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CONFIDENTIAL

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HEALTH OUTCOMES STUDY PROTOCOL

UNIQUE IDENTIFIER HO-17-18934 / 208683

FULL TITLE A cross-sectional survey describing real-world characteristics, treatment pathways and treatment satisfaction amongst patients with Systemic Lupus Erythematosus and renal involvement and patients with Lupus Nephritis: cohorts of the 2015 Adelphi Lupus Disease Specific Programme (DSP) and Lupus Plus Project (LPP)

ABBREVIATED TITLE Renal cohorts of the Adelphi DSP and LPP

FINAL PROTOCOL APPROVED 08 DEC 17

SPONSORSHIP GSK-sponsored study. Adelphi Real World (ARW) annually conducts this syndicated market research survey, and offers the data collected to companies for purchase. GSK have added research questions to supplement the standard survey and are the sponsor of this protocol and the associated analysis plan.

DIVISION Pharma

BUSINESS UNIT Research & Development

DEPARTMENT Value Evidence and Outcomes (VEO)

STUDY ACCOUNTABLE PERSON

CONTRIBUTING AUTHORS (ARW); (ARW); (VEO); (GSK Medical Affairs)

ASSET ID GSK1550188

GSK ASSET Belimumab (Benlysta)

INDICATION Systemic Lupus Erythematosus

REVISION CHRONOLOGY:

Version Date Document Type Change(s) since last version

08 DEC 17 Original n/a

PPD

PPD PPD PPD PPD

PPD

PPD

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PROTOCOL SYNOPSIS

Unique Identifier HO-17-18934 / 208683

Abbreviated Title Renal cohorts of the Adelphi DSP and LPP

GSK Product Belimumab (Benlysta)

Rationale In 2015 GSK sponsored the Lupus Plus Project (LPP), an Adelphi Real World (ARW) cross-sectional survey of SLE patients prescribed belimumab in the US, and the ARW cross sectional Disease Specific Programme (DSP) in SLE and lupus nephritis (LN) patients (HO-15-15509 and HO-15-16709, respectively).

Output from both of the above studies focused on SLE patients. GSK now wish to utilise the 2015 LPP and DSP data to conduct further analysis to inform the understanding of characteristics, treatments and satisfaction amongst two key subgroups; SLE patients with renal involvement and LN patients. This analysis of real world evidence will inform the current understanding of the management of these important patient groups.

Objectives (Primary, Secondary)

The primary objective of this study is to evaluate the characteristics, treatment pathway and patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort, including a descriptive comparison of belimumab- and SOC-treated patients.

The major secondary objective is to evaluate the patient and physician characteristics, treatment pathway, patient-and physician-reported satisfaction with current treatment amongst the LN cohort. Other secondary objectives are: To evaluate the factors associated with patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort. To evaluate the level of concordance between patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort. To describe the drugs for which compliance is a key reason for physician-reported treatment choice amongst the LN cohort. To categorise SLE patients in the DSP into different groups (clusters) such that patients with similar clinical manifestations are clustered together.

Study Design This study is a post-hoc analysis of i) patients with SLE and renal involvement and ii) patients with LN (renal cohorts) included in the 2015 Lupus DSP and 2015 LPP.

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The 2015 Lupus DSP is a descriptive cross-sectional survey of Rheumatologists and Nephrologists and their SLE and LN patients in the US and EU5 (Germany, Italy, Spain, France and UK).

The 2015 Lupus DSP was conducted using market research methodologies and was fielded in July 2015-October 2015.

The survey consists of four parts:

• A face-to-face physician interview

• A 5-day workload form completed by the physician

• A patient record form (PRF) completed by the physician

• A patient self-completion questionnaire (PSC).

This study will also draw on data from the Lupus Plus Project (LPP). The LPP shares the same methodology as the DSP but with a streamlined sample and fieldwork approach (physician interviews and workload forms were not completed in the LPP).

The LPP was fielded from December 2014 until February 2015, sampling Rheumatologists and their prospectively consulting SLE patients, currently prescribed belimumab in the US.

Study Population and Sampling Methods

The study population includes the following patients, and their prescribing physicians:

- SLE patients with renal involvement at any time in their reported history

- Patients with a diagnosis of LN

For the purposes of this study these are collectively referred to as the ‘renal cohorts’ of the DSP and LPP. To conduct cluster analysis, the renal cohorts will be supplemented by the DSP population of patients without renal involvement or LN.

Data Source The data source for this analysis is the 2015 Lupus III DSP and the 2015 LPP.

Data Analysis Methods

The analyses and outputs supporting the primary and key secondary objectives will be descriptive in nature. Descriptive statistics (mean, standard deviation, frequency) will be presented for demographic and clinical variables to describe the study sample. Categorical variables will be presented as frequency and percentage distributions when appropriate. Ordinal variables will be reported as frequencies and percentages and/or medians and interquartile ranges, as

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appropriate for the individual variables. Continuous variables (e.g, age, time since diagnosis, and questions with numeric rating scale responses) will be presented as mean and standard deviations, median and interquartile ranges, and score ranges. Multivariate analyses will be run on dichotomized patient and physician satisfaction with two logistic regressions that include a selection of variables chosen a priori. The clustering analysis will use Latent Class modelling to derive clusters/groups of patients based on their current symptoms and organ involvement.

Sample Size and Power

No power calculations will be conducted since all patients in the DSP and LPP with renal involvement or LN will be included. The sample sizes below are expected. Where variables are available in both the DSP and LPP, the datasets will be merged to allow greater sample for analysis for SLE patients with renal involvement treated with belimumab.

Physicians (US / EU)

PRF (US / EU) PSC (US / EU)

Sample size for primary objective

SLE with renal involvement (SOC-treated by a Rheumatologist)

52 / 115 99 / 195 54 / 114

SLE with renal involvement (belimumab-treated by a Rheumatologist)*

66 / 16 1281 / 20 922 / 16

Sample size for secondary objectives

LN patients (SOC-treated by Rheumatologist)

46 / 83 89 / 131 46 / 77

LN patients (SOC-treated by Nephrologist)

39 / 75 235 / 364 145 / 196

Notes: 1. US PRF sample: n=112 from LPP; n=16 from DSP (random sample). 2. US PSC sample: n=79 from LPP; n=13 from DSP (random sample).

Limitations The 2015 ARW Lupus DSP and LPP are descriptive cross-sectional surveys of existing SLE/LN patients. Due to the nature of the sample, the study is only representative of those currently actively seeking treatment for their SLE/LN (i.e. the consulting population). In this

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analysis, renal involvement amongst patients with SLE was defined by a physician assessment of whether renal system and/or kidneys were involved at any point in their disease history. Physician-assessed severity of renal involvement was not fully reported and renal-specific clinical parameters were not collected. Thus, there are limitations in the interpretation of the type and extent of renal manifestations in this cohort.

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TABLE OF CONTENTS 1 INTRODUCTION/BACKGROUND .............................................................................................. 9

2 OBJECTIVES .............................................................................................................................. 9

2.1 Primary ............................................................................................................................. 9

2.2 Secondary ....................................................................................................................... 10

3 RESEARCH METHODOLOGY ................................................................................................... 10

3.1 Study Design ................................................................................................................... 10

3.2 Study Population ............................................................................................................ 13

3.2.1 Eligibility Criteria ..................................................................................................... 14

3.2.2 Sampling .................................................................................................................. 14

3.3 Data Source / Data Collection ........................................................................................ 14

3.4 Endpoints ........................................................................................................................ 14

3.4.1 Primary Endpoint .................................................................................................... 17

3.4.2 Secondary Endpoint(s) ............................................................................................ 19

3.5 Sample Size / Power Calculations .................................................................................. 22

3.6 Hypotheses ..................................................................................................................... 23

4 DATA ANALYSIS CONSIDERATIONS ........................................................................................ 23

5 LIMITATIONS .......................................................................................................................... 25

6 STUDY CONDUCT, MANAGEMENT & ETHICS ........................................................................ 25

6.1 Ethics Committee/IRB Approval ..................................................................................... 26

6.2 Informed Consent .......................................................................................................... 27

6.3 Data Protection .............................................................................................................. 27

6.4 Personally Identifiable Information (PII) ........................................................................ 27

6.5 Adverse Event (AE), Pregnancy Exposure, and Incident Reporting ............................... 28

7 EXTERNAL INVOLVEMENT ..................................................................................................... 28

7.1 Third Party Supplier ........................................................................................................ 28

7.2 External Expert/Health Care Professionals (Consultants & Research PIs) ..................... 29

8 Appendices ............................................................................................................................ 30

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ABBREVIATIONS

AE Adverse event

ARW Adelphi Real World

DSP Disease Specific Programme

ESOMAR European society for opinion and market research

EU European Union

GSK GlaxoSmithKline

HIPAA Health insurance portability and accountability act

HITECH Health information technology for economic and clinical health act

ICF Informed consent form

ID Identification

IRB Institutional review board

IV Intravenous

LIT Lupus impact tracker

LN Lupus Nephritis

LPP Lupus plus project

MRS Market Research Society

MSA Master services agreement

PFO Patient focused outcomes

PRF Patient record form

PSC Patient self-completion

QC Quality checked

SC Subcutaneous

SLE Systemic lupus erythematosus

SOP Standard operating procedure

TP Third party

US United States

WPAI Work productivity and activity index

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1 INTRODUCTION/BACKGROUND

In 2015 GSK sponsored the lupus plus project (LPP), an Adelphi Real World (ARW) cross-sectional survey of SLE patients prescribed belimumab in the US, and the ARW cross sectional Disease Specific Programme (DSP) in SLE and lupus nephritis (LN) patients.

The LPP (HO-15-15509) captured patient characteristics and patient reported outcomes and perceptions from belimumab patients with the primary objective of describing the degree of treatment satisfaction and the factors associated with it. Further objectives were to assess self-reported impact of belimumab on symptoms, flares and daily activities, to compare patient and physician views of treatment and explore patient preferences for administration routes.

The LPP provided valuable insights into the real-world effectiveness of belimumab whilst also assessing the attitudes, behaviors and satisfaction of belimumab prescribers and patients (Pascoe et al, 2015).

The 2015 Lupus DSP (HO-15-16709) built on findings from the LPP, focusing on outcomes from a large sample of standard of care (SOC) and belimumab-treated patients in the US. The primary objective of the DSP was to describe the degree of physician and patient reported treatment satisfaction, experienced amongst the SLE population, and explore satisfaction amongst subgroups including treatment types. Further objectives were to assess functional and clinical outcomes and to describe differences and similarities between the LPP and DSP cohorts in terms of patient consultation flow, diagnosis, management, satisfaction, health outcomes, functionality and demographics.

Data from the LPP and DSP were merged in order to describe clinical, humanistic and satisfaction outcomes amongst belimumab patients alongside the same outcomes amongst for SOC patients within the SLE population [Pascoe et al, 2017].

Both of the above studies focused on SLE patients. GSK now wish to utilise the 2015 LPP and DSP data to conduct further analysis of the cohort of SLE patients with renal involvement and the cohort of LN patients. In contrast to the initial SLE analyses, this current study aims primarily to characterize these subgroups of patients and elucidate their treatment pathways, not only in the US but also including the EU5 countries; Germany, Italy, Spain, France and UK. A more focused approach will be applied to identifying factors associated with satisfaction with current treatment than was the case in the SLE analysis; with expected factors identified a priori in line with current methodological best practice [Harrell, 2001]. Finally, it is not planned to repeat the original exploratory analysis. Hence this protocol describes a new, targeted study design which will further inform the understanding of the real-world management of these important patient groups.

2 OBJECTIVES

2.1 Primary The primary objective of this study is to describe the characteristics, treatment pathway and patient- and physician-reported satisfaction with current treatment amongst the SLE with renal

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involvement cohort, including a descriptive comparison of belimumab- and SOC-treated patients.

2.2 Secondary The major secondary objective is to describe the patient and physician characteristics, treatment pathway, patient-and physician-reported satisfaction with current treatment amongst the LN cohort.

The other secondary objectives are: To identify the factors associated with patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort. To identify the level of concordance between patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort. To describe the drugs for which compliance is a key reason for physician-reported treatment choice amongst the LN cohort. To categorise SLE patients in the DSP into different groups (clusters) such that patients with similar clinical manifestations are clustered together. Clustering analysis will be based on presence and type of renal involvement, types of current symptomology and types of other organ involvement. The clinical, humanistic and treatment characteristics of each cluster will be described.

3 RESEARCH METHODOLOGY

3.1 Study Design

This study is a post-hoc analysis of patients with SLE and renal involvement and patients with LN (renal cohorts) enrolled to the 2015 Lupus DSP and 2015 LPP (HO-15-15509 and HO-15-16709). Each of these studies were descriptive cross-sectional surveys of Rheumatologists and Nephrologists and their SLE and LN patients in the US and EU5 (Germany, Italy, Spain, France and UK; DSP only). A detailed description of each of these surveys is provided in the subsequent sections.

3.1.1 Lupus III Disease Specific Programme (2015)

The 2015 Adelphi Lupus DSP was conducted in the US & 5EU (France, Germany, Italy, Spain & the UK) from August 2015 until September 2015. GSK purchased access to the US sample. This survey of Rheumatologists and Nephrologists and their respective SLE and LN patients, consisted of four key parts, along with a screening form:

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1. Physician Interview – An hour long face-to-face interview assessing physician attitudes and behaviors in relation to the management and treatment of Lupus

2. Physician workload – A single page form to be completed over a five day working period to asses physician workload (general and Lupus specific)

3. Physician completed patient record forms (PRF)* – physicians answer questions about their consulting SLE and LN patients

4. Patient self-completion (PSC)* – completed by SLE and LN patients

*Bespoke and proprietary GSK questions were added to capture the experience of SLE and LN patients with their current lupus treatment(s) (including belimumab).

The PRFs (n=5 SLE per Rheumatologist / n=5 LN per Nephrologist) were completed by the physician in paper format. The forms were completed once the patient finished their consultation. The physicians only completed forms for patients that satisfied the eligibility criteria as specified in section 3.2.1.

Patients whose information was recorded in the PRFs were also invited to complete a PSC form independently of their physician, immediately after consultation. The PSC forms were completed in the physician’s office (typically in the practice waiting room and independent of their physician) and were returned to the physician in a sealed envelope. This ensured that physicians do not see the patient responses, and therefore future interactions between the doctor and the patient are not influenced.

As remuneration for the time spent completing the survey, physicians were compensated according to fair market research rates, consistent with the time involved. Patients did not receive remuneration for their participation.

Inclusion criteria for physicians

Rheumatologists and Nephrologists were included in the survey upon satisfying the following criteria:

• Qualified (after 1970 and before 2014), currently practicing Rheumatologist/Nephrologist

• Actively involved in the management of SLE/LN patients

• See 5 or more SLE/LN patients a month

Inclusion criteria for patients

Patients were included in the survey upon satisfying the following criteria:

• Adult men and women aged 18 and over

• A current confirmed diagnosis of SLE/LN

• Provided informed consent (i.e. signed the informed consent form)

No exclusion criteria were used in the DSP. The DSP population consists of the following sample sizes (Table 1):

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Table 1: US EU5

Number of Rheumatologists 88 175

Number of Rheumatologist’s SLE random sample patients

502 874

Number of Rheumatologist’s SLE random sample patients who completed a PSC

311 548

Number of Nephrologists 39 75

Number of Nephrologist’s LN random sample patients

238 373

Number of Nephrologist’s LN random sample patients who completed a PSC

146 204

3.1.2 Lupus Plus Project The Adelphi LPP survey was conducted in the US from December 2014 until February 2015. The survey of Rheumatologists and their patients with SLE currently prescribed belimumab, consists of two key parts, along with a screening form:

• Physician completed patient record forms (PRF) – physicians answer questions about their SLE patients taking belimumab. The PRF included a set of GSK proprietary questions pertinent to patient and physician experience with belimumab

• Patient self-completion (PSC) – completed by patients taking belimumab

The PRFs were completed by the physician in a paper format for the next five prospectively consulting SLE patients prescribed belimumab. The forms were completed once the patient finished their consultation. The physician completed forms for patients that satisfy the eligibility criteria as specified in section 3.2.

Patients whose information is recorded on the PRFs are invited to complete a PSC form independently of their physician, immediately after consultation. The PSC forms were completed in the physician’s office (typically in the practice waiting room and independent of their physician) and returned to the physician in a sealed envelope. This ensures that physicians do not see the patient responses, and therefore future interactions between the doctor and the patient are not influenced.

As remuneration for the time spent completing the survey, physicians were compensated according to fair market research rates consistent with the time involved. Patients did not receive remuneration for their participation.

Inclusion criteria for Rheumatologists

Rheumatologists (only) were included in the survey upon satisfying the following criteria:

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• Qualified (after 1970 and before 2014), currently practicing Rheumatologist

• Actively involved in the management of SLE patients

• See 5 or more SLE Benlysta patients per month

Inclusion criteria for patients

Patients were included in the survey upon satisfying the following criteria:

• Adult men and women aged 18 and over

• Confirmed diagnosis of SLE at least 6 months ago

• Currently taking belimumab and have been on belimumab for at least 3 months

• Exclude patients with prior rituximab use before belimumab

• Provided informed consent (i.e. signed the informed consent form) No exclusion criteria were used in the LPP The LPP population consists of the following sample sizes (Table 2):

Table 2: US

Number of Rheumatologists 70

Number of Rheumatologist’s SLE patients who are currently prescribed belimumab

376

Number of Rheumatologist’s SLE patients who are currently prescribed belimumab who have completed a PSC

270

ARW conducted the data collection for the 2015 Lupus DSP and Lupus Plus Project in line with a set of internal Standard Operating Procedures (SOPs) developed to ensure data quality and integrity. These SOPs also adhere to the Health Insurance Portability and Accountability Act (HIPAA) and the Health Information Technology for Economic and Clinical Health (HITECH) Act.

ARW SOPs:

• Quality Control and Data Checking

• Data entry and coding

• Respondent Confidentiality and Data Protection

• Database Transfer

3.2 Study Population

All patients, and their prescribing physicians, in the DSP and LPP meeting the eligibility criteria for this analysis will be included. Appendix E illustrates the included cohorts according to their sources; LPP or DSP.

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To conduct the clustering analysis, the renal cohorts will be supplemented by the DSP population of patients without renal involvement or LN, i.e. the entire DSP population.

3.2.1 Eligibility Criteria

SLE with renal involvement The following inclusion criteria will be applied to the DSP SLE population:

• Patients with the renal system affected either currently and/or at initial diagnosis defined as positive response to the Section B, Q7i of the DSP PRF and/or renal symptoms ever experienced defined as a positive response to the DSP PRF Section B, question 8 (Appendix A).

The following inclusion criteria will be applied to the LPP SLE population:

• Patients suffering kidney involvement currently and/or at diagnosis and/or at any other point, defined as a positive response to LPP PRF section B, questions 1i-iii (Appendix C)

LN The following inclusion criteria will be applied to the DSP population:

• Patients with LN, defined as positive response to the DSP PRF section B, question 1.

3.2.2 Sampling

Physicians were identified by the local fieldwork teams from public lists and selected from a geographic spread of locations in each country, not be confined to large cities or practice centers. Candidate Rheumatologists who met the eligibility criteria were invited to participate in the full survey. Rheumatologists / Nephrologists completed PRFs for each of their next five eligible SLE/LN patients. The sample containing these patients could be considered a convenience sample, given that patients do not have an equal probability of being selected; they are simply the next five patients that are seen in the physician’s practice. However, it is recognised that the process is not completely random, as a patient's propensity to consult their physician, and their current disease severity, does have an influence on their chance of selection, hence the sample should be considered a pragmatic (or convenience) sample.

3.3 Data Source / Data Collection

Lupus III DSP

The physician and patient data to be analyzed in this study will be derived predominantly from the 2015 Lupus DSP, but will also use data from the 2015 LPP to inform the primary objective.

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The 2015 DSP was fielded in the US in July 2015 through to September 2015. Survey data comes from interviews and PRFs completed by the Rheumatologist/Nephrologists and completion of a questionnaire (PSC) by the patient. It should be noted, that the syndicated questions within the DSP are available for purchase by other non-GSK parties (other pharmaceutical companies or healthcare providers), but other sponsors will not have sight of, nor access to the GSK specific questions nor any data generated from these. GSK questions are highlighted in red in Appendices A-D. Physician Interview (Dr Int) Rheumatologists/ Nephrologists completed a one hour interview prior to commencement of the patient record form element of the survey. The interviews were conducted face-to-face by trained interviewers and use a combination of closed and open questions to probe physician perception and behaviors in relation to Lupus management and treatment. The physician interview contains questions regarding:

• Physician demographics: Specialty type, type of practice, gender, date of qualification etc.

• Lupus classification: Organ involvement subgroups and assessment factors

• SLE focus: Referral process, severity/flaring subgroups, treatment usage

• LN focus: Referral process, severity/flaring subgroups, treatment usage, LN/SLE progression

• Lupus assessments: Use of disease activity measures

• Biologic therapy use: Biologic targets, authorization, use/barriers, patient refusal, IV administration, formulation preference

• Treatment usage and awareness: Current usage and planned future usage SLE & LN

• Treatments in development: Spontaneous and prompted awareness of treatments in development

• Treatment goals/importance of treatment attributes and association with current treatments

Patient record form (PRF) Appendix A Rheumatologists / Nephrologists completed PRFs for each of their next five eligible SLE/LN patients. The PRF contains questions regarding:

• Demographics: Age, gender, ethnicity, employment status etc.

• Lupus history and diagnosis (SLE, LN, CLE): Current/previous diagnoses, areas of the body/organs affected, time since diagnosis, severity of disease

• Testing and monitoring

• Symptomatology and comorbidities

• Physician perception of change to patient’s symptoms

• Disease trajectory and flare history

• Medications prescribed (current and prior)

• Reasons for current treatment choice and previous switch/stop

• Eligibility for biologic treatment

• Physician satisfaction with treatment

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• Hospitalisations and consultation history

• Medication compliance

• Convenience

• Eligibility of patient for self-injection Patient Self Completion form (PSC) Appendix B Patients whose information was collected in the PRFs were invited to complete a PSC form independently of their physician, immediately after consultation. Before filling out the questionnaire, informed consent was obtained (Appendix B &D). Subjects had the right to opt-out of the survey at any time. Patients were free to withdraw from the survey after reading the letter explaining the purpose of the study and how the results will be used. Information collected in the PSC includes:

• Demographic information: Age and gender etc.

• Consultation/’patient journey’ data

• Lupus history (time since diagnosis and severity of disease over time)

• Symptom flares

• EQ5D

• Impact of lupus symptoms on work performance: Work Productivity and Activity Impairment Questionnaire (WPAI)

• Impact of Lupus on fatigue (FACIT)

• Knowledge and feelings towards their condition/treatment/doctor

• Feelings towards belimumab

• Impact and concerns of steroid use

• Level of caregiver help needed

• Changes to SLE symptoms since starting belimumab

• Satisfaction with lupus medication (including belimumab)

• Route of administration preference and convenience of IV

• Satisfaction with health care plan and coverage

• Lupus impact tracker (LIT) The EQ-5D (EuroQol 5 dimension) descriptive health profile collects patient responses on mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Patient responses are converted into a continuous summary score that ranges from just less than 0 to 1, where a higher score indicates a better quality of life. The algorithm used to convert patient responses into a summary score varies by country. The WPAI questionnaire is an instrument for assessing work productivity. Over a 7-day recall period, six questions assess the percentage of work time missed (absenteeism), the percentage of time impaired while at work (presenteeism), the percentage of overall work impairment, and the percentage of activity impairment. With the exception of the last subdomain, which assesses regular day to day activities, the WPAI is relevant only for those patients in some form of paid employment.

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The FACIT Fatigue Scale is a 16-item instrument to measure an individual’s level of fatigue during their usual daily activities over the previous 7 day period. The level of fatigue is measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued) The LIT is a 10-item instrument that explores the impact lupus has on a patient’s physical wellbeing, usual activities, responsibilities, mood, cognition, self-confidence and also explores how bothersome the side effects are. The five point scale ranges from “none of the time” to “all of the time” and asks the respondent to reflect on the last 4 weeks (for the purpose of this – point in time – survey recall period will be limited to 1-day). GSK additional questions (Appendices A and B) To supplement the PRF and PSC, patients and their physicians were asked several questions developed specifically by GSK to understand the patient experience with their condition and current treatment in more detail. The additional questions that GSK added to the syndicated research questions are highlighted in red in Appendices. Lupus Plus Project The LPP utilized the same data collection approach as the DSP, collecting data using condensed versions of the PRF and PSC outlined above (Appendix C & D).

3.4 Endpoints

3.4.1 Primary Endpoint

The primary objective of this study is to describe the characteristics, treatment pathway and patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort, including a descriptive comparison of belimumab- and SOC-treated patients. Each of the following will be reported separately for belimumab-treated patients and SOC treated-patients and by region (US vs EU5) within each treatment group, as well as presenting data for the entire cohort with renal involvement. Where variables are not reported in the LPP, given the small sample size of the belimumab-treated cohort in the DSP, these will not be presented by region (annotated with asterisk).

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• Using data from the DSP and LPP PRF describe;

o The demographic characteristics of SLE patients with renal involvement including; gender, age, ethnicity and employment status

o The clinical characteristics of SLE patients with renal involvement

▪ time since diagnosis ▪ disease severity at diagnosis and currently (physician assessment of

mild/moderate/severe) ▪ current disease progression/control (physician assessment of

improving/stable/deteriorating slowly/deteriorating rapidly/unstable) ▪ current other organ involvement (yes/no) ▪ remission status (yes/no) ▪ flare status (current status) ▪ Flare in the last 12 months (yes/no) ▪ Symptomatology currently and ever present (yes/no, by type)*, and ▪ Number of flares in last 12 months by severity (and organ system*)

• Using data from the DSP and LPP PSCs describe the humanistic characteristics of SLE patients with renal involvement, including

o WPAI score o EQ-5D utility score* o FACIT score*.

• Using data from the DSP and LPP PRFs describe the SLE drug treatment pathway of SLE patients with renal involvement including;

o Time to first treatment*. o Treatment algorithm* including; number of treatment lines, duration of lines,

number and type of treatment classes and reasons for switch/stop. o Time to belimumab*, number of prior treatments*, number of prior treatment

classes*, concomitant SLE medications and duration of belimumab treatment will also be described for belimumab patients.

o Current prescribed treatment including; generic names and formulation, current doses, dose frequencies and dosing patterns*, duration of treatment*.

o Ability to reduce steroid medication since starting current lupus medication*. o Reasons for not receiving biologic therapy, amongst those who warrant biologic

therapy* (see PRF section G Q11 for possible reasons).

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• Using data from the DSP and LPP PRF and PSC describe;

o The level of physician reported satisfaction with the current lupus medication (7 point Likert scale of very dissatisfied to very satisfied)

o Reasons for physician dissatisfaction (lack of flare control/side effect/patient not happy with drug/lack of efficacy overall/poor tolerance/patient not compliant with taking drug/other)

o Degree of change in patient’s symptoms since starting current lupus medications (physician-assessed; 5 point Likert scale of symptoms much worse to symptoms much better)

▪ Change in general symptoms ▪ Change in fatigue ▪ Change in pain/achiness

o The level of patient reported satisfaction with current lupus medication (7 point

Likert scale of very dissatisfied to very satisfied)

o Degree of change in patient’s symptoms since starting current lupus medications (patient-assessed; 5 point Likert scale of symptoms much worse to symptoms much better)

▪ Change in general symptoms ▪ Change in fatigue ▪ Change in pain/achiness

3.4.2 Secondary Endpoints

3.5 Secondary The major secondary objective is to describe the patient and physician characteristics, treatment pathway, patient-and physician-reported satisfaction with current treatment amongst the LN cohort. Each of the following objectives will also be described separately for US vs EU5 patients, and by patients with a diagnosis of LN managed by a Rheumatologist and patients with a diagnosis of LN managed by a Nephrologist.

• Using data from the physician interview describe; o Physician (Nephrologist & Rheumatologist) characteristics including; duration

practicing, type of clinical setting, level of center, o Physician (Nephrologist & Rheumatologist perceptions including; categorization

and sizing of patient segments, Lupus workload, factors used to assess patient severity, perception of biologic treatment targets and authorisation to use biologic therapies

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• Using data from the DSP describe the diagnosis of patients with LN, including; time since diagnosis, concomitant SLE diagnosis, timing of concomitant SLE diagnosis, point of renal involvement relative to SLE where applicable, diagnostic tests ever conducted (yes/no and number in prior 12 months; kidney biopsy and urinalysis test - proteins) and HCPs involved in diagnosis and ongoing management.

• Using data from the DSP PRF and PSC describe the;

o Demographic characteristics of LN patients including; gender, age, ethnicity, employment status

o Clinical characteristics of patients with a diagnosis of LN, including; disease severity at diagnosis and currently, (mild/moderate/severe), LN stage (class I to VI), symptomatology currently and ever present, levels of fatigue, flare status (current and number in the last 12 months), severity and duration, current remission status (remission yes/no), other organ involvement.

o Humanistic characteristics of patients with a diagnosis of LN, including EQ-5D-3L utility, WPAI and FACIT scores.

• Using data from the DSP PRF describe the treatment pathway of patients with a diagnosis of LN, including;

o Time to first treatment o Treatment algorithm including; number of treatment lines, duration of lines,

type of treatments class and reasons for switch/stop. o Current prescribed treatment including; generic names and formulation, current

doses, dose frequencies and dosing patterns, duration of treatment. o Ability to reduce steroid medication since starting current lupus medication. o Reasons for not receiving biologic therapy, amongst those who warrant biologic

therapy (see PRF section G Q11 for possible reasons).

• Using data from the DSP PRF and PSC describe the level of patient and physician satisfaction with current control will also be described

o The level of physician reported satisfaction with the current lupus medication (7 point Likert scale of very dissatisfied to very satisfied)

o The level of physician reported satisfaction with each individual immunosuppressant product in the current regimen (7 point Likert scale of completely dissatisfied to completely satisfied)

o The level of patient reported satisfaction with current lupus medication (7 point Likert scale of very dissatisfied to very satisfied)

The other secondary objectives are: To identify the factors associated with patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort.

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o The factors associated with physician and patient reported satisfaction with

current lupus medication amongst SLE patients. The following will be included as covariates in the regression based on analyses of the SLE DSP and LPP cohorts (HO-15-16709 and HO-15-15509):

▪ Time since diagnosis ▪ Current disease progression/control ▪ Whether the patient has flared in the last 12 months ▪ General symptom experience change since initiating current treatment ▪ Fatigue change since initiating current treatment ▪ Pain/achiness change since initiating current treatment ▪ Satisfaction of how often current treatment is taken

To identify the level of concordance between patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohort.

o The level of concordance between physician and patient reported satisfaction with control

To describe the drugs for which compliance is a key reason for physician-reported treatment choice amongst the LN cohort.

• Using data from the DSP, describe the currently prescribed treatments where ‘good patient compliance’ is reported as a key reason for;

o physician choice and/or recommendation for use o area of drug improvement

• Using data from the DSP, describe the products where the reason to change to current regimen includes ‘lack of compliance’.

To categorise SLE patients in the DSP into different groups (clusters) such that patients with similar clinical manifestations are clustered together. Clustering analysis will be based on presence and type of renal involvement (see eligibility criteria section 3.2.1), types of current symptomology (DSP PRF section C, question 1a) and types of other organ involvement (DSP PRF section B, question 7). The clinical, humanistic and treatment characteristics of each cluster will be described.

• Using data from the DSP;

o Explore naturally occurring patient clusters based on current symptomatology and current organ involvement

o Describe the demographic characteristics of each cluster including; gender, age and ethnicity

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o Describe the clinical characteristics of each cluster including; ▪ time since diagnosis ▪ disease severity at diagnosis and currently (physician assessment of

mild/moderate/severe) ▪ current disease progression/control (physician assessment of

improving/stable/deteriorating slowly/deteriorating rapidly/unstable) ▪ current other organ involvement (yes/no) ▪ remission status (yes/no) ▪ flare status (current status) ▪ flare in the last 12 months (yes/no) ▪ symptomatology currently and ever present (yes/no, by type), and ▪ number of flares in last 12 months by severity (and organ system)

o Describe the humanistic burden of each cluster including; ▪ WPAI score ▪ EQ-5D utility score ▪ FACIT score.

o Describe the current treatments of each cluster including;

▪ Current prescribed treatment including; generic names and formulation, current doses, dose frequencies and dosing patterns, duration of treatment

3.6 Sample Size / Power Calculations Analysis pertaining to the primary and secondary endpoints will draw on the study population described above, focusing exclusively on the ‘renal cohorts’ within the DSP and LPP (Table 3.). Exploratory analysis will draw on the entire DSP population described above. No power calculations will be conducted since all patients in the DSP and LPP with renal involvement or LN will be included. The sample sizes below are expected. Where variables are available in both the DSP and LPP, the datasets will be merged to allow greater sample for analysis for SLE patients with renal involvement treated with belimumab.

Table 3: Physicians (US / EU)

PRF (US / EU) PSC (US / EU)

Sample size for primary objective

SLE with renal involvement (SOC-treated by a Rheumatologist)

52 / 115 99 / 195 54 / 114

SLE with renal involvement (belimumab-

66 / 16 128 / 20* 92 / 16**

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treated by a Rheumatologist)*

Sample size for secondary objectives

LN patients (SOC-treated by Rheumatologist)

46 / 83 89 / 131 46 / 77

LN patients (SOC-treated by Nephrologist)

39 / 75 235 / 364 145 / 196

Notes: *1. US PRF sample: n=112 from LPP; n=16 from DSP (random sample). *2. US PSC sample: n=79 from LPP; n=13 from DSP (random sample).

The objectives for this study are mostly descriptive in nature meaning that for the descriptive parts no formal hypotheses require testing. However, the sample size will have a direct impact on the precision of the estimates, e.g. means, percent, etc. The bigger the sample - the more confident we are that the estimate is close to that in the population (from which the sample is drawn), i.e. 95% confidence intervals (CI) would be narrower. Ideally the CI boundaries should be no further from the estimate than a minimal clinically important difference (MCID) and for a continuous, normally distributed variable the MCID can reduce to 25% of that variable’s standard deviation. A sample of at least 62 is required to satisfy that condition. For descriptive analyses that are exploratory (not considered evidence but hypothesis generating only), sample sizes can be smaller than this but care should always be taken when interpreting results from such sample sizes. For the multivariate analysis, a simple rule of thumb states that there should be at least 20 patients for each covariate. Therefore the number of covariates will not exceed 1/20 of the sample size available.

3.7 Hypotheses

The descriptive analyses generated in this study will offer initial exploratory evidence, which can later be used as a catalyst for hypothesis generation. All study findings will be used to support and further understand findings from the other belimumab studies and to inform future research on patient experience and treatment preferences in SLE and LN. The multivariate analyses hypothesise that a given list of variables are associated with both patient and physician satisfaction. These variables are determined a priori based on disease understanding and previous analyses of the SLE DSP and LPP cohorts (HO-15-16709 and HO-15-15509).

4 DATA ANALYSIS CONSIDERATIONS

4.1 Descriptive analysis

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The primary objective that GSK wish to explore are focused on describing the characteristics, treatment pathway of and patient- and physician-reported satisfaction with current treatment amongst the SLE with renal involvement cohorts Whilst these will be described separately for patients treated with belimumab and patients treated with SOC ,no matched cohort comparisons, or other comparative analysis, will be conducted. Similarly, whilst descriptive analysis of the major secondary objective will include reporting of subgroups of nephrologist- and rheumatologist-treated LN patients, no statistical comparison is planned.

For the primary objective, data from the LPP and DSP will be merged to allow analysis of a larger cohort of belimumab-treated patients. However, analysis will be limited to variables reported in both surveys; for example, physician perceptions of SLE and workload will not be reported since these were not collected in the LPP.

Rather than testing specific study hypotheses, the primary and major secondary objectives will be supported by descriptive endpoints. Thus the majority of analyses and outputs will be descriptive in nature and descriptive statistics (mean, standard deviation, frequency) will be presented for demographic and clinical information to describe the study sample. Categorical variables will be presented as frequency and percentage distributions when appropriate. Ordinal variables will be reported as frequencies and percentages and/or medians and interquartile ranges, as appropriate for the individual variables. Continuous variables (e.g, age, time since diagnosis, and questions with numeric rating scale responses) will be presented as mean and standard deviations, median and interquartile ranges, and score ranges.

Data completeness will be indicated by frequencies and percentages. The majority of variables for this analysis will represent observed responses to individual closed-ended questions. These variables will be analysed as observed, with no imputation of missing data or aggregation across questions. 4.2 Factors associated with treatment satisfaction

Multivariate analysis will be conducted to explore the factors associated with, and concordance of, physicians and patient reported satisfaction (other secondary objective). Physician satisfaction will be dichotomized into somewhat satisfied/satisfied/very satisfied versus very dissatisfied/dissatisfied/somewhat dissatisfied/neither satisfied nor dissatisfied. Patient satisfaction will also be dichotomized into somewhat satisfied/satisfied/very satisfied versus very dissatisfied/dissatisfied/somewhat dissatisfied/neither satisfied nor dissatisfied. Two logistic regressions will then be run for both of these, using a number of carefully selected covariates, to assess the drivers of satisfaction. The selection will be based on disease expertise that includes knowledge from similar analyses previously run. Each covariate will have an odds ratio (OR) and a p-value. The OR will indicate the size and direction of that covariate’s relationship with satisfaction. The p-value will indicate if that relationship is statistically significant (a covariate with a p-value < 0.05 will be considered significant). The pseudo R2 for the model will indicate how well the covariates explain the patients’/physicians’ satisfaction. The concordance of patient and physician reported satisfaction will be analysed by

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1. A weighted kappa will indicate the level of agreement between patient and physician as compared to random. A kappa of 1 indicates perfect agreement and a kappa of 0 indicates that the level of agreement is the same as that expected through randomly assigning satisfaction scores.

2. The size and direction of discordance can be measured by categorizing patients into 3 groups and then describing those groups. The 3 groups are defined as

a. Patient and physician agree b. Patient considers themselves more satisfied than the physician c. Patient considers themselves less satisfied than the physician

4.3 Patient clusters Latent Class modelling will be used to derive clusters of patients based on their current symptoms and organ involvement. Models will be generated which vary in the number of derived clusters (varying from 1-6 clusters). The Bayesian information criterion will be used to choose the cluster solution which best fits the data. The probability of membership in each group will be generated for each patient, and patients will be assigned to the group for which they have the highest probability. Latent Class Cluster analysis has been selected as there are some technical advantages over traditional methods (kmeans, kmedians, etc). For example, AIC and BIC are trivially generated for latent class analysis which allows for model selection and posterior membership probabilities are generated rather than just being assigned to a single cluster (though usually they are assigned to a modal class). In addition, variables of different scales (continuous, ordinal, nominal) are accounted for easily in the same model. Descriptive analysis will be conducted for patient demographics, clinical and humanistic characteristics and current treatments within each cluster.

5 LIMITATIONS

The 2015 Adelphi Lupus DSP and LPP are descriptive cross-sectional surveys of existing SLE/LN patients. Due to the nature of the sample, the study is only representative of those currently actively seeking treatment for their SLE/LN (i.e. the consulting population). Combined, the studies only surveys 158 Rheumatologists. As this is a small sample, a further limitation is that this sample may not be representative of the entire US Rheumatologist population. Despite this limitation, steps are taken to avoid potential selection bias, due to variable population densities in different geographical regions in a given country, by selecting appropriately larger samples of physicians in more densely populated areas than in more sparsely populated areas. The aim is to obtain data-rich samples from participating physicians. Furthermore, screening criteria is used to ensure physicians have a sufficient lupus workload to complete the required number of PRFs and to ensure that the sample is not biased by physicians with abnormal workloads. There is also a possibility that only the more motivated patients agree to participate in the survey resulting in potential bias, especially as patients are not remunerated for their time. The

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representativeness of this analysis is also limited by the willingness of subjects with differing characteristics to participate in this study. Previous statistical testing of data collected via the DSP approach has revealed that there are relatively few differences between PSC completers and non-completers, and a similar analysis will be conducted for this DSP to capture any differences. Furthermore, the study is not designed to assess causality but only to identify associations between variables. The study is also cross-sectional; longitudinal studies are required to investigate, robustly, changes in satisfaction and clinical outcomes over time. In the current analysis, renal involvement amongst patients with SLE was defined by a physician assessment of whether renal system and/or kidneys were involved at any point in their disease history. Physician-assessed severity of renal involvement was not fully reported and renal-specific clinical parameters were not collected. Thus, there are limitations in the interpretation of the type and extent of renal manifestations in this cohort. The merging of evidence from the DSP and the LPP to generate a larger sample of belimumab-treated patients introduces some limitations; primarily in that fewer variables are available within the LPP and reporting by geographical region is not reliable for some analyses. However, reporting of the entire cohort includes data from multiple countries, and therefore introduces potential confounders by geography and local prescribing practice. Where regional analyses are not possible, impact on interpretation of the results will be discussed in the final report. Finally, the clustering analysis may generate clusters with small numbers of patients. If certain clusters do arrive at a small size then it will be highlighted as a limitation in the final report and the results interpreted with caution.

6 STUDY CONDUCT, MANAGEMENT & ETHICS

6.1 Ethics Committee/IRB Approval Adelphi successfully sought IRB exemption for both the LPP and DSP (LPP IRB approval number #1-861854-1, DSP IRB approval number #1-908964-1), because all data collected will be aggregated and non-identifiable and no pediatric cases will be included in the sample. In accordance with IRB regulation documents both of these factors exempt the study from approval requirement. ARW independently conducts the DSP as a cross-sectional, market research survey and offers the purchase of the de-identified dataset and analytics to external parties. The GSK study team will not have access to any medical or other record, nor to any data source containing any information about the patient or about the participating physician. ARW take responsibility to ensure that their data collection and data handling comply with all applicable laws, regulations, and guidance regarding patient protection including patient privacy. The ARW fieldwork teams adhere to national data collection regulations [European Society for Opinion and Market Research ESOMAR] (www.esomar.org, 2012), U.S. Department of Health and Human Services

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National Institutes of Health HIPAA (http://privacyruleandresearch.nih.gov/pr_08.asp#8a, 2007), The UK Market Research Society (MRS) (www.mrs.org.uk, 2012).

6.2 Informed Consent

Prior to the completion of any study related activities for the LPP and DSP, patients provided consent to participate in the study by signing the ARW informed consent form, Appendix B & D. This written consent complies with HIPAA and equivalent EU guidelines.

6.3 Data Protection

ARW conduct data collection in line with a set of internal Standard Operating Procedures, developed to ensure data quality and integrity, plus adherence to HIPAA, HITECH and other privacy requirements. These include: • Quality Control and Data Checking • Data entry and coding • Respondent Confidentiality and Data Protection • Database Transfer No patient or physician identifiable data are collected as part of any DSP survey. ARW contracts a third party to conduct the survey fieldwork. The third party conducts the survey according to ARW SOP on data privacy. A unique physician code is recorded on each survey to link the PRFs and PSCs, the code is only for this purpose and is not used for any other administrative purpose. The task orders for both the LPP and DSP request the agency to return the paperwork once collected from respondents, to be shipped to ARW. Moreover, ARW are always blinded to the identity of the physicians and their patients participating in the studies. To clarify, the third party has a list of the physicians involved in the survey, but does not have record of the unique codes and does not retain copies of the surveys or the unique codes. As soon as the surveys have been completed, the third party mails the sealed surveys to ARW. ARW then stores the completed surveys for three years in the secure ARW warehouse. The ARW and GSK study teams therefore have no access to any medical or other record, nor to any data source containing any information about the patient or about the participating physician.

6.4 Personally Identifiable Information (PII) The ARW fieldwork teams adhere to national data collection regulations [ESOMAR (www.esomar.org, 2012), U.S. Department of Health and Human Services National Institutes of Health HIPAA (http://privacyruleandresearch.nih.gov/pr_08.asp#8a, 2007), The UK Market Research Society (www.mrs.org.uk, 2012).

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6.5 Adverse Event (AE), Pregnancy Exposure, and Incident Reporting There is no potential to collect serious and non-serious AEs, pregnancy exposures, or incidents related to any GSK product during the conduct of this research, as the minimum criteria needed to report AEs, pregnancy exposures, and incidents are not present in the data source. This study derives data from a previously completed cross-sectional survey, and as such may be considered a post-hoc analysis. Both the LPP and standard Adelphi DSP survey were reviewed by the GSK clinical safety physician and were not considered to solicit any adverse events that could be directly attributed to belimumab use, therefore there was no requirement to report AEs from the standard LPP and DSP survey. However, the GSK clinical safety team concluded that the additional GSK developed questions, which relate more directly to belimumab, in both the LPP and DSP, warranted AE reporting. As such AEs were reported as follows; LPP AEs were reported to GSK in-line with the AE training received by the Adelphi project team (22.01.15), as outlined in the RAP. AEs for 54 SLE patients (out of the total N=376 sample) were reported to GSK using individual AE forms and a reconciliation form less than 24 hours after initial discovery (27/03/15) upon examination of full dataset add date. No serious adverse events (SAEs) were reported in the LLP DSP AEs were reported to GSK in-line with the AE training received by the Adelphi project team (22.01.15), as outlined in the RAP. AEs for 15 SLE patients (out of the total N=540 sample) were reported to GSK using individual AE forms and a reconciliation form less than 24 hours after initial discovery (09/11/15) upon examination of full dataset add date. No serious adverse events (SAEs) were reported in the DSP.

7 EXTERNAL INVOLVEMENT

7.1 Third Party Supplier The LPP and DSP were conducted by ARW and ARW will deliver the anonymised dataset and analysis pertaining to the research objective above. The primary contact at ARW is

Director (AutoImmune) Adelphi Real World Email:

PPD

PPD

PPD

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7.2 External Expert/Health Care Professionals (Consultants & Research PIs)

Not applicable

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8 Appendix A

CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected bythird party copyright laws and therefore have been excluded.

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Appendix B

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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third partycopyright laws and therefore have been excluded.

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Appendix C

CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected bythird party copyright laws and therefore have been excluded.

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Appendix D

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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third partycopyright laws and therefore have been excluded.

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Appendix E: Patient flow

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9 References

Harrell, F. E. (2001), Regression modeling strategies: With applications to linear models, logistic regression, and survival analysis, Springer-Verlag, New York. Pascoe K, Lobosco S, Bell D, Hoskin B, Ramachandran S, Pobiner B, Chang D (2015); Satisfaction and Impact Associated with Addition of Belimumab to SLE Treatment; ACR/ARHP Annual Meeting; Abstract Number: 741 Pascoe K, Lobosco S, Bell D, Hoskin B, Chang DJ, Pobiner B, Ramachandran S (2017); Patient- and Physician-reported Satisfaction With Systemic Lupus Erythematosus Treatment in US Clinical Practice; Clinical Therapeutics, Sep;39(9):1811-1826