostic Read code or recorded during follow-up after ID0 3. Diagnostic Read code for other chronic lower respiratory conditions recorded ever prior to ID0

Exposures: A period of minimal inhalation therapy is defined as the absence of any inhalation therapy or prescriptions for short-acting bronchodilators starting at the time of spirometry recording closest to first COPD diagnosis (ID1). This period will end at the time of initiation of maintenance inhalation therapy, loss to follow-up or death. A period of maintenance therapy starts with the date of first prescription of LAMA and/or LABA and/or ICS after ID1 and ends with the absence of prescriptions for ≥120 days, at loss to follow-up or death. A period of triple therapy is defined as the presence of overlapping periods covered by prescriptions for LAMA, LABA and ICS, i.e. prescription for a third drug at index date while the first two are still active (based on number of days prescribed at most recent prescription prior to ID2) or prescribed at the same date. Drugs need to be followed by a repeat prescription within 30 days after end of prescription duration during follow- up. The period of triple therapy ends with absence of prescriptions for any of the three drugs for >120 days. A period of poor adherence is defined as a Medication Possession Ratio <40% for LABA, LAMA or ICS in the last 3 consecutive years prior to index date.

Outcomes: Recorded FEV1 values will be compared with predicted values calculated from the Zafari prediction model. For objective 4, the change in FEV1 over time, expressed as ml/year of follow up, will be estimated using a multilevel model for change.

Feasibility: A feasibility check in the OPCRD of the number of patients with a COPD diagnosis, confirmed by spirometry found more than 6,000 patients who fulfilled the inclusion and exclusion criteria for objective 1.

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Statistical Analysis: In mild to moderate COPD patients, all FEV1 values captured in the combined databases when the patient was on minimal therapy will be compared to those predicted by the model developed by Zafari et al. Scatterplots will be produced and the overall root mean squared error (RMSE) of the predicted versus observed FEV1 value will be calculated. The coverage probability, defined as the proportion of the observed FEV1 values falling within the 95% prediction interval for that observation will be determined.

For objective 3, the absolute difference between the individual’s observed FEV1 values after initiation of maintenance therapy and his/her predicted values at that same date (calculated from the Zafari model) will be calculated and distributions will be described. Analyses will be performed for patients with first maintenance therapy being a single inhaler, dual therapy or triple therapy, separately. FEV1 values recorded after a switch from the first maintenance therapy category to another will not be considered. A linear mixed model will be used with the absolute difference between observed and predicted FEV1 value as the outcome variable to estimate the influence of duration of therapy, taking repeated measurements within patients into account.

For objective 4, direct matching will be applied to compare mean observed rates of FEV1 decline between the two study arms. Potential confounders of the association between triple therapy and the rate of FEV1 decline will be identified in a baseline year and the choice of the most relevant confounders will be based on a combination of baseline imbalance, bias potential and expert judgement. For the primary outcome analyses, the change in FEV1 over time will be analysed using a multilevel model for change. The level-1 component of this model will be the individual growth model, representing the change in FEV1 over time within patients. The level-2 component codifies the mean difference in FEV1 decline within matched pairs and the level-3 component will represent the mean population difference in lung function decline between the two study arms. Mixed linear regression will be used to analyse the data. Intercept and slope will be modelled as random effects (to vary across individuals). A matched-pair specific random effect will be added to the model next to covariates representing potential confounders. The time difference between the date at which triple therapy was initiated and the time of first diagnosis will be included into the model as a potential confounder or effect modifier (testing of interaction term with therapy). We will also study whether there is a potential non-linear component of decline during follow-up by including polynomial functions of time into the model. For analysing time-to-event outcomes, unadjusted Kaplan-Meier estimates of the survivor functions are plotted for the matched study arms. A stratified log-rank test will be performed to statistically test significance of observed differences. A stratified Cox proportional hazard model will be used to estimate the hazard ratio with 95% confidence interval for the association between therapy and time to the first event. Conditional negative binomial regression will be used to estimate the adjusted rate ratio with 95% confidence interval for the association between therapy and the number of COPD exacerbations in the outcome year. Conditional logistic regression analyses will be used to estimate the adjusted odds ratio with 95% confidence interval for the association between therapy and treatment success.

11 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 AMENDMENT HISTORY

Date Brief description of change Administrative Change / Amendment / New Protocol Version. 25 April First draft protocol V1.0 5 May Amendments after review V1.1 15 May Amendments after review V1.2 15 June Update Medcodes/Read codes and amendments V1.3 following ISAC protocol 17 July Update following feedback ISAC V1.4

12 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 MILESTONES

Date Deliverables 3 July 2017 Report OPCRD-based Zafari model validation (Objective 1-interim) 1 August 2017 Report OPCRD-based characterisation fast-decliners (Objective 2-interim) Report validation of Zafari model in combined dataset or of new model in CPRD 4 September 2017 dataset (Objective 1) 8 September 2017 Report characterisation fast-decliners in combined dataset (Objective 2)

27 October 2017 Report effects maintenance therapy on FEV1-observed vs predicted (Objective 3) 15 December 2017 Effects triple therapy vs minimal therapy-matched design (Objective 4) 12 March 2018 Delivery first manuscript draft 9 April 2018 Manuscript journal submission

13 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 1. BACKGROUND AND RATIONALE

1.1 Background Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition characterised by non-reversible airflow limitation.8 According to the WHO around 65 million people have a moderate to severe form of the disease worldwide.9 Current WHO estimates predict that by 2030, COPD will become the third leading cause of death globally,10 The estimated direct cost of COPD is substantial. In the European Union, the total direct cost of respiratory disease are estimated to be about 6% of the total health care budget, with COPD accounting to 56% (38.6 billion Euros) of the combined cost of respiratory disease.

The diagnosis of COPD rests on demonstration of chronic airflow obstruction, which is not fully reversible.11 After diagnosis, disease progression is monitored by repeated spirometry measurements to track the decline in Forced Expiratory Volume in one second (FEV1), which, in the UK, should be part of the standard management of COPD in general practice. Concepts relating to the natural history of tobacco-related COPD arise from the landmark study 12 of Fletcher and colleagues. They suggested that lung function (FEV1) declines continuously and smoothly over an individual’s life with a slightly accelerated decline with aging.12 However, susceptible smokers demonstrate a much faster decline and eventually develop clinically severe airflow obstruction, leading to a diagnosis of COPD, mostly when they have mild to moderate disease.12

Figure 1. The decline in lung function with age, smoking, and smoking cessation by Fletcher and Peto12 Tantucci et al. reviewed spirometric data of patients with COPD in the placebo arms of clinical trials and found that lung function decline was most accelerated in patients with moderate COPD (GOLD stage II) (Figure 2).13 The authors highlighted a lack of knowledge about lung function decline in mild disease (FEV1≥80%) and emphasised the need for further studies to determine whether intervention during the initial stages of COPD can ameliorate the progression of the disease.

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Figure 2. Range of average rate of decline in the forced expiratory volume in the first second (FEV1) of chronic obstructive pulmonary disease patients according to initial severity of airflow reduction by Tantucci et al.13 Until recently, the only effective intervention was smoking cessation. However, newly reported large clinical trials have demonstrated modest effects of maintenance inhalation therapy on reduction of lung function decline in patients with COPD.1,2 Post-hoc analyses of the Toward a Revolution in COPD Health (TORCH) study found that the average rate of FEV1 decline among 5,343 former smokers with moderate to severe COPD was 55 ml/year in the placebo group, 42 ml/year in patients treated with long-acting beta-agonists (LABA), 42 ml/year in patients treated with inhaled corticosteroids (ICS) only, and 39 ml/year in the combined ICS/LABA group measured over 3 years.14 The reduction in rate of decline in the ICS/LABA group versus placebo was 16 ml/year (95% confidence interval, 7–25 ml; P<0.001), suggesting that combination therapy (ICS/LABA) slowed the rate of disease progression.2 A subgroup analysis of 2,739 patients with mild to moderate COPD from the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study found that the average rate of FEV1 decline was lower in patients treated with long-acting muscarinic antagonists (LAMA) (43 ml/year) compared with the control group (49 ml/year), providing evidence that LAMA also slows the rate of decline.15 However, these observed effects are relatively small and to be of clinical benefit, these therapies likely need to start early in the course of disease and be prolonged.16 To date, there is a lack of evidence on the effect of triple therapy (ICS/LABA/LAMA) on lung function decline, although several RCTs have found adding a LAMA to ICS/LABA to improve lung function.3-6 Current COPD management guidelines recommend dual and triple therapy, including inhaled corticosteroids (ICS) to be reserved for patients with more severe airflow limitation 11,17 (FEV1<50% predicted). However, triple therapy is often prescribed earlier than GOLD guidelines recommend. A previous study analysing medical records data from the Optimum Patient Care Research Database (OPCRD) suggested that of all patients prescribed triple

15 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 therapy, 25% had this prescribed within 1 year of diagnosis, irrespective of GOLD classification.18 As lung function data are captured in electronic health records in the UK, there is a unique opportunity to study whether early treatment with triple therapy has a beneficial effect on lung function decline. The Lung Health Study (LHS) was a multicentre clinical trial that recruited 5,887 heavy smokers, aged 35-59 years with mild to moderate COPD (FEV1% predicted 55-90%) in 1986- 1988 when recommended pharmacological treatment for COPD was limited to short-acting bronchodilators.19 Patients were randomly assigned to 3 arms of usual care and intervention (smoking cessation) with or without ipratropium. Based on annual follow-up spirometry data during the first 5 years and an extended follow-up measurement at about the 11th year collected in this study, Zafari et al. recently published an externally validated model to predict the natural history of FEV1 decline over time in patients on minimal treatment.7 This framework will allow to enable risk stratification of patients with mild to moderate COPD in terms of their future lung function decline under minimal therapy and to identify patients with rapid disease progression, who can be targeted for intervention.7

16 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 1.2 Rationale COPD manifests itself with symptoms of dyspnoea, chronic cough or sputum, mostly at the time of mild to moderate airflow limitation. To date, there is no conclusive clinical trial evidence that any existing medication for COPD modifies the long-term decline in lung- function.11 Recently reported clinical trials have demonstrated modest effects to slow lung function decline in patients with COPD. However, to be of clinical benefit, these therapies likely need to start early in the course of disease and be prolonged. To our knowledge, the effectiveness of triple therapy as an intervention in patients who were identified as being at high risk of rapid future lung function decline at early stages of disease and who are most likely to benefit from preventive therapies, has never been studied..

This study aims to study 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. First, the study will validate the accuracy of the model developed by Zafari et al. to predict the future rate of FEV1 decline under minimal therapy using lung function test results extracted from General Practice (GP)’s electronic medical records in the UK. Second, the study will characterise patients identified by the prediction model as being at high risk of rapid FEV1 decline under minimal therapy at two moments in time: at first diagnosis of mild to moderate COPD and at initiation of maintenance therapy. Characteristics will be compared with those from patients not at high risk. The third and fourth sub-studies will focus on patients who were identified as being at high risk of rapid lung function decline by the prediction model applied at the time of first diagnosis of mild to moderate COPD. For sub-study 3, FEV1 values recorded during maintenance therapy will be compared with predicted values for minimal inhalation therapy within patients identified as being at high risk of rapid lung function decline by the prediction model. Analyses will be performed for patients with first maintenance therapy being a single inhaler, dual therapy and triple therapy separately. In the fourth sub-study, the effectiveness of triple therapy on FEV1 decline will be studied in a matched study design with similar patients on minimal therapy or patients who are persistently non-adherent to maintenance therapy included in the control arm.

17 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 2. OBJECTIVES AND HYPOTHESES

2.1 First Objective & Hypothesis

Hypothesis: In patients diagnosed with mild to moderate COPD, the rate of FEV1 decline under minimal inhalation therapy corresponds well with the rate of decline predicted by the model published by Zafari et al. using GP’s electronic medical records.

Objective: In later objectives, the Zafari model – a prediction model for lung function decline under minimal therapy- will be used to identify patients at high risk of rapid FEV1 decline. Thus, our first objective concerns the validation of this model: To study whether the observed FEV1 decline during minimal inhalation therapy in patients diagnosed with mild or moderate COPD corresponds with the rate of decline predicted by the model of Zafari et al. 2.2 Second Objective & Hypothesis

Objective: To characterise patients at high risk of rapid FEV1 decline at the time they were identified when diagnosed with mild or moderate COPD and at the time of initiation of maintenance therapy and to compare these characteristics with those of patients not being at high risk of rapid FEV1 decline. 2.3 Third Objective & Hypothesis Hypothesis: Treatment with maintenance therapy, particularly triple therapy, will reduce the rate of lung function decline in patients diagnosed with mild or moderate COPD who are at high risk of rapid lung function decline.

Objective: To compare observed FEV1 values recorded during maintenance therapy with predicted values for minimal inhalation therapy within patients identified as being at high risk of rapid lung function decline by the prediction model. 2.4 Fourth Objective & Hypothesis Hypothesis: Treatment with maintenance therapy, particularly triple therapy, will reduce the rate of lung function decline in patients diagnosed with mild or moderate COPD who are at high risk of rapid lung function decline.

Objective: To study the effectiveness of triple therapy on slowing down the rate of FEV1 decline in patients who were identified as being at high risk of rapid FEV1 decline by comparing the rate of FEV1 decline in patients during triple therapy with that of similar patients during minimal therapy or poor adherence to maintenance therapy.

18 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 3. METHODOLOGY

3.1 Study Design – General Aspects 3.1.1 Objective 1: Validation of Zafari prediction model Patients who are newly diagnosed with mild or moderate COPD and have a positive history of tobacco smoking will be identified at the time of their first FEV1 recording, that is within 3 months prior to and 12 months after their COPD diagnosis. This point will be called Index Date 1 (ID1). Patients will be followed from ID1 until the date at which maintenance therapy is introduced, which will be called Index Date 2 (ID2). All FEV1 values recorded under minimal therapy (no therapy, or short-acting bronchodilators only) during this period between ID1 and ID2 will be used for analyses in patients. The recorded FEV1 values will be compared with the individual’s predicted values at that time as calculated from the model published by Zafari et al.7 (Figure 3) The prediction model will be considered valid when a coverage probability of at least 80% will be achieved (% of observed FEV1 values that fall within the 95% prediction interval for that observation).

Figure 3. Study design objectives 1-3

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3.1.2 Objective 2: Characterisation of patients at high risk of rapid lung function decline If the Zafari model was found to accurately predict the rate of decline in patients with mild to moderate COPD, this model will be used to select patients with a high probability of rapid FEV1 decline under minimal therapy. These patients will be characterised at two moments in time: at time of identification (first FEV1 recording at or around time of first diagnosis of mild to moderate COPD (ID1)) and at the date of initiation of maintenance therapy (ID2). Characteristics will be compared with those from patients not at high risk (Figure 3). If the Zafari model was found not to provide accurate estimates of the predicted rate of decline, a similar new prediction model will be developed from OPCRD data and validated in CPRD data.

3.1.3 Objective 3: Comparison of observed FEV1 decline under maintenance therapy with predicted decline under minimal therapy Patients identified as being at high risk of rapid lung function decline under minimal therapy will be selected using the prediction model (either Zafari or newly-created model). The index date (ID2) will be the date of first initiation of maintenance therapy (Figure 3). All FEV1 values recorded during the period of maintenance therapy will be compared with the patient’s own predicted values under minimal therapy at the same date. Analyses will be performed for patients with first maintenance therapy being a single inhaler, dual therapy and triple therapy separately. FEV1 values recorded after a switch from the first maintenance therapy option to another will not be considered.

3.1.4 Objective 4: Effectiveness of triple therapy on lung function decline Patients identified as being at high risk of rapid lung function decline under minimal therapy, who are initiated on triple therapy will be matched to similar patients from a combined group of patients on minimal therapy or patients who are persistently non-adherent to maintenance therapy (Medication Possession Ratio for maintenance therapies < 40% in 3 consecutive years prior to index date (ID3)). Individual growth models will be used to compare the observed rate of FEV1 decline after ID3 between these two study arms.

3.1.5 Data Source(s) Patient data will be extracted from two large UK primary care databases that will be combined to a single dataset: the Optimum Patient Care Research Database (OPCRD)20 and the Clinical Practice Research Datalink (CPRD).21 The OPCRD is developed, maintained, and owned by Optimum Patient Care (OPC), a social enterprise company that aims to improve patient outcomes through medical research and services. OPC provides evidence-based recommendations to UK general practices through bespoke software and practice reports. The OPCRD currently comprises longitudinal medical records for over 3 million patients from over 601 primary care practices across the UK. It has received a favorable opinion from the Health Research Authority for clinical research use (REC reference: 15/EM/0150). Governance is provided by The Anonymous Data Ethics Protocols and Transparency

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(ADEPT) committee, an independent body of experts and regulators commissioned by the Respiratory Effectiveness Group (REG, http://www.effectivenessevaluation.org/) to govern the standard of research conducted on internationally recognized databases. The CPRD contains de-identified, longitudinal data from 5 million active medical records from more than 600 subscribing practices throughout the UK. It has been widely used for medical and health research. The study will be performed in compliance with all applicable local and international laws and regulations, including without limitation ICH E6 guidelines for Good Clinical Practices. All research conducted by OPRI will be registered on established study databases such as the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP, http://www.encepp.eu/). OPCRD and CPRD data have been combined in multiple previous studies conducted by OPRI. A unique dataset is provided for each study with only the variables necessary to inform the study objectives included. From pooling of data from these two databases for previous studies conducted by OPRI, we observed a 2–4% overlap and we have no reason to expect the percentage overlap to be different from this. We remove duplicates as standard procedure. Throughout construction of the data set for analysis, patient records remained unidentifiable. Initially, the study will use the OPCRD dataset for interim results. This will be followed with the use of a combined CPRD/OPCRD dataset for final results. Hospital Episode Statistics (HES) linkage with CPRD is required to identify COPD-related hospitalisations (HES APC), A&E attendances (HES A&E) and outpatient visits (HES outpatient) for COPD. These analyses will be adjusted for socio-economic status (quintiles of practice-level index of Multiple Deprivation), a potential confounder. 3.2 Study Population The study population will consist of patients with COPD who are registered at general practices providing data to OPCRD and CPRD across England, Scotland, Wales, and Northern Ireland 3.3 Inclusion Criteria 3.3.1 Overall inclusion criteria 1. A diagnostic Read code for COPD as from January 1 2005 (date of first diagnostic Read code / Medcode is ID0) (Appendix 7.1) 2 2. Valid spirometry recorded in period between 3 months before and 12 months after ID0 (date of spirometry is ID1) 3. Evidence of obstruction, defined as FEV1/FVC<0.7 4. Mild or moderate COPD, i.e. FEV1 % predicted ≥50% and ≤90% at ID1 5. Age ≥35 years at ID0 6. ≥1 year of of “up-to-standard” medical records prior to ID1 for baseline characterisation 7. A positive history of tobacco smoking at the time of first COPD diagnosis (ID0) at any recording of smoking status prior to ID0 or at first recording after ID0

2 Time period following QOF indicator for spirometry confirmed COPD diagnosis

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8. Recorded height at adult age (≥21 years) and weight within 5 years of ID1

3.3.2 Additional inclusion criteria objective 1 3 1. “Up-to-standard” follow-up period covering ≥1 spirometry records after ID1 2. Period of minimal inhalation therapy immediately following ID1, defined as no inhalation therapy or only short-acting bronchodilators prescriptions (definition at paragraph 4.2.1)

3.3.3 Additional inclusion criteria objective 3

1. Identified as being at high risk of rapid FEV1 decline at ID1, defined as ≥80% probability of >40ml FEV1 decline per year over 11 years, using prediction model 2. Initiation of maintenance inhalation therapy at any time during follow-up after ID1 (definition at paragraph 4.2.2) (Date of initiation is index date 2 (ID2) 3. “Up-to-standard” follow-up period covering ≥1 spirometry records after ID2

3.3.4 Additional inclusion criteria objective 4

1. Identified as being at high risk of rapid FEV1 decline at ID1, defined as ≥80% probability of >40ml FEV1 decline per year, using prediction model 2. Period of treatment at any time during follow-up after ID1 with (definitions at paragraph of 4.2): a. Triple therapy b. Control therapy: iii. Minimal inhalation therapy for ≥ 1 year iv. Poor adherence to maintenance inhalation therapy other than triple therapy for ≥3 consecutive years Date of triple therapy initiation or matched control date is index date 3 (ID3) 3. “Up-to-standard” follow-up period covering ≥2 follow-up spirometry records during period after ID3

3.4 Exclusion Criteria 1. Active asthma at or after date of first COPD diagnosis, defined as ≥1 diagnostic Read code for asthma or ≥1 asthma monitoring or review Read code recorded (Appendix 7.2) 2. Diagnostic medcode (109958) or Read code (H3B.. or Xac33) for Asthma-COPD overlap syndrome as first COPD diagnostic code or recorded during follow-up 3. Diagnostic medcode or Read code for other chronic lower respiratory 4. Diagnostic medcode or Read code for other chronic lower respiratory conditions recorded ever (Appendix 7.3)

3 The NICE guideline for COPD recommends follow-up reviews, which includes measurement of FEV1. Reviews should be performed at least annually for people with mild/moderate/severe COPD (stages 1–3). The % of patients with a record of FEV1 in the preceding 12 months is a QOF indicator.

22 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 4. VARIABLES AND EPIDEMIOLOGICAL MEASUREMENTS

4.1 Predictors of Zafari model The following variables will be assessed to predict the rate of decline (ml/year) using the Zafari model: 4 1. Baseline FEV1 assessed within 3 months before and 12 months after first COPD diagnostic Read code measured under minimal therapy (paragraph 4.2.1). (ID1) 2. Age at baseline FEV1 recording 3. Sex 4. Weight (kg), closest to ID1, recorded within 5 years 5. Height (m), closest to ID1, recorded after age of 21 6. Smoking history, with the following categories, assessed during the first 5 years of 5 follow-up after ID1 a. Continuous smokers, defined as being recorded as a current smoker at all recordings b. Sustained quitters, defined as being recorded as an ex-smoker at all recordings c. Intermittent quitters, varying recording of being current and ex-smoker 7. Follow-up time from ID1 8. Smoking cessation intervention within 3 months (advice or drugs) after ID1 9. Short-acting bronchodilator prescription within 3 months after ID1

4.2 Therapy exposure

4.2.1 Period of minimal inhalation therapy

A period of minimal inhalation therapy is defined as the absence of any inhalation therapy or prescriptions for short-acting bronchodilators from the time of spirometry recording closest to first COPD diagnosis (ID1). This period will end at the time of initiation of maintenance inhalation therapy (ID2), loss to follow-up or death.

4.2.2 Period of maintenance inhalation therapy

Several objectives specify patients should have a period of maintenance inhalation therapy. This period should include ≥2 prescriptions for the drugs and starts with the date of first prescription of LAMA and/or LABA and/or ICS after ID1 and ends with the absence of prescriptions for >120 days for the same drug, at loss to follow-up or death. Three separate periods will be distinguished: 1. Monotherapy, therapy with one single inhaler (LAMA or LABA or ICS). The period starts at the date of first prescription (ID2), which should be followed by ≥1 repeat prescription within 30 days after prescription duration, and ends when there is no

4 Time period following QOF indicator for spirometry confirmed COPD diagnosis 5 If smoking status is unrecorded in the first 5 years of follow-up, the most recent recording prior to ID1 will be used, assuming that there was no change in smoking behaviour

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consecutive prescription of any of the drugs within 120 days6 of the first repeat prescription. A switch to another type of monotherapy is allowed during follow-up as long as the second drug is prescribed within 120 days of the last prescription of the first drug and there is no consecutive prescription of the first drug. 2. Dual therapy, the presence of overlapping periods covered by ≥ 2 prescriptions for each of two inhalers, i.e. prescription for a second drug at index date while the first drug is still active (based on number of days prescribed at most recent prescription prior to index date) or prescribed at the same date. Drugs need to be followed by a repeat prescription within 30 days after end of prescription duration during follow-up. 3. Triple therapy (paragraph 4.2.3).

4.2.3 Period of triple therapy

A period of triple therapy is defined as the presence of overlapping periods covered by prescriptions for LAMA, LABA and ICS. The period starts at the date when the third drug was dispensed and the first two were still active (based on number of days prescribed at most recent prescription prior to index date) or prescribed at the same date. Drugs need to be followed by a repeat prescription within 30 days after end of prescription duration during follow-up. The period of triple therapy ends with absence of prescriptions for any of the three drugs for >120 days.

4.2.4 Period of poor adherence to maintenance inhalation therapy Objective 4 investigates patients with a period of poor adherence. This period will be defined as a Medication Possession Ratio <40% for LABA, LAMA and ICS in the last 3 consecutive years prior to ID3.

4.3 High risk of rapid FEV1 decline

The primary definition of rapid FEV1 decline will be a predicted decline of ≥40 ml/year over 7 the next 11 years at ID1 following Zafari et al . The primary definition of high risk of rapid decline will be ≥80%. For objective 2, characteristics of patients at high risk of rapid decline will be described for the following combinations of probability of rate of decline: Probability of Cut-point definition rapid FEV decline (ml/year) rapid decline 1 25% 40 50% 40 75% 40 80% 30 40 50 60

6 Prescription data in OPCRD and CPRD do not allow accurate estimation of the duration of a prescription for all patients. Therefore a standard duration of 30 days is assumed. Two consecutive prescriptions will be considered part of the same period if the gap between the end of this period of 30 days and the next prescription will be ≤90 days (≤120 days between two prescriptions)

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4.4.1 Primary end-point objective 4: Rate of FEV1 decline

The change in FEV1 over time, expressed as ml/year of follow up, will be estimated using a multilevel model for change as described in paragraph 5.1.4.2

4.4.2 Secondary endpoints objective 4: Matched comparison of patients on triple therapy with patients on minimal therapy The following secondary outcomes will be analysed:

4.4.2.1 Time to first COPD exacerbation / Exacerbation rate Both the time to the first COPD exacerbation and the number of COPD exacerbations in the first year of follow-up after ID3 (for those who have complete follow-up) will be analysed as secondary outcomes of the analyses for objective 4. COPD exacerbations will be defined as the occurrence of at least one of the following events:  COPD-related hospital attendance / admission AND/OR  Respiratory-related A&E attendance AND/OR  An acute oral corticosteroid (OCS) course AND/OR  Antibiotics prescribed with evidence of a lower respiratory consultation Hospital admissions and A&E attendances will be identified from Read codes / Medcodes referring to a COPD specific admission / attendance or a general admission or attendance code with evidence of a lower respiratory consultation code on the same day (Appendix code lists for symptoms, COPD diagnostic codes and lower respiratory infections). A sensitivity analyses will be performed using HES APC and A&E data in the subpopulation of patients with HES linkage available. Using HES, COPD-related hospital admissions will be identified as hospital spells with ICD-10 codes J40-J44: any COPD-related code as primary diagnosis. Respiratory-related A&E attendances will be identified as events with respiratory conditions as diagnostic code (diag2=25) or ICD-10 codes J40-J44 (first 3 positions diag). Where ≥1 of these events occurred within 2 weeks of each other, they were considered to be the result of the same exacerbation (and only counted once). OCS or antibiotics prescribed at the same day as a COPD review performed within the framework of QOF will not be considered. 4.4.2.2 Time to first hospitalisation for COPD Hospital Episode Statistics (HES), linked to CPRD will be required to analyse the time to the first hospital admission for COPD as primary diagnosis, analysed as secondary outcome.

Two definitions will be used to define occurrence of a hospital admission (spell) for COPD: a. ICD-10 codes J44.0 or J44.1: COPD exacerbations as primary diagnosis

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4.4.2.3 Treatment success Treatment success will be defined over the first year of follow-up as the absence of COPD exacerbations.

4.5 Other Variables and Covariates

4.5.1 Baseline characteristics 1. Age group at index date (years): 2. Sex 3. Smoking status, Read code closest to and within 5 years prior to index date a. Ex-smoker b. Current smoker 4. BMI, calculated from height and weight data if available7 and taken from practice recorded BMI value if not, within 10 years prior to index date a. Underweight: <18.5 b. Normal weight: ≥18.5 and <25 c. Overweight: ≥25 and <30 d. Obese: ≥30 5. Socio-economic status (quintiles of practice-level index of Multiple Deprivation) for analyses on time to hospitalisation performed in CPRD data only

4.5.2 Comorbidities 6. Comorbidities: a. Asthma ever (asthma or monitoring code recorded ever) b. Allergic / non-allergic rhinitis a. Never b. Active8 c. Ever, not active c. Eczema diagnosis a. Never b. Active, defined a diagnostic Read code in baseline year c. Ever, not active d. Nasal polyps ever e. Chronic sinusitis diagnosis ever f. Gastro-oesophageal reflux disease (GERD) g. Diabetes Mellitus ever h. Osteoporosis ever i. Hypertension ever j. Ischaemic heart disease ever

7 Weight (kg) divided by height (metres) squared 8 Active’ refers to those for which a diagnosis was recorded within the baseline year and/or a prior diagnosis was accompanied by a prescription for the comorbidity within the baseline year.

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k. Heart failure ever l. Depression ever m. Anxiety ever n. Obstructive Sleep apnoea ever o. Sleep disorders ever p. Chronic kidney disease ever

7. Charlson co-morbidity index: based on diagnoses ever a. ≤1 b. 2-4 c. ≥5

4.5.3 Clinical characteristics 8. Type of COPD diagnosed (Read code), Emphysema, Bronchitis or Unspecified/Other 9. Modified Medical Research Council (mMRC) dyspnoea score, within 5 years of the index date (see Appendix 7.5): a. 0-1 b. ≥2 c. Unknown 10. Degree of airflow limitation, FEV1% predicted, mean (SD) and categorical: a. Mild: FEV1% predicted ≥80% b. Moderate: FEV1% predicted 50–79% c. Severe: FEV1% predicted 30–49% d. Very severe: FEV1% predicted <30%

22 The formula used to predict FEV1 will be :

For Males: Predicted FEV1= (4.30 x height (m)) – (0.029 x age - 2.49) For Females: Predicted FEV1= (3.95 x height (m)) – (0.025 x age - 2.60)

11. GOLD groups, defined based on a combined assessment of degree of dyspnoea and exacerbation risk following 2017 GOLD recommendations: a. GOLD A: ≤1 COPD exacerbation9 and no hospitalization for COPD in baseline year and mMRC 0–1 b. GOLD B: ≤1 COPD exacerbation and no hospitalization for COPD in baseline year and mMRC ≥2 c. GOLD C: ≥2 COPD exacerbations or ≥1 hospitalization for COPD in baseline year) and mMRC 0–1

9 COPD exacerbation, as the occurrence of one or more of the following events: a. COPD-related hospital attendance / admission AND/OR b. COPD-related A&E attendance AND/OR c. An acute oral corticosteroid course AND/OR d. Antibiotics prescribed with evidence of a lower respiratory consultation

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d. GOLD D: ≥2 COPD exacerbations or ≥1 hospitalization for COPD in baseline year) and mMRC ≥2 e. Unknown 12. Number of COPD exacerbations in the baseline year (definition at paragraph 4.4.2.1) 13. Number of respiratory related outpatient visits in the baseline year 14. Number of COPD-related hospital admissions in the baseline year 15. Number of respiratory-related A&E attendances in the baseline year 16. Acute oral corticosteroids courses, number prescribed in the baseline year 17. Antibiotic courses, number prescribed in the baseline year 18. Cumulative daily dose10 of oral corticosteroids prescribed in baseline year, categorised as; none, <2.5, ≥2.5 and <5, ≥5 and <7.5, and ≥7.5 mg 19. Cumulative daily doses of SABA prescribed in baseline year, grouped as; none, 1-100, 101-200, 201-300, 301-400, and >400 mcg/day, salbutamol equivalent 20. Cumulative daily dose of SAMA prescribed in baseline year, grouped as; none, 1-20, 21-40, 41-60, 61-80, and >80 mcg/day, ipratropium equivalent 21. GP consultations, all and COPD-related

5. STATISTICAL ANALYSIS PLAN

5.1 Statistical Methods – General Aspects

Summary statistics are provided for all variables, for the complete dataset and by patient’s comparison groups. For continuous variables, these include:

 Sample size (n)  Percentage non-missing  Mean ± Standard Deviation for normally distributed variables  Median and Inter-quartile Range (25th and 75th percentiles) for non-normally distributed variables For number of events per year, the summary statistics include:

 Sample size (n)  Count and Percentage by category (distribution): 0, 1, 2, 3 and ≥4 For other categorical variables, the summary statistics include:

 Sample size (n)  Count and Percentage by category (distribution) Characteristics are compared using the chi-squared test for categorical variables in case of sufficient subjects per group compared otherwise, a non-parametric Fisher test will be

10 the cumulative dose prescribed over the baseline year expressed as average dose per day, calculated as: (number of inhalers prescribed in baseline year * doses in pack) / 365) * mcg strength)

28 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 performed. The Kruskal-Wallis equality-of-populations rank test will be used for variables on a continuous or ordinal scale.

5.1.1 First objective(s): Validation of Zafari prediction model

Baseline characteristics of paragraph 4.5.1 will be described for the study population.

5.1.1.1 Validation of predicted FEV1 values during follow up under minimal therapy

In patients with mild or moderate COPD, all FEV1 values captured in the combined databases when the patient was on minimal therapy will be compared to predicted values using the model developed by Zafari et al.7 (See Appendix 7.2). The validity of FEV1 prediction will be assessed in 3 ways: 1. A scatterplot will be produced to plot the observed FEV1 values by the predicted values. 2. The overall root mean squared error (RMSE) of the predicted versus observed FEV1 value will be calculated 3. The coverage probability, defined as the proportion of the observed FEV1 values falling within the 95% prediction interval for that observation will be determined If the Zafari model does not correspond well with the database results, a new model predicting FEV1 in primary care patients will be developed using all the baseline characteristics from OPCRD and validated externally on the data from CPRD. Model fit statistics will be used to assess goodness-of-fit of the model and external validation will be carried out as per validation of the Zafari prediction model. A sensitivity analysis will be performed within the age range 35-60 years following the study by Zafari.

5.1.2 Second objective: Characterisation of patients at high risk of rapid lung function decline

Patient characteristics of paragraph 4.5.1 will be described in patients identified as being at high risk of rapid lung function decline at two moments in time: at time of identification (first FEV1 recording at or around time of first diagnosis of mild to moderate COPD) and at the date of initiation of maintenance therapy. Characteristics will be compared with those from patients not at high risk using the tests described previously to compare summary statistics.

5.1.3 Third Objective: Comparison of individual observed lung function decline under maintenance therapy with predicted rate under minimal therapy

The absolute difference between the individual’s observed FEV1 values after initiation of maintenance therapy and his/her predicted values at that same date (calculated from the Zafari model) will be calculated. The differences will be compared for patients initiated on therapy with a single inhaler, dual therapy and triple therapy. FEV1 values recorded after a switch from the first maintenance therapy category to another will not be considered. The distribution of the individual differences between observed and predicted FEV1 values will be plotted by duration of therapy for the different therapy options separately.

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A linear mixed model will be used with the absolute difference between observed and predicted FEV1 value as the outcome variable to estimate the influence of duration of therapy, taking repeated measurements within patients into account. A mean lower value of 10 ml at the time of maintenance therapy will be considered relevant.

5.1.4 Fourth Objective: effectiveness of triple therapy on lung function decline and secondary COPD outcomes 5.1.4.1 Matching

Potential confounders of the association between triple therapy and the rate of FEV1 decline are identified based on a combination of baseline imbalance, bias potential and expert judgement, and the most relevant confounders will be used for direct matching. Direct matching can only use a limited number of variables to match on without restricting the patient population too much, and it is therefore necessary to exclude variables that do not relevantly affect the association of interest. After matching this approach will be repeated in the matched sample to identify any residual confounding, selecting confounders for direct adjustment in the outcome analyses. Patients will be directly matched on the availability of CPRD-HES linkage in order to be able to perform the analyses on the secondary outcome of hospitalisation within the same study populations if numbers of patients that can be matched are not substantially reduced.

Baseline balance A characterisation of all baseline demographic, co-morbidity, indicators of disease severity and other patient characteristic variables will be carried out and presented for each arm. The difference between the arms will be quantified using the Standardized Mean Difference (SMD).23 This measure is not affected by the number of observations, and thus a better way to judge imbalance than a p-value of a hypothesis test of difference. The SMD will be calculated for both continuous and categorical variables as described in Table 1. An SMD ≤0.1 indicates sufficient balance between the treatment and the reference (control) group.

Table 1. Formulae for Standardised Mean Difference Covariate type Formula

Continuous (푥̅̅̅푡− 푥̅̅̅푟̅ ) 푆푀퐷 = 2 2 , √푠푡 + 푠푟 2

where 푥̅푡 , 푥̅̅̅푟̅ denote the sample means and 푠푡 ,푠푟 the standard deviations

(푝̂ − 푝̂) Binary 푆푀퐷 = 푡 푟 , √푝̂푡(1−푝̂푡)+푝̂푟(1−푝̂푟) 2

where 푝̂푡 , 푝̂푟 denote the proportion of patients in each category

Categorical (>2 categories) 푆푀퐷 = √(푇 − 퐶)′푆−1(푇 − 퐶)

where 푆 is a (푘 − 1) × (푘 − 1) covariance matrix:

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푝1̂ 푘 (1 − 푝1̂ 푘) + 푝̂2푘 (1−푝̂ ) 2푘 , 푘 = 푙 푆 = [푆 ] = { 2 푘푙 푝̂ 푝̂ + 푝̂ 푝̂ 1푘 1푙 2푘 2푙 , 푘 ≠ 푙 2

, 푇 = (푝12̂ , … , 푝1̂ 푘 )′ , 퐶 = (푝̂22 , … , 푝̂2푘 )′ and 푝̂푗푘 = 푃 (푐푎푡푒푔표푟푦 푘|푡푟푒푎푡푚푒푛푡 푎푟푚 푗) , 푗 = 1,2 , 푘 = 2,3, … , 푘

Bias potential Bias potential assesses the degree to which the observed association between the exposure of interest and the outcome is affected by conditioning on the variable. Bias potential will be measured using the relative change in coefficient (RCC) of the exposure when the covariate is added into the model predicting the primary outcome.

Table 2. Formulae for Relative Change in Co-efficient Outcome type Regression type Formula

Continuous Linear (훽푐푟푢푑푒 − 훽푎푑푗푢푠푡푒푑) 푅퐶퐶 = 푎푏푠 { } 훽푐푟푢푑푒

Binary Logistic

Time-to-event Cox-Proportional 푅퐶퐶 = 푎푏푠(1 − 푒(훽푐푟푢푑푒− 훽푎푑푗푢푠푡푒푑)) Hazard

Count Poisson

Where 훽푐푟푢푑푒the co-efficient of exposure in the crude is model and 훽푎푑푗푢푠푡푒푑 is the co-efficient of exposure after adding the covariate in the model.

It is called bias potential since the bias was estimated without other covariates in the model. To what extent a variable introduces bias into a model will depend on the total model. Baseline balance and bias potential statistics will be presented to the steering committee with recommendations for the final selection of variables to be used for matching. In general, this will include unbalanced characteristics (SMD>0.1) with bias potential defined as more than 2% change in coefficient (RCC>0.02).

Matching process Exact matching for categorical variables and matching within a maximum calliper (maximum distance allowed within matched pairs) for continuous variables will be used to match patients using nearest neighbour variable mixed matching with a match maximum of 1:3 without replacement. In case of multiple eligible periods for a patient, only one period can contribute to the matching. Matching will be repeated several times with a different patient sequence to select

31 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 the run that results in the highest number of patients and/or the best baseline balance. The actual number of variables used for the matching will largely depend on the degree of restriction caused by the matching process. In case too many patients are excluded, because they cannot be matched to controls, the number of matching variables will be reduced or the calliper of individual variables will be increased. In case no satisfactory number of matched patients can be achieved with a minimum set of confounders, a different approach towards handling confounding will be chosen. These methods include propensity score based approaches (using the score for matching, regression adjustment or inverse probability of treatment weighting (IPTW)) or direct regression adjustment. Missing data will be treated as missing completely at random and will not be imputed, except for the numbers of days that a prescription drug was supplied, where a selective imputation based on previous dosing and future dosing information for that individual and for that drug will be used. If the information is still missing, mode numbers of doses given per day for a given drug strength and number of doses per prescription will be imputed. If a selected confounder has more than 20% of missing data it will not be used for matching. If the percentage of missing data is below 20%, the variable will be encoded into a categorical variable, adding a category for the observations with missing values, enabling this variable to be used for matching.

Post-matching evaluation The quality of the matching will be evaluated using the same methods as used to identify the confounders: standardised mean difference in combination with bias potential. For each outcome cohort baseline characterisation of the matched sample will be carried out using the same statistics as used in the unmatched baseline characterisation: descriptive statistics, standardised mean difference and bias potential. All variables with less than 10% missing values in each treatment arm, showing a bias potential of at least 2% will be identified and analyses will be adjusted for these confounders.

5.1.4.2 Outcome analyses objective 4

For the primary outcome analyses, the change in FEV1 over time during the therapy under study will be analysed using a multilevel model for change. The level-1 component of this model will be the individual growth model, representing the change in FEV1 over time within patients. The level-2 component codifies the mean difference in FEV1 decline within matched pairs and the level-3 component will represent the mean population difference in lung function decline between the two study arms. Mixed linear regression will be used to analyse the data. Intercept and slope will be modelled as random effects (to vary across individuals). A matched-pair specific random effect will be added to the model next to covariates representing potential confounders. FEV1 values after a therapy change will not be considered.

For analysing time-to-event outcomes, unadjusted Kaplan-Meier estimates of the survivor functions are plotted for the matched study arms. Patients will be censored at loss to follow-up or death, but not at a therapy change as this is likely to be related to the risk of event occurrence (informative censoring). A stratified log-rank test will be performed to statistically test significance of observed differences.24

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A stratified Cox proportional hazard model will be used to estimate the hazard ratio with 95% confidence interval for the association between therapy and time to the first event. The analytic start time for the analysis will be ID3.

Conditional negative binomial regression will be used to estimate the adjusted rate ratio with 95% confidence interval for the association between therapy and the number of COPD exacerbations in the first year of follow-up for those who have complete follow-up.

Conditional logistic regression analyses will be used to estimate the adjusted odds ratio with 95% confidence interval for the association between therapy and treatment success over the first year of follow-up.

5.2 Bias

5.2.1 Methods to Minimize Bias

Bias by indication in the analyses of objective 4 will be addressed by matching. Confounders are identified based on a combination of baseline imbalance, bias potential and expert judgement, and the most important ones are used for direct matching. After matching this approach is repeated in the matched sample to identify any residual confounding, selecting confounders for direct adjustment in the outcome analyses.

5.2.2 Strengths and Limitations

1. The OPCRD and CPRD datasets represent information collected for clinical and routine use rather than specifically for research purposes. Although extensive quality control and validity checks are conducted at the practice level, the validity and completeness of individual patient records cannot be assessed. Although annual review of patients with COPD, including spirometry is part of the Quality Outcomes Framework, the incentive programme for all GP surgeries in the UK, missing data will occur. 2. Misclassification of patients with diagnosed COPD cannot be excluded, although Read codes alone were found to be sufficient to identify patients with COPD25 3. The Lung Health Study (LHS) was a long-term clinical trial of smoking intervention and inhaled short-acting bronchodilator therapy in middle-aged smokers with mild to moderate COPD recruited in 1986-88 at the time that maintenance therapy was not indicated. Patients from OPCRD/CPRD on minimal therapy after first diagnosis may therefore differ from patients recruited for the LHS. 4. COPD is a heterogeneous disease with variation in individual rates of lung function decline. The Zafari model is inevitably a simplified version of the underlying disease processes.7 5. The Zafari prediction model was based on 5 years with annual spirometry through the Lung Health Study. The extension to 11 years was based on a final follow up of patients who were not lost to follow up, who may/may not have had treatment changes outside of minimal treatment.

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6. Lung function measurements after a change in therapy will not be considered in order to study the effect of the treatment under study, which may bias the results in case the rate of lung function decline is different in patients who change therapy from patients who continue to be followed. 7. There are multiple strategies adopted by health care workers when recording acute COPD exacerbations in the UK Electronic Health Records. A validation study of several methods of identifying COPD exacerbations found that only about one half of the events were recorded using specific diagnostic Read codes, whilst the remaining events were recorded only as prescriptions of COPD-specific antibiotics and/or OCS.26 Our algorithm has not specifically been validated, but is in line with the recommendation to use a combination of OCS and/or antibiotics prescriptions with evidence of a lower respiratory consultation. 8. Only known and measurable patient characteristics can be accounted for in matched analyses. Residual confounding or indication bias can therefore not be excluded. 9. Not all patients in GOLD are eligible to be linked to HES. 10. Recording of the diagnosis condition leading to an A&E attendance is not mandatory resulting in low levels of recording. This will potentially impact the identification of COPD-related events in A&E

5.3 Sample Size and Power Calculations

A feasibility check in OPCRD found more than 6,000 patients with COPD who fulfilled the inclusion and exclusion criteria for objective 1. At least a similar amount of patients are expected to be available from CPRD. Zafari et al found that the interval for the annual rate of decline that contained 95% of individuals was -83 to 15 ml/year for sustained quitters and -124 to -15 ml/year for smokers with standard deviations of 25 and 28 ml/year respectively.7 Assuming a standard deviation of 28 ml/year for the annual decline, 166 patients would be required in both study arms of objective 4 to find a 10 ml lower decline in patients treated with triple therapy, assuming a 40 ml decline in the selected group of rapid decliners under minimal therapy (30 ml vs. 40 ml) with 90% statistical power and α=0.05 The power analyses will be updated based on the results from objective 1 to provide more accurate information on the variability of FEV1 decline.

5.4 Communication Plan

5.4.1 Publication Plan

Results will be published in a manuscript.

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1. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet (London, England). 2009;374(9696):1171-1178. 2. Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178(4):332-338. 3. Singh D, Brooks J, Hagan G, Cahn A, O'Connor BJ. Superiority of "triple" therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD. Thorax. 2008;63(7):592-598. 4. Frith PA, Thompson PJ, Ratnavadivel R, et al. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Thorax. 2015;70(6):519-527. 5. Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet (London, England). 2016;388(10048):963-973. 6. Siler TM, Kerwin E, Singletary K, Brooks J, Church A. Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, Double-Blind Studies. Copd. 2016;13(1):1-10. 7. Zafari Z, Sin DD, Postma DS, et al. Individualized prediction of lung-function decline in chronic obstructive pulmonary disease. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2016;188(14):1004-1011. 8. Global Initiative for Chronic Obstructive Lung Disease I. POCKET GUIDE TO COPD DIAGNOSIS, MANAGEMENT, AND PREVENTION. 2016. 9. (WHO) WHO. Burden of COPD. 2016. 10. (WHO) WHO. Chronic Obstructive Pulmonary Disease (COPD). 2016. 11. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from: http://www.goldcopd.org/. 12. Fletcher C, Peto R. The natural history of chronic airflow obstruction. British medical journal. 1977;1(6077):1645-1648. 13. Tantucci C, Modina D. Lung function decline in COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:95-99. 14. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775- 789. 15. Decramer M, Celli B, Kesten S, et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009;374(9696):1171- 1178.

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16. Gladysheva ES, Malhotra A, Owens RL. Influencing the decline of lung function in COPD: use of pharmacotherapy. Int J Chron Obstruct Pulmon Dis. 2010;5:153-164. 17. Centre NCG. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care London: National Clinical Guideline Centre. Available from: http://guidance.nice.org.uk/CG101/Guidance/pdf/English. National Clinical Guideline Centre;2010. 18. Brusselle G, Price D, Gruffydd-Jones K, et al. The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. Int J Chron Obstruct Pulmon Dis. 2015;10:2207-2217. 19. Anthonisen NR. Lessons from the Lung Health Study. Proceedings of the American Thoracic Society. 2004;1(2):143-145. 20. Optimum Patient Care Research Database (OPCRD) http://optimumpatientcare.org/opcrd/. 21. The Clinical Practice Research Datalink https://www.cprd.com/home/. 22. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. The European respiratory journal Supplement. 1993;16:5-40. 23. Stuart EA. Matching methods for causal inference: A review and a look forward. Statistical science : a review journal of the Institute of Mathematical Statistics. 2010;25(1):1-21. 24. Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Statistics in Medicine. 2014;33:1242-1258. 25. Quint JK, Mullerova H, DiSantostefano RL, et al. Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD- GOLD). BMJ open. 2014;4(7):e005540. 26. Rothnie KJ, Mullerova H, Hurst JR, et al. Validation of the Recording of Acute Exacerbations of COPD in UK Primary Care Electronic Healthcare Records. PloS one. 2016;11(3):e0151357.

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7.1 Diagnostic Read codes for COPD

Medcode Readcode Term 794 H32..00 Emphysema 998 H3...11 Chronic obstructive airways disease 1001 H3...00 Chronic obstructive pulmonary disease 3243 H31..00 Chronic bronchitis 5710 H3z..00 Chronic obstructive airways disease NOS 5798 H312000 Chronic asthmatic bronchitis 5909 H312011 Chronic wheezy bronchitis 9876 H38..00 Severe chronic obstructive pulmonary disease 10802 H37..00 Moderate chronic obstructive pulmonary disease 10863 H36..00 Mild chronic obstructive pulmonary disease 10980 H322.00 Centrilobular emphysema 11150 H311.00 Mucopurulent chronic bronchitis 12166 H3y..00 Other specified chronic obstructive airways disease 14798 H312100 Emphysematous bronchitis 15157 H31z.00 Chronic bronchitis NOS 15626 H310000 Chronic catarrhal bronchitis 16410 H32yz00 Other emphysema NOS 23492 H320z00 Chronic bullous emphysema NOS 24248 H313.00 Mixed simple and mucopurulent chronic bronchitis 25603 H310.00 Simple chronic bronchitis 26125 H312300 Bronchiolitis obliterans 26306 H320.00 Chronic bullous emphysema 27819 H312.00 Obstructive chronic bronchitis 33450 H32z.00 Emphysema NOS 37247 H3z..11 Chronic obstructive pulmonary disease NOS 37959 H311100 Fetid chronic bronchitis 40159 H311000 Purulent chronic bronchitis 40788 H32y.00 Other emphysema 44525 H312z00 Obstructive chronic bronchitis NOS 45089 H31y100 Chronic tracheobronchitis 46578 H321.00 Panlobular emphysema 56860 H320000 Segmental bullous emphysema 59263 H32y111 Acute interstitial emphysema 60188 H320200 Giant bullous emphysema

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61118 H310z00 Simple chronic bronchitis NOS 61513 H311z00 Mucopurulent chronic bronchitis NOS 63216 H464100 Obliterative bronchiolitis due to chemical fumes 63479 H32y200 MacLeod's unilateral emphysema 64721 H464000 Chronic emphysema due to chemical fumes 65733 Hyu3100 [X]Other specified chronic obstructive pulmonary disease 66043 H31y.00 Other chronic bronchitis 66058 Hyu3000 [X]Other emphysema 67040 H3y..11 Other specified chronic obstructive pulmonary disease 68066 H31yz00 Other chronic bronchitis NOS 68662 H320100 Zonal bullous emphysema 70787 H32y100 Atrophic (senile) emphysema 92955 H32y000 Acute vesicular emphysema 93568 H39..00 Very severe chronic obstructive pulmonary disease 99536 H320300 Bullous emphysema with collapse 103733 H320311 Tension pneumatocoele 104608 H3A..00 End stage chronic obstructive airways disease 106650 H583200 Eosinophilic bronchitis 109958 H3B..00 Asthma-chronic obstructive pulmonary disease overlap syndrome 111668 H32yz11 Sawyer - Jones syndrome

38 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 MEDCODE Read_code Read_term 78 H33.. Asthma 185 H333. Acute exacerbation of asthma 232 H33z1 Asthma attack 233 H33z0 Status asthmaticus NOS 1208 H330. Extrinsic (atopic) asthma 1555 H33.. Asthma 2290 H330. Extrinsic (atopic) asthma 3018 663V1 Mild asthma 3366 663V3 Severe asthma 3458 663V0 Occasional asthma 3665 H331. Intrinsic asthma 4442 H33z. Asthma unspecified 4606 H33zz Asthma NOS 4892 H33z0 Status asthmaticus NOS 5267 H331. Intrinsic asthma 5627 H3300 Extrinsic asthma without status asthmaticus 5798 H3120 Chronic asthmatic bronchitis 5867 173A. Exercise induced asthma 5909 H3120 Chronic asthmatic bronchitis 6707 H3301 Extrinsic asthma with status asthmaticus 7058 8H2P. Emergency admission, asthma 7146 H330. Extrinsic (atopic) asthma 7191 663P. Asthma limiting activities 7378 663U. Asthma management plan given 7416 663N. Asthma disturbing sleep 7731 H330. Extrinsic (atopic) asthma 8335 H33z1 Asthma attack 9018 663y. Number of asthma exacerbations in past year 9552 66Y5. Change in asthma management plan 9663 66Y9. Step up change in asthma management plan 10043 66YJ. Asthma annual review 10274 8B3j. Asthma medication review 10487 663j. Asthma - currently active 11022 178.. Asthma trigger 11370 1O2.. Asthma confirmed 12987 H33z2 Late-onset asthma 13064 663V. Asthma severity 13065 663V2 Moderate asthma 13173 663O. Asthma not disturbing sleep

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13174 663Q. Asthma not limiting activities 13175 663N2 Asthma disturbs sleep frequently 14777 H3300 Extrinsic asthma without status asthmaticus 15248 H330. Extrinsic (atopic) asthma 16070 H33zz Asthma NOS 16667 8795. Asthma control step 2 16785 8794. Asthma control step 1 18207 H33zz Asthma NOS 18223 66YA. Step down change in asthma management plan 18224 8796. Asthma control step 3 18323 H3311 Intrinsic asthma with status asthmaticus 18692 9hA.. Exception reporting: asthma quality indicators 19519 663p. Asthma treatment compliance unsatisfactory 19520 663n. Asthma treatment compliance satisfactory 20860 8798. Asthma control step 5 20886 8797. Asthma control step 4 21232 H33zz Asthma NOS 22752 173c. Occupational asthma 24479 663d. Emergency asthma admission since last appointment 24506 8791. Further asthma - drug prevent. 24884 663u. Asthma causes daytime symptoms 1 to 2 times per week 25181 663e. Asthma restricts exercise 25796 H332. Mixed asthma 26496 679J. Health education - asthma 26501 663s. Asthma never causes daytime symptoms 26503 663v. Asthma causes daytime symptoms most days 26504 663f. Asthma never restricts exercise 26506 6630. Asthma severely restricts exercise 26861 663e0 Asthma sometimes restricts exercise 27926 H3301 Extrinsic asthma with status asthmaticus 29325 H3310 Intrinsic asthma without status asthmaticus 29645 8793. Asthma control step 0 30815 663N0 Asthma causing night waking 31225 663t. Asthma causes daytime symptoms 1 to 2 times per month 32727 H33z. Asthma unspecified 38143 663O0 Asthma never disturbs sleep 38144 663w. Asthma limits walking up hills or stairs 38145 663x. Asthma limits walking on the flat 38146 663N1 Asthma disturbs sleep weekly 39570 663r. Asthma causes night symptoms 1 to 2 times per month 40823 H334. Brittle asthma 41017 1780. Aspirin induced asthma

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42824 663q. Asthma daytime symptoms 45073 H331z Intrinsic asthma NOS 45782 H330z Extrinsic asthma NOS 47337 663m. Asthma accident and emergency attendance since last visit 47684 H47y0 Detergent asthma 58196 H3311 Intrinsic asthma with status asthmaticus 93736 388t. Royal College of Physicians asthma assessment 93738 388t. Royal College of Physicians asthma assessment 98185 38DL. Asthma control test 99793 8CMA0 Patient has a written asthma personal action plan 100107 679J0 Health education - asthma self management 100397 38DT. Asthma control questionnaire 100740 679J1 Health education - structured asthma discussion 102170 66Yp. Asthma review using Roy Colleg of Physicians three questions 102209 38DV. Mini asthma quality of life questionnaire 102301 1787. Asthma trigger - seasonal 102341 1781 Asthma trigger - pollen 102395 66Yr. Asthma causes symptoms most nights 102400 66Yq. Asthma causes night time symptoms 1 to 2 times per week 102449 1789. Asthma trigger - respiratory infection 102713 663P0 Asthma limits activities 1 to 2 times per month 102871 178B. Asthma trigger - exercise 102888 663P1 Asthma limits activities 1 to 2 times per week 102952 1783. Asthma trigger - warm air 103318 679J2 Health education - structured patient focused asthma discuss 103321 1786. Asthma trigger - animals 103631 388t0 Royal College Physician asthma assessment 3 question score 103813 1788. Asthma trigger - cold air 103944 178A. Asthma trigger - airborne dust 103945 1785. Asthma trigger - damp 103952 1784. Asthma trigger - emotion 103955 1782. Asthma trigger - tobacco smoke 103998 663P2 Asthma limits activities most days 106805 H335. Chronic asthma with fixed airflow obstruction 109958 H3B.. Asthma-chronic obstructive pulmonary disease overlap syndrom Xac33 Asthma-chronic obstructive pulmonary disease overlap syndrome Xaa7B Chronic asthma with fixed airflow obstruction XaLPE Nocturnal asthma X101x Allergic asthma XE0YQ Allergic atopic asthma XE0ZP Extrinsic asthma - atopy (& pollen) X1021 Allergic non-atopic asthma

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X101y Extrinsic asthma with asthma attack X101z Allergic asthma NEC XE0YR Extrinsic asthma without status asthmaticus XE0YS Extrinsic asthma with status asthmaticus XE0YT Non-allergic asthma X1022 Intrinsic asthma with asthma attack XE0YU Intrinsic asthma with status asthmaticus X1024 Aspirin-sensitive asthma with nasal polyps Xa0lZ Asthmatic bronchitis Xa9zf Acute asthma X102D Status asthmaticus XE0YV Status asthmaticus NOS XE0YW Asthma attack XM0s2 Asthma attack NOS Ua1AX Brittle asthma X101u Late onset asthma XE0YX Asthma NOS XE0ZR Asthma: [intrinsic] or [late onset] XE0ZT Asthma: [NOS] or [attack] X1020 Hay fever with asthma XM1Xb Asthma monitoring XaIeq Asthma annual review XaIfK Asthma medication review XaR8K Did not attend asthma review XaYZB Asthma self-management plan review XaIu5 Asthma monitoring by nurse XaIu6 Asthma monitoring by doctor XaX3n Asthma review using Royal College of Physicians three questions Xac8 Telehealth asthma monitoring XaIRN Asthma monitoring due XaBU2 Asthma monitoring call Xabj3 Asthma monitoring invitation email Xabiu Asthma monitoring invitation SMS (short message service) text message Asthma monitoring SMS (short message service) text message third XacM1 invitation Asthma monitoring SMS (short message service) text message second XacM0 invitation Asthma monitoring SMS (short message service) text message first XacLz invitation XE2Na Asthma monitoring admin. XM1U3 Asthma clinic administration XaBU3 Asthma monitoring status

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XaIRN Asthma monitoring due XE2Nb Asthma monitoring check done YE1mA Asthma monitored (& check done) Xa8Hn Asthma control steps XaDvK Asthma - currently active XaIfK Asthma medication review XaIIW Asthma accident and emergency attendance since last visit XaIIX Asthma treatment compliance satisfactory XaIIY Asthma treatment compliance unsatisfactory XaIIZ Asthma daytime symptoms XaINa Asthma never causes daytime symptoms XaINb Asthma causes daytime symptoms 1 to 2 times per month XaINc Asthma causes daytime symptoms 1 to 2 times per week XaINd Asthma causes daytime symptoms most days XaINf Asthma limits walking up hills or stairs XaINg Asthma limits walking on the flat XaINZ Asthma causes night symptoms 1 to 2 times per month XaIoE Asthma night-time symptoms XaIQ4 Change in asthma management plan XaIQD Step up change in asthma management plan XaIQE Step down change in asthma management plan XaIuG Asthma confirmed XaNKw Royal College of Physicians asthma assessment XaQHq Asthma control test XaQig Asthma control questionnaire XaQih Mini asthma quality of life questionnaire XaRFi Patient has a written asthma personal action plan XaRFj Health education - asthma self management XaRFk Health education - structured asthma discussion XaRFl Health education - structured patient focused asthma discussion XaXa0 Royal College of Physicians asthma assessment three questions score XaXZm Asthma causes night time symptoms 1 to 2 times per week XaXZp Asthma causes symptoms most nights XaXZs Asthma limits activities 1 to 2 times per month XaXZu Asthma limits activities 1 to 2 times per week XaXZx Asthma limits activities most days XaY2V Asthma never causes night symptoms XaYb8 Asthma self-management plan agreed XaYZB Asthma self-management plan review

43 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 7.3 Read codes other chronic respiratory conditions MEDCODE Read_code Read_term 2680 23E5. O/E - fibrosis of lung present 7994 23E5. O/E - fibrosis of lung present 16741 A114. Tuberculous fibrosis of lung 14913 A1202 Tuberculous hydrothorax 65117 A7899 HIV disease resulting in lymphoid interstitial pneumonitis 33980 AD50. Sarcoidosis of lung 58841 AD52. Sarcoidosis of lung with sarcoidosis of lymph nodes 72595 AD54. Sarcoidosis of inferior turbinates 34075 B2... Malig neop of respiratory tract and intrathoracic organs 45307 B2... Malig neop of respiratory tract and intrathoracic organs 13243 B22.. Malignant neoplasm of trachea, bronchus and lung 15221 B220. Malignant neoplasm of trachea 103946 B2201 Malignant neoplasm of mucosa of trachea 37810 B220z Malignant neoplasm of trachea NOS 12870 B221. Malignant neoplasm of main bronchus 17391 B2210 Malignant neoplasm of carina of bronchus 33444 B2211 Malignant neoplasm of hilus of lung 21698 B221z Malignant neoplasm of main bronchus NOS 10358 B222. Malignant neoplasm of upper lobe, bronchus or lung 20170 B222. Malignant neoplasm of upper lobe, bronchus or lung 31700 B2220 Malignant neoplasm of upper lobe bronchus 25886 B2221 Malignant neoplasm of upper lobe of lung 44169 B222z Malignant neoplasm of upper lobe, bronchus or lung NOS 31268 B223. Malignant neoplasm of middle lobe, bronchus or lung 41523 B2230 Malignant neoplasm of middle lobe bronchus 39923 B2231 Malignant neoplasm of middle lobe of lung 54134 B223z Malignant neoplasm of middle lobe, bronchus or lung NOS 31188 B224. Malignant neoplasm of lower lobe, bronchus or lung 18678 B2240 Malignant neoplasm of lower lobe bronchus 12582 B2241 Malignant neoplasm of lower lobe of lung 42566 B224z Malignant neoplasm of lower lobe, bronchus or lung NOS 36371 B225. Malignant neoplasm of overlapping lesion of bronchus & lung 7484 B226. Mesothelioma 38961 B22y. Malignant neoplasm of other sites of bronchus or lung 2587 B22z. Malignant neoplasm of bronchus or lung NOS 3903 B22z. Malignant neoplasm of bronchus or lung NOS 31573 B23.. Malignant neoplasm of pleura 67107 B230. Malignant neoplasm of parietal pleura 106194 B231. Malignant neoplasm of visceral pleura

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9600 B232. Mesothelioma of pleura 98104 B23y. Malignant neoplasm of other specified pleura 34742 B23z. Malignant neoplasm of pleura NOS 62556 B24.. Malignant neoplasm of thymus, heart and mediastinum 27715 B242. Malignant neoplasm of anterior mediastinum 92720 B243. Malignant neoplasm of posterior mediastinum 61064 B24X. Malignant neoplasm of mediastinum, part unspecified 100232 B24y. Malig neop of other site of heart, thymus and mediastinum 66750 B24z. Malignant neoplasm of heart, thymus and mediastinum NOS 39531 B25.. Malig neo, overlapping lesion of heart, mediastinum & pleura 66646 B26.. Malignant neoplasm, overlap lesion of resp & intrathor orgs 44356 B2z.. Malig neop other/ill-defined sites resp/intrathoracic organs 65793 B2z0. Malig neop of upper respiratory tract, part unspecified 29283 B2zy. Malignant neoplasm of other site of respiratory tract 42569 B2zz. Malignant neoplasm of respiratory tract NOS 6471 B57.. Secondary malig neop of respiratory and digestive systems 24301 B57.. Secondary malig neop of respiratory and digestive systems 35053 B57.. Secondary malig neop of respiratory and digestive systems 4137 B570. Secondary malignant neoplasm of lung 51551 B571. Secondary malignant neoplasm of mediastinum 16213 B572. Secondary malignant neoplasm of pleura 62584 B573. Secondary malignant neoplasm of other respiratory organs 66083 B57z. Secondary malig neop of respiratory or digestive system NOS 64050 B81.. Carcinoma in situ of respiratory system 51714 B811. Carcinoma in situ of trachea 9267 B812. Carcinoma in situ of bronchus and lung 49159 B8120 Carcinoma in situ of carina of bronchus 35058 B8121 Carcinoma in situ of main bronchus 37579 B8122 Carcinoma in situ of upper lobe bronchus and lung 47897 B8123 Carcinoma in situ of middle lobe bronchus and lung 52373 B8124 Carcinoma in situ of lower lobe bronchus and lung 25372 B812z Carcinoma in situ of bronchus or lung NOS 59426 B81y. Carcinoma in situ of other specified part respiratory system 97954 B81y. Carcinoma in situ of other specified part respiratory system 46497 B81y0 Carcinoma in situ of pleura 40595 Byu20 [X]Malignant neoplasm of bronchus or lung, unspecified 93380 C10N1 Cystic fibrosis related diabetes mellitus 6220 C370. Cystic fibrosis 13264 C370. Cystic fibrosis 24137 C370. Cystic fibrosis 65344 C3700 Cystic fibrosis with no meconium ileus 36622 C3701 Cystic fibrosis with meconium ileus

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69017 C3701 Cystic fibrosis with meconium ileus 18914 C3702 Cystic fibrosis with pulmonary manifestations 18905 C3703 Cystic fibrosis with intestinal manifestations 100610 C3704 Arthropathy in cystic fibrosis 103224 C3705 Cystic fibrosis with distal intestinal obstruction syndrome 110454 C3707 Liver disease due to cystic fibrosis 102922 C3708 Cystic fibrosis related cirrhosis 106432 C3709 Exacerbation of cystic fibrosis 73065 C370y Cystic fibrosis with other manifestations 49770 C370z Cystic fibrosis NOS 11312 H35.. Extrinsic allergic alveolitis 103637 H35.. Extrinsic allergic alveolitis 15588 H350. Farmers' lung 62200 H351. Bagassosis 27345 H352. Bird-fancier's lung 54822 H3520 Budgerigar-fanciers' lung 31447 H3521 Pigeon-fanciers' lung 36240 H352z Bird-fancier's lung NOS 93206 H353. Suberosis ( cork-handlers' lung ) 67709 H354. Malt workers' lung 41694 H355. Mushroom workers' lung 56652 H356. Maple bark strippers' lung 51858 H35y. Other allergic alveolitis 91989 H35y0 Cheese-washers' lung 53943 H35y1 Coffee-workers' lung 70286 H35y2 Fish-meal workers' lung 45427 H35y5 Pituitary snuff-takers' disease 93353 H35y6 Sequoiosis (red-cedar asthma) 39478 H35y7 Wood asthma 69452 H35y8 Air-conditioner and humidifier lung 55552 H35yz Other allergic alveolitis NOS 62442 H35z0 Allergic extrinsic alveolitis NOS 11833 H35z1 Hypersensitivity pneumonitis NOS 21257 H4... Lung disease due to external agents 21973 H4... Lung disease due to external agents 25013 H4... Lung disease due to external agents 19492 H40.. Coal workers' pneumoconiosis 8303 H41.. Asbestosis 5005 H410. Pleural plaque disease due to asbestosis 100994 H410. Pleural plaque disease due to asbestosis 51410 H41z. Asbestosis NOS 46460 H42.. Silica and silicate pneumoconiosis

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60805 H420. Talc pneumoconiosis 62233 H421. Simple silicosis 71853 H422. Complicated silicosis 89206 H423. Massive silicotic fibrosis 23446 H42z. Silica pneumoconiosis NOS 65376 H43.. Pneumoconiosis due to other inorganic dust 94894 H431. Bauxite fibrosis of lung 49194 H432. Berylliosis 94575 H433. Graphite fibrosis of lung 30235 H434. Siderosis 93577 H435. Stannosis 23461 H43z. Pneumoconiosis due to inorganic dust NOS 60313 H44.. Pneumopathy due to inhalation of other dust 37365 H440. Byssinosis 26442 H441. Cannabinosis 73414 H44z. Pneumopathy due to inhalation of other dust NOS 31423 H45.. Pneumoconiosis NOS 63172 H450. Pneumoconiosis associated with tuberculosis 31722 H46.. Respiratory disease due to chemical fumes and vapours 47142 H464. Chronic respiratory conditions due to chemical fumes 63216 H4641 Obliterative bronchiolitis due to chemical fumes 47782 H4642 Chronic pulmonary fibrosis due to chemical fumes 70815 H464z Chronic respiratory conditions due to chemical fumes NOS 104557 H465. Chemical-induced pulmonary oedema 48647 H46z. Respiratory conditions due to chemical fumes NOS 33663 H46zz Respiratory conditions due to chemical fumes NOS 41015 H4710 Lipoid pneumonia (exogenous) 43285 H48.. Progressive massive fibrosis 38985 H4y.. Other specified lung diseases due to external agent 69914 H4y1. Chronic pulmonary radiation disease 22536 H4y10 Chronic pulmonary fibrosis following radiation 50374 H4y1z Chronic pulmonary radiation disease NOS 44015 H4y2. Drug-induced interstitial lung disorders 43417 H4y21 Chronic drug-induced interstitial lung disorders 55557 H4yy. Other external agent causing respiratory condition 62707 H4yz. External agent causing respiratory conditions NOS 34001 H4z.. Lung disease due to external agents NOS 66856 H5000 Empyema with bronchocutaneous fistula 34651 H5001 Empyema with bronchopleural fistula 99547 H5004 Empyema with pleural fistula NOS 6624 H5010 Pleural abscess 44425 H5012 Pleural empyema

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38052 H5013 Lung empyema NOS 46628 H5015 Pyopneumothorax 102492 H510C Pleural plaque 30065 H51y. Other pleural effusion excluding mention of tuberculosis 57092 H51y0 Encysted pleurisy 7593 H51y7 Malignant pleural effusion 18081 H51yz Other pleural effusion 947 H51z. Pleural effusion NOS 30214 H54.. Pulmonary congestion and hypostasis 38297 H540. Pulmonary hypostasis 46405 H540z Pulmonary hypostasis NOS 26082 H5410 Chronic pulmonary oedema 7321 H541z Pulmonary oedema NOS 61229 H54z. Pulmonary congestion and hypostasis NOS 7791 H55.. Postinflammatory pulmonary fibrosis 40953 H55.. Postinflammatory pulmonary fibrosis 31806 H56.. Other alveolar and parietoalveolar disease 61119 H560. Pulmonary alveolar proteinosis 27348 H561. Idiopathic pulmonary haemosiderosis 68814 H562. Pulmonary alveolar microlithiasis 5519 H563. Idiopathic fibrosing alveolitis 6837 H563. Idiopathic fibrosing alveolitis 63174 H563. Idiopathic fibrosing alveolitis 103753 H563. Idiopathic fibrosing alveolitis 94136 H5630 Alveolar capillary block 6051 H5631 Diffuse pulmonary fibrosis 103472 H5632 Pulmonary fibrosis 103559 H5633 Usual interstitial pneumonitis 28229 H563z Idiopathic fibrosing alveolitis NOS 33830 H56yz Other alveolar and parietoalveolar disease NOS 15815 H56z. Alveolar and parietoalveolar disease NOS 54010 H57y0 Pulmonary amyloidosis 3859 H57y2 Pulmonary sarcoidosis 31319 H5830 Loeffler's syndrome 39706 H5840 Postoperative pulmonary oedema 93880 H5850 Pulmonary insufficiency following shock 72221 H5851 Pulmonary insufficiency following surgery 96754 H5852 Pulmonary insufficiency following trauma 24466 H58y0 Broncholithiasis 8317 H58y3 Interstitial lung disease NEC 103785 H58y5 Respiratory bronchiolitis associated interstitial lung dis 109815 H58y6 Interstitial lung disease due to collagen vascular disease

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104915 H58y7 Interstitial lung disease due to connective tissue disease 11665 H5X.. Pleural condition, unspecified 49709 H5y30 Fibrosis of mediastinum 59188 Hy02. Chronic pulmonary insufficiency following surgery 110883 Hyu4. [X]Lung diseases due to external agents 105939 Hyu40 [X]Pneumoconiosis due to other dust containing silica 53851 Hyu42 [X]Airway disease due to other specific organic dusts 106515 Hyu43 [X]Hypersensitivity pneumonitis due to other organic dusts 110881 Hyu44 [X]Upper resp inflammation/chemicals,gases,fumes,vapours,NEC 105628 Hyu48 [X]Chronic+other pulmonary manifestations due to radiation 100577 Hyu49 [X]Respiratory conditions/other specified external agents 106925 Hyu4A [X]Respiratory conditions due to unspecified external agent 54706 Hyu5. [X]Other resp diseases principally affecting interstitium 65060 Hyu50 [X]Other interstitial pulmonary diseases with fibrosis 91912 Hyu51 [X]Other specified interstitial pulmonary diseases 54669 Hyu6. [X]Suppurative & necrotic conditions of lower respir tract 52850 Hyu70 [X]Pleural effusion in conditions classified elsewhere 56427 P861. Congenital bronchiectasis 38298 PK35. Kartagener's syndrome 93098 SP130 Mendelson's syndrome as a complication of care X00lU Nasal sarcoidosis X00nm Laryngeal sarcoidosis X100V Chronic pulmonary coccidioidomycosis X1012 Benign asbestos pleural effusion X1013 Drug-induced pleural effusion X1014 Meigs syndrome X101a Primary ciliary dyskinesia due to transposition of ciliary microtubules X101b Immotile cilia syndrome due to defective radial spokes X101c Immotile cilia syndrome due to excessively long cilia X101d Young's syndrome X101e Rutland ciliary disorientation syndrome X101T Pleural plaque X101U Asbestos-induced pleural plaque X102c Post-upper airway obstruction pulmonary oedema X102d Toxic pulmonary oedema X102e Chemical-induced pulmonary oedema X102F Allergic bronchopulmonary aspergillosis X102I Pulmonary histiocytosis X X102J Animal handlers' lung Seasonal cryptogenic organising pneumonia with biochemical X102k cholestasis X102K Dog house disease

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X102l Diffuse infiltrative lung disease X102L Dry rot lung X102M Lycoperdonosis X102n Idiopathic diffuse pulmonary ossification X102N Wheat weevil disease X102o Micronodular pulmonary ossification X102O New Guinea lung X102p Diffuse pulmonary neurofibromatosis X102P Paprika splitters' lung X102q Pulmonary tuberose sclerosis X102Q Pyrethrum alveolitis X102R Rodent handlers' lung X102s Pulmonary lipid storage disease X102S Sewage workers' lung X102t Bronchocentric granulomatosis X102T Summer-type hypersensitivity pneumonitis X102U Vineyard sprayers' lung X102u Fibrosis of lung X102V Interstitial lung disease X102v Usual interstitial pneumonitis X102w Desquamative interstitial pneumonitis X102x Lymphoid interstitial pneumonitis X102y Giant cell interstitial pneumonitis X102Z Neurogenic pulmonary oedema X1030 Toxic diffuse interstitial pulmonary fibrosis X1031 Drug-induced diffuse interstitial pulmonary fibrosis X1032 Localised pulmonary fibrosis X1033 Mediastinal radiation fibrosis X103a Erionite pneumoconiosis X103b Kaolin pneumoconiosis X103c Metal pneumoconiosis X103d Antimony pneumoconiosis X103e Argyro-siderosis X103f Barium pneumoconiosis X103G Radiation-induced fibrous mediastinitis X103i Chronic berylliosis X103j Cerium pneumoconiosis X103k Hard metal pneumoconiosis X103l Nickel pneumoconiosis X103m Thorium pneumoconiosis X103N Mediastinal lymph node sarcoidosis X103n Zirconium pneumoconiosis

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X103o Mica pneumoconiosis X103p Mixed mineral dust pneumoconiosis X103q Liparosis X103r Slate pneumoconiosis X103s Diatomite pneumoconiosis X103v Chronic silicosis X103W Simple pneumoconiosis X103w Silicotuberculosis X103X Complicated pneumoconiosis X103x Wollastonite pneumoconiosis X103Y Rheumatoid pneumoconiosis X103Z Bentonite pneumoconiosis X1043 Stage 1 pulmonary sarcoidosis X1044 Stage 2 pulmonary sarcoidosis X1045 Stage 3 pulmonary sarcoidosis X1046 Stage 4 pulmonary sarcoidosis X1047 Endobronchial sarcoidosis X1048 Necrotising sarcoid granulomatosis X1049 Sarcoid pulmonary calcification X2032 Pulmonary tumour embolism X20GM Nasopharyngeal sarcoidosis X309R Cystic fibrosis of pancreas X70Qb Chronic necrotising pulmonary aspergillosis X70Ra Chronic pulmonary African histoplasmosis X70Rg Chronic pulmonary blastomycosis X77nT Carcinoid bronchial adenoma X78kV Metastasis to bronchus X78kX Secondary lymphangitic carcinoma X78kY Lymphangitis carcinomatosa X78Py Tumour of lower respiratory tract X78Q6 Tumour of bronchus X78Q7 Malignant tumour of bronchus X78Q8 Squamous cell carcinoma of bronchus X78QA Carcinoma in situ of bronchus X78QD Papilloma of bronchus X78QE Tumour of lung parenchyma X78QF Malignant tumour of lung parenchyma X78QG Adenocarcinoma of lung X78QI Carcinoid tumour of lung X78QJ Carcinoma of lung parenchyma X78QK Large cell carcinoma of lung X78QL Clear cell carcinoma of lung

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X78QM Giant cell carcinoma of lung X78QN Small cell carcinoma of lung X78QO Oat cell carcinoma of lung X78QP Squamous cell carcinoma of lung X78QQ Epithelioid haemangioendothelioma of lung X78QR Lymphomatoid granulomatosis of lung X78QS Non-small cell lung cancer X78QT Pancoast tumour X78QU Carcinoma in situ of lung parenchyma X78QW Histiocytoma of lung X78QX Adenoma of lung X78QY Intrapulmonary teratoma X78QZ Hamartoma of lung Xa08A Chronic pulmonary insufficiency of prematurity Xa0IL Malignant pleural effusion Xa0kb Tropical pulmonary eosinophilia Xa0KF Tumour of lung Xa0KG Malignant tumour of lung Xa0lb Pleural effusion Xa0Xi Pulmonary lymphangioleiomyomatosis Xa3A4 Metastasis to bronchus of unknown primary Xa3A5 Metastasis to lung of unknown primary Xa6YO Pulmonary oedema Xa98a Bronchial adenoma Xa9Bw Pneumoconiosis Xa9By Diffuse pulmonary calcinosis XaB1L Haemorrhagic pleural effusion XaBAp Bronchioloalveolar adenocarcinoma of lung XaBDb Cystic fibrosis with other manifestations XaCL7 Sarcoidosis of inferior turbinates XaEJe Squamous cell carcinoma of bronchus in left lower lobe XaEJf Squamous cell carcinoma of bronchus in left upper lobe XaEJg Squamous cell carcinoma of bronchus in right lower lobe XaEJh Squamous cell carcinoma of bronchus in right middle lobe XaEJi Squamous cell carcinoma of bronchus in right upper lobe XaFr7 Local recurrence of malignant tumour of lung XaJlX [X]Hepatopulmonary syndrome XaMzI Cystic fibrosis related diabetes mellitus XaREa Liver disease due to cystic fibrosis XaREX Arthropathy in cystic fibrosis XaREZ Cystic fibrosis with distal intestinal obstruction syndrome XaXlE Respiratory bronchiolitis associated interstitial lung disease

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XaXlF Interstitial lung disease due to collagen vascular disease XaXlJ Interstitial lung disease due to connective tissue disease XaZr7 Exacerbation of cystic fibrosis XE0Ya Post-inflammatory pulmonary fibrosis XE0Yb Cryptogenic fibrosing alveolitis XE0Yd Trauma and postoperative pulmonary insufficiency XE0Ye Adult respiratory distress syndrome XE0YY Lung disease due to external agents XE0Zn Lung: [pulmonary oedema NOS] or [congestion] XE0Zr Idiopath. fibrosing alveolitis (& Hamman-Rich syndrome) XE0ZZ (Pneumoconiosis NOS) or (siderosis) XE1vb Malignant neoplasm of upper lobe, bronchus or lung XE1vc Malignant neoplasm of bronchus or lung NOS XE1yJ Ca main bronchus XE1yL Ca upper lobe bronchus/lung XE1yN Ca middle lobe bronchus/lung XE1yP Ca lower lobe bronchus/lung XE2wL Tuberculous pleural empyema XE2wM Pleural empyema XE2wN Pleural empyema with fistula XE2wP Pleural empyema with no fistula XE2wR Pleural empyema NOS

53 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 7.4 Zafari prediction model

The Zafari model predicts the FEV1 value and the rate of decline in ml/year at different follow-up times7. The regression formula is: FEV1t = β0 + β.X + β0'.t + β'.X.t + β0".t2 + (intsmo + intipra) + e with FEVt representing FEV1 at tth follow-up year and e representing an independent nor- mally distributed error term. X’s are the set of covariates. Intercept, β0, and slope, β0', were modelled as random effect (to vary across individuals), and other coefficients were modelled as fixed effect. β coefficients predict the baseline FEV1 and β' coefficients predict the slope of FEV1 change over time, β0" captures the potential nonlinear component of decline, and intsmo and intipra represent smoking-cessation and ipratropium interventions that model 1-time jump in FEV1 after the baseline visit for those who quit smoking or received ipratropium (these 2 variables were set to 0 for all 3 arms for the baseline visit because baseline FEV1 was measured before the initiation of interventions). This model connects serial FEV1 measurements for an individual through a multivariate normal distribution, enabling conditional prediction of future FEV1 values based on observable characteristics, baseline FEV1 and, potentially, previous FEV1 values as described in appendix 2 of the manuscript.

Table 3. Zafari model predicting baseline FEV1 and rate of decline per year

Baseline FEV1 Rate of FEV1change per year Parameters Effect 95% CI P- Effect 95% CI P- (ml) Value (ml/year) Value Intercept (-1318.79, (-460.76, 1425.8 4170.39) 0.3 -179.5 101.76) 0.2 Baseline age (year) -4.82 (-17.03, 7.39) 0.4 2.36 (1.09, 3.62) 0.0003 Sex (male vs (456.73, (-10.09, - female) 482.8 508.87) <.0001 -7.39 4.7) <.0001 Weight (kg) -0.41 (-1.17, 0.35) 0.3 0.13 (0.05, 0.21) 0.002 Height (m) (-4895.28, (-243.08, -1875.9 1143.48) 0.2 66.8 376.68) 0.7 Height2 (m2) (1082.46, (-73.8, 1952.7 2822.94) <.0001 15.65 105.1) 0.7 Continuous smoker* (vs. sustained (-87.87, - quitters) -76.34 64.81) <.0001 -25.52 (-28.04, -23) <.0001 Intermittent quitter* (vs. sustained (-54.22, - (-13.02, - quitters) -41.59 28.96) <.0001 -10.23 7.44) <.0001 Baseline age* (-1.36, - height2 -8.37 (-12.44, -4.3) <.0001 -0.94 0.52) <.0001

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Time (year) (-0.59, - NA NA NA -0.44 0.29) <.0001 Parameters Effect on one time jump in FEV1 Intervention (19.69, (smoking) 28.3 36.91) <.0001 Intervention (23.63, (ipratropium) 33.34 43.05) <.0001 Appendix to: Zafari Z, Sin DD, Postma DS, et al. Individualized prediction of lung function decline in chronic obstructive pulmonary disease. 95% CI: 95% confidence interval, FEV1: forced expiratory volume in 1 second, variables of this table will predict the rate of FEV1 decline (i.e., FEV1(y) – FEV1 (0)= y * (intercept +ß1 * X1 + ß2 * X2 +….) + ß* intervention + ε, where y represents the year, ‘x’s are the set of covariates, and ε representing an error term). *: dummy variable.

55 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 7.5 MRC Dyspnoea Scale

MRC Dyspnoea Scale Grade Degree of breathlessness related to activity 0 Not troubled by breathless except on strenuous exercise Short of breath when hurrying on a level or when walking up a 1 slight hill Walks slower than most people on the level, stops after a mile or 2 so, or stops after 15 minutes walking at own pace Stops for breath after walking 100 yards, or after a few minutes on 3 level ground Too breathless to leave the house, or breathless when 4 dressing/undressing

56 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017 7.6 Co-morbidities Read codes

7.6.1 Diagnosis of Asthma MEDCODE Read_code Read_term 78 H33.. Asthma 185 H333. Acute exacerbation of asthma 232 H33z1 Asthma attack 233 H33z0 Status asthmaticus NOS 1208 H330. Extrinsic (atopic) asthma 1555 H33.. Asthma 2290 H330. Extrinsic (atopic) asthma 3018 663V1 Mild asthma 3366 663V3 Severe asthma 3458 663V0 Occasional asthma 3665 H331. Intrinsic asthma 4442 H33z. Asthma unspecified 4606 H33zz Asthma NOS 4892 H33z0 Status asthmaticus NOS 5267 H331. Intrinsic asthma 5627 H3300 Extrinsic asthma without status asthmaticus 5798 H3120 Chronic asthmatic bronchitis 5867 173A. Exercise induced asthma 5909 H3120 Chronic asthmatic bronchitis 6707 H3301 Extrinsic asthma with status asthmaticus 7058 8H2P. Emergency admission, asthma 7146 H330. Extrinsic (atopic) asthma 7191 663P. Asthma limiting activities 7378 663U. Asthma management plan given 7416 663N. Asthma disturbing sleep 7731 H330. Extrinsic (atopic) asthma 8335 H33z1 Asthma attack 9018 663y. Number of asthma exacerbations in past year 9552 66Y5. Change in asthma management plan 9663 66Y9. Step up change in asthma management plan 10043 66YJ. Asthma annual review 10274 8B3j. Asthma medication review 10487 663j. Asthma - currently active 11022 178.. Asthma trigger 11370 1O2.. Asthma confirmed 12987 H33z2 Late-onset asthma

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13064 663V. Asthma severity 13065 663V2 Moderate asthma 13173 663O. Asthma not disturbing sleep 13174 663Q. Asthma not limiting activities 13175 663N2 Asthma disturbs sleep frequently 14777 H3300 Extrinsic asthma without status asthmaticus 15248 H330. Extrinsic (atopic) asthma 16070 H33zz Asthma NOS 16667 8795. Asthma control step 2 16785 8794. Asthma control step 1 18207 H33zz Asthma NOS 18223 66YA. Step down change in asthma management plan 18224 8796. Asthma control step 3 18323 H3311 Intrinsic asthma with status asthmaticus 18692 9hA.. Exception reporting: asthma quality indicators 19519 663p. Asthma treatment compliance unsatisfactory 19520 663n. Asthma treatment compliance satisfactory 20860 8798. Asthma control step 5 20886 8797. Asthma control step 4 21232 H33zz Asthma NOS 22752 173c. Occupational asthma 24479 663d. Emergency asthma admission since last appointment 24506 8791. Further asthma - drug prevent. 24884 663u. Asthma causes daytime symptoms 1 to 2 times per week 25181 663e. Asthma restricts exercise 25796 H332. Mixed asthma 26496 679J. Health education - asthma 26501 663s. Asthma never causes daytime symptoms 26503 663v. Asthma causes daytime symptoms most days 26504 663f. Asthma never restricts exercise 26506 6630. Asthma severely restricts exercise 26861 663e0 Asthma sometimes restricts exercise 27926 H3301 Extrinsic asthma with status asthmaticus 29325 H3310 Intrinsic asthma without status asthmaticus 29645 8793. Asthma control step 0 30815 663N0 Asthma causing night waking 31225 663t. Asthma causes daytime symptoms 1 to 2 times per month 32727 H33z. Asthma unspecified 38143 663O0 Asthma never disturbs sleep 38144 663w. Asthma limits walking up hills or stairs

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38145 663x. Asthma limits walking on the flat 38146 663N1 Asthma disturbs sleep weekly 39570 663r. Asthma causes night symptoms 1 to 2 times per month 40823 H334. Brittle asthma 41017 1780. Aspirin induced asthma 42824 663q. Asthma daytime symptoms 45073 H331z Intrinsic asthma NOS 45782 H330z Extrinsic asthma NOS 47337 663m. Asthma accident and emergency attendance since last visit 47684 H47y0 Detergent asthma 58196 H3311 Intrinsic asthma with status asthmaticus 93736 388t. Royal College of Physicians asthma assessment 93738 388t. Royal College of Physicians asthma assessment 98185 38DL. Asthma control test 99793 8CMA0 Patient has a written asthma personal action plan 100107 679J0 Health education - asthma self management 100397 38DT. Asthma control questionnaire 100740 679J1 Health education - structured asthma discussion 102170 66Yp. Asthma review using Roy Colleg of Physicians three questions 102209 38DV. Mini asthma quality of life questionnaire 102301 1787. Asthma trigger - seasonal 102341 1781 Asthma trigger - pollen 102395 66Yr. Asthma causes symptoms most nights 102400 66Yq. Asthma causes night time symptoms 1 to 2 times per week 102449 1789. Asthma trigger - respiratory infection 102713 663P0 Asthma limits activities 1 to 2 times per month 102871 178B. Asthma trigger - exercise 102888 663P1 Asthma limits activities 1 to 2 times per week 102952 1783. Asthma trigger - warm air 103318 679J2 Health education - structured patient focused asthma discuss 103321 1786. Asthma trigger - animals 103631 388t0 Royal College Physician asthma assessment 3 question score 103813 1788. Asthma trigger - cold air 103944 178A. Asthma trigger - airborne dust 103945 1785. Asthma trigger - damp 103952 1784. Asthma trigger - emotion 103955 1782. Asthma trigger - tobacco smoke 103998 663P2 Asthma limits activities most days 106805 H335. Chronic asthma with fixed airflow obstruction 109958 H3B.. Asthma-chronic obstructive pulmonary disease overlap syndrom

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Xac33 Asthma-chronic obstructive pulmonary disease overlap syndrome Xaa7B Chronic asthma with fixed airflow obstruction XaLPE Nocturnal asthma X101x Allergic asthma XE0YQ Allergic atopic asthma XE0ZP Extrinsic asthma - atopy (& pollen) X1021 Allergic non-atopic asthma X101y Extrinsic asthma with asthma attack X101z Allergic asthma NEC XE0YR Extrinsic asthma without status asthmaticus XE0YS Extrinsic asthma with status asthmaticus XE0YT Non-allergic asthma X1022 Intrinsic asthma with asthma attack XE0YU Intrinsic asthma with status asthmaticus X1024 Aspirin-sensitive asthma with nasal polyps Xa0lZ Asthmatic bronchitis Xa9zf Acute asthma X102D Status asthmaticus XE0YV Status asthmaticus NOS XE0YW Asthma attack XM0s2 Asthma attack NOS Ua1AX Brittle asthma X101u Late onset asthma XE0YX Asthma NOS XE0ZR Asthma: [intrinsic] or [late onset] XE0ZT Asthma: [NOS] or [attack] X1020 Hay fever with asthma XM1Xb Asthma monitoring XaIeq Asthma annual review XaIfK Asthma medication review XaR8K Did not attend asthma review XaYZB Asthma self-management plan review XaIu5 Asthma monitoring by nurse XaIu6 Asthma monitoring by doctor XaX3n Asthma review using Royal College of Physicians three questions Xac8 Telehealth asthma monitoring XaIRN Asthma monitoring due XaBU2 Asthma monitoring call Xabj3 Asthma monitoring invitation email Asthma monitoring invitation SMS (short message service) text Xabiu message

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Asthma monitoring SMS (short message service) text message XacM1 third invitation Asthma monitoring SMS (short message service) text message XacM0 second invitation Asthma monitoring SMS (short message service) text message XacLz first invitation XE2Na Asthma monitoring admin. XM1U3 Asthma clinic administration XaBU3 Asthma monitoring status XaIRN Asthma monitoring due XE2Nb Asthma monitoring check done YE1mA Asthma monitored (& check done) Xa8Hn Asthma control steps XaDvK Asthma - currently active XaIfK Asthma medication review XaIIW Asthma accident and emergency attendance since last visit XaIIX Asthma treatment compliance satisfactory XaIIY Asthma treatment compliance unsatisfactory XaIIZ Asthma daytime symptoms XaINa Asthma never causes daytime symptoms XaINb Asthma causes daytime symptoms 1 to 2 times per month XaINc Asthma causes daytime symptoms 1 to 2 times per week XaINd Asthma causes daytime symptoms most days XaINf Asthma limits walking up hills or stairs XaINg Asthma limits walking on the flat XaINZ Asthma causes night symptoms 1 to 2 times per month XaIoE Asthma night-time symptoms XaIQ4 Change in asthma management plan XaIQD Step up change in asthma management plan XaIQE Step down change in asthma management plan XaIuG Asthma confirmed XaNKw Royal College of Physicians asthma assessment XaQHq Asthma control test XaQig Asthma control questionnaire XaQih Mini asthma quality of life questionnaire XaRFi Patient has a written asthma personal action plan XaRFj Health education - asthma self management XaRFk Health education - structured asthma discussion XaRFl Health education - structured patient focused asthma discussion Royal College of Physicians asthma assessment three questions XaXa0 score

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XaXZm Asthma causes night time symptoms 1 to 2 times per week XaXZp Asthma causes symptoms most nights XaXZs Asthma limits activities 1 to 2 times per month XaXZu Asthma limits activities 1 to 2 times per week XaXZx Asthma limits activities most days XaY2V Asthma never causes night symptoms XaYb8 Asthma self-management plan agreed XaYZB Asthma self-management plan review

7.6.2 Allergic or non-allergic rhinitis diagnosis MEDCODE Read_code Read_term 121 H170. Allergic rhinitis due to pollens 175 H17.. Allergic rhinitis 774 H120. Chronic rhinitis 775 H172. Allergic rhinitis due to unspecified allergen 805 H1201 Chronic catarrhal rhinitis 964 H17z. Allergic rhinitis NOS 1108 H18.. Vasomotor rhinitis 1468 H17.. Allergic rhinitis 1838 H170. Allergic rhinitis due to pollens 1930 H171. Allergic rhinitis due to other allergens 2372 H171. Allergic rhinitis due to other allergens 2769 H1201 Chronic catarrhal rhinitis 3162 H171. Allergic rhinitis due to other allergens 3798 H172. Allergic rhinitis due to unspecified allergen 4861 H171. Allergic rhinitis due to other allergens 8975 H120. Chronic rhinitis 13377 H171. Allergic rhinitis due to other allergens 14645 H120z Chronic rhinitis NOS 15553 H1202 Chronic hypertrophic rhinitis 16134 H171. Allergic rhinitis due to other allergens 16158 H1204 Chronic infective rhinitis 16441 H1203 Chronic atrophic rhinitis 18572 H17.. Allergic rhinitis 24163 H170. Allergic rhinitis due to pollens 28589 H1200 Chronic simple rhinitis 30375 H171. Allergic rhinitis due to other allergens 42065 H1206 Chronic membranous rhinitis 42556 H1205 Chronic ulcerative rhinitis

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47599 Hyu21 [X]Other allergic rhinitis 72490 Hyu20 [X]Other seasonal allergic rhinitis 104543 H1207 Chronic fibrinous rhinitis X00ky Rhinitis sicca X00kz Rhinitis caseosa X00l1 Eosinophilic non-allergic rhinitis X00l2 NINA - Non-infective non-allergic rhinitis X00l2 Non-infective non-allergic rhinitis X00l8 Hay fever - other allergen X00l9 Hay fever - unspecified allergen X00lA Perennial allergic rhinitis X00lB Perennial allergic rhinitis with seasonal variation X00Zj Hay fever conjunctivitis X1020 Hay fever with asthma Xa0lX Seasonal allergic rhinitis Xa2dV Ozaena XaNkV Acute rhinosinusitis XE0Xx Chronic rhinitis XE0Xy Chronic catarrhal rhinitis XE0Y5 Allergic rhinitis XE0Y6 Allergic rhinitis due to other allergens XE0Y7 Allergic rhinitis due to unspecified allergen XE2QI Allergic rhinitis due to pollens XE2RT Chronic rhinitis (& ozaena)

7.6.3 Allergic rhinitis drugs Prodcodes for CPRD

PRODCODE GEMSCRIPTCODE PRODUCTNAME 70 70930020 Cetirizine 10mg tablets 88 65229020 Beclometasone 50micrograms/dose nasal spray 92 69707020 Loratadine 10mg tablets 154 66905020 Terfenadine 60mg tablets 168 53733020 Piriject 10mg/ml Injection (Link Pharmaceuticals Ltd) 189 51730020 Sudafed non-drowsy 30mg/5ml Oral solution (Pfizer Consumer Healthcare Ltd) 233 52011020 Triludan 60mg Tablet (Hoechst Marion Roussel) 330 53228020 Hismanal 10mg Tablet (Janssen-Cilag Ltd) 353 48016020 Actifed multi-action dry cough Oral solution (Pfizer Consumer Healthcare Ltd) 533 51157020 Piriton 4mg Tablet (Stafford-Miller Ltd) 558 58268020 Dimotane plus Oral solution (Wyeth Pharmaceuticals) 629 57397020 Piriton 2mg/5ml syrup (GlaxoSmithKline Consumer Healthcare)

63 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

683 48231020 Atarax 25mg Tablet (Pfizer Ltd) 686 79198020 Piriton 4mg tablets (GlaxoSmithKline Consumer Healthcare) Beconase 50microgram/actuation Nasal spray suspension (Allen & Hanburys 844 48313020 Ltd) 878 63331020 Hydroxyzine 10mg tablets 884 58892020 Chlorphenamine 4mg tablets 888 48314020 Beconase Aqueous 50micrograms/dose nasal spray (GlaxoSmithKline UK Ltd) 894 60148020 Astemizole 10mg tablets 897 83499020 Nasobec Aqueous 50micrograms/dose nasal spray (Teva UK Ltd) 918 51103020 Phenergan 10mg tablets (Sanofi) 943 52706020 Flixonase 50micrograms/dose aqueous nasal spray (GlaxoSmithKline UK Ltd) 944 66906020 Terfenadine 30mg/5ml suspension 950 61021020 Alimemazine 7.5mg/5ml oral solution 952 52141020 Vallergan 7.5mg/5ml Oral solution (Castlemead Healthcare Ltd) 961 51158020 Piriton 2mg/5ml Oral solution (Stafford-Miller Ltd) 1015 69711020 Clarityn 10mg Tablet (Schering-Plough Ltd) 1077 69712020 Clarityn 5mg/5ml syrup (Schering-Plough Ltd) 1084 84724020 Telfast 180mg tablets (Sanofi) 1085 84169020 Nasacort 55micrograms/dose nasal spray (Sanofi) 1095 84714020 Nasonex 50micrograms/dose nasal spray (Merck Sharp & Dohme Ltd) 1244 53331020 Dimotane 2mg/5ml Oral solution (Wyeth Pharmaceuticals) 1281 51729020 Sudafed non-drowsy 60mg Tablet (Pfizer Consumer Healthcare Ltd) 1282 48993020 Dimotane la 12mg Tablet (Wyeth Pharmaceuticals) 1305 61233020 Chlorphenamine 10mg/1ml solution for injection ampoules 1323 66334020 Pseudoephedrine hydrochloride 60mg tablets 1405 52013020 Triludan 30mg/5ml sugar free Oral suspension (Hoechst Marion Roussel) 1419 51449020 Rynacrom Capsule (Rpr / Fisons) 1420 53216020 Rynacrom Nasal spray (Pantheon Healthcare Ltd) 1421 53217020 Rynacrom 4% Nasal spray (Pantheon Healthcare Ltd) 1436 49782020 Haymine tablets (Chemidex Pharma Ltd) 1443 68661020 Zirtek 10mg tablets (UCB Pharma Ltd) 1525 66335020 Pseudoephedrine 30mg/5ml oral solution 1546 63332020 Hydroxyzine 25mg tablets 1549 61228020 Chlorphenamine 2mg/5ml oral solution 1554 69708020 Loratadine 5mg/5ml oral solution 1610 51105020 Phenergan 5mg/5ml elixir (Sanofi) 1723 52730020 Vallergan forte 30mg/5ml Oral solution (Castlemead Healthcare Ltd) 1799 84167020 Triamcinolone 55micrograms/dose nasal spray 1855 84708020 Mometasone 50micrograms/dose nasal spray 1864 55061020 Sudafed sa 120mg Capsule (Wellcome Medical Division) 1913 48230020 Atarax 10mg Tablet (Pfizer Ltd)

64 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

1978 65228020 Beclometasone 50 micrograms/actuation nasal spray 1998 72203020 Promethazine 5mg/5ml oral solution sugar free 2018 74607020 Diphenhydramine 50mg tablets 2037 53694020 Rhinocort 50microgram/actuation Nasal spray (AstraZeneca UK Ltd) 2049 73436020 Rhinocort Aqua 100micrograms/dose nasal spray (AstraZeneca UK Ltd) 2090 68390020 Dimotane plus la Tablet (Wyeth Pharmaceuticals) 2150 51792020 Syntaris 25microgram/actuation Nasal spray (Roche Products Ltd) 2161 84287020 Fexofenadine 180mg tablets 2189 69259020 Acrivastine 8mg capsules 2196 53209020 Rynacrom Nasal spray (Chemist Brokers) 2263 83727020 Beconase Hayfever 50micrograms/dose nasal spray (Omega Pharma Ltd) 2336 51502020 Fluticasone propionate 50micrograms/dose nasal spray 2349 63333020 Hydroxyzine 10mg/5ml oral solution 2405 52140020 Vallergan 10mg Tablet (Castlemead Healthcare Ltd) 2570 61022020 Alimemazine 30mg/5ml oral solution 2602 84286020 Fexofenadine 120mg tablets 2604 51159020 Piriton 12mg Spandets (Stafford-Miller Ltd) 2623 62612020 Fenostil retard 2.5mg Tablet (Novartis Consumer Health UK Ltd) 2734 68662020 Zirtek 1mg/ml Oral solution (UCB Pharma Ltd) 2740 84289020 Telfast 120mg tablets (Sanofi) 2750 74601020 Nytol 25mg Tablet (Stafford-Miller Ltd) 2792 63896020 Ketotifen 1mg/5ml oral solution sugar free 2817 49391020 Fabahistin 50mg Tablet (Bayer Plc) 2916 70931020 Cetirizine 1mg/ml oral solution sugar free 3027 52965020 Terfenadine 30mg tablets 3081 48232020 Atarax 10mg/5ml Oral solution (Pfizer Ltd) 3113 61072020 Sodium cromoglicate 2%w/v nasal drops 3184 61020020 Alimemazine 10mg tablets 3201 67339020 Brompheniramine maleate 12mg modified-release tablets 3218 53212020 Rynacrom Nasal drops (Rpr / Fisons) 3230 60149020 Astemizole 5mg/5ml sugar free oral suspension 3373 61715020 Cyproheptadine 4mg tablets 3374 63895020 Ketotifen 1mg tablets 3448 53328020 Dimotane 4mg Tablet (Wyeth Pharmaceuticals) 3525 69224020 Semprex 8mg capsules (GlaxoSmithKline UK Ltd) 3581 61388020 Clemastine 1mg tablets 3602 64424020 Mequitazine 5mg Tablet 3787 52326020 Zaditen 1mg Tablet (Novartis Pharmaceuticals UK Ltd) 4087 64315020 Mebhydrolin 50mg Tablet 4124 57485020 Daneral sa 75mg Tablet (Hoechst Marion Roussel)

65 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

4133 53229020 Hismanal 5mg/5ml Oral suspension (Janssen-Cilag Ltd) 4162 58262020 Benadryl 25mg Capsule (Parke-davis Research Laboratories) 4203 71664020 Medised Liquid (SSL International Plc) 4245 49820020 Histryl spansule 5 5mg Spansule (Menley and Jones) 4253 53346020 Dimotapp la Tablet (Wyeth Consumer Healthcare) 4299 61961020 Flunisolide 25micrograms/dose nasal spray 4311 86384020 Mizolastine 10mg modified-release tablets 4324 49001020 Dimotapp Oral solution (Wyeth Consumer Healthcare) 4325 64248020 Brompheniramine maleate 4mg tablets 4360 58271020 Dimotane plus Oral solution (Wyeth Pharmaceuticals) 4421 69875020 Pseudoephedrine hydrochloride 60mg / Triprolidine 2.5mg tablets 4560 84796020 Rhinolast allergy 0.10% Nasal spray (AHA Sales Services Ltd) 4718 50406020 Migraleve - 1 Tablet (Pfizer Consumer Healthcare Ltd) 4824 68756020 Ucerax 10mg/5ml syrup (UCB Pharma Ltd) 4850 51503020 Fluticasone 400microgram/unit dose nasal drops 5139 78825020 Nytol one a night 50mg Tablet (Stafford-Miller Ltd) 5362 84996020 Neoclarityn 5mg tablets (Merck Sharp & Dohme Ltd) 5380 79389020 Desloratadine 5mg tablets 5450 74605020 Diphenhydramine 25mg tablets 5498 71764020 Propain caplet (Sankyo Pharma UK Ltd) 5536 83217020 Flixonase Nasule 400microgram/unit dose nasal drops (GlaxoSmithKline UK Ltd) 5561 66289020 Promethazine hydrochloride 10mg tablets 5610 51064020 Periactin 4mg tablets (Teva UK Ltd) 5671 86337020 Benadryl Allergy Relief 8mg capsules (McNeil Products Ltd) 5685 85209020 Syndol easy to swallow Tablet (SSL International Plc) 5730 82074020 Levocetirizine 5mg tablets 5732 61230020 Chlorphenamine 2mg/5ml oral solution sugar free 5901 82079020 Xyzal 5mg tablets (UCB Pharma Ltd) 6086 79698020 Syntaris 0.025% nasal spray (Teva UK Ltd) 6103 81030020 Zirtek Allergy 10mg tablets (UCB Pharma Ltd) 6348 77872020 Piriteze Allergy 10mg tablets (GlaxoSmithKline Consumer Healthcare) 6427 81696020 Zirtek Allergy 1mg/ml oral solution (UCB Pharma Ltd) 6496 73349020 Budesonide 100micrograms/dose nasal spray 6546 87864020 Rhinocort Aqua 64 nasal spray (AstraZeneca UK Ltd) 6665 86403020 Paracetamol with codeine & buclizine tablet 6978 87862020 Budesonide 64micrograms/dose nasal spray 7363 70611020 Betamethasone 0.1% ear/eye/nose drops 7438 51097020 Phenergan 25mg/ml Injection (Aventis Pharma) 7463 70149020 Galpseud 60mg tablets (Thornton & Ross Ltd) Actifed multi-action chesty cough Oral solution (Pfizer Consumer Healthcare 7512 53511020 Ltd)

66 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

7591 70150020 Galpseud 30mg/5ml linctus (Thornton & Ross Ltd) 7594 61071020 Sodium cromoglicate inhalation capsules 7601 65653020 Pheniramine maleate 75mg tablet 7689 50873020 Optimine 1mg Tablet (Schering-Plough Ltd) 8341 57941020 Galpseud Plus linctus (Thornton & Ross Ltd) 8398 67289020 Triprolidine hcl 10mg modified-release tablet 8458 51838020 Tavegil 1mg tablets (Novartis Consumer Health UK Ltd) 8669 51951020 Tinset Tablet (Janssen-Cilag Ltd) 8670 65252020 Oxatomide Tablet Beconase 50microgram/actuation Nasal spray suspension (Allen & Hanburys 8779 48315020 Ltd) 8820 62658020 Diphenydramine 25mg capsules 8998 53762020 Histryl paediatric Spansule (Menley and Jones) 9461 86388020 Mizollen 10mg modified-release tablets (Sanofi) 9514 66336020 Pseudoephedrine 30mg/5ml oral solution sugar free 9635 52327020 Zaditen 1mg/5ml Oral solution (Novartis Pharmaceuticals UK Ltd) 9780 86366020 Benadryl one a day 10mg Tablet (Pfizer Consumer Healthcare Ltd) 9782 80897020 Benadryl Allergy Relief Plus Decongestant capsules (McNeil Products Ltd) Pseudoephedrine 30mg/5ml / Chlorphenamine 2mg/5ml oral solution sugar 9815 57931020 free 9947 70551020 Dextromethorphan 14mg with Diphenydramine HCl 6.5mg/5ml oral solution 9950 87762020 Piriteze Allergy 1mg/ml syrup (GlaxoSmithKline Consumer Healthcare) 9983 86933020 Fexofenadine 30mg tablets 10047 84864020 Hayfever and allergy relief 10mg Tablet (A A H Pharmaceuticals Ltd) 10087 80877020 Pseudoephedrine 60mg / Acrivastine 8mg capsules 10097 86261020 Benadryl One A Day Relief 10mg tablets (McNeil Products Ltd) 10099 71315020 Paracetamol 500mg with codeine phosphate 8mg & buclizine 6.25mg 10224 76994020 Pseudoephedrine 120mg modified-release tablets 10228 80648020 Sudafed 12 Hour Decongestant 120mg tablets (McNeil Products Ltd) 10327 64071020 Pseudoephedrine 120mg modified-release capsules 10488 57794020 Primalan 5mg Tablet (Rhone-Poulenc Rorer Ltd) 10569 48007020 Actidil 2.5mg Tablet (Wellcome Medical Division) 10773 60173020 Azatadine maleate 1mg tablets 10803 61716020 Cyproheptadine 2mg/5ml oral solution 10828 48743020 Congesteze Oral solution (Schering-Plough Ltd) 10840 49392020 Fabahistin 50mg/5ml Liquid (Bayer Plc) 10901 71660020 Paracetamol with promethazine hydrochloride 120mg+1.5mg/5ml suspension 11417 77994020 Mistamine 10mg modified-release tablets (Galderma (UK) Ltd) 11456 86638020 Beclo-Aqua 50micrograms/dose nasal spray (Galen Ltd) 11509 70216020 Diphenydramine with ammonium chloride oral solution

67 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

Flixonase allergy 50 microgram/spray Spray (GlaxoSmithKline Consumer 11772 75644020 Healthcare) 11945 51785020 Syndol Tablet (SSL International Plc) 11985 80887020 Piriton Allergy 4mg tablets (GlaxoSmithKline Consumer Healthcare) 12029 70141020 Pseudoephedrine with azatidine maleate tablet 12056 48008020 Actidil 2mg/5ml Oral solution (Wellcome Medical Division) 12114 51065020 Periactin 2mg/5ml Oral solution (Merck Sharp & Dohme Ltd) 12214 66286020 Promethazine hydrochloride 25mg/ml injection 12249 67286020 Triprolidine hcl 2mg/5ml elixir 12532 51264020 Pro-actidil 10mg Tablet (Wellcome Medical Division) 12589 79170020 Syntaris hayfever 25microgram/actuation Nasal spray (Roche Consumer Health) 13330 73706020 Terfinax 60mg Tablet (Ashbourne Pharmaceuticals Ltd) 13541 48011020 Multi-Action Actifed 60mg/2.5mg tablets (McNeil Products Ltd) 13700 73707020 Terfinax 120mg Tablet (Ashbourne Pharmaceuticals Ltd) 13956 71093020 Ephedrine hydrochloride 15mg / Chlorphenamine 10mg tablets Medised infant 120mg + 12.5mg / 5ml Oral solution (Seton Scholl Healthcare 14151 81803020 Plc) 14973 53740020 Vistamethasone 0.1% ear/eye/nose drops (Martindale Pharmaceuticals Ltd) 14989 59741020 Diphenydramine 50mg capsules 14990 66342020 Pseudoephedrine Expectorant 15241 77583020 Sudafed non-drowsy dual relief Capsule (Pfizer Consumer Healthcare Ltd) 15308 83816020 Vivabec 50micrograms/dose nasal spray (Lexon (UK) Ltd) 15403 67285020 Triprolidine hcl 2.5mg Tablet 15626 48998020 Dimotapp paediatric Oral solution (Wyeth Consumer Healthcare) 15946 64056020 Cetirizine 10mg tablets (A A H Pharmaceuticals Ltd) 16228 65641020 Thephorin 25mg Tablet (Sinclair IS Pharma Plc) 16295 79928020 Beclomist 50microgram/actuation Spray (Co-Pharma Ltd) 16461 79202020 Nytol One-A-Night 50mg tablets (Omega Pharma Ltd) 16478 87037020 Hayleve 4mg tablets (Genesis Pharmaceuticals Ltd) 16644 65638020 Phenindamine tartrate 25mg tablet 17036 86935020 Telfast 30mg tablets (Sanofi) 17127 79200020 Nytol 25mg tablets (Omega Pharma Ltd) 17219 50169020 Lergoban 5mg Tablet (3M Health Care Ltd) 17220 62674020 Diphenylpyraline HCl 5mg tablets Nasobec hayfever 50microgram/actuation Nasal spray suspension (Norton 17772 79487020 Consumer Distributed by Manx) 17784 68755020 Ucerax 25mg tablets (UCB Pharma Ltd) 17879 53918020 Congesteze Oral solution (Schering-Plough Ltd) 18121 88622020 Galsud 30mg/5ml linctus (Thornton & Ross Ltd) 18608 76542020 Care Hayfever Relief 50micrograms/dose nasal spray (Thornton & Ross Ltd) 18618 82890020 Zonivent 50microgram/actuation Spray (Ashbourne Pharmaceuticals Ltd)

68 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

18906 74606020 Diphenhydramine 10mg/5ml oral solution 18919 81928020 Lemsip cold and flu sachets (Reckitt Benckiser Healthcare (UK) Ltd) 19174 84271020 Benadryl allergy 1mg/ml Oral solution (Pfizer Consumer Healthcare Ltd) Tixylix night-time 1.5mg+1.5mg/5ml Oral solution (Novartis Consumer Health 19479 83636020 UK Ltd) 19854 87456020 Propain plus Tablet (Ceuta Healthcare Ltd) 19917 66339020 Pseudoephedrine 60mg with paracetamol 500mg tablet 19990 82204020 Rino Clenil 50micrograms/dose nasal spray (Chiesi Ltd) Paracetamol 400mg with codeine phosphate 10mg with diphenhydramine 5mg 20077 71757020 & caffeine 50mg tablet 20162 77896020 Clarityn Allergy 10mg tablets (Bayer Plc) Paracetamol 450mg with codeine phosphate 10mg with doxylamine 5mg & 20256 71760020 caffeine 30mg tablet 20265 56502020 Beclometasone 50microgram/actuation Nasal Spray (Numark Management Ltd) Beconase Hayfever Relief for Adults 50micrograms/dose nasal spray (Omega 20356 89346020 Pharma Ltd) 20435 87212020 Sudafed non-drowsy congestion relief Capsule (McNeil Products Ltd) 20784 70142020 Pseudoephedrine with azatidine maleate oral solution 20853 71763020 Propain Tablet (Sankyo Pharma UK Ltd) 20886 86265020 Cetirocol 10mg tablets (Teva UK Ltd) 20906 77517020 Pollenase Hayfever 50micrograms/dose nasal spray (E M Pharma) 20914 84338020 Aller-Eze 140micrograms/dose nasal spray (Novartis Consumer Health UK Ltd) 21024 48742020 Congesteze Tablet (Schering-Plough Ltd) 21090 75410020 Medinex 10mg/5ml Oral solution (Wyeth Consumer Healthcare) 21746 51087020 Pharmidone Tablet (Pharmacia Ltd) 21818 75425020 Histafen 60mg Tablet (Berk Pharmaceuticals Ltd) 22050 91243020 Sudafed Non-Drowsy Children's 30mg/5ml syrup (McNeil Products Ltd) Lemsip cold and flu combined relief 300mg+5mg+25mg Capsule (Reckitt 22125 50848020 Benckiser Healthcare (UK) Ltd) Paracetamol with promethazine hydrochloride 120mg+1.5mg/5ml suspension 22236 83229020 sugar free colour free Tixylix night-time 1.5mg+1.5mg/5ml Oral solution (Novartis Consumer Health 22267 83635020 UK Ltd) Lemsip flu 12 hr Modified-release capsule (Reckitt Benckiser Healthcare (UK) 22283 85582020 Ltd) 22337 70231020 Pseudoephedrine with chlorphenamine & pholcodine oral solution 22357 89236020 Nasofan 50micrograms/dose aqueous nasal spray (Teva UK Ltd) Tixylix catarrh 7mg + 550microgram/5ml Oral solution (Novartis Consumer 22425 80178020 Health UK Ltd) 22759 90611020 Zirtek Allergy Relief for Children 1mg/ml oral solution (UCB Pharma Ltd) 23044 74602020 Nytol 25mg Tablet (Stafford-Miller Ltd) Promethazine hydrochloride 1.5mg with paracetamol 120mg/5ml oral solution 23052 83231020 colour free and sugar free

69 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

23054 71094020 Ephedrine HCl with Chlorphenamine 4mg with 1mg/5ml oral solution sugar free 23076 70351020 Allerief 2mg/5ml oral solution (Orbis Consumer Products Ltd) 23318 81813020 Sinutab nightime Tablet (Warner Lambert UK Ltd) Codeine phosphate with diphenhydramine with paracetamol with 23580 70266020 phenylephrine with caffeine with vitamin c tablets 23875 59137020 Alunex 4mg Tablet (M A Steinhard Ltd) Tramazoline with dexamethasone 120 micrograms + 20 micrograms Nasal spray 23928 86706020 suspension Paracetamol with diphenhydramine with codeine with phenylephrine with 24187 70244020 caffeine & vitamin c tablet 24445 71659020 Paracetamol with promethazine hydrochloride tablet 24996 71309020 Codeine phosphate 8mg with paracetamol 500mg with buclizine 6.25mg tablets 25035 73348020 Budesonide 50micrograms.actuation nasal spray 25091 81450020 Terfenor forte 120mg Tablet (IVAX Pharmaceuticals UK Ltd) Diphenhydramine with ammonium chloride and menthol 14mg+135mg+1.1mg 25237 86692020 oral solution sugar free 25782 65601020 Cetirizine 1mg/ml oral solution sugar free (Teva UK Ltd) 25783 89008020 Cetec 10mg tablets (Herbal Concepts Ltd) 25999 56520020 Beclometasone 50micrograms/dose nasal spray (A A H Pharmaceuticals Ltd) Phenylephrine with diphenhydramine, paracetamol, codeine, caffeine & vitamin 26291 70300020 c tablet 26294 82100020 Benylin day and night Cold treatment (Pfizer Consumer Healthcare Ltd) 26386 88620020 Galsud 60mg tablets (Thornton & Ross Ltd) 26646 82483020 Galpharm Non-Drowsy Allergy Relief 10mg tablets (Galpharm International Ltd) 26707 77897020 Clarityn Allergy 5mg/5ml syrup (Bayer Plc) 26744 76168020 Expulin decongestant sugar free Oral solution (Shire Pharmaceuticals Ltd) 27117 84937020 Calimal 4mg tablets (Sussex Pharmaceutical Ltd) 27118 82628020 Nightcalm 25mg tablets (Galpharm International Ltd) 27128 82794020 Paracets plus Capsule (Sussex Pharmaceutical Ltd) 27153 62602020 Dimethindene maleate 2.5mg modified-release tablets 27337 62749020 Benylin four flu Liquid (Pfizer Consumer Healthcare Ltd) 27438 75926020 Pseudoephedrine 45mg with ibuprofen 300mg modified-release capsule 27726 66345020 Pseudoephedrine 120mg modified release capsule 27781 59093020 Beclometasone 50micrograms/dose nasal spray (Mylan Ltd) 27804 62750020 Benylin four flu Tablet (Pfizer Consumer Healthcare Ltd) 27812 55412020 Chlorphenamine 4mg tablets (Sussex Pharmaceutical Ltd) 27979 87186020 Lemsip max cold and flu Capsule (Reckitt Benckiser Healthcare (UK) Ltd) 28519 75925020 Pseudoephedrine 30mg with ibuprofen 200mg tablet 28639 55885020 Terfenadine 60mg Tablet (Lagap) 28792 83233020 Medised colour and sf 120mg+1.5mg/5ml Liquid (SSL International Plc) 28822 75900020 Ibuprofen with pseudoephedrine hc 400mg + 60mg Liquid

70 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

Triprolidine hcl and dextromethorphan 625micrograms with 5mg/5ml sugar 29228 79232020 free Liquid 29297 63789020 Cetirizine 10mg tablets (Teva UK Ltd) 29459 63842020 Cetirizine 10mg Tablet (Niche Generics Ltd) 29558 80213020 Maximum flu strength Tablet (Wockhardt UK Ltd) 29633 84038020 Meltus Decongestant 30mg/5ml oral solution (SSL International Plc) 29666 64529020 Cetirizine 10mg tablets (Sandoz Ltd) 29732 83632020 Promethazine hydrochloride 1.5mg with pholcodine 1.5mg/5ml oral solution 29825 82013020 Resiston ONE Nasal spray suspension (Rpr / Fisons) 29872 55408020 Chlorphenamine 4mg tablets (A A H Pharmaceuticals Ltd) 30101 65282020 Loratadine 10mg tablets (Actavis UK Ltd) 30397 75426020 Histafen 120mg Tablet (Berk Pharmaceuticals Ltd) 30508 84843020 Zirtek Allergy Relief 10mg tablets (UCB Pharma Ltd) Contac Non Drowsy 12 Hour Relief 120mg modified-release capsules (Omega 30536 70900020 Pharma Ltd) Phenylephrine with brompheniramine & phenylpropanolamine modified 30839 70297020 release tablet 30928 62812020 Chlorphenamine 10mg/1ml solution for injection ampoules (Kyowa Kirin Ltd) 30992 77982020 Dreemon 25mg tablets (E M Pharma) 31177 65563020 Loratadine 5mg/5ml oral solution (Actavis UK Ltd) 31364 89130020 Non-drowsy allergy relief Tablet (A A H Pharmaceuticals Ltd) 31409 61394020 Aller-eze original 1mg Tablet (Novartis Consumer Health UK Ltd) 31525 63472020 Chlorphenamine 2mg/5ml oral solution sugar free (A A H Pharmaceuticals Ltd) 31639 77729020 Unichem allergy relief 4mg Tablet (Unichem) 31717 87184020 Lemsip max cold and flu lemon Sachets (Reckitt Benckiser Healthcare (UK) Ltd) 31818 62424020 Chlorphenamine 2mg/5ml oral solution sugar free (Sandoz Ltd) 31889 82130020 Ziz 10mg tablets (Chatfield Laboratories) Galpharm Hayfever and Allergy Relief 10mg tablets (Galpharm International 31891 86360020 Ltd) 32035 86099020 Paracetamol 240mg with phenylephrine 2.5mg sachet 32240 56879020 Chlorphenamine 4mg tablets (Actavis UK Ltd) Guanor chesty cough 7mg + 550microgram/5ml Oral solution (Rosemont 32246 75334020 Pharmaceuticals Ltd) 32443 80446020 Pollenase Antihistamine 4mg tablets (E M Pharma) 32609 50302020 Real lemon cold 750mg+10mg+60mg Powder (Sterwin Medicines) 32676 84460020 Bronalin decongestant 30mg/5ml Oral solution (SSL International Plc) 32704 86005020 Advil cold and sinus 200mg+30mg Tablet (Wyeth Consumer Healthcare) 32749 79298020 Terfenor 60mg Tablet (IVAX Pharmaceuticals UK Ltd) 32873 60820020 Beclometasone 50micrograms/dose nasal spray (Actavis UK Ltd) 32962 59757020 Chlorphenamine 4mg tablets (Teva UK Ltd) 32963 81927020 Lemsip lemcap Capsule (Reckitt Benckiser Healthcare (UK) Ltd)

71 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

Lemsip children's six plus cold and flu relief 240mg+2.5mg Sachets (Reckitt 33042 55076020 Benckiser Healthcare (UK) Ltd) Pseudoephedrine with dextromethorphan diphenhydramine & menthol oral 33061 72863020 solution 33230 71668020 Promethazine hydrochloride 1.5mg with paracetamol 120mg/5ml oral solution 33235 91075020 Hayfever and allergy relief 10mg Tablet (Herbal Concepts Ltd) 33428 62672020 Diphenylpyraline HCl 5mg modified-release capsules 33526 83601020 Hismanal 10mg Tablet (Johnson+Johnson MSD Consumer Pharmaceuticals) 33576 81698020 Owbridges childrens Liquid (Chefaro UK Ltd) 33709 64712020 Cetirizine 1mg/ml oral solution sugar free (A A H Pharmaceuticals Ltd) 33893 65273020 Loratadine 10mg tablets (Teva UK Ltd) 33954 79285020 Promethazine hydrochloride 50mg with pethidine 100mg/2ml injection 34082 89186020 Non-drowsy allergy relief 5mg/5ml Oral solution (A A H Pharmaceuticals Ltd) 34136 61229020 Chlorphenamine 12mg modified-release tablets 34262 66625020 Loratadine 5mg/5ml oral solution (Teva UK Ltd) 34304 65279020 Loratadine 10mg tablets (Mylan Ltd) 34333 65276020 Loratadine 10mg Tablet (Niche Generics Ltd) 34538 63813020 Cetirizine 10mg tablets (Mylan Ltd) 34752 65295020 Loratadine 10mg tablets (Zentiva) 34753 65317020 Loratadine 10mg tablets (A A H Pharmaceuticals Ltd) 34755 67680020 Loratadine 5mg/5ml oral solution (A A H Pharmaceuticals Ltd) 34875 61619020 Budesonide 100micrograms/dose nasal spray (Mylan Ltd) 35139 90815020 Benadryl Allergy Children's 6+ 1mg/ml oral solution (McNeil Products Ltd) 35233 89762020 Chesty cough Oral solution (A A H Pharmaceuticals Ltd) 35437 93495020 Phenergan 25mg/1ml solution for injection ampoules (Sanofi) 35846 93493020 Promethazine 25mg/1ml solution for injection ampoules 36093 93485020 Levocetirizine 500micrograms/ml oral solution sugar free 36201 92911020 Hay-Rite Allergy 10mg tablets (Teva UK Ltd) 36284 72799020 Cetirizine 1mg/ml Oral solution (Hillcross Pharmaceuticals Ltd) 36425 89274020 Hayfever relief 50microgram/actuation Spray (A A H Pharmaceuticals Ltd) 36522 70234020 Expulin sugar free Oral solution (Shire Pharmaceuticals Ltd) Actifed junior cough relief 625microgram + 5mg/5ml Oral solution (Warner 36536 66357020 Lambert UK Ltd) 36589 80716020 Pollenase Allergy 2mg/5ml syrup (E M Pharma) 36715 81441020 Seldane 120mg Tablet (Hoechst Marion Roussel) 36828 93841020 Xyzal 0.5mg/ml oral solution (UCB Pharma Ltd) 37093 93585020 ALLERcalm Allergy Relief 4mg tablets (Actavis UK Ltd) Codeine phosphate with paracetamol, doxylamine and caffeine 10mg with 37348 71809020 450mg with 5mg with 30mg tablets 37785 74229020 Fexofenadine 180mg tablets (Zentiva) 37834 71135020 Chlorphenamine 4mg tablets (Almus Pharmaceuticals Ltd)

72 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

37854 94347020 Nasobec Hayfever 50micrograms/dose nasal spray (Teva UK Ltd) 38104 79204020 Nytol 25mg Tablet (GlaxoSmithKline Consumer Healthcare) 38112 79299020 Terfenor 30mg Tablet (IVAX Pharmaceuticals UK Ltd) 38307 93423020 Pollenshield Hayfever Relief 10mg tablets (Actavis UK Ltd) Diphenhydramine with ammonium chloride and menthol 14mg+135mg+1.1mg 38806 90139020 oral solution sugar free 39455 94815020 Fluticasone furoate 27.5micrograms/dose nasal spray 39529 96413020 Avamys 27.5micrograms/dose nasal spray (GlaxoSmithKline UK Ltd) 39593 96367020 Sudafed Decongestant 30mg/5ml liquid (McNeil Products Ltd) 39644 96622020 Sudafed non-drowsy decongestant 60mg Tablet (McNeil Products Ltd) 39657 96149020 Neoclarityn 2.5mg/5ml oral solution (Merck Sharp & Dohme Ltd) 39668 96459020 Benadryl Allergy 1mg/ml oral solution (McNeil Products Ltd) Fluticasone propionate 50micrograms/dose nasal spray (A A H Pharmaceuticals 39733 70960020 Ltd) 39739 95954020 Sudafed non-drowsy congestion & headache Capsule (McNeil Products Ltd) 39743 66448020 Cetirizine 1mg/ml Oral solution (Ratiopharm UK Ltd) 40150 65360020 Cetirizine 1mg/ml Oral solution (Lagap) Beclometasone hayfever 50microgram/actuation Nasal Spray (Dominion 40156 59247020 Pharma) 40446 96851020 Nasacort Allergy 55micrograms/dose nasal spray (Sanofi) 40462 97107020 Vallergan 7.5mg/5ml syrup (Sanofi) 40470 87870020 Sleep aid 50mg Tablet (A A H Pharmaceuticals Ltd) 40472 97094020 Atarax 25mg tablets (Alliance Pharmaceuticals Ltd) 40475 97105020 Vallergan 10mg tablets (Sanofi) 40510 97092020 Atarax 10mg tablets (Alliance Pharmaceuticals Ltd) 40687 97109020 Vallergan Forte 30mg/5ml syrup (Sanofi) 40731 97119020 Rupatadine 10mg tablets 40783 76061020 Levocetirizine 5mg tablets (Teva UK Ltd) Vicks sinex decongestant Capsule (Procter & Gamble (Health & Beauty Care) 40880 91103020 Ltd) Paracetamol with phenylephrine & paracetamol with phenylephrine & caffeine 40948 91444020 capsule 40959 97129020 Rupafin 10mg tablets (GlaxoSmithKline UK Ltd) 41142 96832020 Sudafed non-drowsy sinus & pain Capsule (McNeil Products Ltd) 41965 64089020 Cetirizine 10mg tablets (Actavis UK Ltd) 42009 68471020 Chlorphenamine 4mg Tablet (Genesis Medical Ltd) 42064 64252020 Brompheniramine maleate with pseudoephedrine hc oral solution 42298 74078020 Fexofenadine 120mg tablets (A A H Pharmaceuticals Ltd) 42393 98007020 Desloratadine 2.5mg/5ml oral solution sugar free 42469 69872020 Pseudoephedrine with guaifenesin & triprolidine oral solution 42470 84048020 AllerTek 10mg tablets (Ratiopharm UK Ltd) 42577 84234020 Pollon-eze 10mg Tablet (Johnson+Johnson MSD Consumer Pharmaceuticals)

73 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

42937 98343020 Betnesol 0.1% eye/ear/nose drops (Focus Pharmaceuticals Ltd) 43133 75505020 Cetirizine 1mg/ml oral solution sugar free (Pinewood Healthcare) 43204 73433020 Paracetamol 500mg with phenylephrine 6.1mg & caffeine 25mg tablet 43366 87192020 Histergan 10mg/5ml syrup (Norma Chemicals Ltd) 43415 94128020 Chlorphenamine 50mg/5ml oral solution 43446 92987020 Hydroxyzine Oral suspension 43521 60659020 Chlorphenamine 4mg Tablet (Family Health) 43978 74082020 Fexofenadine 180mg tablets (A A H Pharmaceuticals Ltd) 44037 98602020 Zaditen 1mg tablets (CD Pharma AB) 44121 98611020 Benadryl One A Day 10mg tablets (McNeil Products Ltd) 44497 99023020 Sudafed 12 hour decongestant Modified-release tablet (McNeil Products Ltd) 44500 99015020 Sudafed Decongestant 60mg tablets (McNeil Products Ltd) 44554 99011020 Sudafed decongestant Liquid (McNeil Products Ltd) 44870 75500020 Aller-eze clear 60mg Tablet (Novartis Consumer Health UK Ltd) 44892 99013020 Sudafed sinus pressure & pain Tablet (McNeil Products Ltd) 44927 98604020 Zaditen 1mg/5ml elixir (CD Pharma AB) 44984 99124020 Sudafed decongestant & pain Tablet (McNeil Products Ltd) 45134 99263020 Rhinolast allergy 0.10% Nasal spray (Meda Pharmaceuticals Ltd) 45227 66007020 Loratadine 10mg tablets (Sandoz Ltd) 45239 64551020 Cetirizine 10mg tablets (Fannin UK Ltd) 45253 63893020 Cetirizine 10mg tablets (Sterwin Medicines) 45266 64198020 Cetirizine 10mg tablets (Dexcel-Pharma Ltd) 45517 99456020 Nasofan Allergy 50micrograms/dose nasal spray (Teva UK Ltd) 45627 98268020 Pollenshield Hayfever 10mg tablets (Actavis UK Ltd) 45710 96804020 Histease allergy relief 10mg Tablet (Dr Reddy's Laboratories (UK) Ltd) 45908 99600020 Pirinase Hayfever 0.05% nasal spray (GlaxoSmithKline Consumer Healthcare) 46498 77653020 Paracetamol 1000mg with phenylephrine 12mg & ascorbic acid 100mg sachet 46501 69396020 Loratadine 10mg tablets (Ranbaxy (UK) Ltd) 46684 99805020 Bilastine 20mg tablets 46914 61677020 Chlorphenamine 4mg tablets (Vantage) 47448 69882020 Triprolidine hcl with pseudoephedrine and dextromethorphan linctus 48222 41246020 Cetirizine 10mg capsules 48492 08877020 Beclometasone Hayfever Relief 50micrograms/dose nasal spray (Numark Ltd) 49112 03038020 Telfast 120mg tablets (Lexon (UK) Ltd) Flixonase Nasule 400microgram/unit dose nasal drops (Mawdsley-Brooks & 50398 08914020 Company Ltd) 50505 02985020 Sleepeaze 25mg tablets (The Boots Company Plc) 50608 02807020 Zirtek 5mg/5ml oral solution (Sigma Pharmaceuticals Plc) Flixonase Nasule 400microgram/unit dose nasal drops (Sigma Pharmaceuticals 50743 08913020 Plc) 51067 08921020 Nasonex 50micrograms/dose nasal spray (Sigma Pharmaceuticals Plc)

74 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

51215 44130020 Loratadine 10mg oral lyophilisates sugar free 51438 94102020 Dimenhydrinate oral liquid 51673 03041020 Telfast 120mg tablets (Necessity Supplies Ltd) 51799 39336020 Beconase Aqueous 50micrograms/dose nasal spray (DE Pharmaceuticals) 51976 41247020 Benadryl Allergy Liquid Release 10mg capsules (McNeil Products Ltd) 52190 03051020 Telfast 180mg tablets (Lexon (UK) Ltd) 52957 03054020 Telfast 180mg tablets (Necessity Supplies Ltd) 52961 03122020 Pseudoephedrine 30mg/5ml oral solution (Sigma Pharmaceuticals Plc) 53473 08922020 Nasonex 50micrograms/dose nasal spray (Mawdsley-Brooks & Company Ltd) Beclometasone 50micrograms/dose nasal spray (Alliance Healthcare 53830 08874020 (Distribution) Ltd) 54261 41204020 Midetorin 2.5mg/5ml oral solution (Actavis UK Ltd) 55150 44131020 Clarityn Rapide Allergy 10mg tablets (Bayer Plc) 55185 46146020 Prevalin Allergy nasal spray (Omega Pharma Ltd) 55186 46144020 Prevalin Allergy for kids nasal spray (Omega Pharma Ltd) 55227 08876020 Beclometasone 50micrograms/dose nasal spray (Vantage) 55290 73431020 Paracetamol 300mg with phenylephrine 5mg & caffeine 25mg capsule 55383 03047020 Fexofenadine 180mg tablets (Alliance Healthcare (Distribution) Ltd) Fluticasone propionate 50micrograms/dose / Azelastine 137micrograms/dose 55411 47951020 nasal spray Dymista 137micrograms/dose / 50micrograms/dose nasal spray (Meda 55435 47952020 Pharmaceuticals Ltd) 55492 75257020 Cetirizine 10mg tablets (Almus Pharmaceuticals Ltd) 55536 02973020 Chlorphenamine 4mg tablets (Strides Shasun (UK) Ltd) 56450 08883020 Budesonide 100micrograms/dose nasal spray (Sigma Pharmaceuticals Plc) 56585 35342020 Sodium cromoglicate 100mg/5ml oral solution 56798 02978020 Lloydspharmacy Allergy Relief 2mg/5ml syrup (Lloyds Pharmacy Ltd) 56877 73461020 Coldrex Tablet (GlaxoSmithKline UK Ltd) 56903 66849020 Cetirizine 1mg/ml oral solution sugar free (Sandoz Ltd) 57004 99807020 Ilaxten 20mg tablets (A. Menarini Farmaceutica Internazionale SRL) Fluticasone propionate 50micrograms/dose nasal spray (Sigma Pharmaceuticals 57010 08908020 Plc) 57517 08919020 Nasonex 50micrograms/dose nasal spray (Waymade Healthcare Plc) 57547 03024020 Clarityn 5mg/5ml syrup (Waymade Healthcare Plc) 57584 02804020 Zirtek 5mg/5ml oral solution (Dowelhurst Ltd) 57636 00064020 Desloratadine 5mg tablets (A A H Pharmaceuticals Ltd) 58379 03009020 Cetirizine 10mg tablets (Chanelle Medical UK Ltd) 58424 12522020 Care Decongestant 30mg/5ml oral liquid (Thornton & Ross Ltd) 58808 15634021 Chlorphenamine 4mg tablets (Waymade Healthcare Plc) 59210 03012020 Cetirizine 10mg tablets (Bristol Laboratories Ltd) 59329 03001020 Cetirizine 10mg tablets (Alliance Healthcare (Distribution) Ltd)

75 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

59556 02971020 Chlorphenamine 4mg tablets (Sigma Pharmaceuticals Plc) 59752 02809020 Cetirizine 1mg/ml oral solution sugar free (Actavis UK Ltd) 60103 03033020 Fexofenadine 120mg tablets (Kent Pharmaceuticals Ltd) 60266 21437021 Mometasone 50micrograms/dose nasal spray (A A H Pharmaceuticals Ltd) 60280 02965020 Chlorphenamine 4mg tablets (Alliance Healthcare (Distribution) Ltd) 60287 21436021 Mometasone 50micrograms/dose nasal spray (Sandoz Ltd) 60438 08906020 Flixonase 50micrograms/dose aqueous nasal spray (DE Pharmaceuticals) 61064 47213020 Cetirizine 1mg/ml oral solution sugar free (Waymade Healthcare Plc) 61110 02972020 Numark Antihistamine 4mg tablets (Numark Ltd) 61174 76297020 Cetirizine 10mg tablets (Wockhardt UK Ltd) 61263 41351020 Boots Allergy Relief Antihistamine 4mg tablets (The Boots Company Plc) 61275 47212020 Cetirizine 10mg tablets (Waymade Healthcare Plc) 62117 03007020 Cetirizine 10mg tablets (Dr Reddy's Laboratories (UK) Ltd) 62590 34117020 Promethazine 25mg/5ml oral suspension 62861 03055020 Fexofenadine 180mg tablets (Dr Reddy's Laboratories (UK) Ltd) 62888 87194020 Histergan 25mg tablets (Norma Chemicals Ltd) 62980 34115020 Promethazine 25mg/5ml oral solution 63109 03036020 Fexofenadine 120mg tablets (Actavis UK Ltd) 63647 78533020 Loratadine 10mg tablets (Almus Pharmaceuticals Ltd) 63651 55940020 Terfenadine 120mg Tablet (Approved Prescription Services Ltd) 63669 70138020 Pseudoephedrine with brompheniramine modified-release tablet 63671 84371020 Vantage galpseud 60mg Tablet (Hillcross Pharmaceuticals Ltd) 63948 31330021 Benadryl Allergy Children's 1mg/ml oral solution (McNeil Products Ltd) 64159 76408020 Fexofenadine 120mg tablets (Mylan Ltd) 64730 52817021 Beconase Aqueous 50micrograms/dose nasal spray (Lexon (UK) Ltd) 64948 21438021 Mometasone 50micrograms/dose nasal spray (Teva UK Ltd) 65198 52818021 Mometasone 50micrograms/dose nasal spray (Sigma Pharmaceuticals Plc) Boots Pharmacy Hayfever and Allergy 50micrograms/dose nasal spray (The 65598 41412020 Boots Company Plc) 65609 52833021 Betnesol 0.1% eye/ear/nose drops (Lexon (UK) Ltd) 65693 29591020 Alimemazine 5mg/5ml oral solution 65780 74226020 Fexofenadine 120mg tablets (Zentiva) 66169 44453020 Avamys 27.5micrograms/dose nasal spray (Waymade Healthcare Plc) 66342 70229020 Pseudoephedrine with chlorphenamine & pholcodine oral solution sugar free Pirinase Hayfever Relief for Adults 0.05% nasal spray (GlaxoSmithKline 66433 61377021 Consumer Healthcare) 66466 39780020 Desloratadine 5mg tablets (Actavis UK Ltd) 66777 29749021 Betamethasone 0.1% ear/eye/nose drops (Icarus Pharmaceuticals Ltd) 66844 11051020 Avamys 27.5micrograms/dose nasal spray (Lexon (UK) Ltd) 66965 20134020 Hydroxyzine 5mg/5ml oral suspension

76 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

Fluticasone propionate 50micrograms/dose nasal spray (Kent Pharmaceuticals 67102 08904020 Ltd) 67198 03049020 Fexofenadine 180mg tablets (Actavis UK Ltd) 67203 20132020 Hydroxyzine 5mg/5ml oral solution Beconase Aqueous 50micrograms/dose nasal spray (Mawdsley-Brooks & 67228 08878020 Company Ltd) 67244 14755021 Brompheniramine 12mg modified-release capsules 67296 03026020 Loratadine 5mg/5ml oral solution (Kent Pharmaceuticals Ltd) Beechams flu plus 1000mg+10mg+40mg Powder (GlaxoSmithKline Consumer 67370 80224020 Healthcare) 67557 52314021 Beclometasone 50micrograms/dose nasal spray (Sigma Pharmaceuticals Plc) 67658 27259021 Allacan 10mg tablets (Bristol Laboratories Ltd) 67873 32408020 Hydroxyzine 25mg/5ml oral solution 68007 48003021 BecoAllergy 10mg tablets (Omega Pharma Ltd) 68040 17382020 Rhinocort Aqua 64 nasal spray (Mawdsley-Brooks & Company Ltd) 68117 08912020 Flixonase 50micrograms/dose aqueous nasal spray (Necessity Supplies Ltd) 68597 75283020 Loratadine 5mg/5ml oral solution (Mylan Ltd) 68650 35309020 Fexofenadine 120mg/5ml oral suspension

7.6.4 Allergic rhinitis drugs Readcode for OPCRD

Read_code Read_term aa5.. Sodium cromoglicate [gastro-intestinal use] bn21. Stugeron Forte 75mg capsule bn2z. Cinnarizine 75mg capsule c71.. Sodium cromoglicate [asthma] c74.. Nedocromil sodium [asthma] c8... Antihistamines c81.. Astemizole c811. Hismanal 10mg tablet c812. Hismanal 5mg/5mL suspension c813. Astemizole 10mg tablet c814. Astemizole 5mg/5mL suspension c82.. Azatadine maleate c821. Optimine 1mg tablet c822. Optimine 500micrograms/5mL syrup c82y. Azatadine maleate 1mg tablet c82z. Azatadine maleate 500micrograms/5mL syrup c83.. Brompheniramine maleate c831. Dimotane 4mg tablet c832. Dimotane 2mg/5mL elixir c833. Dimotane LA 12mg m/r tablet

77 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

c83x. Brompheniramine maleate 4mg tablet c83y. Brompheniramine maleate 2mg/5mL elixir c83z. Brompheniramine maleate 12mg m/r tablet c84.. Chlorpheniramine maleate c841. Chlorphenamine maleate 4mg tablet c842. Alunex 4mg tablet c843. Piriton 4mg tablet c844. Piriton 12mg m/r tablet c845. Piriton 2mg/5mL syrup c846. Piriject 10mg/1mL injection c847. Pollenase Antihistamine 4mg tablet c848. Rhino-syrup Allergy 2mg/5mL sugar free syrup c849. Pollenase Allergy Syrup 2mg/5mL sugar free syrup c84A. Allerief 2mg/5mL s/f oral solution c84B. Vantage Antihistamine 4mg tablet c84C. Hayleve 4mg tablet c84D. Allergy Relief Antihistamine 4mg tablet c84E. ALLERCALM 4mg tablets c84v. Chlorphenamine maleate 2mg/5mL s/f oral solution c84w. Chlorphenamine maleate 2mg/5mL sugar free syrup c84x. Chlorpheniramine 12mg m/r tablet c84y. Chlorphenamine maleate 2mg/5mL syrup c84z. Chlorphenamine maleate 10mg/1mL injection c85.. Clemastine c851. Tavegil 1mg tablet c852. Tavegil 500micrograms/5mL elixir c853. Aller-eze tablet c854. Clemastine+phenylpropanolamine 0.5/25mg tablet c855. Aller-eze Plus tablet c85y. Clemastine 1mg tablet c85z. Clemastine 500micrograms/5mL elixir c87.. Dimethindene maleate c871. Fenostil Retard 2.5mg m/r tablet c87z. Dimethindene maleate 2.5mg m/r tablet c88.. Diphenhydramine hydrochloride [antihistamine] c881. Benadryl 25mg capsule c882. Nytol 25mg Caplet c883. Diphenhydramine hydrochloride 25mg tablet c884. Diphenhydramine hydrochloride 10mg/5mL syrup c885. Medinex 10mg/5mL syrup

78 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

c886. Nytol One-A-Night 50mg tablet c887. Diphenhydramine hydrochloride 50mg tablet c888. Nightcalm 25mg tablet c889. Paxidorm 25mg tablet c88A. Sleepia 50mg capsule c88B. Dreemon 25mg tablet c88C. Dreemon 10mg/5mL syrup c88D. Histergan 10mg/5mL syrup c88E. Histergan 25mg tablet c88F. Mandalyn Paediatric 6.25mg/5mL syrup c88G. Vantage Pharmacy Sleep Aid 50mg tablet c88H. Care Night Time Sleep Aid 25mg tablet c88I. GALPHARM ONE A NIGHT NIGHTCALM 50mg tablets c88x. Diphenhydramine hydrochloride 6.25mg/5mL syrup c88y. Diphenhydramine hydrochloride 50mg capsule c88z. Diphenhydramine hydrochloride 25mg capsule c89.. Diphenylpyraline hydrochloride c891. Histryl Spansule 5mg m/r capsule c892. Histryl Paediatric Spansule 2.5mg m/r capsule c893. Lergoban 5mg m/r tablet c89x. Diphenylpyraline 5mg m/r capsule c89y. Diphenylpyraline 2.5mg m/r capsule c89z. Diphenylpyraline 5mg m/r tablet c8a.. Hydroxyzine hydrochloride [antihististamine] c8c.. Mebhydrolin c8c1. Fabahistin 50mg tablet c8c2. Fabahistin 50mg/5mL mixture c8cy. Mebhydrolin 50mg tablet c8cz. Mebhydrolin 50mg/5mL mixture c8d.. Mepyramine maleate [antihistamine] c8d1. Anthisan 50mg tablet c8dz. Mepyramine maleate 50mg tablet c8e.. Mequitazine c8e1. Primalan 5mg tablet c8ez. Mequitazine 5mg tablet c8f.. Oxatomide c8f1. Tinset 30mg tablet c8fz. Oxatomide 30mg tablet c8g.. Phenindamine tartrate c8g1. Thephorin 25mg tablet

79 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

c8gz. Phenindamine tartrate 25mg tablet c8h.. Pheniramine maleate c8h1. Daneral SA 75mg m/r tablet c8hz. Pheniramine maleate 75mg m/r tablet c8i.. Promethazine hydrochhloride [antihistamine] c8i1. Phenergan 10mg tablet c8i2. Phenergan 25mg tablet c8i3. Phenergan 5mg/5mL elixir c8i4. Phenergan 25mg/1mL injection c8i5. Phenergan 50mg/2mL injection c8i6. Phenergan Nightime 25mg tablet c8i8. Ziz Forte 25mg tablet c8i9. SOMINEX 20mg tablets c8iu. PROMETHAZINE 20mg tablets c8iv. Promethazine hydrochloride 10mg tablet c8iw. Promethazine hydrochloride 25mg tablet c8ix. Promethazine hydrochloride 5mg/5mL elixir c8iy. Promethazine hydrochloride 25mg/1mL injection c8iz. Promethazine hydrochloride 50mg/2mL injection c8j.. Terfenadine product c8j1. Triludan 60mg tablet c8j2. Triludan 30mg/5mL suspension c8j3. Triludan Forte 120mg tablet c8j4. Triludan 30mg/5mL s/f suspension c8j5. Terfenadine 120mg tablet c8j6. Histafen 60mg tablet c8j7. Terfinax 60mg tablet c8j8. Antihistamine Forte 120mg tablet c8j9. Histafen 120mg tablet c8jA. Terfenadine 30mg tablet c8jB. Terfenor 30mg tablet c8jC. Terfenor Forte 120mg tablet c8jD. Antihistamine 60mg tablet c8jE. Terfinax 120mg tablet c8jF. Aller-eze Clear tablet c8jy. Terfenadine 60mg tablet c8jz. Terfenadine 30mg/5mL s/f suspension c8k.. Trimeprazine tartrate [antihistamine] c8k1. Vallergan 10mg tablet c8k2. Vallergan 7.5mg/5mL syrup

80 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

c8k3. Vallergan Forte 30mg/5mL syrup c8k4. Vallergan 10mg tablets 28CP c8kx. Alimemazine tartrate 10mg tablet c8ky. Alimemazine tartrate 7.5mg/5mL syrup c8kz. Alimemazine tartrate 30mg/5mL syrup c8l.. Triprolidine hydrochloride c8l1. Actidil 2.5mg tablet c8l2. Actidil 2mg/5mL elixir c8l3. Pro-actidil 10mg m/r tablet c8lx. Triprolidine 2.5mg tablet c8ly. Triprolidine 2mg/5mL elixir c8lz. Triprolidine hydrochloride 10mg m/r tablet c8m.. Acrivastine c8m1. Acrivastine 8mg capsule c8m2. Semprex 8mg capsule c8m3. Benadryl Allergy Relief 8mg capsule c8n.. Cetirizine hydrochloride c8n1. Cetirizine dihydrochloride 10mg tablet c8n2. Zirtek Allergy 10mg tablet c8n3. Cetirizine dihydrochloride 1mg/1mL s/f oral solution c8n4. Zirtek Allergy 1mg/mL s/f oral solution c8n5. Cetirocol 10mg tablet c8n6. Piriteze 10mg tablet c8n8. Galpharm Hayfever and Allergy Relief 10mg tablet c8nA. Zirtek Allergy Relief 10mg tablet c8nB. Benadryl One A Day 10mg tablet c8nC. Cetirizine 10mg Allergy Relief One A Day tablet c8nD. Care Cetirizine Hayfever Relief 10mg tablet c8nE. Benadryl Allergy 1mg/mL s/f oral solution c8nG. Numark Hayfever and Allergy Relief 10mg tablet c8nH. Piriteze Allergy Syrup 1mg/1mL s/f oral solution c8nI. Galpharm Allergy Relief 1mg/1mL s/f oral solution c8nJ. Vantage Hayfever and Allergy Relief 10mg tablet c8nK. POLLENSHIELD HAYFEVER RELIEF 10mg tablets c8nL. BENADRYL ALLERGY LIQUID RELEASE 10mg capsules c8nM. CETIRIZINE 10mg capsules c8o.. Loratadine product c8o1. Loratadine 10mg tablet c8o2. Clarityn 10mg tablet c8o3. Loratadine 5mg/5mL syrup

81 Non-Interventional Study Protocol Study Code << DXXXRXXX >> Version 14 July 2017 Date 14 July 2017

c8o4. Clarityn 5mg/5mL syrup c8o5. Clarityn Allergy 5mg/5mL syrup c8o6. Clarityn Allergy 10mg tablet c8o7. Galpharm Non-Drowsy Allergy Relief 10mg tablet c8o8. Numark Non-Drowsy Allergy Relief 10mg tablet c8o9. Galpharm Non-Drowsy Hayfever & Allergy Relief 10mg tablet c8oA. Galpharm Non-Drowsy Allergy Relief 5mg/5mL syrup c8oB. Vantage Pharmacy Non-Drowsy Allergy Relief 10mg tablet c8oC. Vantage Non-Drowsy Allergy Relief 5mg/5mL syrup c8p.. Fexofenadine c8p1. Fexofenadine hydrochloride 120mg tablet c8p2. Telfast 120 tablet c8p3. Fexofenadine hydrochloride 180mg tablet c8p4. Telfast 180 tablet c8p5. Fexofenadine hydrochloride 30mg tablet c8p6. Telfast 30 tablet c8q.. Mizolastine product c8q1. Mizolastine 10mg m/r tablet c8q2. Mizollen 10mg m/r tablet c8q3. Mistamine 10mg m/r tablet c8r.. Desloratadine c8r1. Neoclarityn 5mg tablet c8r2. Neoclarityn 0.5mg/mL syrup c8r3. NEOCLARITYN 2.5mg/5mL oral solution c8rx. DESLORATADINE 2.5mg/5mL oral solution c8ry. Desloratadine 0.5mg/mL syrup c8rz. Desloratadine 5mg tablet c8s.. Levocetirizine c8s1. Xyzal 5mg tablet c8s2. XYZAL 500micrograms/mL oral solution c8sy. LEVOCETIRIZINE DIHYDROCHLORIDE 500micrograms/mL oral solution c8sz. Levocetirizine dihydrochloride 5mg tablet c8t.. Epinastine c8u.. RUPATADINE c8u1. RUPAFIN 10mg tablets c8uz. RUPATADINE 10mg tablets c8v.. BILASTINE c8v1. ILAXTEN 20mg tablets c8v2. BILASTINE 20mg tablets c91.. Pollen allergy preparations

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STANDARDISED ALLERGEN EXTRACT GRASS POLLEN TIMOTHY (Phleum pratense) 75,000 SQ- c91f. T oral lyophilisate c91g. GRAZAX 75,000 SQ-T oral lyophilisate d19.. Promethazine hydrochloride [hypnotic] see section c8I.. d28.. Hydroxyzine HCl [anxiolytic] d281. Atarax 10mg tablet d282. Atarax 25mg tablet d283. Atarax 10mg/5mL syrup d284. Ucerax 25mg tablet d285. Ucerax 10mg/5mL syrup d28x. Hydroxyzine hydrochloride 10mg tablet d28y. Hydroxyzine hydrochloride 25mg tablet d28z. Hydroxyzine hydrochloride 10mg/5mL syrup dh31. Stugeron 15mg tablet dh32. Cinaziere 15mg tablet dh3z. Cinnarizine 15mg tablet dh5.. Dimenhydrinate dh51. Dramamine 50mg tablet dh5z. Dimenhydrinate 50mg tablet dh6.. Diphenhydramine hydrochloride [nausea] dh9.. Meclozine hydrochloride dh91. Ancoloxin tablet dh92. Meclozine 12.5mg pastille dh93. Traveleeze Soft and Chewy 12.5mg pastille dh94. Meclozine hydrochloride 12.5mg tablet dh95. Sea-Legs 12.5mg tablet dha.. Mepyramine maleate [nausea] dhf.. Promethazine [nausea] [see c8i..] dhg.. Promethazine theoclate dhg1. Avomine 25mg tablet dhg2. VERTIGON 25mg tablets dhgz. Promethazine theoclate 25mg tablet dhr.. CINNARIZINE+DIMENHYDRINATE dhr1. CINNARIZINE+DIMENHYDRINATE 20mg/40mg tablets dhr2. ARLEVERT 20mg/40mg tablets k61.. Antazoline k6l.. Olopatadine l8... Drugs used in nasal allergy l81.. BECLOMETASONE DIPROPIONATE [NOSE] l811. BECONASE 50micrograms nasal spray l812. BECONASE AQUEOUS 50microgram nasal spray

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l813. ZONIVENT AQUANASAL 50micrograms spray l814. BECONASE HAYFEVER 50micrograms aqueous nasal spray l815. NASOBEC AQUEOUS 50micrograms nasal spray l816. NASOBEC HAYFEVER 50micrograms nasal spray l817. *BECLO-AQUA 50 nasal spray l818. BECLOMIST 50micrograms nasal spray l819. VIVABEC 50micrograms nasal spray l81a. CARE HAYFEVER RELIEF 50micrograms nasal spray l81b. RINO CLENIL 50micrograms nasal spray l81c. POLLENASE 50micrograms nasal spray l81d. VANTAGE HAYFEVER RELIEF 50micrograms nasal spray l81e. BECONASE HAYFEVER RELIEF FOR ADULTS 50micrograms nasal spray l81y. BECLOMETHASONE 50micrograms nasal spray l81z. BECLOMETASONE 50micrograms aqueous nasal spray l82.. BETAMETHASONE SOD PHOSPHATE [NOSE] l821. *BETNESOL nose drops 5mL l822. BETNESOL 0.1% nose drops 10mL l823. VISTA-METHASONE 0.1% nose drops 5mL l824. VISTA-METHASONE 0.1% nose drops 10mL l825. BETNESOL-N nose drops 10mL l826. BETAMETHASONE SODIUM PHOSPHATE+NEOMYCIN SULFATE 0.1%/0.5% nose drops l827. VISTA-METHASONE N nose drops 5mL l828. VISTA-METHASONE N nose drops 10mL l82z. BETAMETHASONE 0.1% nose drops l83.. BUDESONIDE [NOSE] l831. RHINOCORT 50micrograms nasal spray l832. RHINOCORT AQUA 100micrograms nasal spray l833. RHINOCORT AQUA 64micrograms nasal spray l83x. BUDESONIDE 64micrograms aqueous nasal spray l83y. BUDESONIDE 100micrograms aqueous nasal spray l83z. BUDESONIDE 50micrograms nasal spray l84.. FLUNISOLIDE l841. SYNTARIS 25micrograms nasal spray l84z. FLUNISOLIDE 25micrograms nasal spray l85.. SODIUM CROMOGLICATE [NOSE] l851. Rynacrom 10mg insufflation cartridge l852. *RYNACROM INSUFFLATOR l853. Rynacrom 2% nose drops 15mL l854. *RYNACROM 2% nasal spray 26mL l855. Rynacrom compound Nasal spray 26mL

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l856. Rynacrom 4% nasal spray 22mL l857. Resiston One nasal spray l858. Vividrin 2% nasal spray l859. Rynacrom Allergy nasal spray 10mL l85v. Sodium cromoglicate 4% nasal spray l85w. Sodium cromoglycate 10mg insufflation cartridge l85x. Sodium cromoglycate 2% nasal drops l85y. Sodium cromoglicate 2% nasal spray l85z. Sodium cromoglicate compound 2% nasal spray l86.. IPRATROPIUM BROMIDE [2] l861. IPRATROPIUM 20micrograms nasal spray l862. RINATEC 20micrograms nasal spray l863. IPRATROPIUM 0.03% aqueous nasal spray l864. RINATEC 0.03% aqueous nasal spray l865. RINATEC 21micrograms nasal spray l866. IPRATROPIUM BROMIDE 21micrograms nasal spray l87.. Azelastine hydrochloride l871. Azelastine hydrochloride 0.1% nasal spray l872. Rhinolast 0.1% nasal spray 10mL l873. Rhinolast 0.1% nasal spray 20mL l874. Rhinolast Hayfever 0.1% nasal spray 5mL l875. Aller-Eze 0.1% nasal spray 5mL l876. Rhinolast 0.1% nasal spray 22mL l877. RHINOLAST ALLERGY 0.1% nasal spray 5mL l88.. FLUTICASONE [NOSE] l881. FLUTICASONE PROPIONATE 50micrograms nasal spray l882. FLIXONASE 50micrograms nasal spray l883. FLIXONASE 400micrograms Nasules l884. Flixonase Allergy 50micrograms aqueous nasal spray l885. NASOFAN AQUEOUS 50micrograms nasal spray l886. AVAMYS 27.5micrograms nasal spray l887. FLUTICASONE FUROATE 27.5micrograms nasal spray l88z. FLUTICASONE PROPIONATE 400micrograms single-use nasal drops l89.. Nedocromil sodium [nose] l891. Nedocromil sodium 1% nasal spray l892. Tilarin 1% nasal spray l8A.. Levocabastine hydrochloride [nose] l8A1. Levocabastine 0.5mg/mL nasal spray l8A2. Livostin 0.5mg/ml nasal spray 10mL l8A3. Livostin Direct 0.5mg/mL nasal spray 5mL

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l8B.. TRIAMCINOLONE ACETONIDE [NOSE] l8B1. TRIAMCINOLONE ACETONIDE 55micrograms aqueous nasal spray l8B2. NASACORT 55micrograms aqueous nasal spray l8C.. Tramazoline hydrochloride+dexamethasone isonicotinate l8C1. Dexa-Rhinaspray Duo aqueous nasal spray l8D.. MOMETASONE FUROATE MONOHYDRATE [NOSE] l8D1. NASONEX 0.05% aqueous nasal spray l8Dz. MOMETASONE FUROATE MONOHYDRATE 0.05% aqueous nasal spray l8E.. AZELASTINE HYDROCHLORIDE+FLUTICASONE PROPIONATE l8E1. DYMISTA 137micrograms/50micrograms nasal spray l8E2. AZELASTINE HCL+FLUTICASONE PROPION 137mcg/50mcg nasal spray l9... Topical Nasal decongestants l927. Decongestant 0.05% nasal spray 22mL l95.. Compound Nasal decongestants l952. Otrivine-Antistin nose drops l953. Otrivine-Antistin nasal spray la17. Vibrocil nose drops 15mL la18. Vibrocil nose gel 12g la19. Vibrocil Nasal spray 10mL lA31. CARE ALLERGY DEFENCE powder nasal spray 200dose m342. Anthisan cream 25g m348. Anthisan Plus Sting Relief spray m34y. Mepyramine maleate+benzocaine 2%/2% spray m34z. Mepyramine maleate 2% cream o59.. Promethazine HCl [anaesthesia] o5b.. Trimeprazine tartrate [anaesthesia] x0024 Clemastine+phenylpropanolamine x00A2 Promethazine product x00Ca Treemix allergy initial kit x00Cb Alutard artemisia allergy maintenance kit x00Ce Alutard grass allergy maintenance kit x00Ci Alutard timothy grass allergy maintenance kit x00CJ Alutard artemisia allergy initial kit x00Ck Artemisia allergy maintenance kit x00CM Alutard grass allergy initial kit x00Co Grass allergy maintenance kit x00CQ Alutard timothy grass allergy initial kit x00CR Alutard treemix allergy initial kit x00CS Artemisia allergy initial kit x00CV Grass allergy initial kit

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x00CZ Timothy grass allergy initial kit x00ez Calimal 4mg tablet x00f3 Clemastine 1.34mg tablet x00fo Pollon-eze 10mg tablet x00FS Anthisan cream x00ft Promethazine hydrochloride 20mg tablet x00fy Seldane 120mg tablet x00g1 Sominex 20mg tablet x00Xd Rynacrom 2% nasal drops x00Xf Rynacrom 4% nasal spray x00Xg Rynacrom Compound nasal spray x01Dm Antiallergenic drugs x01Dn H1 antihistamine x01Do Non-sedating antihistamine x01Dp Azelastine x01Dq Cetirizine x01Dr Sedating antihistamine x01Ds Azatadine x01Dt Brompheniramine x01Du Chlorphenamine x01Dv Cinnarizine x01Dx Dimethindene x01Dy Vibrocil nasal spray x01Dz Vibrocil nose gel x01E0 Vibrocil nose drops x01E1 Diphenhydramine product x01E2 Diphenylpyraline x01E3 Hydroxyzine x01E4 Mepyramine x01E5 Phenindamine x01E6 Pheniramine x01E8 Oral promethazine x01E9 Parenteral promethazine x01EA Triprolidine x01EB Alimemazine x01ED Cromoglycate and related antiallergenic x01eh Terfex 60mg tablet x01EI Rynacrom 2% nasal spray x01EJ Nedocromil x02KI Q-Mazine 5mg/5mL syrup

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x02MT Lodoxamide x03am Levocabastine product x03ao Livostin 0.5mg/mL nasal spray x03hH Decongestant 0.05% nasal spray x03lb Rhinolast Allergy 0.1% nasal spray x04r5 Rynacrom Allergy nasal spray x04xH Silver birch allergy initial kit x04xI Silver birch allergy maintenance kit x04xJ Alutard silver birch allergy initial kit x04xK Alutard silver birch allergy maintenance kit x04xx Emedastine x05kr Nasal mometasone x05lZ Aller-Eze 0.1% nasal spray x05s1 Rhinolast 0.1% nasal spray x05Zm Livostin Direct 0.5mg/mL nasal spray

7.6.5 Eczema diagnosis MEDCODE Read_code Read_term 230 M12z1 Eczema NOS 488 M12z0 Dermatitis NOS 610 M112. Infantile eczema 900 M2522 Cheiropompholyx 1095 M12z1 Eczema NOS 1240 M113. Flexural eczema 1424 M12z2 Infected eczema 1427 M12.. Contact dermatitis and other eczemas 1578 M2521 Pompholyx unspecified 1741 M111. Atopic dermatitis/eczema 1961 M12y8 Contact dermatitis due to metals 3699 M12z3 Hand eczema 4684 M119. Discoid eczema 5000 M102. Infectious eczematoid dermatitis 5391 M12.. Contact dermatitis and other eczemas 5869 M114. Allergic (intrinsic) eczema 6180 M11z. Atopic dermatitis NOS 6399 M12.. Contact dermatitis and other eczemas 6728 M102. Infectious eczematoid dermatitis 8884 M10.. Erythematosquamous dermatosis 8994 M12z4 Erythrodermic eczema 9335 M129. Irritant contact dermatitis

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10840 M117. Neurodermatitis - atopic 11132 M1280 Allergic contact dermatitis due to adhesives 13223 M11.. Atopic dermatitis and related conditions 13371 M12y8 Contact dermatitis due to metals 13389 M131. Ingestion dermatitis due to food 14690 F4D3. Noninfected eyelid dermatosis 15627 M12.. Contact dermatitis and other eczemas 15879 F4D31 Contact or allergic eyelid dermatitis 16685 F4D31 Contact or allergic eyelid dermatitis 16832 F4D31 Contact or allergic eyelid dermatitis 20394 M10z. Erythematosquamous dermatosis NOS 25178 M2523 Podopompholyx 29774 M12A1 Drug photoallergic response 30664 M1285 Allergic contact dermatitis due to food in contact with skin 31882 M1292 Irritant contact dermatitis due to other chemical products 32406 M12A0 Drug phototoxic response 35602 M183z Lichenification NOS 35645 M13y. Ingestion dermatitis due to other specified substance 35797 M125z Contact dermatitis due to food NOS 35803 M13.. Ingestion dermatitis 38383 M1283 Allergic contact dermatitis due to dyes 38673 M115. Besnier's prurigo 39721 Myu2. [X]Dermatitis and eczema 43313 Myu21 [X]Allergic contact dermatitis due to oth chemical products 43888 M1294 Irritant contact dermatitis due to plants, except food 44559 M13z. Ingestion dermatitis NOS 47312 Myu2C [X]Other specified dermatitis 50306 M1290 Irritant contact dermatitis due to cosmetics 53384 F4D5. Other eyelid infective dermatitis 54207 F4D3z Noninfected eyelid dermatoses NOS 59349 M1y1. Cutaneous autosensitization 59742 Myu23 [X]Allergic contact dermatitis due to other agents 62943 M1293 Irritant contact dermatitis due to food in contact with skin 63904 F4D4. Infective eyelid dermatitis of types resulting in deformity 64542 M125z Contact dermatitis due to food NOS 66631 M1291 Irritant contact dermatitis due drugs in contact with skin 72696 Myu27 [X]Unspecified contact dermatitis due to other agents 100100 8HTu. Referral to eczema clinic 100551 Myu26 [X]Unspcfd contact dermatitis due to other chemical products Ua1AR Occupational eczema

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X00YO Blepharitis in seborrhoeic eczema X40Fx Nipple eczema X5005 Eczema vaccinatum X503l Friction eczema X503m Friction palmar eczema X504O Fibreglass dermatitis X504r Photosensitisation reaction X504s Phototoxic reaction X504t Phytophotodermatitis X504u Strimmer dermatitis X504v Photoallergic eczema X5051 Chronic actinic dermatitis X505a Apron pattern of vesicular eczema of hands X505b Implant allergic nickel contact dermatitis X505c Hyperkeratotic eczema of palms and soles X505d Constitutional discoid hand eczema X505e Constitutional fingertip eczema X505f Constitutional eczema of feet X505g Acute podopompholyx X505H Cactus dermatitis X505h Chronic podopompholyx X505i Hyperkeratotic eczema of soles X505K Eczema X505k Discoid hand eczema X505L Hand eczema X505M Constitutional eczema X505N Atopic eczema of hands X505P Discoid atopic dermatitis X505Q Erythrodermic atopic eczema X505R Follicular atopic dermatitis X505r Grease contact dermatitis X505s Oil contact dermatitis X505S Pruriginous atopic dermatitis X505t Elastoplast contact dermatitis X505T Photosensitive atopic eczema X505u Egg contact dermatitis X505U Photoallergic contact dermatitis X505V Constitutional eczema of hands and feet X505W Acute cheiropodopompholyx X505w Perfume contact dermatitis

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X505X Hyperkeratotic eczema of hands and feet X505x Allergic contact dermatitis X505Y Discoid hand eczema X505y Nickel sensitivity X505Z Constitutional eczema of hands X505z Implant allergic nickel contact dermatitis X5060 Ingested allergen contact dermatitis X5061 Photoallergic contact dermatitis X5062 Occupational allergic contact dermatitis X5063 Irritant contact dermatitis X5064 Acute irritant contact dermatitis X5065 Subacute irritant contact dermatitis X5066 Chronic irritant contact dermatitis X506E Subacute prurigo X506F Chronic prurigo X506G Dermographic prurigo X506H Prurigo pigmentosa X506I Juvenile plantar dermatosis X506L Chronic superficial scaly dermatitis X506M Eosinophilic pustular folliculitis X506N Exudative discoid and lichenoid dermatosis X506O Papular eczema with elimination of papillary oedema X506P Desiccation eczema X506Q Asteatotic eczema X506T Erythroderma X506U Site-specific eczema X50Gj Eczematous drug eruption X50Gm Drug-induced erythroderma Xa0p8 Dermatitis of eyelid Xa0Wg Baboon syndrome Xa0WJ Swimming pool dermatitis Xa1dl Unclassifiable eczema Xa7lb Eczema of wrist Xa7lZ Eczema of face XaBml Eczema of leg XaBmm Eczema of foot XaBsL Chronic lichenified atopic dermatitis XaINM Exacerbation of eczema XaL2Q Periocular dermatitis XaY4o Infected eczema

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XE1Av Eczema NOS XE1Aw Ingestion dermatitis due to drugs XE1C6 Atopic eczema/dermatitis NOS XM1GA Pompholyx XM1PZ Dermatitis medicamentosa

7.6.6 Nasal polyps MEDCODE Read_code Read_term 977 H110. Polyp of nasal cavity 4341 H11y2 Polyp of maxillary sinus 4686 H11.. Nasal polyps 11744 H11y1 Polyp of ethmoidal sinus 14749 H110z Polyp of nasal cavity NOS 14888 H11z. Nasal polyp NOS 19742 H11y. Other polyp of sinus 31837 H1100 Choanal polyp 35897 H11y2 Polyp of maxillary sinus 36229 H1110 Woakes' ethmoiditis 44518 H11yz Other polyp of sinus NOS 44934 H111. Polypoid sinus degeneration 47466 H1101 Nasopharyngeal polyp 50528 H111z Polypoid sinus degeneration NOS 56372 H11y. Other polyp of sinus 61281 H11y3 Polyp of sphenoidal sinus 69765 Hyu23 [X]Other polyp of sinus 91482 H11y0 Polyp of frontal sinus X1024 Aspirin-sensitive asthma with nasal polyps Xa0MF Nasal sinus polyp XE0Xw Maxillary sinus polyp

7.6.7 Chronic sinusitis diagnosis and treatment procedures MEDCODE Read_code Read_term 848 74112 Intranasal antrostomy 1140 7415y Operation on unspecified nasal sinus NOS 1400 74145 Antral washout - nasal 1673 74122 Intranasal ethmoidectomy 1674 H132. Chronic ethmoidal sinusitis 2233 H13y1 Pansinusitis 2257 H13.. Chronic sinusitis 2984 H131. Frontal sinusitis

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3624 H130. Maxillary sinusitis 3938 74102 Caldwell Luc drainage of maxillary antrum 4128 7414z Other specified operation on unspecified nasal sinus 4433 H130. Chronic maxillary sinusitis 4640 7410y Nasal sinus operations 5437 H13z. Chronic sinusitis NOS 6491 7416. FESS/Therapeutic endoscopy of nose and sinus 7243 7416. FESS/Post operative division of adhesions 7738 7415. FESS - diagnostic endoscopy of nose and sinus 7981 7411. Other operations on maxillary antrum 8220 74164 FESS/Uncinectomy 10546 H13.. Chronic rhinosinusitis 11711 7413. Operations on sphenoid sinus 12747 74120 External frontoethmoidectomy 15163 H131. Chronic frontal sinusitis 16022 74144 Lateral rhinotomy 16626 7416F FESS - post operative removal of polyps (local anaesthetic) 17173 H135. Recurrent sinusitis 18083 7416D FESS - post operative suction clearance (local anaesthetic) 18271 74115 Puncture of maxillary antrum 18302 74131 Drainage of sphenoid sinus 18572 H17.. Allergic rhinosinusitis 18869 74170 FESS/Antrostomy via middle meatus 19480 741z. Other specified operations on nasal sinus 19995 7412y Other operation on maxillary antrum NOS 20806 7415. FESS - diagnostic nasal antroscopy 20832 74166 FESS/Anterior ethmoidectomy 21213 74128 Radical frontal sinus antrostomy 21923 7416. FESS/Therapeutic nasal antroscopy 22555 74132 Puncture of sphenoid sinus 23673 74146 BAWO 23740 7410. Operations on maxillary antrum using sublabial approach 24535 74117 Removal of antrochoanal polyp 25174 7411y Bilateral antral washout 27869 74129 Frontal sinusotomy NEC 28764 7411. Reconstruction of maxillary antrum 30744 74123 External ethmoidectomy 32764 74101 Ligation of maxillary artery using sublabial approach 33336 7413z Other specified operation on sphenoid sinus 33603 7411G Intranasal antrostomy and excision lesion maxillary antrum

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33709 7416A FESS/Diagnostic endoscopy of nose or sinus NOS 33756 7M1B0 Nasal sinus operations NOS 33922 74168 FESS/Anterior and posterior ethmoidectomy 33956 7411. Intranasal antrostomy and biopsy of maxillary antrum 34107 7411F Reconstruction of maxilla with bone graft 34165 74123 Transantral ethmoidectomy 34257 74113 Intranasal antrostomy and drainage 34973 7417y FESS - therapeutic endoscopy of nose or sinus NOS 35389 7416C FESS/Excisional surgery to middle turbinate 36047 7414. Operations on unspecified nasal sinus 37481 74169 FESS/Sphenoidectomy 39139 741y. Other operations on frontal sinus NOS 39381 7412. Operations on frontal sinus 39469 74124 Horgan transantral ethmoidectomy 39501 H13y0 Chronic pansinusitis 41457 74111 Drainage of maxillary antrum NEC 41877 74117 Radical maxillary antrotomy 41887 7415z FESS/Diagnostic endoscopy of nose or sinus OS 42166 7416y Functional endoscopic sinus surg - polypectomy nasal sinus 42196 7413y Operation on frontal sinus NOS 44432 74115 Closure of fistula between maxillary antrum and mouth 44645 74145 Catheterisation of nasal sinus 44876 74114 Biopsy of lesion of maxillary antrum 45832 74143 Biopsy of lesion of nasal sinus NEC 45995 7416z FESS - therapeutic endoscopy of nose or sinus OS 46336 7416B FESS/Antrostomy via inferior meatus 48497 74116 Irrigation of maxillary antrum NEC 48703 H133. Chronic sphenoidal sinusitis 48896 74127 Craniofacial ethmoidectomy 49348 74167 FESS/Anterior ethmoidectomy and frontal recess dissection 49369 74147 Direct closure of defect of nasal sinus 49548 H13y. Other chronic sinusitis 50787 74125 Bone flap to frontal sinus 53961 7411z Other specified other operation on maxillary antrum 54292 74112 Excision of lesion of maxillary antrum 54375 H13yz Other chronic sinusitis NOS 57098 74103 Irrigation of maxillary antrum using sublabial approach 59019 74165 FESS/Uncinectomy and excision of bulla 59339 74161 FESS - diagnostic antroscopy via middle meatus 60356 74126 Trephine of frontal sinus

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61629 74110 Transantral vidian nerve neurectomy using sublabial approach 62763 7414. Reconstruction of defect of nasal sinus 62936 74163 FESS/Therapeutic antroscopy via middle meatus 63552 74120 Killian external frontoethmoidectomy 63733 Hyu22 [X]Other chronic sinusitis 64359 7412z Other specified operation on frontal sinus 64766 74141 Excision of nasal sinus NEC 66885 74121 Ogston external frontoethmoidectomy 67200 74142 Excision of lesion of nasal sinus 67275 7414B Reconstruct defect nasal sinus c microvascular transfer flap 68003 7M1B1 Functional endoscopic sinus surgery 68405 7414A Operation on sphenoid sinus NOS 69374 7414y Reconstruction of defect of nasal sinus with bone graft 70776 74120 Reconstruction of defect of maxilla with skin graft 73094 SN31. Aerosinusitis 86064 7M1B1 Functional endoscopic nasal surgery 88274 74140 Repair of sphenoidal sinus 90287 74130 Median drainage of frontal sinus 91681 74150 Reconstruction of defect of nasal sinus with local flap 92311 741.. Frontal sinus osteoplasty 92967 7417z Other specified other operations on frontal sinus 94014 7417. Other operations on frontal sinus 95634 74118 Denker radical maxillary antrotomy 95857 74119 Direct closure of defect of maxilla 96692 7410z Operation on maxillary antrum using sublabial approach OS 97338 7411D Reconstruction of maxilla with local flap 99561 74162 FESS/Therapeutic antroscopy via inferior meatus 100959 7418. Diagnostic nasendoscopy 103022 74151 FESS - diagnostic antroscopy via canine fossa 105121 74152 FESS - diagnostic antroscopy via inferior meatus 105781 7411A Operation on maxillary antrum using sublabial approach NOS 110252 74148 Reconstruction of defect of nasal sinus with skin graft X00IB Transantral vidian nerve neurectomy X00Ig Intranasal optic nerve decompression X00m6 Chronic anterior ethmoidal sinusitis X00m7 Chronic anterior ethmoidal sinusitis X00m8 Chronic panethmoidal sinusitis X00m9 Chronic osteomeatal disease X00mA Chronic frontoethmoidal sinusitis X00oh Operation on maxillary antrum

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X00oi Reconstruction of maxillary antrum X00oj Irrigation of maxillary antrum NEC X00ok Inferior meatal antrostomy X00ol Middle meatal antrostomy X00om Removal of foreign body from maxillary antrum X00oO Excision of concha bullosa X00op Operation via maxillary antrum X00oR Transantral ligation of maxillary artery X00ou Operation on frontoethmoidal sinuses X00ov Transorbital ethmoidectomy X00ow External frontoethmosphenoidectomy X00ow External frontoethmosphenoidectomy X00ox Intranasal frontal recess dissection X00oy Intranasal frontoethmoidectomy X00oz Intranasal frontoethmosphenoidectomy X00oz Intranasal frontoethmosphenoidectomy X00p4 Biopsy of ethmoid sinus X00p5 Biopsy of frontal sinus X00p6 Obliteration of frontal sinus X00p8 Biopsy of sphenoid sinus X00p9 Cannulation and irrigation of sphenoid sinus X00pA Biopsy of nasal sinus X00pB Suction clearance of nasal sinus X00pC Reconstruction of defect of nasal sinus X00pD Diagnostic endoscopy of nose and sinuses X00pE Diagnostic nasendoscopy X00pF Sleep nasendoscopy X00pH Diagnostic antroscopy via inferior meatus X00pI Diagnostic antroscopy via middle meatus X00Tm Intranasal orbital decompression X00Tn Transantral transethmoidal orbital decompression X00VJ Intranasal dacryocystorhinostomy Xa0CA Uncinectomy and polypectomy Xa2j1 Extended ethmoidectomy Xa3mN Nasal sinus puncture and irrigation Xa3mY Nasal sinus puncture Xa3n5 External maxillary antrostomy Xa3nb Nasal sinusotomy - other Xa3nc Frontal sinusectomy Xa3zL Frontonasal duct dilatation

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Xa9eL Irrigation of maxillary antrum XaamF Diagnostic endoscopic examination of nasal cavity Diagnostic endoscopic examination of nasal cavity and biopsy of XaapZ lesion of nasal cavity Xaasx Drainage of frontal sinus Xaat0 Excision of lesion from sphenoid sinus XaAuv Removal of tooth from maxillary antrum XaBSt Intranasal antrostomy and biopsy of maxillary antrum XaBSv Intranasal antrostomy and excision of lesion of maxillary antrum XaBXU Frontal sinusotomy XaC3l Sphenoidotomy XaDtW Repair of oroantral fistula - immediate XaDtX Repair of oroantral fistula - established XaEId Bilateral antral washout FESS - Functional endoscopic sinus surgery - XaI9v sphenoethmoidectomy FESS - Functional endoscopic sinus surgery - posterior XaIA2 ethmoidectomy Functional endoscopic sinus surgery - polypectomy of nasal XaIwR sinus XaLn4 Other specified other operations on frontal sinus XaLn5 Other operations on frontal sinus NOS XaLn6 Other operations on frontal sinus XaLn7 Frontal sinus osteoplasty XaLn8 Median drainage of frontal sinus XaLn9 Repair of sphenoidal sinus XaPJX Endoscopic balloon dilatation of ostium of paranasal sinus XE05q Other operations on maxillary antrum XE05r Intranasal antrostomy XE05s Drainage of maxillary antrum XE05t Radical maxillary antrotomy XE05u External frontoethmoidectomy XE05v Transantral ethmoidectomy XE05v Transantral ethmoidectomy XE05w Operation on unspecified nasal sinus Nasal sinus operations (& [antrostomy] or [frontal] or XE0L4 [maxillary]) XE0L6 (External maxillary antrostomy) or (Caldwell-Luc operation) XE0L8 Frontal sinus: [sinusotomy] or [exploration] XE0LA Excision sinus: [frontal] or [ethmoid] XE0LC Nasal sinusectomy - other XE0Y0 Chronic maxillary sinusitis

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XE0Y1 Chronic frontal sinusitis XM0nO Exploration of frontal sinus XM0nP Ethmoidectomy XM16a Nasal sinus irrigation XM1HU Howarth's operation

7.6.8 Gastro-oesophageal reflux MEDCODE Read_code Read_term 592 J101. Oesophagitis 984 J10y4 Oesopheal reflux without mention of oesophagitis 1327 J10y4 Oesopheal reflux without mention of oesophagitis 2281 J10y4 Oesopheal reflux without mention of oesophagitis 2535 J1011 Reflux oesophagitis 4614 J1016 Ulcerative oesophagitis 5283 J1016 Ulcerative oesophagitis 5596 J1025 Barrett's ulcer of oesophagus 7104 J1011 Reflux oesophagitis 7577 1957. Gastric reflux 8259 760L5 Insertion of Angelchick prosthesis 8321 760L8 Laparoscopic Nissen fundoplication using abdominal approach 9115 760L0 Antireflux fundoplication using thoracic approach 10000 760L2 Antireflux fundoplication using abdominal approach 10199 760M2 Removal of Angelchick prosthesis 14713 760L0 Antireflux fundoplication using thoracic approach 14760 J101z Oesophagitis NOS 14910 76130 Gastroplasty NEC 15054 J1011 Reflux oesophagitis 15579 J1011 Reflux oesophagitis 16450 J1011 Reflux oesophagitis 16605 J1011 Reflux oesophagitis 17263 760L. Antireflux operations 17610 760L2 Antireflux fundoplication using abdominal approach 18174 760L7 Endoscopic Nissen fundoplication using thoracic approach 18211 760L. Antireflux operations 18741 760M0 Revision of fundoplication of stomach 18981 760L6 Oesophagogastric fundoplasty 20955 760L0 Antireflux fundoplication using thoracic approach 24021 J1020 Peptic ulcer of oesophagus 24021 J1020 Gastro-oesophageal reflux disease with ulceration 25610 J10y4 Oesopheal reflux without mention of oesophagitis

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28400 76180 Gastropexy NEC 28619 760Lz Antireflux operation NOS 34005 760Ly Other specified antireflux operation 35037 J101y Other specified oesophagitis 39323 J1015 Phlegmonous oesophagitis 45360 760L3 Antireflux gastropexy 47261 760L6 Oesophagogastric fundoplasty 48146 760L3 Antireflux gastropexy 51400 760M. Revision of antireflux operations 53657 760L1 Antireflux operation using thoracic approach NEC 61616 760L3 Antireflux gastropexy 67258 760Mz Revision of antireflux operation NOS 68276 760L1 Antireflux operation using thoracic approach NEC 99526 J10y6 Barrett's oesophagus 103564 760L4 Antireflux procedure and gastroplasty HFQ 109010 J1017 Eosinophilic oesophagitis Ua1kQ Gastric reflux X20UN Total fundoplication X20UO Total fundoplication using abdominal approach X20UP Partial fundoplication X20UQ Partial fundoplication using abdominal approach X20UR Anterior gastropexy X20US Posterior gastropexy X20UT Gastroplasty X20UU Longitudinal gastroplasty X20UV Collis-Belsey procedure X20UW Collis-Nissen procedure X20UX V-Y gastroplasty X20UY Antireflux prosthesis procedure X20UZ Replacement of implanted antireflux prosthesis X3003 Gastro-oesophageal reflux disease X3004 Biliary oesophagitis X3005 Peptic stricture of oesophagus X3007 Barrett's oesophagus with oesophagitis Xa1q7 Peptic oesophagitis Xa3lg Cardioplasty Xa7Ta Moderate gastric reflux Xa7Tb Minimal gastric reflux Xa7TZ Excessive gastric reflux Xa84y Partial fundoplication using thoracic approach

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Xa84z Fundoplication Xa8bS Adjustment of implanted antireflux prosthesis Xa8bT Removal of implanted antireflux prosthesis Xa8Oq Gastropexy Xa9Bz Barrett's oesophagus XaB18 Revision gastropexy XaDt8 Insertion of antireflux prosthesis XaEY7 Laparoscopic Nissen fundoplication using abdominal approach XaEYg Endoscopic Nissen fundoplication using thoracic approach XE0aL Gastro-oesophageal reflux disease with oesophagitis XE0aO Gastro-oesophageal reflux disease without oesophagitis XE0Ca Antireflux fundoplication using abdominal approach XE0Cb Antireflux gastropexy XE0Cc Oesophagogastric fundoplasty XE0CY Oesophageal reflux operation XE0CZ Antireflux fundoplication using thoracic approach XM009 Total fundoplication using thoracic approach

7.6.9 Diabetes Mellitus MEDCODE Read_code Read_term 506 C1001 Diabetes mellitus, adult onset, no mention of complication 711 C10.. Diabetes mellitus 758 C10F. Type 2 diabetes mellitus 1038 C1000 Diabetes mellitus, juvenile type, no mention of complication 1323 F420. Diabetic retinopathy 1407 C10FJ Insulin treated Type 2 diabetes mellitus 1549 C10E. Type 1 diabetes mellitus 1647 C108. Insulin dependent diabetes mellitus 1682 C101. Diabetes mellitus with ketoacidosis 1684 66A4. Diabetic on oral treatment 2340 F3813 Myasthenic syndrome due to diabetic amyotrophy 2342 F372. Polyneuropathy in diabetes 2475 C104. Diabetes mellitus with renal manifestation 2478 66AJ1 Brittle diabetes 2986 F4202 Preproliferative diabetic retinopathy 3286 F4201 Proliferative diabetic retinopathy 3837 F4204 Diabetic maculopathy 4513 C109. Non-insulin dependent diabetes mellitus 5002 F372. Polyneuropathy in diabetes 5884 C109. Non-insulin dependent diabetes mellitus

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6509 C1087 Insulin dependent diabetes mellitus with retinopathy 6791 C1088 Insulin dependent diabetes mellitus - poor control 7069 F4200 Background diabetic retinopathy 7795 C106. Diabetes mellitus with neurological manifestation 8403 C1097 Non-insulin dependent diabetes mellitus - poor control 10098 C10yy Other specified diabetes mellitus with other spec comps 10099 F4203 Advanced diabetic maculopathy 10418 C10ED Type 1 diabetes mellitus with nephropathy 10659 F4640 Diabetic cataract 10692 C10EM Type 1 diabetes mellitus with ketoacidosis 10755 F4206 Non proliferative diabetic retinopathy 11041 9h41. Excepted from diabetes quality indicators: Patient unsuitable 11348 9h42. Excepted from diabetes quality indicators: Informed dissent 11551 C10B. Diabetes mellitus induced by steroids 11626 F420z Diabetic retinopathy NOS 12213 8BL2. Patient on maximal tolerated therapy for diabetes 12455 C10E. Type 1 diabetes mellitus 12640 C10FC Type 2 diabetes mellitus with nephropathy 12736 C10F5 Type 2 diabetes mellitus with gangrene 13279 C104y Other specified diabetes mellitus with renal complications 14803 C1001 Diabetes mellitus, adult onset, no mention of complication 14889 C1001 Diabetes mellitus, adult onset, no mention of complication 15690 C103. Diabetes mellitus with ketoacidotic coma 16230 C106. Diabetes mellitus with neurological manifestation 16491 C106. Diabetes mellitus with neurological manifestation 16502 C104. Diabetes mellitus with renal manifestation 17067 F1711 Autonomic neuropathy due to diabetes 17095 2G5A. O/E - Right diabetic foot at risk 17247 F35z0 Diabetic mononeuritis NOS 17262 C1096 Non-insulin-dependent diabetes mellitus with retinopathy 17313 F4407 Diabetic iritis 17545 C108F Insulin dependent diabetes mellitus with diabetic cataract 17858 C108. Insulin dependent diabetes mellitus 17859 C109. Non-insulin dependent diabetes mellitus 18143 C109G Non-insulin dependent diabetes mellitus with arthropathy 18209 C1090 Non-insulin-dependent diabetes mellitus with renal comps 18219 C109. Non-insulin dependent diabetes mellitus 18230 C108J Insulin dependent diab mell with neuropathic arthropathy 18264 C109J Insulin treated Type 2 diabetes mellitus 18278 C109J Insulin treated Type 2 diabetes mellitus

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18387 C10E7 Type 1 diabetes mellitus with retinopathy 18390 C10FM Type 2 diabetes mellitus with persistent microalbuminuria 18425 C10FB Type 2 diabetes mellitus with polyneuropathy 18496 C10F6 Type 2 diabetes mellitus with retinopathy 18505 C108. Insulin dependent diabetes mellitus 18642 C10EH Type 1 diabetes mellitus with arthropathy 18683 C10E5 Type 1 diabetes mellitus with ulcer 18777 C10F0 Type 2 diabetes mellitus with renal complications 18824 8I3W. Diabetic foot examination declined 21482 C102. Diabetes mellitus with hyperosmolar coma 21983 C1080 Insulin-dependent diabetes mellitus with renal complications 22487 C10N. Secondary diabetes mellitus 22573 C106z Diabetes mellitus NOS with neurological manifestation 22871 C10EP Type 1 diabetes mellitus with exudative maculopathy 22884 C10F. Type 2 diabetes mellitus 24035 E0314 Subacute confusional state, of cerebrovascular origin 24423 C108. Insulin dependent diabetes mellitus 24458 C1097 Non-insulin dependent diabetes mellitus - poor control 24490 C1000 Diabetes mellitus, juvenile type, no mention of complication 24571 F3722 Asymptomatic diabetic neuropathy 24693 C109G Non-insulin dependent diabetes mellitus with arthropathy 24694 C108B Insulin dependent diabetes mellitus with mononeuropathy 24836 C109C Non-insulin dependent diabetes mellitus with nephropathy 25114 E0304 Acute confusional state, of cerebrovascular origin 25591 C10FQ Type 2 diabetes mellitus with exudative maculopathy 25627 C10F7 Type 2 diabetes mellitus - poor control 26054 C10FL Type 2 diabetes mellitus with persistent proteinuria 26108 C10B0 Steroid induced diabetes mellitus without complication 26664 2G5B. O/E - Left diabetic foot at risk 26666 2G5E. O/E - Right diabetic foot at low risk 26667 2G5I. O/E - Left diabetic foot at low risk 26855 C1084 Unstable insulin dependent diabetes mellitus 28622 21263 Diabetes resolved 29979 C1099 Non-insulin-dependent diabetes mellitus without complication 30294 C10EL Type 1 diabetes mellitus with persistent microalbuminuria 30323 C10EK Type 1 diabetes mellitus with persistent proteinuria 30477 F4207 High risk proliferative diabetic retinopathy 31156 2G5J. O/E - Left diabetic foot at moderate risk 31157 2G5F. O/E - Right diabetic foot at moderate risk 31171 2G5G. O/E - Right diabetic foot at high risk

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31172 2G5K. O/E - Left diabetic foot at high risk 31310 C1089 Insulin dependent diabetes maturity onset 31790 F372. Polyneuropathy in diabetes 32193 C11y0 Steroid induced diabetes 32193 C11y0 Steroid-induced diabetes 32403 C107. Diabetes mellitus with peripheral circulatory disorder 32556 C107. Diabetes mellitus with peripheral circulatory disorder 32627 C10FN Type 2 diabetes mellitus with ketoacidosis 33254 C105. Diabetes mellitus with ophthalmic manifestation 33343 C10y. Diabetes mellitus with other specified manifestation 33807 C1072 Diabetes mellitus, adult with gangrene 33969 C10A1 Malnutrition-related diabetes mellitus with ketoacidosis 34268 C10F2 Type 2 diabetes mellitus with neurological complications 34283 C105z Diabetes mellitus NOS with ophthalmic manifestation 34450 C10FK Hyperosmolar non-ketotic state in type 2 diabetes mellitus 34912 C1094 Non-insulin dependent diabetes mellitus with ulcer 35105 C1041 Diabetes mellitus, adult onset, with renal manifestation 35107 C104z Diabetes mellitus with nephropathy NOS 35116 2G5L. O/E - Left diabetic foot - ulcerated 35288 C10E8 Type 1 diabetes mellitus - poor control 35316 2G5H. O/E - Right diabetic foot - ulcerated 35385 C10FH Type 2 diabetes mellitus with neuropathic arthropathy 35399 C107. Diabetes mellitus with peripheral circulatory disorder 35785 F3721 Chronic painful diabetic neuropathy 36633 C109K Hyperosmolar non-ketotic state in type 2 diabetes mellitus 36695 C10D. Diabetes mellitus autosomal dominant type 2 37315 F3y0. Diabetic mononeuropathy 37648 C109J Insulin treated Type 2 diabetes mellitus 37806 C10FF Type 2 diabetes mellitus with peripheral angiopathy 37957 C10K. Type A insulin resistance 38161 C1087 Insulin dependent diabetes mellitus with retinopathy 38617 C101y Other specified diabetes mellitus with ketoacidosis 38986 C100. Diabetes mellitus with no mention of complication 39070 C10EE Type 1 diabetes mellitus with hypoglycaemic coma 39317 C1061 Diabetes mellitus, adult onset, + neurological manifestation 39420 F3813 Myasthenic syndrome due to diabetic amyotrophy 39809 C108J Insulin dependent diab mell with neuropathic arthropathy 40023 C1020 Diabetes mellitus, juvenile type, with hyperosmolar coma 40401 C1095 Non-insulin dependent diabetes mellitus with gangrene 40682 C10E9 Type 1 diabetes mellitus maturity onset

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40837 C10EN Type 1 diabetes mellitus with ketoacidotic coma 40962 C109H Non-insulin dependent d m with neuropathic arthropathy 41049 C1087 Insulin dependent diabetes mellitus with retinopathy 41389 C1051 Diabetes mellitus, adult onset, + ophthalmic manifestation 41686 Cyu20 [X]Other specified diabetes mellitus 41686 Cyu20 [X]Other specified diabetes mellitus 41716 C108C Insulin dependent diabetes mellitus with polyneuropathy 42505 C101z Diabetes mellitus NOS with ketoacidosis 42567 C1030 Diabetes mellitus, juvenile type, with ketoacidotic coma 42729 C108E Insulin dependent diabetes mellitus with hypoglycaemic coma 42762 C1096 Non-insulin-dependent diabetes mellitus with retinopathy 42831 C10E2 Type 1 diabetes mellitus with neurological complications 43139 C1021 Diabetes mellitus, adult onset, with hyperosmolar coma 43227 C10F3 Type 2 diabetes mellitus with multiple complications 43453 C10C. Diabetes mellitus autosomal dominant 43785 C109D Non-insulin dependent diabetes mellitus with hypoglyca coma 43857 C10M. Lipoatrophic diabetes mellitus 43921 C10E4 Unstable type 1 diabetes mellitus 44033 F3450 Diabetic mononeuritis multiplex 44260 C108F Insulin dependent diabetes mellitus with diabetic cataract 44440 C108E Insulin dependent diabetes mellitus with hypoglycaemic coma 44443 C1085 Insulin dependent diabetes mellitus with ulcer 44779 C109E Non-insulin depend diabetes mellitus with diabetic cataract 44982 C10FE Type 2 diabetes mellitus with diabetic cataract 45276 C10E3 Type 1 diabetes mellitus with multiple complications 45467 C109B Non-insulin dependent diabetes mellitus with polyneuropathy 45491 C10z. Diabetes mellitus with unspecified complication 45913 C1097 Non-insulin dependent diabetes mellitus - poor control 45914 C1088 Insulin dependent diabetes mellitus - poor control 45919 C1092 Non-insulin-dependent diabetes mellitus with neuro comps 46150 C1095 Non-insulin dependent diabetes mellitus with gangrene 46290 C108y Other specified diabetes mellitus with multiple comps 46301 C10EC Type 1 diabetes mellitus with polyneuropathy 46624 C10C. Diabetes mellitus autosomal dominant 46850 C1088 Insulin dependent diabetes mellitus - poor control 46917 C10FD Type 2 diabetes mellitus with hypoglycaemic coma 46963 C1080 Insulin-dependent diabetes mellitus with renal complications 47011 8Hj0. Referral to diabetes structured education programme 47315 C10F7 Type 2 diabetes mellitus - poor control 47321 C10F1 Type 2 diabetes mellitus with ophthalmic complications

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47377 C105y Other specified diabetes mellitus with ophthalmic complicatn 47409 C109B Non-insulin dependent diabetes mellitus with polyneuropathy 47582 C10E0 Type 1 diabetes mellitus with renal complications 47584 F4205 Advanced diabetic retinal disease 47649 C10E1 Type 1 diabetes mellitus with ophthalmic complications 47650 C10E3 Type 1 diabetes mellitus with multiple complications 47816 C109H Non-insulin dependent d m with neuropathic arthropathy 47954 C10F9 Type 2 diabetes mellitus without complication 48078 F3720 Acute painful diabetic neuropathy 48192 C109E Non-insulin depend diabetes mellitus with diabetic cataract 49074 C10F4 Type 2 diabetes mellitus with ulcer 49146 C1082 Insulin-dependent diabetes mellitus with neurological comps 49276 C1081 Insulin-dependent diabetes mellitus with ophthalmic comps 49554 C10EF Type 1 diabetes mellitus with diabetic cataract 49655 C10F6 Type 2 diabetes mellitus with retinopathy 49869 C109G Non-insulin dependent diabetes mellitus with arthropathy 49949 C10E4 Unstable type 1 diabetes mellitus 50225 C1090 Non-insulin-dependent diabetes mellitus with renal comps 50429 C1091 Non-insulin-dependent diabetes mellitus with ophthalm comps 50527 C10FB Type 2 diabetes mellitus with polyneuropathy 50609 L1806 Pre-existing diabetes mellitus, non-insulin-dependent 50813 C109A Non-insulin dependent diabetes mellitus with mononeuropathy 50960 L1805 Pre-existing diabetes mellitus, insulin-dependent 50972 C100z Diabetes mellitus NOS with no mention of complication 51261 C10E. Type 1 diabetes mellitus 51697 C10G. Secondary pancreatic diabetes mellitus 51756 C10FP Type 2 diabetes mellitus with ketoacidotic coma 51957 C1085 Insulin dependent diabetes mellitus with ulcer 52104 C1083 Insulin dependent diabetes mellitus with multiple complicatn 52236 C10A. Malnutrition-related diabetes mellitus 52283 C1082 Insulin-dependent diabetes mellitus with neurological comps 52303 C1090 Non-insulin-dependent diabetes mellitus with renal comps 53200 C1010 Diabetes mellitus, juvenile type, with ketoacidosis 53392 C10F9 Type 2 diabetes mellitus without complication 54008 C10EJ Type 1 diabetes mellitus with neuropathic arthropathy 54212 C109F Non-insulin-dependent d m with peripheral angiopath 54600 C10E4 Unstable type 1 diabetes mellitus 54856 C1011 Diabetes mellitus, adult onset, with ketoacidosis 54899 C109F Non-insulin-dependent d m with peripheral angiopath 55075 C1094 Non-insulin dependent diabetes mellitus with ulcer

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55239 C10EQ Type 1 diabetes mellitus with gastroparesis 55842 C1092 Non-insulin-dependent diabetes mellitus with neuro comps 56268 C109D Non-insulin dependent diabetes mellitus with hypoglyca coma 56448 C108A Insulin-dependent diabetes without complication 56803 C1074 NIDDM with peripheral circulatory disorder 56885 C10K0 Type A insulin resistance without complication 57278 C10F0 Type 2 diabetes mellitus with renal complications 57621 C108D Insulin dependent diabetes mellitus with nephropathy 58604 C1096 Non-insulin-dependent diabetes mellitus with retinopathy 59253 C10FG Type 2 diabetes mellitus with arthropathy 59288 C103y Other specified diabetes mellitus with coma 59365 C109C Non-insulin dependent diabetes mellitus with nephropathy 59725 C1091 Non-insulin-dependent diabetes mellitus with ophthalm comps 59903 C106. Diabetes mellitus with neurological manifestation 59991 C10D. Diabetes mellitus autosomal dominant type 2 60107 C1084 Unstable insulin dependent diabetes mellitus 60208 C108J Insulin dependent diab mell with neuropathic arthropathy 60499 C1086 Insulin dependent diabetes mellitus with gangrene 60699 C109F Non-insulin-dependent d m with peripheral angiopath 60796 C10FL Type 2 diabetes mellitus with persistent proteinuria 61071 C109D Non-insulin dependent diabetes mellitus with hypoglyca coma 61122 C10H. Diabetes mellitus induced by non-steroid drugs 61344 C1080 Insulin-dependent diabetes mellitus with renal complications 61523 C106y Other specified diabetes mellitus with neurological comps 61829 C1082 Insulin-dependent diabetes mellitus with neurological comps 62107 C1095 Non-insulin dependent diabetes mellitus with gangrene 62146 C1093 Non-insulin-dependent diabetes mellitus with multiple comps 62209 C10EM Type 1 diabetes mellitus with ketoacidosis 62352 C108H Insulin dependent diabetes mellitus with arthropathy 62613 C10EA Type 1 diabetes mellitus without complication 62674 C10FA Type 2 diabetes mellitus with mononeuropathy 63017 C1089 Insulin dependent diabetes maturity onset 63357 C1071 Diabetes mellitus, adult, + peripheral circulatory disorder 63371 C10y1 Diabetes mellitus, adult, + other specified manifestation 63690 C10FR Type 2 diabetes mellitus with gastroparesis 63762 C10z1 Diabetes mellitus, adult onset, + unspecified complication 64283 C10zy Other specified diabetes mellitus with unspecified comps 64357 C10zz Diabetes mellitus NOS with unspecified complication 64446 C108G Insulin dependent diab mell with peripheral angiopathy 64449 C108z Unspecified diabetes mellitus with multiple complications

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64571 C109C Non-insulin dependent diabetes mellitus with nephropathy 64668 C10FJ Insulin treated Type 2 diabetes mellitus 65025 C107z Diabetes mellitus NOS with peripheral circulatory disorder 65062 C103z Diabetes mellitus NOS with ketoacidotic coma 65267 C10F3 Type 2 diabetes mellitus with multiple complications 65463 F4208 High risk non proliferative diabetic retinopathy 65616 C108H Insulin dependent diabetes mellitus with arthropathy 65704 C1094 Non-insulin dependent diabetes mellitus with ulcer 66145 C10EN Type 1 diabetes mellitus with ketoacidotic coma 66675 C10A0 Malnutrition-related diabetes mellitus with coma 66872 C108D Insulin dependent diabetes mellitus with nephropathy 66965 C109H Non-insulin dependent d m with neuropathic arthropathy 67212 C10H0 DM induced by non-steroid drugs without complication 67853 C1060 Diabetes mellitus, juvenile, + neurological manifestation 67905 C1092 Non-insulin-dependent diabetes mellitus with neuro comps 68105 C10EB Type 1 diabetes mellitus with mononeuropathy 68390 C1085 Insulin dependent diabetes mellitus with ulcer 68517 C10J. Insulin autoimmune syndrome 68792 C10z0 Diabetes mellitus, juvenile type, + unspecified complication 68843 C1031 Diabetes mellitus, adult onset, with ketoacidotic coma 69124 C1073 IDDM with peripheral circulatory disorder 69278 C109E Non-insulin depend diabetes mellitus with diabetic cataract 69676 C10EA Type 1 diabetes mellitus without complication 69748 C1050 Diabetes mellitus, juvenile type, + ophthalmic manifestation 69993 C10E6 Type 1 diabetes mellitus with gangrene 70316 C1091 Non-insulin-dependent diabetes mellitus with ophthalm comps 70448 C1070 Diabetes mellitus, juvenile +peripheral circulatory disorder 70766 C108E Insulin dependent diabetes mellitus with hypoglycaemic coma 70821 C10yz Diabetes mellitus NOS with other specified manifestation 72320 C109A Non-insulin dependent diabetes mellitus with mononeuropathy 72345 C102z Diabetes mellitus NOS with hyperosmolar coma 72702 C10E8 Type 1 diabetes mellitus - poor control 85991 C10FM Type 2 diabetes mellitus with persistent microalbuminuria 91646 C10F4 Type 2 diabetes mellitus with ulcer 91942 C10E3 Type 1 diabetes mellitus with multiple complications 91943 C10EC Type 1 diabetes mellitus with polyneuropathy 93380 C10N1 Cystic fibrosis related diabetes mellitus 93468 C10EG Type 1 diabetes mellitus with peripheral angiopathy 93657 8Hj4. Referral to DESMOND diabetes structured education programme 93704 8Hj3. Referral to DAFNE diabetes structured education programme

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93727 C10FE Type 2 diabetes mellitus with diabetic cataract 93854 9OLM. Diabetes structured education programme declined 93870 8Hj5. Referral to XPERT diabetes structured education programme 93875 C10E7 Type 1 diabetes mellitus with retinopathy 93878 C10E5 Type 1 diabetes mellitus with ulcer 93922 C1040 Diabetes mellitus, juvenile type, with renal manifestation 94383 C10N0 Secondary diabetes mellitus without complication 95343 C10E7 Type 1 diabetes mellitus with retinopathy 95351 C10FA Type 2 diabetes mellitus with mononeuropathy 95539 C10FS Maternally inherited diabetes mellitus 95636 C10ER Latent autoimmune diabetes mellitus in adult 95992 C108A Insulin-dependent diabetes without complication 96235 C10E9 Type 1 diabetes mellitus maturity onset 96506 C10G0 Secondary pancreatic diabetes mellitus without complication 97446 C1089 Insulin dependent diabetes maturity onset 97474 C1084 Unstable insulin dependent diabetes mellitus 97849 C10E9 Type 1 diabetes mellitus maturity onset 97894 C10EP Type 1 diabetes mellitus with exudative maculopathy 98071 C10E1 Type 1 diabetes mellitus with ophthalmic complications 98392 C10C. Diabetes mellitus autosomal dominant 98616 C10F2 Type 2 diabetes mellitus with neurological complications 98704 C10E5 Type 1 diabetes mellitus with ulcer 98723 C10FD Type 2 diabetes mellitus with hypoglycaemic coma 99231 C108B Insulin dependent diabetes mellitus with mononeuropathy 99311 C10E1 Type 1 diabetes mellitus with ophthalmic complications 99716 C10EE Type 1 diabetes mellitus with hypoglycaemic coma 99719 C10EA Type 1 diabetes mellitus without complication 100292 Cyu23 [X]Unspecified diabetes mellitus with renal complications 100347 C10A5 Malnutritn-relat diabetes melitus wth periph circul complctn 100770 C10EF Type 1 diabetes mellitus with diabetic cataract 100964 C10F1 Type 2 diabetes mellitus with ophthalmic complications 101311 C10EC Type 1 diabetes mellitus with polyneuropathy 101735 C10E2 Type 1 diabetes mellitus with neurological complications 101834 9h43. Excepted from diabetes quality indicators: service unavailable 102112 C10E6 Type 1 diabetes mellitus with gangrene 102163 C10ED Type 1 diabetes mellitus with nephropathy 102201 C10FC Type 2 diabetes mellitus with nephropathy 102620 C10EL Type 1 diabetes mellitus with persistent microalbuminuria 102740 C1081 Insulin-dependent diabetes mellitus with ophthalmic comps 102946 C10E0 Type 1 diabetes mellitus with renal complications

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Referral to diabetes education and self management for ongoing and newly 103543 8IE9. diagnosed structured programme declined 103902 C10FG Type 2 diabetes mellitus with arthropathy 104323 C10F5 Type 2 diabetes mellitus with gangrene 104639 C10FF Type 2 diabetes mellitus with peripheral angiopathy 105337 C10E8 Type 1 diabetes mellitus - poor control 105740 2G5d. O/E - Left diabetic foot at increased risk 105741 2G5e. O/E - Right diabetic foot at increased risk 105784 C1099 Non-insulin-dependent diabetes mellitus without complication 106061 C10FP Type 2 diabetes mellitus with ketoacidotic coma 106528 C10FN Type 2 diabetes mellitus with ketoacidosis 106953 8IEa. Referral to DAFNE diabetes structured education programme declined 107414 8I94. Diabetes structured education programme not available 107464 66AS0 Diabetes Year of Care annual review 107603 C10P. Diabetes mellitus in remission 107701 C10FK Hyperosmolar non-ketotic state in type 2 diabetes mellitus 107824 C10P1 Type II diabetes mellitus in remission 108005 C1093 Non-insulin-dependent diabetes mellitus with multiple comps 108007 C1083 Insulin dependent diabetes mellitus with multiple complicatn 108360 C10P0 Type I diabetes mellitus in remission 108724 C10EQ Type 1 diabetes mellitus with gastroparesis 109051 C10E6 Type 1 diabetes mellitus with gangrene 109103 C1099 Non-insulin-dependent diabetes mellitus without complication 109133 L1807 Pre-existing malnutrition-related diabetes mellitus 109197 C10FH Type 2 diabetes mellitus with neuropathic arthropathy 109628 C10P0 Type I diabetes mellitus in remission 109837 C10E0 Type 1 diabetes mellitus with renal complications 109865 C109B Non-insulin dependent diabetes mellitus with polyneuropathy 110400 C108F Insulin dependent diabetes mellitus with diabetic cataract 110611 C10P1 Type II diabetes mellitus in remission 110997 C10y0 Diabetes mellitus, juvenile, + other specified manifestation 110997 C10y0 Diabetes mellitus, juvenile type, with other specified manifestation 111106 C108A Insulin-dependent diabetes without complication C107y Other specified diabetes mellitus with peripheral circulatory complications C10A2 Malnutrition-related diabetes mellitus with renal complications C10A3 Malnutrition-related diabetes mellitus with ophthalmic complications C10A4 Malnutrition-related diabetes mellitus with neurological complications C10A6 Malnutrition-related diabetes mellitus with multiple complications C10A7 Malnutrition-related diabetes mellitus without complications C10AW Malnutrition-related diabetes mellitus with unspecified complications C10AX Malnutrition-related diabetes mellitus with other specified complications

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C10J0 Insulin autoimmune syndrome without complication C10L. Fibrocalculous pancreatopathy C10L0 Fibrocalculous pancreatopathy without complication C10M0 Lipoatrophic diabetes mellitus without complication C10Q. Maturity onset diabetes of the young type 5 Cyu21 [X]Malnutrition-related diabetes mellitus with other specified complications Cyu22 [X]Malnutrition-related diabetes mellitus with unspecified complications Lyu29 [X]Pre-existing diabetes mellitus, unspecified X40J4 Type I diabetes mellitus X40J5 Type II diabetes mellitus X40J6 Insulin treated Type 2 diabetes mellitus X40J7 Malnutrition-related diabetes mellitus X40J8 Malnutrition-related diabetes mellitus - fibrocalculous X40J9 Malnutrition-related diabetes mellitus - protein-deficient X40JA Secondary diabetes mellitus X40Ja Abnormal metabolic state in diabetes mellitus X40JB Secondary pancreatic diabetes mellitus X40Jb Diabetic severe hyperglycaemia X40JC Secondary endocrine diabetes mellitus X40Jc Poor glycaemic control X40JI Diabetes mellitus autosomal dominant X40JJ Diabetes mellitus autosomal dominant type 2 X40JK Polyglandular autoimmune syndrome - type II X40JS Hyperproinsulinemia X40JY Insulin-dependent diabetes mellitus secretory diarrhoea syndrome X40JZ Diabetes-deafness syndrome maternally transmitted Xa3ee Diabetes with ketoacidosis - no coma Xa4g7 Unstable type I diabetes mellitus Xaagd Diabetes mellitus in remission Xaage Type I diabetes mellitus in remission Xaagf Type II diabetes mellitus in remission XaCJ2 Diabetic hyperosmolar non-ketotic state XacoB Maturity onset diabetes of the young type 5 XacsX Diabetic on oral treatment and glucagon-like peptide 1 receptor agonist XaELP Type I diabetes mellitus without complication XaELQ Type II diabetes mellitus without complication XaEnn Type I diabetes mellitus with mononeuropathy XaEno Type I diabetes mellitus with polyneuropathy XaEnp Type II diabetes mellitus with mononeuropathy XaEnq Type II diabetes mellitus with polyneuropathy

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XaF04 Type I diabetes mellitus with nephropathy XaF05 Type II diabetes mellitus with nephropathy XaFm8 Type I diabetes mellitus with diabetic cataract XaFmA Type II diabetes mellitus with diabetic cataract XaFmK Type I diabetes mellitus with peripheral angiopathy XaFmL Type I diabetes mellitus with arthropathy XaFmM Type I diabetes mellitus with neuropathic arthropathy XaFn7 Type II diabetes mellitus with peripheral angiopathy XaFn8 Type II diabetes mellitus with arthropathy XaFn9 Type II diabetes mellitus with neuropathic arthropathy XaFWG Type I diabetes mellitus with hypoglycaemic coma XaFWI Type II diabetes mellitus with hypoglycaemic coma XaIfG Type II diabetes on insulin XaIfI Type II diabetes on diet only XaIrf Hyperosmolar non-ketotic state in type II diabetes mellitus XaIzM Type 1 diabetes mellitus with persistent proteinuria XaIzN Type 1 diabetes mellitus with persistent microalbuminuria XaIzQ Type II diabetes mellitus with persistent proteinuria XaIzR Type II diabetes mellitus with persistent microalbuminuria XaJlL Secondary pancreatic diabetes mellitus without complication XaJlM Diabetes mellitus induced by non-steroid drugs without complication XaJlP Fibrocalculous pancreatopathy without complication XaJlR Secondary diabetes mellitus without complication XaJQp Type II diabetes mellitus with exudative maculopathy XaJSr Type 1 diabetes mellitus with exudative maculopathy XaJUI Diabetes mellitus induced by non-steroid drugs XaKyW Type 1 diabetes mellitus with gastroparesis XaKyX Type II diabetes mellitus with gastroparesis XaMzI Cystic fibrosis related diabetes mellitus XaOPt Maternally inherited diabetes mellitus XE10E Diabetes mellitus, juvenile type, with no mention of complication XE10F Diabetes mellitus, adult onset, with no mention of complication XE10G Diabetes mellitus with renal manifestation XE10H Diabetes mellitus with neurological manifestation XE10I Diabetes mellitus with peripheral circulatory disorder XE128 Diabetes mellitus (& [ketoacidosis]) XE12A Diabetes mellitus: [adult onset] or [noninsulin dependent] XE12C Diabetes mellitus: [juvenile] or [insulin dependent] XE12G Diabetes + eye manifestation (& [cataract] or [retinopathy]) XE12K Diabetes: [peripheral circulatory disease] or [gangrene]

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XE12M Diabetes with other complications XM19j [EDTA] Diabetes Type II (non-insulin-dependent) associated with renal failure XM1Qx Diabetes mellitus with gangrene XM1Xk Unstable diabetes XSETH Maturity onset diabetes mellitus in young XSETI Fibrocalculous pancreatic diabetes XSETK Drug-induced diabetes mellitus XSETp Diabetes mellitus due to insulin receptor antibodies

7.6.10 Osteoporosis diagnosis Red codes will be checked for a value of ≤ -2.5 for a diagnosis

MEDCODE read_code read_term 277 N330. Osteoporosis 3346 N330B Vertebral osteoporosis 4013 N331L Collapse of vertebra due to osteoporosis NOS 5841 N331J Collapse of lumbar vertebra due to osteoporosis 9700 N3302 Postmenopausal osteoporosis 11503 N331M Fragility fracture due to unspecified osteoporosis 12673 N3319 Osteoporosis + pathological fracture thoracic vertebrae 13987 58E4. Forearm DXA scan result osteoporotic 14967 N3300 Osteoporosis, unspecified 16307 N3301 Senile osteoporosis 16857 N330C Osteoporosis localized to spine 17377 N3318 Osteoporosis + pathological fracture lumbar vertebrae 18825 NyuB8 [X]Unspecified osteoporosis with pathological fracture 19048 N331K Collapse of thoracic vertebra due to osteoporosis 24093 N3305 Drug-induced osteoporosis 25650 N330D Osteoporosis due to corticosteroids 27597 N3316 Idiopathic osteoporosis with pathological fracture 31580 N330A Osteoporosis in endocrine disorders 33526 N3313 Osteoporosis of disuse with pathological fracture 34798 N330z Osteoporosis NOS 36432 N3746 Osteoporotic kyphosis 38395 N331B Postmenopausal osteoporosis with pathological fracture 39217 58EM. Lumbar DXA scan result osteoporotic 39334 N3312 Postoophorectomy osteoporosis with pathological fracture 40428 N3303 Idiopathic osteoporosis 40904 58EE. Hip DXA scan T score 41755 NyuB1 [X]Other osteoporosis

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42354 58EG. Hip DXA scan result osteoporotic 45736 N331H Collapse of cervical vertebra due to osteoporosis 46510 58EA. Heel DXA scan result osteoporotic 46894 N3315 Drug-induced osteoporosis with pathological fracture 48772 N331A Osteoporosis + pathological fracture cervical vertebrae 57301 NyuB0 [X]Other osteoporosis with pathological fracture 62702 N3304 Dissuse osteoporosis 68019 N3314 Postsurgical malabsorption osteoporosis with path fracture 70349 N3306 Postoophorectomy osteoporosis 93497 N331N Fragility fracture 93655 N3307 Postsurgical malabsorption osteoporosis 93705 N331M Fragility fracture due to unspecified osteoporosis 93981 N331N Fragility fracture 96342 58EV. Femoral neck DEXA scan result osteoporotic 101443 9hP0. Excepted from osteoporosis quality indicators: patient unsuitable 102730 NyuB2 [X]Osteoporosis in other disorders classified elsewhere X70At Adult idiopathic generalised osteoporosis X70Au Juvenile idiopathic generalised osteoporosis X70Av Secondary generalised osteoporosis X70Aw Regional migrating osteoporosis X70Az Disappearing bone disease X70B0 Secondary localised osteoporosis X70B1 Post-irradiation osteoporosis Xa0AZ Primary osteoporosis Xa1k0 Regional osteoporosis XaC12 Osteoporosis localised to spine XaIP4 Osteoporosis due to corticosteroids XaISa Osteoporosis risk assessment done XaISb Osteoporosis risk assessment refused XaISc Osteoporosis risk assessment defaulted XaISP Osteoporosis monitoring administration XaISQ Attends osteoporosis monitoring XaISR Refuses osteoporosis monitoring XaISS Osteoporosis monitoring default XaIST Osteoporosis monitoring first letter XaISU Osteoporosis monitoring second letter XaISV Osteoporosis monitoring third letter XaISW Osteoporosis monitoring verbal invitation XaISX Osteoporosis monitoring telephone invitation XaISY Osteoporosis monitoring deleted

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XaISZ Osteoporosis monitoring check done XaX3Q Exception reporting: osteoporosis quality indicators XaX3W Excepted from osteoporosis quality indicators: informed dissent XE1GA Localised disuse osteoporosis

7.6.11 Hypertension MEDCODE Read_code Read_term 204 G2... Hypertensive disease 351 G20.. Essential hypertension 799 G20.. Essential hypertension 1894 G201. Benign essential hypertension 3269 21261 Hypertension resolved 3712 G20z. Essential hypertension NOS 4372 G202. Systolic hypertension 4668 G22.. Hypertensive renal disease 7057 G2z.. Hypertensive disease NOS 7329 G24.. Secondary hypertension 8732 G2... Hypertensive disease 8857 G21z0 Hypertensive heart disease NOS without CCF 10818 G20z. Essential hypertension NOS 11056 8BL0. Patient on maximal tolerated antihypertensive therapy 15106 G22z. Hypertensive renal disease NOS 15377 G200. Malignant essential hypertension 16059 G24z. Secondary hypertension NOS 16173 G21zz Hypertensive heart disease NOS 16292 G21.. Hypertensive heart disease 17434 G22.. Hypertensive renal disease 18765 G2y.. Other specified hypertensive disease 21837 G232. Hypertensive heart&renal dis wth (congestive) heart failure 25371 G2410 Secondary benign renovascular hypertension 28684 G233. Hypertensive heart and renal disease with renal failure 29310 G22z. Hypertensive renal disease NOS 31341 G24z1 Hypertension secondary to drug 31387 G24z0 Secondary renovascular hypertension NOS 31464 G21z. Hypertensive heart disease NOS 31755 G240. Secondary malignant hypertension 32423 G222. Hypertensive renal disease with renal failure 32976 61462 Hypertension induced by oral contraceptive pill 34744 G244. Hypertension secondary to endocrine disorders 39649 G220. Malignant hypertensive renal disease

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42229 G24zz Secondary hypertension NOS 43935 G221. Benign hypertensive renal disease 50157 G210. Malignant hypertensive heart disease 51635 G241z Secondary benign hypertension NOS 52127 G2111 Benign hypertensive heart disease with CCF 52427 G211. Benign hypertensive heart disease 57288 G241. Secondary benign hypertension 57987 G234. Hyperten heart&renal dis+both(congestv)heart and renal fail 59383 G2400 Secondary malignant renovascular hypertension 60655 L1280 Pre-exist hyperten heart dis compl preg childbth+puerperium 61166 G21z0 Hypertensive heart disease NOS without CCF 61660 G2110 Benign hypertensive heart disease without CCF 62718 G21z1 Hypertensive heart disease NOS with CCF 63000 G231. Benign hypertensive heart and renal disease 63466 G23.. Hypertensive heart and renal disease 64127 L1210 Renal hypertension in pregnancy/childbirth/puerp unspecified 67232 G230. Malignant hypertensive heart and renal disease 68659 G23z. Hypertensive heart and renal disease NOS 69753 Gyu2. [X]Hypertensive diseases 71717 L1211 Renal hypertension in pregnancy/childbirth/puerp - delivered 72668 G2101 Malignant hypertensive heart disease with CCF 73293 G240z Secondary malignant hypertension NOS 83473 G203. Diastolic hypertension 93143 L121. Renal hypertension in pregnancy/childbirth/puerperium 94718 L121z Renal hypertension in pregnancy/childbirth/puerperium NOS 95334 G2100 Malignant hypertensive heart disease without CCF 97349 L1213 Renal hypertension in preg/childbirth/puerp - not delivered 97533 Gyu21 [X]Hypertension secondary to other renal disorders 98230 67H8. Lifestyle advice regarding hypertension 102458 Gyu20 [X]Other secondary hypertension 103046 G210z Malignant hypertensive heart disease NOS 105274 G28.. Stage 2 hypertension (NICE - Nat Ins for Hth Clin Excl 2011) 105316 G25.. Stage 1 hypertension (NICE - Nat Ins for Hth Clin Excl 2011) 105371 G25.. Stage 1 hypertension (NICE - Nat Ins for Hth Clin Excl 2011) 105480 G27.. Hypertension resistant to drug therapy 105487 G26.. Severe hypertension (Nat Inst for Health Clinical Ex 2011) 105938 G211z Benign hypertensive heart disease NOS 105989 G26.. Severe hypertension (Nat Inst for Health Clinical Ex 2011) 107704 G20.. Essential hypertension 108136 G250. Stage 1 hyperten (NICE 2011) without evidnce end organ damge

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108840 L1212 Renal hypertension in preg/childb/puerp -deliv with p/n comp 109797 G251. Stage 1 hyperten (NICE 2011) with evidnce end organ damge Xa0Cs Labile hypertension Xa0kX Renovascular hypertension Xa3fQ Malignant hypertension Xab9L Stage 1 hypertension (NICE 2011) without evidence of end organ damage Xab9M Stage 1 hypertension (NICE 2011) with evidence of end organ damage XaZbT Hypertension resistant to drug therapy Stage 2 hypertension (NICE - National Institute for Health and Clinical XaZbz Excellence 2011) Stage 1 hypertension (NICE - National Institute for Health and Clinical XaZWm Excellence 2011) Severe hypertension (NICE - National Institute for Health and Clinical XaZWn Excellence 2011) XaZzo Nocturnal hypertension XE0Ub Hypertension XE0Uc Essential hypertension XE0Ud Essential hypertension NOS XE0Ue Hypertensive heart disease NOS without congestive cardiac failure XE0Uf Hypertensive renal disease XE0Ug Hypertensive renal disease NOS XE0W8 (Hypertensive disease) or (hypertension) XM1Qp Cardiomegaly - hypertensive XSDSb Diastolic hypertension

7.6.12 Ischaemic heart disease MEDCODE Read_code Read_term 240 G3... Ischaemic heart disease 241 G30.. Acute myocardial infarction 737 792.. Coronary artery operations 1204 G30.. Acute myocardial infarction 1344 G340. Coronary atherosclerosis 1414 G33z3 Angina on effort 1430 G33.. Angina pectoris 1431 G311. Preinfarction syndrome 1655 G340. Coronary atherosclerosis 1676 G3z.. Ischaemic heart disease NOS 1677 G30.. Acute myocardial infarction 1678 G308. Inferior myocardial infarction NOS 1792 G3... Ischaemic heart disease 2491 G30.. Acute myocardial infarction

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3704 G307. Acute subendocardial infarction 3999 G3400 Single coronary vessel disease 4017 G32.. Old myocardial infarction 4656 G311. Preinfarction syndrome 5030 ZV45K [V]Presence of coronary artery bypass graft 5254 G3401 Double coronary vessel disease 5387 G301. Other specified anterior myocardial infarction 5413 G340. Coronary atherosclerosis 5674 ZV45K [V]Presence of coronary artery bypass graft 5744 79275 Open angioplasty of coronary artery 5904 792.. Coronary artery operations 7320 G343. Ischaemic cardiomyopathy 7347 G3111 Unstable angina 7696 G33z2 Syncope anginosa 7783 323.. ECG: myocardial infarction 8246 322.. ECG: myocardial ischaemia 8568 G37.. Cardiac syndrome X 8935 G302. Acute inferolateral infarction 9276 G31y0 Acute coronary insufficiency 9413 G31y. Other acute and subacute ischaemic heart disease 9507 G3070 Acute non-Q wave infarction 9555 G33z5 Post infarct angina 10260 6A4.. Coronary heart disease review 10562 G3071 Acute non-ST segment elevation myocardial infarction 10603 792z. Coronary artery operations NOS 11048 G331. Prinzmetal's angina 11648 8B3k. Coronary heart disease medication review 11983 G3115 Acute coronary syndrome 12139 G300. Acute anterolateral infarction 12229 G30X0 Acute ST segment elevation myocardial infarction 12627 9N0k. Seen in heart failure clinic 12734 SP076 Coronary artery bypass graft occlusion 12804 G33z7 Stable angina 12986 G331. Prinzmetal's angina 13185 662K. Angina control 13187 662N. CHD monitoring 13566 G30.. Acute myocardial infarction 13571 G30.. Acute myocardial infarction 14658 G30z. Acute myocardial infarction NOS 14782 662K2 Angina control - improving

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14897 G301z Anterior myocardial infarction NOS 14898 G305. Lateral myocardial infarction NOS 15349 662Kz Angina control NOS 15373 662K1 Angina control - poor 15661 G310. Postmyocardial infarction syndrome 15754 G34z. Other chronic ischaemic heart disease NOS 16408 G32.. Old myocardial infarction 17133 G30A. Mural thrombosis 17307 G3112 Angina at rest 17464 G32.. Old myocardial infarction 17689 G30.. Acute myocardial infarction 17872 G3011 Acute anteroseptal infarction 18118 G3114 Worsening angina 18125 G3300 Nocturnal angina 18135 6A2.. Coronary heart disease annual review 18643 ZV458 [V]Presence of coronary angioplasty implant and graft 18842 G35.. Subsequent myocardial infarction 18889 G34z0 Asymptomatic coronary heart disease 18913 ZV457 [V]Presence of aortocoronary bypass graft 19542 662K0 Angina control - good 19655 G311. Preinfarction syndrome 20095 G330. Angina decubitus 20416 G3... Ischaemic heart disease 21844 G31y3 Transient myocardial ischaemia 22020 792B0 Endarterectomy of coronary artery NEC 22383 G3y.. Other specified ischaemic heart disease 23078 G34y1 Chronic myocardial ischaemia 23579 G310. Postmyocardial infarction syndrome 23708 G361. Atrial septal defect/curr comp folow acut myocardal infarct 23892 G304. Posterior myocardial infarction NOS 24126 G360. Haemopericardium/current comp folow acut myocard infarct 24540 G34y0 Chronic coronary insufficiency 24783 G3... Ischaemic heart disease 25842 G33z. Angina pectoris NOS 26863 G33z6 New onset angina 27951 G31.. Other acute and subacute ischaemic heart disease 27977 G31yz Other acute and subacute ischaemic heart disease NOS 28138 G34.. Other chronic ischaemic heart disease 28554 G33zz Angina pectoris NOS 28736 G30y0 Acute atrial infarction

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29300 662K3 Angina control - worsening 29421 G344. Silent myocardial ischaemia 29553 G366. Thrombosis atrium,auric append&vent/curr comp foll acute MI 29643 G303. Acute inferoposterior infarction 29758 G30X. Acute transmural myocardial infarction of unspecif site 29902 G330z Angina decubitus NOS 30330 G309. Acute Q-wave infarct 30421 G30.. Acute myocardial infarction 32272 G38.. Postoperative myocardial infarction 32450 G33z4 Ischaemic chest pain 32854 G30B. Acute posterolateral myocardial infarction 32911 9Or.. Heart failure monitoring administration 33620 792B. Repair of coronary artery NEC 34328 G3113 Refractory angina 34633 G34y. Other specified chronic ischaemic heart disease 34803 G30y. Other acute myocardial infarction 35119 G501. Post infarction pericarditis 35373 9Ob0. Attends coronary heart disease monitoring 35713 G34yz Other specified chronic ischaemic heart disease NOS 36423 G36.. Certain current complication follow acute myocardial infarct 36523 G311. Preinfarction syndrome 36609 G342. Atherosclerotic cardiovascular disease 36854 G332. Coronary artery spasm 37657 G362. Ventric septal defect/curr comp fol acut myocardal infarctn 38609 G351. Subsequent myocardial infarction of inferior wall 39449 G312. Coronary thrombosis not resulting in myocardial infarction 39500 9Ob8. Coronary heart disease monitoring check done 39655 G311. Preinfarction syndrome 39693 G31y2 Subendocardial ischaemia 40429 G3010 Acute anteroapical infarction 41221 G30y2 Acute septal infarction 41757 7927z Other open operation on coronary artery NOS 41835 G384. Postoperative subendocardial myocardial infarction 45809 G350. Subsequent myocardial infarction of anterior wall 45960 8B27. Antianginal therapy 46017 G30yz Other acute myocardial infarction NOS 46112 G380. Postoperative transmural myocardial infarction anterior wall 46166 G35X. Subsequent myocardial infarction of unspecified site 46276 G381. Postoperative transmural myocardial infarction inferior wall 54251 G311z Preinfarction syndrome NOS

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54535 G33z1 Stenocardia 55137 G3110 Myocardial infarction aborted 59032 323Z. ECG: myocardial infarct NOS 59189 G363. Ruptur cardiac wall w'out haemopericard/cur comp fol ac MI 59940 G364. Ruptur chordae tendinae/curr comp fol acute myocard infarct 61072 G3110 Myocardial infarction aborted 62626 G30y1 Acute papillary muscle infarction 63467 G306. True posterior myocardial infarction 66388 G33z0 Status anginosus 68357 G31y1 Microinfarction of heart 68748 G38z. Postoperative myocardial infarction, unspecified 69474 G365. Rupture papillary muscle/curr comp fol acute myocard infarct 72562 G353. Subsequent myocardial infarction of other sites 95550 8H2V. Admit ischaemic heart disease emergency 100437 9hM.. Exception reporting: myocardial infarction quality indicator 101695 9hM0. Exc myocard infarction quality indicators: informed dissent 102917 9hM1. Exc myocar infarction quality indicators: patient unsuitable 105479 G39.. Coronary microvascular disease 106812 G383. Postoperative transmural myocardial infarction unspec site X2006 Triple vessel disease of the heart X2007 Angina at rest X2008 Stable angina X2009 Unstable angina X200A New onset angina X200a Silent myocardial infarction X200B Coronary spasm X200C Myocardial ischaemia X200c Cardiac syndrome X X200D Silent myocardial ischaemia X200d Post-infarction ventricular septal defect X200E Myocardial infarction X200e Cardiac rupture after acute myocardial infarction X200G Acute Q wave infarction - anteroseptal X200H Acute non-Q wave infarction - anteroseptal X200I Acute Q wave infarction - anterolateral X200J Acute non-Q wave infarction - anterolateral X200K Acute inferior myocardial infarction X200L Acute Q wave infarction - inferior X200M Acute non-Q wave infarction - inferior X200N Acute Q wave infarction - inferolateral

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X200O Acute non-Q wave infarction - inferolateral X200P Acute lateral myocardial infarction X200Q Acute Q wave infarction - lateral X200R Acute non-Q wave infarction - lateral X200S Acute widespread myocardial infarction X200T Acute Q wave infarction - widespread X200U Acute non-Q wave infarction - widespread X200V Acute posterior myocardial infarction Xa0YL Acute anterior myocardial infarction XaAC3 Acute Q wave myocardial infarction XaAzi Acute non-Q wave infarction XaD2b Postoperative myocardial infarction XaD2e Postoperative transmural myocardial infarction of inferior wall XaD2f Postoperative transmural myocardial infarction of other sites Postoperative transmural myocardial infarction of unspecified XaD2g site XaD2h Postoperative subendocardial myocardial infarction XaD2i Postoperative myocardial infarction, unspecified XaEgZ Non-Q wave myocardial infarction XaEXt Post infarct angina XaFsG Refractory angina XaFsH Transient myocardial ischaemia XaG1Q Asymptomatic coronary heart disease XaIf1 First myocardial infarction XaINF Acute coronary syndrome XaIwM Acute ST segment elevation myocardial infarction XaIwY Acute non-ST segment elevation myocardial infarction XaJX0 Acute posterolateral myocardial infarction XE0Uh Acute myocardial infarction XE0Ui Worsening angina XE0WC Acute/subacute ischaemic heart disease NOS XE0WG Chronic ischaemic heart disease NOS XSDT6 Coronary artery atheroma

7.6.13 Heart Failure MEDCODE Read_code Read_term 398 G580. Congestive heart failure 884 G581. Left ventricular failure 1223 G58.. Heart failure 2062 G58.. Heart failure

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2906 G580. Congestive heart failure 4024 G58z. Heart failure NOS 5255 G5810 Acute left ventricular failure 5942 G581. Left ventricular failure 9524 G580. Congestive heart failure 9913 1O1.. Heart failure confirmed 10079 G580. Congestive heart failure 10154 G580. Congestive heart failure 11424 G5803 Compensated cardiac failure 12590 G58z. Heart failure NOS 13189 662g. New York Heart Association classification - class II 17278 G58z. Heart failure NOS 17851 8HBE. Heart failure follow-up 18853 662f. New York Heart Association classification - class I 19066 662h. New York Heart Association classification - class III 23481 G581. Left ventricular failure 23707 G5800 Acute congestive heart failure 27884 G5802 Decompensated cardiac failure 27964 G582. Acute heart failure 32671 G5801 Chronic congestive heart failure 32898 8H2S. Admit heart failure emergency 43618 G581. Left ventricular failure 51214 662i. New York Heart Association classification - class IV 52127 G2111 Benign hypertensive heart disease with CCF 62718 G21z1 Hypertensive heart disease NOS with CCF 94870 G5804 Congestive heart failure due to valvular disease 96799 G5y4z Post cardiac operation heart failure NOS 101137 G583. Heart failure with normal ejection fraction 101138 G583. Heart failure with normal ejection fraction 106897 G583. Heart failure with normal ejection fraction 11284 585f. Echocardiogram shows left ventricular systolic dysfunction 11351 585g. Echocardiogram shows left ventricular systolic dysfunction Excepted from heart failure quality indicators: Patient 30749 9hH0. unsuitable Excepted from heart failure quality indicators: Informed 64062 9hH1. dissent 22262 G1yz1 Rheumatic left ventricular failure X202k Heart failure as a complication of care XaEgY Refractory heart failure XaIQM Heart failure follow-up XaIQN Heart failure annual review

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XaJ9G New York Heart Association classification - class I XaJ9H New York Heart Association classification - class II XaJ9I New York Heart Association classification - class III XaJ9J New York Heart Association classification - class IV XaO5n Congestive heart failure due to valvular disease XaWyi Heart failure with normal ejection fraction XE0V8 Biventricular failure XE0V9 Heart failure NOS XE2QG Left ventricular failure

7.6.14 Depression MEDCODE Read_code Read_term 324 E2B.. Depressive disorder NEC 543 Eu32z [X]Depressive episode, unspecified 595 E112. Single major depressive episode 655 E2003 Anxiety with depression 1055 E135. Agitated depression 2970 Eu32z [X]Depressive episode, unspecified 2972 E2B0. Postviral depression 3291 Eu32z [X]Depressive episode, unspecified 3292 Eu33. [X]Recurrent depressive disorder 4323 E2B1. Chronic depression 4639 Eu32. [X]Depressive episode 5879 E112. Single major depressive episode 5987 Eu32z [X]Depressive episode, unspecified 6482 E1137 Recurrent depression 6546 E112. Single major depressive episode 6854 Eu32y [X]Other depressive episodes 6932 E113. Recurrent major depressive episode 6950 E112. Single major depressive episode 7011 E112z Single major depressive episode NOS 7604 Eu32. [X]Depressive episode 7737 Eu341 [X]Dysthymia 7749 Eu412 [X]Mixed anxiety and depressive disorder 7953 Eu341 [X]Dysthymia 8478 E130. Reactive depressive psychosis 8584 Eu341 [X]Dysthymia 8826 Eu33. [X]Recurrent depressive disorder 8851 Eu33. [X]Recurrent depressive disorder 8902 Eu33. [X]Recurrent depressive disorder

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9055 Eu32. [X]Depressive episode 9183 E11z2 Masked depression 9211 Eu321 [X]Moderate depressive episode 10290 Eu341 [X]Dysthymia 10610 E112. Single major depressive episode 10667 Eu324 [X]Mild depression 10720 Eu32y [X]Other depressive episodes 10825 E118. Seasonal affective disorder 11055 Eu251 [X]Schizoaffective disorder, depressive type 11252 Eu332 [X]Recurr depress disorder cur epi severe without psyc sympt 11329 Eu332 [X]Recurr depress disorder cur epi severe without psyc sympt 11717 Eu320 [X]Mild depressive episode 11913 Eu412 [X]Mixed anxiety and depressive disorder 12099 Eu323 [X]Severe depressive episode with psychotic symptoms 12122 9H91. Depression medication review 12399 9H90. Depression annual review 14709 E1132 Recurrent major depressive episodes, moderate 15099 E113. Recurrent major depressive episode 15155 E1122 Single major depressive episode, moderate 15219 E1123 Single major depressive episode, severe, without mention of psychosis 15220 Eu341 [X]Dysthymia 16506 E1121 Single major depressive episode, mild 16632 E291. Prolonged depressive reaction 16861 Eu333 [X]Recurrent depress disorder cur epi severe with psyc symp 17770 E130. Reactive depressive psychosis 18510 Eu32. [X]Depressive episode 19696 Eu33. [X]Recurrent depressive disorder 20785 Eu204 [X]Post-schizophrenic depression 21887 E0021 Senile dementia with depression 22116 Eu334 [X]Recurrent depressive disorder, currently in remission 22116 Eu334 [X]Recurrent depressive disorder, currently in remission 22806 Eu322 [X]Severe depressive episode without psychotic symptoms 23731 Eu333 [X]Recurrent depress disorder cur epi severe with psyc symp 24112 Eu323 [X]Severe depressive episode with psychotic symptoms 24171 E1134 Recurrent major depressive episodes, severe, with psychosis 25563 E113z Recurrent major depressive episode NOS Recurrent major depressive episodes, severe, without mention of 25697 E1133 psychosis 27491 E11y2 Atypical depressive disorder 27677 E0013 Presenile dementia with depression 28248 Eu32z [X]Depressive episode, unspecified

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28677 Eu333 [X]Recurrent depress disorder cur epi severe with psyc symp 28756 Eu33. [X]Recurrent depressive disorder 28863 Eu323 [X]Severe depressive episode with psychotic symptoms 28970 9hC0. Excepted from depression quality indicators: Patient unsuitable 29342 E1131 Recurrent major depressive episodes, mild 29451 Eu332 [X]Recurr depress disorder cur epi severe without psyc sympt 29520 Eu331 [X]Recurrent depressive disorder, current episode moderate 29784 Eu330 [X]Recurrent depressive disorder, current episode mild 30405 9H92. Depression interim review 30583 9k4.. Depression - enhanced services administration 31757 Eu333 [X]Recurrent depress disorder cur epi severe with psyc symp 32159 E1124 Single major depressive episode, severe, with psychosis 32941 Eu333 [X]Recurrent depress disorder cur epi severe with psyc symp 33469 Eu332 [X]Recurr depress disorder cur epi severe without psyc sympt 34390 E1120 Single major depressive episode, unspecified 35274 Eu251 [X]Schizoaffective disorder, depressive type 35671 E1130 Recurrent major depressive episodes, unspecified 36616 Eu33z [X]Recurrent depressive disorder, unspecified 37764 Eu333 [X]Recurrent depress disorder cur epi severe with psyc symp 41022 Eu251 [X]Schizoaffective disorder, depressive type 41989 Eu322 [X]Severe depressive episode without psychotic symptoms 42931 9HA0. On depression register 43239 9hC1. Excepted from depression quality indicators: Informed dissent 43324 E1125 Single major depressive episode, in partial or unspecified remission 44300 Eu33z [X]Recurrent depressive disorder, unspecified 47009 Eu333 [X]Recurrent depress disorder cur epi severe with psyc symp 47731 Eu33y [X]Other recurrent depressive disorders 47731 Eu33y [X]Other recurrent depressive disorders 52678 Eu323 [X]Severe depressive episode with psychotic symptoms 55384 E1136 Recurrent major depressive episodes, in full remission 56273 E1135 Recurrent major depressive episodes, in partial or unspecified remission 56609 Eu32y [X]Other depressive episodes 57409 E1126 Single major depressive episode, in full remission 59386 Eu322 [X]Severe depressive episode without psychotic symptoms 73991 Eu332 [X]Recurr depress disorder cur epi severe without psyc sympt 98252 Eu326 [X]Major depression, moderately severe 98346 Eu325 [X]Major depression, mild 98414 Eu327 [X]Major depression, severe without psychotic symptoms 98417 Eu328 [X]Major depression, severe with psychotic symptoms

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7.6.15 Anxiety MEDCODE Read_code Read_term 131 1B13. Anxiousness 462 E2001 Panic disorder 514 1B12. Nerves - nervousness 636 E200. Anxiety states 655 E2003 Anxiety with depression 1131 E204. Neurotic depression reactive type 1510 E202B Cancer phobia 1723 E2028 Claustrophobia 1758 E2004 Chronic anxiety 1907 E202. Phobic disorders 2300 E2020 Phobia unspecified 2366 E202C Dental phobia 2571 Eu400 [X]Agoraphobia 2639 E204. Neurotic depression reactive type 3076 E2021 Agoraphobia with panic attacks 3208 E203. Obsessive-compulsive disorders 3328 1B1.. General nervous symptoms 3586 1B12. Nerves - nervousness 4069 E2001 Panic disorder 4081 Eu410 [X]Panic disorder [episodic paroxysmal anxiety] 4167 E202A Fear of flying 4534 E200z Anxiety state NOS 4634 E2005 Recurrent anxiety 4659 E2002 Generalised anxiety disorder 5347 1B1H. Frightened 5678 E2030 Compulsive neurosis 5902 1B13. Anxiousness 6071 E202E Fear of pregnancy 6408 Eu410 [X]Panic disorder [episodic paroxysmal anxiety] 6939 E2000 Anxiety state unspecified 7222 Eu40z [X]Phobic anxiety disorder, unspecified 7749 Eu412 [X]Mixed anxiety and depressive disorder 8205 Eu410 [X]Panic disorder [episodic paroxysmal anxiety] 9125 8G94. Anxiety management training 9386 Eu40. [X]Phobic anxiety disorders 9785 Eu402 [X]Specific (isolated) phobias 9944 E202. Phobic disorders 10390 E202D Fear of death

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11280 Eu402 [X]Specific (isolated) phobias 11602 Eu401 [X]Social phobias 11913 Eu412 [X]Mixed anxiety and depressive disorder 12635 Eu402 [X]Specific (isolated) phobias 12838 E2022 Agoraphobia without mention of panic attacks 14729 E202z Phobic disorder NOS 14890 Eu400 [X]Agoraphobia 15292 E2620 Cardiac neurosis 16199 E2023 Social phobia, fear of eating in public 16638 E202. Phobic disorders 16729 Eu400 [X]Agoraphobia 17687 Eu515 [X]Nightmares 18248 Eu402 [X]Specific (isolated) phobias 18603 E2025 Social phobia, fear of public washing 19129 1B1H. Frightened 20089 1B1Z. General nervous symptom NOS 20163 1B1H. Frightened 20773 Eu054 [X]Organic anxiety disorder 23838 Eu41z [X]Anxiety disorder, unspecified 24066 Eu41y [X]Other specified anxiety disorders 25638 Eu41z [X]Anxiety disorder, unspecified 28106 E2026 Acrophobia 28167 Eu41y [X]Other specified anxiety disorders 28925 8HHp. Referral for guided self-help for anxiety 28938 E2027 Animal phobia 29322 E201B Compensation neurosis 29608 1B12. Nerves - nervousness 31672 E2029 Fear of crowds 31957 E2024 Social phobia, fear of public speaking 32841 8HHq. Referral for guided self-help for depression 34064 Eu40z [X]Phobic anxiety disorder, unspecified 38543 E202z Phobic disorder NOS 42000 E20y. Other neurotic disorders 42788 Eu401 [X]Social phobias 43050 E20yz Other neurotic disorder NOS 44305 Eu515 [X]Nightmares 44321 Eu413 [X]Other mixed anxiety disorders 47365 E203. Obsessive-compulsive disorders 67898 Eu40z [X]Phobic anxiety disorder, unspecified 67965 Eu402 [X]Specific (isolated) phobias

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93401 1B13. Anxiousness 107410 173f. Anxiety about breathlessness X00RP Organic anxiety disorder X00Sa Non-situational panic attack X00Sb Anxiety depression X00Sb Mixed anxiety and depressive disorder X00Sc Anxiety hysteria X00Sd Stage fright X00Se Examination fear X00SV Agoraphobia X00SV Agoraphobia X00SW Social phobia X00SX Specific phobia X00SY Needle phobia X00SZ Situational panic attack X00T7 Anxious personality disorder X761a Fear of swallowing X761b Fear of collapsing X761c Fear of fainting X761d Fear of having a heart attack X761e Fear of shaking X761f Fear of sweating X761g Fear of dying X761h Fear of going crazy X761i Fear of losing emotional control X761j Fear of becoming fat X761k Anxiety about social functioning X761l Fear of appearing ridiculous X761L Persistant anxiety depression X761L Seasonal affective disorder X761m Fear of saying the wrong thing X761N Anxiety and fear X761n Fear of going out X761p Fear of empty streets X761q Fear of open spaces X761r Fear of crossing streets X761T Anxiety about health X761t Fear of transport X761U Fear of losing control of bowels X761u Social fear

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X761v Fear of activities in public X761w Fear of eating in public X761W Fear of vomiting in public X761X Fear of having a fit X761x Fear of public speaking X761Y Fear of choking X761y Fear of using public toilets X761Z Anxiety about blushing X761z Fear of writing in public X7620 Fear of social group activities X7621 Fear of being in a small group X7622 Fear of social gatherings X7623 Fear of speaking on the phone X7624 Fear of speaking to people in authority X7625 Fear of being laughed at X7626 Fear of being watched X7627 Specific fear X7628 Fear of natural phenomena X7629 Fear of the dark X762A Fear of animals X762B Fear of feathers X762C Fear of enclosed spaces X762E Fear of tunnels X762F Fear of phone boxes X762G Fear of flying X762H Flying phobia X762I Fear associated with illness and body function X762J Fear of anaesthetic X762K Fear of general anaesthetic X762L Fear of awareness under general anaesthetic X762M Fear of not waking from general anaesthetic X762N Fear of local anaesthetic X762O Fear of problem after anaesthetic X762R Fear of surgical masks X762S Fear of hospitals X762T Fear of death X762U Fear of contracting disease X762V Fear of infection X762W Fear of contracting venereal disease X762X Fear of contracting HIV infection

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X762Y Fear of contracting radiation sickness X762Z Fear of the bogey man Xa00r Fear of heights Xa00s Fear of water Xa0XB Fear relating to body function Xa0Xc Anxiety about appearing ridiculous Xa0Xd Anxiety about saying the wrong thing Xa0XG Anxiety about losing control of bowels Xa0XH Anxiety about wetting self Xa0XI Anxiety about vomiting in public Xa0XJ Anxiety about having a fit Xa0XK Anxiety about choking Xa0XM Anxiety about swallowing Xa0XN Anxiety about collapsing Xa0XO Anxiety about shaking Xa0XP Anxiety about sweating Xa0XQ Anxiety about dying Xa0XR Anxiety about going crazy Xa0XS Anxiety about losing emotional control Xa0XU Anxiety about becoming fat Xa0XU Anxiety about obesity Xa0XX Anxiety about fainting Xa0XY Anxiety about having a heart attack Xa19B Performance anxiety Xa1a8 Examination phobia Xa1Ev Fear of needles Xa3Vj Panic Xa3Vk Fear of insects Xa3Vl Fear of birds Xa3WH Fear associated with healthcare Xa3WI Fear of blood Xa3WJ Fear of getting cancer Xa7k9 Parental anxiety Xa7kB Anxiety attack Xa7lj Cancer phobia Xa7lx Pre-examination nerves Xaafv Anxiety about breathlessness XaB95 Other manic-depressive psychos XaB96 Other phobias XaboM Referral for guided self-help for anxiety declined

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XaECG Anxiety counselling XaEG0 Dysmorphophobia XaIvf Fear of falling XaIwe HAD scale: anxiety score XaKUk Anxiety Management Training XaNkT Generalised anxiety disorder 7 item score XaP8d Stranger anxiety XaZJQ Generalised anxiety disorder 2 scale XE0ra Nervousness XE0rb Anxiety XE0ri Fear XE1Y7 Panic disorder XE1Y7 Episodic paroxysmal anxiety disorder XE1YA Phobic anxiety disorder XE1YB Phobic disorder NOS XE1YB Phobic disorder NOS XM00G Separation anxiety XM1OD Hydrophobia

7.6.16 Obstructive Sleep Apnea MEDCODE Read_code Read_term 7603 Fy03. Sleep apnoea 8148 Fy03. Sleep apnoea 22418 8724. CPAP - Continuous positive airways pressure 48539 R0051 [D]Insomnia with sleep apnoea XE2nU [D]Hypersomnia with sleep apnoea XaEGP [D]Sleep apnoea syndrome X0087 Alveolar sleep apnoea X0085 Central sleep apnoea Ub1LF Continuous CPAP X71a7 CPAP - Continuous positive airways pressure X00pW Excision reduction of tongue X20M9 Fit appliance for sleep apnoea X00pZ Geniotubercle advancement X00pX Hyoid bone expansion X00pY Hyoid bone suspension X20M9 Insertion of appliance for sleep apnoea Ub1LE Intermittent CPAP XaBI1 Laser assisted uvulopalatopharyngoplasty X0086 Mixed sleep apnoea

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X0084 Obstructive sleep apnoea Ub1LG Periodic CPAP X00pU Pharyngeal operation for obstructive sleep apnoea and snoring XaK94 Radiofrequency somnoplasty X0083 Sleep apnoea X20L9 Take impression for sleep apnoea appliance 75274 Uvulopalatopharyngoplasty

7.6.17 Sleep disorders MEDCODE Read_code Read_term 750 R0052 [D]Insomnia NOS 1244 R0050 [D]Sleep disturbance, unspecified 2129 E2749 Nightmares 2506 R0053 [D]Hypersomnia with sleep apnoea 2578 R060B [D]Snoring 3523 1B1B0 Initial insomnia 4023 E2741 Insomnia NOS 4537 1B1B. C/O - insomnia 4597 1B1B2 Late insomnia 5636 1C7.. Snoring symptoms 5675 1B1B1 Middle insomnia 6943 Eu513 [X]Sleepwalking 7409 E2745 Jet lag - disorder 8084 R005. [D]Insomnia - symptom 8310 1B1B. C/O - insomnia 8913 E2748 Sleep terrors 9536 1B1D. Nightmares - symptom 10349 R005. [D]Insomnia - symptom 10421 Fy01. Disorders of excessive somnolence 10982 E2743 Hypersomnia: [transient] or [NOS] 11721 E2747 Somnambulism - sleep walking 11779 F271. Narcoleptic syndrome 15387 1B1D. Nightmares - symptom 15407 R005z [D]Sleep dysfunction NOS 15515 E2741 Insomnia NOS 15732 R0056 [D]Sleep rhythm irregular 16115 E2742 Persistent insomnia 16447 R0055 [D]Sleep rhythm inversion 17687 Eu515 [X]Nightmares 19514 E274D (Repetitive intrusions of sleep) or (restless sleep)

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20438 R0053 [D]Hypersomnia with sleep apnoea 21305 1B1B. C/O - insomnia 25939 E2744 Persistent hypersomnia 26547 R0054 [D]Hypersomnia NOS 26836 F27z. Cataplexy or narcolepsy NOS 29370 1C72. Snores 29641 1C7Z. Snoring symptom NOS 30626 Eu510 [X]Nonorganic insomnia 31236 R005. [D]Insomnia - symptom 36301 R0053 [D]Hypersomnia with sleep apnoea 36745 E274F Reversed sleep-wake cycle 36992 E2743 Hypersomnia: [transient] or [NOS] 39990 E274B Repeated rapid eye movement sleep interruptions 41737 R0059 [D]Sleep dysfunction with arousal disturbance 44305 Eu515 [X]Nightmares 48539 R0051 [D]Insomnia with sleep apnoea 48783 E274D (Repetitive intrusions of sleep) or (restless sleep) 54458 R0058 [D]Sleep dysfunction with sleep stage disturbance 58911 R0057 [D]Sleep-wake rhythm non-24-hour cycle 59939 1C71. Does not snore 68497 F27.. Cataplexy and narcolepsy X007s Insomnia NOS X007u Difficulty getting to sleep X007v Broken sleep X007w Excessive sleep X007x Hypersomnia NOS X007y Hypersomnia of non-organic origin X007z Excessive daytime sleepiness - normal night sleep X0080 Excessive day and night-time sleepiness X0081 Postviral excessive daytime sleepiness X0082 Excess daytime sleepiness with sleep paralysis X0088 Transient sleep-wake rhythm disorder X0089 Delayed sleep phase syndrome X008A Non-24 hour sleep-wake cycle X76AE Sleep rhythm problem X76AF Cannot sleep at all X76AG Not getting enough sleep X76AJ Wakes and cannot sleep again X76AK Early waking X76AL Circumstances interfere with sleep

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X76AM Symptoms interfere with sleep X76AN Restless sleep X76AO Unrefreshed by sleep X76AQ Oversleeps X76AR Always sleepy X77iA Sleep EEG - sleep-deprived patient Xa0Kk Sleep paralysis Xa7wV Difficulty sleeping XaFqr Poor sleep pattern XaIv5 Early morning waking XaZKa Excessive somnolence XE1Yg Transient insomnia XE1Yh Transient hypersomnia XE2Pv Sleeplessness XM06i Sleep problem XM06j Irregular sleep-wake pattern XM06k Disorder of sleep-wake cycle XSGLz Light sleep

7.6.18 Chronic Kidney disease MEDCODE Read_code Read_term 350 K06.. Renal failure unspecified 512 K05.. Chronic renal failure 2994 7L1A1 Peritoneal dialysis 2996 7L1A2 Haemodialysis NEC 4809 K06.. Renal failure unspecified 6712 K050. End stage renal failure 6842 K060. Renal impairment 8037 7L1B0 Insertion of chronic ambulatory peritoneal dialysis catheter 10081 K05.. Chronic renal failure 11554 SP154 Renal failure as a complication of care 11773 7L1A. Compensation for renal failure 11787 K060. Renal impairment 12479 1Z13. Chronic kidney disease stage 4 12566 1Z12. Chronic kidney disease stage 3 12585 1Z14. Chronic kidney disease stage 5 20073 7L1A0 Renal dialysis 21837 G232. Hypertensive heart&renal dis wth (congestive) heart failure 22252 ZV451 [V]Renal dialysis status 23773 7L1B1 Removal of chronic ambulatory peritoneal dialysis catheter

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24292 SP154 Renal failure as a complication of care 28684 G233. Hypertensive heart and renal disease with renal failure 30709 7L1C0 Insertion of temporary peritoneal dialysis catheter 30735 6AA.. Chronic kidney disease annual review 30739 9Ot0. Chronic kidney disease monitoring first letter 30756 7L1A5 Continuous ambulatory peritoneal dialysis 31549 7L1A. Compensation for renal failure 32423 G222. Hypertensive renal disease with renal failure 36442 7L1B. Chronic ambulatory peritoneal dialysis catheter procedure (& placement) 39598 SP154 Renal failure as a complication of care 41013 K08y3 Renal function impairment with growth failure 47342 Q48y0 Congenital renal failure 48022 7L1Ay Other specified compensation for renal failure 52123 8882. Intestinal dialysis 53852 K05.. Chronic renal failure 53940 Kyu21 [X]Other chronic renal failure 55858 SP154 Renal failure as a complication of care 56760 7L1B. Chronic ambulatory peritoneal dialysis catheter procedure (& placement) 57987 G234. Hyperten heart&renal dis+both(congestv)heart and renal fail Hypertensive heart and renal disease with both (congestive) heart failure and 57987 G234. renal failure Other specified placement of ambulatory apparatus for compensation for 59194 7L1By renal failure 61930 Kyu2. [X]Renal failure 64636 7L1Az Compensation for renal failure NOS 64828 7L1A6 Peritoneal dialysis NEC 65089 7L1Cz Placement of other apparatus for compensation for renal failure NOS 69679 9Ot4. Chronic kidney disease monitoring telephone invite 71124 7L1A3 Haemofiltration 71271 9Ot.. Chronic kidney disease monitoring administration 71314 L093. Renal failure following abortive pregnancy 72962 9Ot1. Chronic kidney disease monitoring second letter 72964 9Ot2. Chronic kidney disease monitoring third letter 83513 7L1C. Placement of other apparatus for compensation for renal failure 88494 9Ot3. Chronic kidney disease monitoring verbal invite 88597 7L1A4 Automated peritoneal dialysis 89332 9Ot5. Predicted stage chronic kidney disease 94793 1Z1B. Chronic kidney disease stage 3 with proteinuria 94965 1Z15. Chronic kidney disease stage 3A 95122 1Z1H. Chronic kidney disease stage 4 with proteinuria 95123 1Z1C. Chronic kidney disease stage 3 without proteinuria

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95145 1Z1B. Chronic kidney disease stage 3 with proteinuria 95175 1Z1E. Chronic kidney disease stage 3A without proteinuria 95176 1Z1E. Chronic kidney disease stage 3A without proteinuria 95177 1Z1G. Chronic kidney disease stage 3B without proteinuria 95178 1Z1F. Chronic kidney disease stage 3B with proteinuria 95179 1Z16. Chronic kidney disease stage 3B 95180 1Z1F. Chronic kidney disease stage 3B with proteinuria 95188 1Z1C. Chronic kidney disease stage 3 without proteinuria 95405 1Z1L. Chronic kidney disease stage 5 without proteinuria 95406 1Z1J. Chronic kidney disease stage 4 without proteinuria 95508 1Z1K. Chronic kidney disease stage 5 with proteinuria 97587 1Z1J. Chronic kidney disease stage 4 without proteinuria 97683 1Z1L. Chronic kidney disease stage 5 without proteinuria 99160 1Z1K. Chronic kidney disease stage 5 with proteinuria 99312 1Z1H. Chronic kidney disease stage 4 with proteinuria 100633 1Z1G. Chronic kidney disease stage 3B without proteinuria 101756 7L1A0 Renal dialysis 104586 7L1B2 Flushing of peritoneal dialysis catheter 104619 K053. Chronic kidney disease stage 3 104963 K054. Chronic kidney disease stage 4 104981 K05.. Chronic renal failure 105151 K055. Chronic kidney disease stage 5 107771 K06.. Renal failure unspecified Other specified placement of other apparatus for compensation for renal 107901 7L1Cy failure 108494 8877. Ultrafiltration 109657 1Z1Y. CKD with GFR category G3b & albuminuria category A2 109804 1Z1T. CKD with GFR category G3a & albuminuria category A1 109805 1Z1V. CKD with GFR category G3a & albuminuria category A2 109884 SP0H. Disorder associated with dialysis 109904 1Z1b. CKD with GFR category G4 & albuminuria category A2 109905 1Z1W. CKD with GFR category G3a & albuminuria category A3 109963 1Z1X. CKD with GFR category G3b & albuminuria category A1 109980 1Z1a. CKD with GFR category G4 & albuminuria category A1 109981 1Z1e. CKD with GFR category G5 & albuminuria category A2 109990 1Z1Z. CKD with GFR category G3b & albuminuria category A3 110003 1Z1N. CKD with GFR category G1 & albuminuria category A2 110033 1Z1M. CKD with GFR category G1 & albuminuria category A1 110108 1Z1R. CKD with GFR category G2 & albuminuria category A2 110133 1Z1d. CKD with GFR category G5 & albuminuria category A1 110251 1Z1S. CKD with GFR category G2 & albuminuria category A3

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110269 1Z1Q. CKD with GFR category G2 & albuminuria category A1 110467 1Z1f. CKD with GFR category G5 & albuminuria category A3 110484 1Z1P. CKD with GFR category G1 & albuminuria category A3 110626 1Z1c. CKD with GFR category G4 & albuminuria category A3 Ua1IM Chronic peritoneal dialysis Ua1IN Stab peritoneal dialysis X01AF Intermittent haemodialysis X01AG Intermittent haemodialysis with sequential ultrafiltration X01AH Intermittent haemodialysis with continuous ultrafiltration X01AI Continuous haemodialysis X01AJ Continuous arteriovenous haemodialysis X01AK Continuous venovenous haemodialysis X01AL Haemofiltration X01AM Intermittent haemofiltration X01AN Continuous haemofiltration X01AO Continuous arteriovenous haemofiltration X01AP Continuous venovenous haemofiltration X01AQ Haemodiafiltration X01AR Intermittent haemodiafiltration X01AS Continuous haemodiafiltration X01AT Continuous arteriovenous haemodiafiltration X01AU Continuous venovenous haemodiafiltration X40bz Renewal of chronic ambulatory peritoneal dialysis catheter X40c0 Adjustment of chronic ambulatory peritoneal dialysis catheter X40c1 Aspiration of chronic ambulatory peritoneal dialysis catheter X40c2 Flushing of chronic ambulatory peritoneal dialysis catheter X40c3 Continuous ambulatory peritoneal dialysis X40c4 Continuous cycling peritoneal dialysis X40c5 Intermittent peritoneal dialysis X40c6 Tidal peritoneal dialysis X40c7 Night-time intermittent peritoneal dialysis Xa402 Extracorporeal kidney Xa8S7 Haemodialysis XaM2A Automated peritoneal dialysis XaMFs Chronic kidney disease monitoring administration XaMFt Chronic kidney disease monitoring first letter XaMFu Chronic kidney disease monitoring second letter XaMFv Chronic kidney disease monitoring third letter XaMFw Chronic kidney disease monitoring verbal invite XaMFx Chronic kidney disease monitoring telephone invite

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XaMGE Chronic kidney disease annual review XaMJD Chronic kidney disease monitoring XaMMt Peritoneal dialysis NEC XaMtq Extracorporeal albumin haemodialysis XaNCL Did not attend chronic kidney disease monitoring clinic XE0Jg Renal dialysis XE2u6 Chronic ambulatory peritoneal dialysis catheter procedure

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