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SPONSOR SIGNATORY

Protocol ID: HO 12 12891

Title: Reasons for Discontinuation of Injectable Therapy among Type 2 Diabetes Mellitus Patients in theUS

Version: 1.0

Date: 27 June 2013

NAME TITLE / ROLE SIGNATURE DATEThe author confirms that this document has been prepared in accordance with policies & procedures andthat relevant input has been obtained and incorporated from contributory authors & reviewers.

Study Accountable Person / Author iSign signature block iSign signature block

The USHO Therapy Area Director signs to confirm that the document meets the USHO standards, policiesand procedures.

USHO Therapy Area Director iSign signature block iSign signature block

The Business Unit VP signs to confirm that the document meets the USHO standards, policies andprocedures.

Health Outcomes VP iSign signature block iSign signature block

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PROTOCOL SYNOPSIS

Unique Identifier HO-12-12891

Abbreviated Title Reasons for T2DM Injectable Therapy Discontinuation

GSK Product Albiglutide

Rationale GSK is currently developing albiglutide, a long-acting GLP-1 receptor agonist for treatment of type 2 diabetes mellitus (T2DM). Patients prescribed currently marketed GLP-1 agonists have shown high rates of non-persistence (discontinuation) in the first year. In this proposed study, GSK would like to identify self-reported reasons for non-persistence among patients initiating an injectable diabetes medication as well as describe the decision-making process for discontinuation. The results of this study will be used by GSK to better understand reasons for non-persistence, plan post-launch adherence programs for albiglutide patients, and determine the feasibility of assessing comparative medication persistence in a post-launch randomized pragmatic trial.

Objectives (Primary, Secondary & Exploratory)

The overall purpose of the current study is to better understand the reasons for discontinuation (non-persistence) for injectable therapy among T2DM patients in the US, as well as to uncover the decision-making process for discontinuation. Three medications are of particular interest: exenatide QW (Bydureon), liraglutide (Victoza), insulin. These medications were selected for focus because they are commonly used as the first injectable medication that a T2DM patient is prescribed and because they have all been shown to have high discontinuation rates in the first year after initiation. These medications also present a range of profiles in terms of dosing frequency, cost, side effects, and other attributes expected to be related to persistence.

Primary objective: Describing the discontinuation decision-making process (i.e. interactions with physician, family and friends), identifying patients’ reasons for discontinuation, and quantifying the contribution of each reason to overall discontinuation ratess

Secondary objectives: Describing characteristics of patients who initiated insulin, Victoza, or Bydureon, stratified by discontinuation status Identifying any meaningful differences between continuers and discontinuers in terms of perceived or experienced barriers to

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taking the medications, stratified by medication Assessing initial reaction to being prescribed an injectable medication Quantifying how soon patients fill their prescription after receiving a prescription from a physician and how quickly they begin taking the medication Identifying reasons why patients did not fill their prescription after receiving it from their physician Identifying patient support groups or resources respondents belong to or are affiliated with and the extent to which the patient perceived them as useful

Study Design Internet-based cross-sectional survey conducted in 2 phases: Phase 1 will be conducted among self reported T2DM patients in the US (age 18+) who, in the past year, were newly prescribed exenatide QW (Bydureon), liraglutide (Victoza) or insulin (including those who filled and didn’t fill the prescription). The phase 1 survey will focus on retrospective self-reported medication history and experience.

Phase 2 of this study will be conducted online among those respondents who are persistent on therapy at the point of the first survey. Patients who were actively taking their medication at the time of the first survey (phase 1 “continuers”) will be re-contacted 3 months later to ask if they are still taking the medication. If they are not, they will be surveyed at that time about the discontinuation process.

Study Population and Sampling Methods

Patients will be recruited from Harris Interactive’s Chronic Illness Panel (CIP) and/or other third party online panels.

Inclusion criteria assessed during screening:

US Adult age 18+

Diagnosed with T2DM

Newly prescribed exenatide QW (Bydureon), liraglutide (Victoza) or insulin in the past year

Data Source A survey instrument will be developed, including a combination of validated scales (as appropriate) and custom survey questions that will be used to address the key research questions. The survey will be administered on-line.

Data Analysis Methods Primary endpoint: Reasons for injectable therapy discontinuation. Patients will be asked to indicate experienced barriers to taking their injectable medication and, if they discontinued, which barriers were reasons that they discontinued or did not take their medication as

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prescribed.

This study is considered exploratory in nature with a primary goal of identifying which barriers are most commonly associated with discontinuing injectable T2DM therapy. All survey variables will be analyzed descriptively and stratified by medication and discontinuation status. Counts and proportions with exact 95% confidence limits will be calculated for dichotomous and polychotomous variables. The relationship between demographic characteristics and reasons for discontinuation will be measuring using risk ratios with 95% confidence limits.

Sample Size and Power For Phase 1, the total sample size is 2,000 T2DM patients. Based on preliminary analyses of data on US utilization patterns, we expect to identify approximately 200 respondents who initiated Bydureon, 600 who initiated Victoza, and 1,200 who initiated insulin, with at least half of each having discontinued or switched to another medication.

Limitations A potential limitation is the administration of the survey online, restricting participation to those with internet access and computer skills.

We are relying on self report for determining disease status, medication history, and recall of the discontinuation process. We will incorporate repeated logic checks for certain key questions such as diabetes status and identity of medications taken. Nevertheless, some recall error will be inevitable. In addition, participation in the survey is voluntary, and the patients who ultimately choose to participate in the survey may not be representative of US patients with T2DM who have been treated with GLP-1 therapy.

This study is exploratory in nature, and the results would need to be confirmed before making inference to a broader population. In addition, the number of respondents for some strata will likely be small.

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TABLE OF CONTENTS – TO BE UPDATED WHEN PROTOCOL IS FINALIZED 1. INTRODUCTION/BACKGROUND ................................................................................................... 8

2. OBJECTIVES ............................................................................................................................... ......11

2.1. Primary............................................................................................................................... ............. 11

2.2. Secondary............................................................................................................................... ......... 11

2.3. Exploratory ............................................................................................................................... ......11

3. RESEARCH METHODOLOGY........................................................................................................ 12

3.1. STUDY DESIGN............................................................................................................................ 12

3.2. STUDY POPULATION ............................................................................................................. 12

3.2.1. ELIGIBILITY CRITERIA...................................................................................................... 12

3.2.2. SAMPLING ............................................................................................................................ 14

3.3. DATA SOURCE / DATA COLLECTION................................................................................. 16

3.3.1. ENDPOINTS .......................................................................................................................... 16

3.4. SAMPLE SIZE / POWER CALCULATIONS........................................................................... 18

3.5. HYPOTHESES ....................................................................................................................... 18

4. DATA ANALYSIS CONSIDERATIONS ..................................................................................... 18

5. LIMITATIONS............................................................................................................................... 20

6. STUDY CONDUCT, MANAGEMENT & ETHICS ..................................................................... 20

6.1. ETHICS/IRB APPROVAL......................................................................................................... 20

6.2. INFORMED CONSENT ............................................................................................................ 20

6.3. DATA PRIVACY ....................................................................................................................... 20

6.4. PERSONALLY IDENTIFIABLE INFORMATION (PII) ......................................................... 22

6.5. AE REPORTING ........................................................................................................................ 22

6.6. DATA STORAGE/ARCHIVAL ................................................................................................ 22

7. EXTERNAL INVOLVEMENT ......................................................................................................... 23

7.1. Third Party Supplier (Company Name, Address & Staff Names/Email/Phone) ............................ 23

7.2. External Expert/Health Care Professionals (Consultants & Research PIs)..................................... 23

MILESTONES............................................................................................................................... ............. 24

DATA DISSEMINATION PLAN.............................................................................................................. 25

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ABBREVIATIONS

T2DM Type 2 Diabetes Mellitus GLP-1 Glucagon-like Peptide-1 GI Gastrointestinal HbA1c Glycosylated Hemoglobin/Hemoglobin A1c OAD Oral Antidiabetic Medication IRB Institutional Review Board CIP Chronic Illness Panel

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1. INTRODUCTION/BACKGROUND

Diabetes is a group of diseases marked by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.i Diabetes is a major public health concern in the US and worldwide. It accounted for $174 billion in direct and indirect costs in the US in 2007.i In 2010, the prevalence of diagnosed and undiagnosed diabetes for US adults 20 years of age or older was estimated at 25.6 million people, or 11.3% of the population.i

In adults, type 2 diabetes (T2DM) accounts for about 90 to 95 percent of all diagnosed cases of diabetes.i T2DM usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. T2DM is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity.i Treatment of diabetes often involves significant lifestyle adjustments such as insulin therapy, regular glucose monitoring, and changes in diet. Diabetes is a leading cause of blindness, end-stage renal disease, and non-traumatic lower limb amputation, and is a major risk factor for coronary artery disease and stroke.ii

Over time, most patients with T2DM experience progressive ß-cell dysfunction and will require insulin therapy, either alone or in combination with oral agents.iii However, some insulin regimens may be associated with hypoglycemia and/or weight gain. Fear of hypoglycemia is considered a barrier to treatment adherence and overall glucose control and has been associated with reduced patient-reported well-being and perceived health status. Weight gain may be particularly undesirable, in that up to 80% of patients with T2DM are overweight or obese, and increasing obesity may worsen insulin resistance and increase cardiovascular risk and disease burden.iv

Given these factors, there is an interest in therapies that are weight neutral (or promote weight loss in overweight patients), minimize the risk of hypoglycemia, and exploit physiologic mechanisms to modify T2DM. Incretin-based therapies, including GLP-1 receptor agonists, unlike many other antidiabetic therapies, do not induce weight gain. These agents exert physiological effects similar to those of native GLP-1, including enhancement of glucose-dependent insulin secretion and suppression of inappropriately high glucagon secretion. Furthermore, they also slow gastric emptying and reduce food intake.v

GSK is currently developing albiglutide, a long-acting GLP-1 receptor agonist. Albiglutide is administered as a once weekly subcutaneous injection. It is anticipated that this will lead to greater adherence over liraglutide which requires daily injections. In addition, albiglutide has demonstrated a better gastrointestinal (GI) safety profile with respect to nausea and vomiting.vi

Medication adherence is generally defined as the extent to which patients take medications as prescribed by their health care providers.vii In contrast, medication persistence is the act of continuing the treatment for the prescribed duration. Typical adherence rates for prescription medications are approximately 50% to 76%,viii,ix,x and non-adherence has been estimated to be clinically significant in half of patients.ix The importance of medication adherence and the consequences of non-adherence cannot be overstated, as poor adherence has been associated

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with disease morbidity and progression, death, and increased health care utilization and costs.vii,xi Because diabetes is a long-term chronic illness and the effects of poor adherence are not immediately evident, the potential for long-term sub-optimal adherence to therapy for people with this disease is substantial. Poor adherence to diabetes medication has been shown to lead to negative outcomes in both clinical and economic terms.xii,xiii Improving adherence has been shown to result in improved clinical outcomes reported as percentage improvement in HbA1c. For each 10% increase in adherence, HbA1c levels have been shown to improve between 0.14% and 0.02%.xiv,xv

We expect to use the results of this study to identify patient-related barriers to medication adherence and persistence that may be avoided by using Albiglutide. In particular, albiglutide is expected to have a favorable profile in terms of nausea and vomiting (compared to other GLP-1s), frequency of administration (compared to Victoza and insulin), frequency of blood glucose monitoring (compared to insulin), and needle size (compared to Bydureon). Therefore, as an example, identifying the frequency of discontinuation related to nausea and vomiting will allow us to estimate the proportion of current patients who may have better persistence when treated with albiglutide.

Ongoing GSK research in non-adherence and non-persistence of diabetes medications

The study covered in this protocol is one of several ongoing or planned GSK studies related to non-adherence or non-persistence (i.e. discontinuation) of injectable diabetes medications. The overall goals for the entire research program are:

• Determining the frequency of non-adherence or non-persistence with patients prescribed GLP-1 receptor agonists

• Demonstrating barriers to adherence and persistence experienced with currently marketed injectable diabetes medications

• Understanding the HCP/patient decision-making process when a medication barrier emerges

• Identifying GLP-1 adherence problems that can be prevented with appropriate patient programs or interventions

• Measuring the value of albiglutide medication/device attributes from the patient perspective

• Demonstrating the level of persistence that can be achieved with albiglutide in a real-world setting

A WWEpi-led study is underway to address the first goal above using data from the Marketscan database. In preliminary results, we found that gaps between medication fills were not a common problem among patients initiating a GLP-1 agonist, whereas non-persistence was frequent. As measured by pharmacy claims, approximately 80% of patients initiating treatment with a GLP-1 agonist discontinued (or switched) their medication within a year. This discontinuation rate was much higher than for DPP-4 inhibitors or other diabetes medications.

The study presented in this protocol, in conjunction with study HO-11-764 (currently ongoing), is designed to address the second and third goals above by determining self-reported reasons for non-persistence as well as the decision-making process for

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discontinuation.

The results of this study will be used by GSK to better understand reasons for non-persistence, plan post-launch adherence programs for albiglutide patients, and determine the feasibility of assessing comparative medication persistence in a post-launch randomized pragmatic trial.

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2. OBJECTIVES

The overall purpose of the current study is to better understand the reasons for discontinuation (non-persistence) for injectable therapy among T2DM patients in the US, as well as to uncover the decision-making process for discontinuation. Three medications are of particular interest: exenatide QW (Bydureon), liraglutide (Victoza), and insulin. These medications were selected for focus because they are commonly used as the first injectable medication that a T2DM patient is prescribed and because they have all been shown to have high discontinuation rates in the first year after initiation. These medications also present a range of profiles in terms of dosing frequency, cost, side effects, and other attributes expected to be related to persistence.

2.1. Primary

Describing the discontinuation decision-making process (i.e. interactions with physician, family and friends), identifying patients’ reasons for discontinuation, and quantifying the contribution of each reason to overall discontinuation rates

2.2. Secondary

Describing characteristics of patients who initiated insulin, Victoza, or Bydureon, stratified by discontinuation status Identifying any meaningful differences between continuers and discontinuers in terms of perceived or experienced barriers to taking the medications, stratified by medication Assessing initial reaction to being prescribed an injectable medication Quantifying how soon patients fill their prescription after receiving a prescription from a physician and how quickly they begin taking the medication Identifying reasons why patients did not fill their prescription after receiving it from their physicianIdentifying patient support groups or resources respondents belong to or are affiliated with and the extent to which the patient perceived them as useful

2.3. Exploratory

N/A

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3. RESEARCH METHODOLOGY

3.1. STUDY DESIGNThere will be 2 phases to this cross-sectional internet-based survey. Phase 1 will be conducted using a 20 minute online survey among self reported T2DM patients in the US (age 18+) who, in the past year, were newly prescribed exenatide QW (Bydureon), liraglutide (Victoza) or insulin. (including those who filled and didn’t fill the prescription) The phase 1 survey will focus on retrospective self-reported medication history and experience. We expect about half of respondents to be patients who are currently taking the medication and about half to be those who discontinued therapy.

Phase 2 of this study will be conducted online among those respondents who are persistent on therapy at the point of the first survey. Patients who were actively taking their medication at the time of the first survey (phase 1 “continuers”) will be re-contacted 3 months later to ask if they are still taking the medication. If they are not, they will be surveyed at that time about the discontinuation process.

The two main reasons for conducting phase 2 relate to 1) increasing the quality and precision of the data on the discontinuation process and 2) increasing the number of responses for discontinuers. In GSK’s previous survey of non-persistence, patients were contacted 9-12 months after discontinuation and concern was raised about the quality of recall. This study will attempt to capture more respondents who recently discontinued and might therefore have more accurate recall of the discontinuation process.

3.2. STUDY POPULATION

3.2.1. ELIGIBILITY CRITERIA

The study will include T2DM patients in the US (age 18+) who, based on self report, have been prescribed exenatide QW (Bydureon), liraglutide (Victoza) or insulin in the past year.

3.2.1.1. Inclusion Criteria (Phase 1)

US Adult age 18+ Diagnosed with T2DM Received a new prescription for exenatide QW (Bydureon), liraglutide (Victoza) or insulin in the past year (including those who filled and didn’t fill the prescription)

3.2.1.2. Exclusion Criteria

Not US Adult age 18+ and/or

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Not diagnosed with T2DM and/or Has not received a prescription for exenatide QW (Bydureon), liraglutide (Victoza) or insulin in the past year

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3.2.1.3. Inclusion Criteria (Phase 2)

Phase 1 patients who were actively taking their medication at the time of the first survey and expressed interest in completing phase 2

3.2.1.4. Exclusion Criteria (Phase 2)

Phase 1 patients who discontinued therapy prior to phase 1 survey and/or do not express interest in completing phase 2

3.2.2. SAMPLING

For phase 1 of data collection, all patients will be recruited from Harris Interactive’s Chronic Illness Panel (CIP) and/or other third party online panels. Online patient panels provide access to patients who have previously identified themselves as having T2DM in a screening questionnaire conducted by the panel agency. Potential respondents will receive a survey invitation via email including information for accessing the online survey. The online survey will be password protected to avoid multiple completions by any one respondent. Regardless of the sample source, all respondents will be rescreened within the survey to ensure they have been diagnosed with T2DM and meet all other qualification criteria. Those who do not meet the inclusion criteria will exit the survey as soon as it is identified that they do not qualify, while those who do qualify will continue to answer questions until they have completed the entire survey. Survey instructions or questions will be revised based on findings of the pretest.

This study is expected to identify 2,000 eligible respondents with completed surveys. No specific quotas will be set around any demographic variables. The population of interest includes low-prevalence subgroups, such as those who have started taking Victoza or Bydureon in the past year (estimated to be ~3% and 0.6% of the T2DM population, respectively). In the event a respondent has started taking more than one of the three medications of interest in the past year, the patient will be asked to answer survey questions related to the sub-group with the lowest prevalence – first Bydureon, then Victoza then insulin. (see Figure 1 below)

We will obtain the following demographics and clinical characteristics from each respondent: age, race, marital status, employment status, health insurance coverage, duration of diabetes, all diabetes medications taken in the past, all diabetes medications currently taken, and number of medications for other conditions.

Phase 2 respondents will be taken from the phase 1 sample. At the end of the phase 1 survey, patients who were actively taking their medication at the time of the first survey (phase 1 “continuers”) will be invited to participate in the phase 2 research.

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3.3. DATA SOURCE / DATA COLLECTION

A survey instrument that ensures all primary research objectives and analytic goals are met will be developed. A combination of validated scales (as appropriate) and custom survey questions will be used to address the key research questions.

A central independent review board (IRB) will be utilized to obtain appropriate approvals for the survey instrument and procedures. The approved survey instrument will then be programmed for online administration.

The online survey will be pretested with a small group of respondents (n=12) prior to full launch. The primary goals of pretesting are to identify any questions that are confusing, difficult to answer, or at an inappropriate literacy level. The pretests will take place after the survey is designed and programmed, but before it is rolled-out to the entire study population. Potential pretest respondents will be pre-screened over the telephone to ensure that they meet study qualifications (e.g., T2DM patients who have recently started on one of the target medications) and will then be invited to participate in a 45 minute qualitative interview where they will go through the online survey as a moderator observes and asks probing questions about the participants’ understanding. Pretest participants will be given a $100 honorarium

If recruiting Bydureon patients proves to be not feasible based on the initial recruitment strategy, these patients will be recruited through patient organizations or associations who would provide contact information for these patients. Messages will also be posted with a link to the survey screener on online forums in an attempt to obtain Bydureon patients. Some examples of these online forums include the American Diabetes Association, WebMd, and Google Forums.

Phase 2 will be conducted online among respondents from the first survey. At the end of the first survey, respondents who are persistent on therapy - “continuers” – will be invited to take part in the follow-up phase. Those who indicate they are interested will receive an email invitation to participate once the follow-up survey has been approved by GSK and programmed.

The self administered survey will be programmed and hosted online. Each survey will be password protected to avoid multiple completions by any one respondent. Respondents will be given a unique ID and password to be used to access the survey.

3.3.1. ENDPOINTS

3.3.1.1. Primary Endpoint

• Reasons for injectable therapy discontinuation. Patients will be asked to indicate

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experienced barriers to taking their injectable medication and, if they discontinued, which barriers were reasons that they discontinued or did not take their medication as prescribed. Patients will be provided a list of specific barriers that may influence discontinuation, including doctor recommendations, medication costs, and expectations about the medication. In addition, patients will be asked specifically how the decision to discontinue their injectable medication was made: by the patient, by the provider, by both the patient and the provider, by a family member, or other.

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3.3.1.2. Secondary Endpoint(s) • Treatment satisfaction and burden. Treatment satisfaction with injectable diabetes

medication that patients are currently taking will be assessed using treatment satisfaction scales (e.g., TSQM). Specifically, questions related to medication burden (number of pills or injections and total co-pays), general health and well-being, impact on daily activities (physical and emotional burden of the medication), impact on lifestyle activities (flexibility of diet and exercise), and general satisfaction will be included.

3.3.1.3. Exploratory Endpoint(s) Not applicable

3.4. SAMPLE SIZE / POWER CALCULATIONS

For Phase 1, the total sample size is 2,000 T2DM patients. Based on preliminary analyses of data on US utilization patterns, we expect to identify approximately 200 respondents who initiated Bydureon, 600 who initiated Victoza, and 1,200 who initiated insulin, with at least half of each having discontinued or switched to another medication.

Phase 2 will consist of Phase 1 respondents who indicate they are persistent on therapy – phase 1 “continuers” – and agree to participate in the phase 2 follow-up survey. The sample size for Phase 2 will be dictated by the number of willing respondents meeting the inclusion criteria.

3.5. HYPOTHESES

Because this study will use observational survey data with substantial uncertainties, unknowns, and potential confounders, this study is considered exploratory in nature with a primary goal of estimating which characteristics are most commonly associated with discontinuing injectable T2DM therapy.

4. DATA ANALYSIS CONSIDERATIONS

All survey variables will be analyzed descriptively and stratified by medication and discontinuation status. Counts and proportions with exact 95% confidence limits will be calcualted for dichotomous and polychotomous variables. (See partial table of hypothetical results below.) The relationship between demographic characteristics and reasons for discontinuation will be measuring using risk ratios with 95% confidence limits. This study is not intended to make statistical comparisons between medications.

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Example Table: Reported Reasons for Bydureon Discontinuation (N=90 discontinuers)

ReasonReported as reason for discontinuation

N (%) 95% CLIt was too expensive 36 (40.0 %) 29.8 – 50.9%The needle was too big 18 (20.0%) 12.3 – 29.8%

Hypothetical results

As a sensitivity analysis, primary results will be calculated with data weighted to account for a respondent’s propensity to be online. For example, as a result of the choices Internet respondents make, respondents in the survey may differ in fundamental ways from the population of interest in attitude and behavior as well as demographics. We will use previously evaluated demographic questions and propensity score questions to calculate the weights. In order to correct for attitudinal differences typically found in online respondents, Harris Interactive employed a propensity score weighting method. This general technique has been in use since the early 1980s. Harris Interactive includes a proprietary set of questions within each survey that has been tested in prior web and phone-based surveys. Based on the responses a survey participant gives to these questions, that person is assigned a “propensity score” that is used in the weighting process. xvi

As a second sensitivity analysis, we will assess if any differences exist in primary outcomes between those who reported discontinuation in phase 1 vs. phase 2. As part of this analysis, we will evaluate the association, if any, between the duration of therapy and frequency of reported reasons for discontinuation.

Logistic regression will be used to measure the association between barriers (perceived or experienced) and discontinuation status. These measures of association would be stratified by medication. For this particular study, we will not conduct any multivariate analyses or predictive modeling.

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5. LIMITATIONS

A potential limitation is the administration of the survey online. Although computer use is becoming increasingly common among a diverse array of age and socio-demographic groups, use of an online survey restricts participation to those with internet access and computer skills. In order to minimize these potential biases both demographic and propensity weighting will be applied. Given that internet penetration in the US is high – nearing 80% – and continuing to increase, differences between US internet users and the general research/study population are expected to be limited.

We are relying on self report for determining disease status, medication history, and recall of the discontinuation process. We will incorporate repeated logic checks for certain key questions such as diabetes status and identity of medications taken. Nevertheless, some recall error will be inevitable. In addition, participation in the survey is voluntary, and the patients who ultimately choose to participate in the survey may not be representative of US patients with T2DM who have been treated with GLP-1 therapy.

This study is exploratory in nature, and the results would need to be confirmed before making inference to a broader population. In addition, the number of respondents for some strata will likely be small, leading to wide confidence limits from the proportions calculated and more uncertainty in making inferences from respondent data.

6. STUDY CONDUCT, MANAGEMENT & ETHICS

6.1. ETHICS/IRB APPROVAL Following GSK’s approval of study documents, the survey will be submitted for IRB review.

GSK shall provide any necessary assistance or documents for the submission to the IRB. Subject recruitment will not begin until IRB approval of all components of the study is obtained.

6.2. INFORMED CONSENT

Before a respondent can proceed with the survey, they will be required to agree to an informed consent statement acknowledging their understanding of the research study, and any potential risks and benefits of study participation.

6.3. DATA PRIVACY

As a public company (NASDAQ symbol: HPOL), Harris Interactive complies with SEC rules and regulations. Because Harris Interactive collects, transfers and uses personally-identifiable information of market research participants, Harris Interactive also complies with

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U.S. and foreign privacy laws, such as the Gramm-Leach-Bliley Act, the Health Insurance Portability and Accountability Act and the Children’s Online Privacy Protection Act. Further, through the Safe Harbor framework implemented by the U.S. Department of Commerce, Harris Interactive has certified compliance with the stringent data protection requirements set forth in the European Union’s Data Protection Directive. Information about the U.S. Department of Commerce Safe Harbor certification program and Harris Interactive’s certification can be found at http://export.gov/safeharbor/. Harris Interactive is also a licensee of the TRUSTe Privacy Program.

Commencing in 2012, Harris Interactive is undergoing an annual SSAE16 SOC2 audit certification. Client confidential information is stored on Harris Interactive’s servers, secured by Windows / Linux file permissions access with failed attempts being logged. Harris Interactive has deployed Symantec EndPoint Protection on all laptops which ensures that all hard drives are encrypted. Our CommVault backup software also enables us to encrypt data stored on backup media. Whenever Harris Interactive receives any customer lists (or any other personally identifiable information) for use in connection with a market research study, Harris Interactive requires that such information be sent via a secure method (e.g. FTP site or encrypted email attachment) and such information is stored in our secure environment. Harris Interactive also conducts due diligence on all of its vendors, and requires that they sign comprehensive agreements containing stringent confidentiality and data security requirements.

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6.4. PERSONALLY IDENTIFIABLE INFORMATION (PII)

Individual identifiers from personal information will be removed and anonymous data will be disclosed to GSK.

6.5. AE REPORTING

There are no pharmaceutical products or other treatments administered as part of this study. The informed consent statement advises subjects to contact their physician directly if they experience any illness, health problems or concerns, but some subjects may instead spontaneously report a medical event in the open ended responses in the survey. In the case Harris Interactive discovers an adverse event for a GSK product, the adverse event will be reported to GSK pharmacovigilance within one working day of the study staff’s knowledge of the event. The minimum criteria for reporting an adverse event include an identifiable subject, reporter, medicinal product, and event.

Should a serious adverse event (SAE) not involving a GSK product occur and become known to Harris Interactive, they will report the SAE to Medwatch and alert them to the SAE within one working day.

A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose:

Is fatal

Is life threatening (places the subject at immediate risk of death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Other significant medical hazard

It is recommended that as much information as possible be collected at the time of the SAE report submission, however the minimum required data elements for an SAE case to be valid are: an identifiable reporter, an identifiable patient, an adverse reaction, and a suspect product.

6.6. DATA STORAGE/ARCHIVAL To enable evaluations and/or audits from GlaxoSmithKline, LLC, Harris Interactive agrees to keep records, including the identity of all participants (sufficient information to link records and surveys), and electronic data. Harris Interactive will store study records on their secure servers for a period of 6 years.

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7. EXTERNAL INVOLVEMENT

7.1. Third Party Supplier (Company Name, Address & Staff Names/Email/Phone)

Harris Interactive 60 Corporate Woods Rochester, NY 14623

Research Director

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

Not applicable

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MILESTONES

MILESTONE GUIDANCE OR POLICY

REQUIREMENT

FORECAST DATE

MM-YYYYForecast Final Protocol Approval 07-2013

Forecast GSK CSR Protocol Summary FPA Actual + 30 days

Forecast Statistical Analysis Plan Approved 10-2013

Forecast Statistical Analysis Complete 12-2013

Forecast Final Study Report Complete SAC Actual + 6 months 02-2014

Forecast GSK CSR Results Summary Posting SAC Actual + 8 months

Forecast Manuscript Submission SAC Actual + 18 months 04-2014

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Oralpresentation

ISPORAnnualInternationalMeeting

Montreal,Quebec

June, 2014

DISCLOSURE PLAN

FORECASTGSK CSR PROTOCOL SUMMARY(FPA + 30 DAYS)

08 2013

GSK CSR RESULTS SUMMARY(SAC + 8 MONTHS)

08 2014

FULL PROTOCOL POSTING DATE(Manuscript submission actual + 30 days)

i National Diabetes Statistics, 2011. Obtained from the website: http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm. Accessed on 25 July 2011. ii Miser W. The Management of Type 2 diabetes Mellitus FOCUS on Quality. Prim Care Clin Office Pract. 2007; 34:1-38. iii UK Prospective Diabetes Study 24: A 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med. 1998; 128:165-75. iv Van Gaal LF, Gutkin SW, Nauck MA. Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control? European Journal of Endocrinology. 2008; 158(1):773-84. v Dicembrini I, Pala L, Rotella CM. From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy. Exp Diabetes Res. 2011; 2011:898913. Epub 2011 Jun 23. vi Rosenstock J, Reusch J, Bush M, Yang F, Murray S. The Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes: A Randomized Controlled Trial Exploring Weekly, Biweekly, and Monthly Dosing. Diabetes Care. ePublish Ahead of Print July 10, 2009. vii Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005; 353:487-97. viii Haynes RB, Yao X, Degani A, Kripalani S, Garg A, McDonald HP. Interventions for enhancing medication adherence. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD000011.

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ix Rosen MI, Rigsby MO, Salahi JT, Ryan CE, Cramer JA. Electronic monitoring and counseling to improve medication adherence. Behav Res Therapy. 2004; 42:409-22. x Miller NH. Compliance with treatment regimens in chronic asymptomatic diseases. Am J Med.1997; 102(2A):43-49. xi Cleemput I, Kesteloot K, DeGeest S. A review of the literature on the economics of noncompliance: Room for methodological improvement. Health Policy. 2002; 59:65-94. xii Pladevall M, Williams LK, Potts LA, et al. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes. Diabetes Care. 2004; 27:2800-05. xiii Lee WC, Balu S, Cobden D, et al. Prevalence and economic consequences of medication adherence in diabetes: a systematic literature review. Manag Care Interface. 2006; 19:31-41. xiv Rhee MK, Slocum W, Ziemer DC, et al. Patient adherence improves glycemic control. Diabetes Educ. 2005; 31:240-50. xv Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006; 166:1836-41.xvi Duffy B, Smith K, Terhanian G, Bremer J. Comparing data from online and face-to-face surveys. International Journal of Market Research 2005;47(6):615-639.