health outcomes protocol unique identifier … › ctr-gsk-7381 › 117295 › ... · abbreviated...

HEALTH OUTCOMES PROTOCOL

UNIQUE IDENTIFIER BLM117295 / HO-12-12600 (Second Amendment)

ABBREVIATED TITLE Collecting Additional Lab Test Results in OBSErve

FINAL PROTOCOL

APPROVED 12-23-2013

FULL TITLE “Phase II Evaluation of Use of Belimumab in Clinical Practice

Settings in the US ”

1st Amendment: Version includes the collection of additional

lab test results at 0, 6 and 12 months in OBSErve. Approved

by PRC in December 2013.

2nd

Amendment: Version includes the collection of

additional lab test results 24 mos. post belimumab use in

OBSErve.

SPONSORSHIP Sponsored, Supported, Collaboration, ISS

DIVISION Pharma

BUSINESS UNIT Research & Development

US Medical Affairs

DEPARTMENT USHO

HO STUDY

ACCOUNTABLE

PERSON(S)

PhD

Director, US Health Outcomes

5 Moore Drive

Research Triangle Park, NC 27709

Phone Number:

Email:

CONTRIBUTING

AUTHORS

RETENTION CATEGORY

INFORMATION TYPE Health Outcomes Observational (Non-Interventional) Protocol

KEY WORDS / MESH

HEADINGS / META DATA

Real world effectiveness; SLE; lab tests;

ASSET ID Benlysta

GSK ASSET Belimumab (Benlysta®)

INDICATION SLE

2

SPONSOR SIGNATORY

Upload to iSign, enter names of signatories (must have BioSafe Digital Credential), submit for

electronic signature. Once signatures are complete, store in IMMS & archive to PIER.

NAME HERE

HO Study Accountable Person

DD-MMM-YYYY

Date

Group HO VP/Director

Date

Medical (GML/MDL/PPL/PMAL/RMD/Equivalent)

Date

Intellectual Property

Date

Trademarks

Date

Global Clinical Safety & Pharmacovigilance

Date

Statistics

Date

Enter other signatory Name/Role as needed

Date

HO PROTOCOL REVIEW COMMITTEE APPROVAL

HO PRC CHAIR

Date Approved

3

PROTOCOL SYNOPSIS

Unique Identifier BLM117295 / HO-12-12600 (First Amendment)

Abbreviated Title Collecting Additional Lab Test Results in OBSErve

“Phase II Evaluation of Use of Belimumab in Clinical Practice

Settings in the US ”

GSK Product Belimumab (Benlysta®)

Rationale The ‘Evaluation of Use of Belimumab in Clinical Practice Settings in

the U.S. (OBServe)’study has two phases as follows:

Phase I study, the baseline wave was completed in September 2012.

This phase enrolled N = 501 patients who have received at least 8

infusions of belimumab.

Phase II is an on-going study that is designed to follow Phase I

patients over a 24-month period. This phase is currently following

patients 24-months post- belimumab initiation. (

To-date, lab test data has not been collected on the patient case report

forms (CRFs). This is a gap that GSK would like to address by

conducting a similar retrospective chart review specifically for lab test

data. The goal is to describe the relationship based on changes in lab

values to other disease measures such as overall improvement, steroid

reduction, etc. to provide a more complete picture of the effectiveness

of Benlysta® (belimumab).

Given the above main study objective, GSK has expressed an interest

to collect lab test data at baseline / 0 (belimumab initiation), 6 and 12

months post-belimumab initiation. Medical Data Analytics (MDA)

proposes to collect these data with the same methodology, traditional

hard copy paper form, as was employed in Phase I and Phase II.

This second amendment includes the collection of lab test data at 24

months post-belimumab initiation.

Objectives

(Primary and

Secondary)

The primary objective of this additional or supplemental study is to describe

changes of lab test results of immunology, hematology, renal functions at 0

(belimumab initiation), 6, 12 and 24 months after initiation in SLE patients

newly treated with belimumab.

A secondary objective will be to relate lab data to the primary and secondary

clinical endpoints collected in the original OBSErve to estimate how they

change over time in relation to each other.

4

The specific routine lab tests to be collected include the following:

1. CBC (WBC, hemoglobin, platelet count )

2. Renal function tests (serum creatinine, spot urine protein/creatinine ratio)

3. ESR

4. CRP

5. Liver function tests (ALT, AST)

6. Immunological tests (anti-nuclear antibody/ANA, anti-dsDNA antibody,

anti-Sm antibody)

7. Complement studies (C3 and C4)

8. Fasting lipid profile (Total cholesterol, LDL, HDL)

5

Study Design This study design will be identical to Phase I and Phase II OBSErve

study which is a double-blinded retrospective chart review.

The study subjects will include the original N = 501 Phase I patients

enrolled in OBSErve. Lab test data will be collected at the same time

points the original CRFs were completed, that is, at baseline / 0

(belimumab initiation), 6 , 12 and 24 months post-belimumab

initiation. Therefore, the collected lab test data can be associated with

other data collected in the original patient CRFs.

Medical Data Analytics (MDA) will collect the lab data via traditional

hard copy form (same methodology employed in Phase I and Phase

II).

Study Population and

Sampling Methods

The study is a multi-center retrospective observational medical chart

review. A total of N = 92 rheumatology practices that participated in

Phase I will be re-contacted and invited to participate in the study. It

is anticipated that re-contacting physicians 12 months after the original

data collection will likely result in 30% to 40% physician attrition

rates due non-interest or inadequate honorarium. It is estimated that

we will have between 55 and 65 study participants.

The starting patient sample will be N = 501 belimumab patients who

have been enrolled in Phase I and will be re-enrolled for this

supplemental study. Based on the estimated attrition rates, we

estimate an ending patient sample of N = 400 belimumab patients with

lab test data at baseline / 0 (belimumab initiation), 6, 12 and 24

months post-belimumab initiation.

Data Source Retrospective lab test data will be collected from patient medical

records at baseline / 0 (belimumab initiation), 6, 12 and 24 months

post-belimumab initiation. The study period dates will be based on

individual patient’s belimumab initiation date.

Data Analysis Methods Lab test data will be collected retrospectively (from patient medical

charts) from belimumab initiation through 12 months and at 24

months post-belimumab initiation. Lab test data will not be collected

at the 18 month post-belimumab initiation period.

A data entry program will be developed, tested and de-bugged and

implemented using CsPro software.

To satisfy the primary research objectives univariate and bivariate

analyses will be conducted for the purpose of describing the lab test

data (descriptive statistics will be included for each test). Specifically,

test of significance will be performed to show lab data changes at

6

baseline / 0 (belimumab initiation), at 6 months post, 12 months post-

belimumab and 24 months post-belimumab initiation.

To address the secondary objective, that is, determine the relationship

between the lab test data and clinical endpoints collected in the original

OBSErve, e.g., disease activity assessment, steroid use, etc., at baseline / 0

(belimumab initiation), at 6 months post, 12 months post and 24

months postbelimumab initiation, the following statistical analyses

will be considered and details of each will be included in the statistical

analysis plan (SAP).

• T-test at the 95% confidence level

• ANOVA (Analysis of variance)

• Linear regression

• Correlation analysis

Sample Size and Power Considering the descriptive nature of the study, no formal sample size

calculation is needed since no hypotheses will be tested.

Limitations The study population is composed of patients who are prescribed

belimumab shortly after approval of the medication and who received

at least 8 infusions. Extrapolation of results from this patient

population to other SLE patients needs to be considered with caution.

Treatment patterns, clinical outcomes and resource use data represent

only the practices of physicians participating in the study and may

vary from those of non-participating physicians. Additionally, any

resource use incurred by the patient outside of the participating

physician’s practice that the physician has not been made aware of are

likely to be underreported.

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TABLE OF CONTENTS

ABBREVIATIONS ...................................................................................................................8

1. INTRODUCTION / BACKGROUND ..................................................................................9

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

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

2.2. Secondary .........................................................................................................................9

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

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

3.2. Study Populations ...........................................................................................................12

3.2.1. Eligibility Criteria ..................................................... Error! Bookmark not defined.

3.2.2. Sampling ................................................................... Error! Bookmark not defined.

3.3. Data Source / Data Collection ........................................................................................12

3.3.1. Endpoints .................................................................. Error! Bookmark not defined.

3.3.1.1. Primary Endpoint ............................................... Error! Bookmark not defined.

3.3.1.2. Secondary Endpoint(s) .......................................................................................13

3.4. Sample Size / Power Calculations ..................................................................................13

3.5. Hypotheses .....................................................................................................................13

4. DATA ANALYSIS CONSIDERATIONS ..........................................................................13

5. LIMITATIONS ................................................ ERROR! BOOKMARK NOT DEFINED.

6. STUDY CONDUCT, MANAGEMENT AND ETHICSERROR! BOOKMARK NOT DEFINED.

6.1. Ethics / IRB Approval ....................................................................................................15

6.2. Informed Consent ...........................................................................................................15

6.3. Data Privacy ...................................................................................................................15

6.4. Personally Identifiable Information (PII) .......................................................................15

6.5. AE Reporting ..................................................................................................................15

6.6. Data Storage / Archival ..................................................................................................16

7. EXTERNAL INVOLVEMENT ...................... ERROR! BOOKMARK NOT DEFINED.

MILESTONES .........................................................................................................................17

DATA DISSEMINATION PLAN ...........................................................................................18

8

ABBREVIATIONS

ANOVA Analysis of variance

CRF Patient Case Report Form

CSPro Census and Survey Processing System

GSK GlaxoSmithKline PLC

HIPAA Health Insurance Portability and Accountability Act

IRB Institutional Review Board

MDA Medical Data Analytics

SAP Statistical Analysis Plan

TAP Targeted Abstraction Process

U.S. United States

9

1. INTRODUCTION/BACKGROUND

The OBSErve study has two phases:

Phase I study, the baseline wave was completed in September 2012. This phase enrolled N =

501 patients who have received at least 8 infusions of belimumab.

Phase II is an on-going study that is designed to follow Phase I patients over a 24-month

period. This phase is currently following patients 24-months post- belimumab initiation.

To-date, lab test data has not been collected on the patient case report forms (CRFs). This is a gap

that GSK would like to address by conducting a similar retrospective chart review specifically for lab

test data. The goal is to describe the relationship based on changes in lab values to other disease

measures such as overall improvement, steroid reduction, etc. to provide a more complete picture of

the effectiveness of Benlysta® (belimumab).

Given the data gap and study objectives, GSK has expressed an interest to collect lab test data at 0 /

baseline (belimumab initiation), 6, 12 and 24 months post-belimumab initiation. Medical Data

Analytics (MDA) proposes to collect these data with the same methodology, that is traditional hard

copy paper form, as was employed in Phase I and Phase II.

2. OBJECTIVES

2.1. Primary

The primary objective of this additional or supplemental study is to describe changes of lab test

results of immunology, hematology, renal functions at 0 (belimumab initiation), 6, 12 and 24

months after initiation in SLE patients newly treated with belimumab.

2.2. Secondary

A secondary objective will be to relate lab data to the primary and secondary clinical endpoints

collected in the original OBSErve to estimate how they change over time in relation to each

other.




3. ESR

4. CRP


6. Immunological tests (anti-nuclear antibody/ANA, anti-dsDNA antibody, anti-Sm antibody)



10

3. RESEARCH METHODOLOGY

3.1. STUDY DESIGN

This study design will be identical to the Phase I and Phase II OBSErve which is a double-

blinded retrospective chart review. The study subjects will include the original N = 501 patients

enrolled in OBSErve. Lab data will be collected at the same time points the original CRFs were

completed and follow the same time points for future CRFs. Therefore, the collected lab data can

be associated with other data collected in the original CRF.

The study design will adhere to HIPAA (Health Insurance Portability and Accountability Act. A

supplemental institutional review board (IRB) application will be submitted to the

The steps to be undertaken by MDA will be as follows:

1. Finalize the patient CRF for the additional lab test data to be collected. Each CRF will

contain the following information areas:

a. Pre-populated CRF with patient demographics and clinical characteristics to be

pulled from Phase I data.

b. Lab tests of interest (see below) conducted, date of each and results will be collected

for three time periods (at 0 / baseline, 6 and 12 months post-belimumab initiation).



3. ESR

4. CRP


6. Immunological tests (anti-nuclear antibody/ANA, anti-dsDNA antibody,

anti-Sm antibody)



c. The estimated time that it would take each physician to document or report on 12 –

15 lab tests is estimated to take about 85 – 105 minutes to complete each CRF. The

estimated breakdown is as follows:

i. 10 – 15 minutes: at 0 or belimumab initiation

ii. 25 – 30 minute: at 6 months

iii. 25 – 30 minutes: at 12 months

iv. 25 – 30 minutes: at 24 months

2. Submit the supplemental study application. An amendment will be submitted to

include the added 24 month period.

3. Upon receipt of the approval letter, re-contact all 92 study physicians and conduct

follow-ups via phone, e-mail and fax.

4. Review completed CRFs and edit / code and conduct data entry, data validation and data

processing.

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5. Develop the supplemental statistical analysis plan (SAP) to include the table shells.

6. Conduct data analysis to include total belimumab patients and sub-groups of interest by race /

ethnicity, baseline disease activitity assessment, and baseline renal involvement through renal

function tests to determine how renal functions change in patients with baseline renal

involvement within the US belimumab label.

7. Prepare and submit a final report using the GSK template.

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3.2. STUDY POPULATIONS

A total of N = 92 rheumatologists will be re-contatced and N = 501 belimumab patients will be

re-enrolled in the study.

3.2.1. ELIGIBILITY CRITERIA

The study subjects will include the original N = 501 belimumab patients enrolled in Phase I

(OBSErve.) study.

3.2.2. SAMPLING

Based on the assumed patient attrition rates, we estimate an ending sample of about N = 400

belimumab patients with lab test data for the same / identical three time periods, that is, at 0 /

baseline (belimumab initiation) , 6, 12 and 24 months post-belimumab initiation..

3.3. DATA SOURCE / DATA COLLECTION

Lab test data will be sourced from patient medical records for the same time periods as in Phase I

and Phase II OBSErve study.

Study data collection will adhere to Targeted Abstraction Process (TAP™), MDA’s core data

collection method that employs strict guidelines for data collection and processing.

TAP is based on best practices for data collection from the standards imposed on clinical trials.

TAP is utilized by MDA in all chart abstraction studies, specifically, studies that investigate

treatment patterns and patient characteristics.

Physician involvement is an important and distinguishing feature of TAP. Physicians are

recruited for study participation with the understanding that they will act as study

investigators with responsibility for patient selection, chart data abstraction and data

validation/resolution. This responsibility and direct involvement by physicians enhances data

quality through minimization of inaccurate, missing or incomplete data and data

misinterpretation that often occur in such studies. TAP consists of the following key steps:

- Conduct of pilot / pre-test with at minimum 3 physicians

- Recruitment of target physician specialties

- Development of detailed study instructions

- Thorough training of internal staff in all aspects of the study

- Study monitoring and physician follow up

- CRF editing / manual review and coding

- Data validations (30% random CRF, 100% validated against source document),

frequency distributions , arrays and machine validations

- Documentation of missing data and resolution with physicians

3.3.1. ENDPOINTS

3.3.1.1. Primary Endpoint

To describe changes of lab test results of immunology, hematology, renal functions at 0 /

baseline (belimumab initiation), 6, 12 and 24 months after initiation in SLE patients

newly treated with belimumab.

13

3.3.1.2. Secondary Endpoint(s)

A secondary objective will be to relate lab data to the primary and secondary clinical

endpoints collected in the original OBSErve to estimate how they change over time in

relation to each other.




3. ESR

4. CRP


6. Immunological tests (anti-nuclear antibody/ANA, anti-dsDNA antibody, anti-Sm

antibody)



3.4. SAMPLE SIZE / POWER CALCULATIONS

Starting sample is N = 501 and estimated ending sample is N = 400 (based on Phase II patient

attritions, e.g., lost to follow-up and discontinued belimumab).

Considering the descriptive nature of the study, no formal sample size calculation is needed.

3.5. HYPOTHESES

The study will be descriptive in nature and there is no planned hypothesis testing.

4. DATA ANALYSIS CONSIDERATIONS

Lab test data will be collected retrospectively (from patient medical charts) at baseline / 0 (belimumab

initiation), at 6 months post, at 12 months post and at 24 months post-belimumab initiation.

A data entry program will be developed, tested and de-bugged and implemented using CsPro (Census

and Survey Processing System) software.

To satisfy the primary research objectives univariate and bivariate analyses will be conducted for the

purpose of describing the lab test data (descriptive statistics will be included for each test).

Specifically, test of significance will be performed to show lab data changes at baseline / 0

(belimumab initiation), at 6 months post, at 12 months post and at 24 months post-belimumab

initiation.

To address the secondary objective, that is, determine the relationship between the lab test data and

clinical endpoints collected in the original Phase I and Phase II OBSErve at baseline / 0 (belimumab

initiation), at 6 months post. at 12 months post and at 24 months post-belimumab initiation, the

following statistical analyses will be considered and details of each will be included in the statistical

analysis plan (SAP) to be developed.

• T-test at the 95% confidence level

• ANOVA (Analysis of variance)

• Linear regression

• Correlation analysis

14

Preliminary clinical endpoints include the following:

• Overall clinical response (Worse, No Improvement, <20%, 20-49%, 50-79% and >80%)

• Disease severity assessment (mild, moderate, severe)

• Steroid use (steroid sparing)

• Selena-Sledai score • Others TBD

5. LIMITATIONS

The study population is composed of patients who are prescribed belimumab shortly after approval of

the medication and who received at least 8 infusions. Extrapolation of results from this patient

population to other SLE patients needs to be considered with caution. Treatment patterns, clinical

outcomes and resource use data represent only the practices of physicians participating in the study

and may vary from those of non-participating physicians.

6. STUDY CONDUCT, MANAGEMENT & ETHICS

6.1. ETHICS/IRB APPROVAL

An Institutional Review Board (IRB) application for approval will be filed with

MDA uses for the majority of chart review projects. An amendment will be filed

with the to include the added 24 months post-belimumab initiation period.

All aspects of this study will be conducted in compliance with Health Insurance Portability and

Accountability Act (HIPAA) regulations. Physicians will be provided with a Limited Data Use

Agreement which will require their signature for study participation.

6.2. INFORMED CONSENT

An exemption from patient consenting will be sought owing to the retrospective, double-blinded

study design, the collection of de-identified data and the reporting of only anonymized data.

6.3. DATA PRIVACY

In this double-blinded study, participating physicians, who act as Study Investigators (SIs) and

patients will remain anonymous and all data will be de-identified. All data is collected and processed

with adequate precautions to ensure confidentially and compliance with applicable data privacy

protection laws and regulations.

Participating physicians / Study Investigators (SIs) will be responsible for the medical data

abstraction following MDA’s Target Abstraction Process (TAP), and importantly, no personal data

(e.g., patient names, address and data of birth) will be collected. As an additional safeguard,

physicians are instructed to assign a unique patient identifier to be used for follow-up for data

validation and/or for missing data.

6.4. PERSONALLY IDENTIFIABLE INFORMATION (PII)

The confidentiality of records that could identify patients within the database must be protected,

respecting the privacy and confidentiality rules in accordance with the applicable regulatory

requirement(s).

Patient / Subject data is collected in a manner that subjects cannot be identified, directly or through

identifiers linked to the subjects. Patient / Subject data remains anonymous and all data are de-

identified. No personal data (e.g., patient names, address and data of birth) will be collected.

Only the participating physicians / Study Investigators have access to the link between patient’s

assigned code and the patient’s identity. Data that could directly identify the patient will not be

15

collected in the “study database”.

6.5. AE REPORTING

Adverse event (AE) data will not be collected in this supplemental study. AE reporting in accordance

with GSK guidelines has been completed during the Phase I and Phase II OBSErve.

6.6. DATA STORAGE/ARCHIVAL

All study records and source documents will be retained for the maximum period required by

applicable regulations and guidelines or for the period specificed by the sponsor, whichever is longer.

7. EXTERNAL INVOLVEMENT

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

EVP, Research Operations

Medical Data Analytics (MDA)

A Division of Market Certitude, LLC

4 Gatehall Drive

2nd Floor

Parsippany, NJ 07054

Tel No:

Fax No.

Mobile:

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

Dr. Dr.

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MILESTONES

MILESTONE GUIDANCE OR

POLICY

REQUIREMENT

FORECAST

DATE MM-YYYY

Forecast Final Protocol Approval

12-2013

Forecast GSK CSR Protocol Summary

FPA Actual + 30 days

Forecast Statistical Analysis Plan Approved

03-2014

Forecast Statistical Analysis Complete

Forecast Final Study Report Complete

SAC Actual + 6 months 07-2014

Forecast GSK CSR Results Summary Posting

SAC Actual + 8 months

Forecast Manuscript Submission

SAC Actual + 18 months

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DATA DISSEMINATION PLAN The data collected in this supplement protocol will be published along with the data from the original protocol. No separate publications are planned at this moment. Attach the Manuscript & Congress Presentation Data Dissemination Plan (DDP) in the MCQP DDP PowerPoint template. Should include the following information:

MANUSCRIPT PUBLICATION(S) Note: Only 1 primary manuscript per study is permitted unless approval from Medical. The lab data will be incorporated into the final manuscript for the OBSErve so no separate manuscript will be written.

STUDY ID PUBLICATION SHORT TITLE

LEAD AUTHOR

STUDY ACCOUNTABLE

PERSON

ESTIMATED SUBMISSION DATE

(< SAC + 18 months)

TARGET JOURNAL

CONGRESS PRESENTATION(S) The lab data will be incorporated into the final planned abstract for the OBSErve for ACR 2014.

STUDY ID ABSTRACT SHORT TITLE

PRESENTER POSTER OR ORAL

PRESENTATION

CONGRESS CONGRESS LOCATION

CONGRESS DATE

DISCLOSURE PLAN

FORECAST

GSK CSR PROTOCOL SUMMARY (FPA + 30 DAYS)

GSK CSR RESULTS SUMMARY (SAC + 8 MONTHS)

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

health outcomes protocol unique identifier … › ctr-gsk-7381 › 117295 › ... · abbreviated...

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