DISC0VER DISCovERing Treatment Reality of type 2 Diabetes in Real World settings.

UNIT PENELITIAN DAN PENGEMBANGAI{
(LITBANG) FAKULTAS KEDOKTERAN
U N I VERTAS UDAYANA,iRUMAH SAICT TJMIJM
PUSAT SANGLAH DENPASAR
Jlrr P. Serangan Dps.

Bali(80114) Email. litbang.unud.rsup@gnail.com Telp. (0361)

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4, (0361)227911-15(p.227)

Nomor : ((26 nsr't.t+.2Litban{2015
Lampiran : 1 lembar
Perihal : Penyerahan Elftical Clemcmce
Kepada

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Dr.dr. Made Ratna Saraswati. SpPD-KEMD
di-Tempat
Dengan hormat,
Bersama ini kami menyerahkan Erft ical Clearance lKeterangan Kelaikan Etik Nomor :
1800ruN. 14.2l1,itban!2015, tsrtanggal, 26 Nopember 2015
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Jika ada perubahan yang menyangkut dengan hal penelitian tersebut mohon melaporkan ke Komisi Etik
Litbang FK UNUDIRSUP Sanglah Denpasar.

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Demikian kami sampaikan, atas perhatian dan keriasamanya kami ucapkan terimakasih.
Denpasar,

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Tembusan:
1. Dirut RSUP Sanglah Denpasar c.q. Ka. Bagian Diklat

2. Ka. Poli Penyakit Dalam RSIIP Sanglah Denpasar
3. Ka. Diabetic Centre RSUP Sanglah Denpasar

4. Arsip.-

UNIT PENELITIAN DAN PENGEMBANGAN
(LITBANG) FAKULTAS KEDOKTERAN
UNTVERTAS UDAYANA/RUMAH SAKIT UMUM
PUSAT SANGLAH DENPASAR
.lalan P. Serangan Denpasar Bali (80114) Email : l.itbang.rmud.rsup(@gmail-com Telp. (0361) 24453 4, (0361)227911-15(p.227)

ETHICAL CLEARANCE
NO. 1 800/LrN

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This is to ceftily that following study project entitled

:

"DISCOWR: DISCOVERing Treatment Reality of

Type 2 Diabetes in Real World Settings."

Principal Investigator : Dr.dr. Made Ratna Salaswati, SpPD-KEMD
Other Researchers : dr. Made Pande Dwipayana, SpPD-KEMD

Research Development: RSUP Sanglah Denpasar'

Plotocol

Number

: 833.03.3-2015

Has been evaluated in accordance with the ethical aspects in using human being as a study subject and
consideled proper to be executed.

1.

2.

Progless lepoft every...... month
Final leport

81010198702100r

NIP. I953013tl

Non-Interventional Study (NIS) Primary Protocol Amendment

NIS D-code

1

DISCOVER D1690R00002

NIS Primary Protocol Dated

20 November 2014 (version 2)

Date

01 July 2015

Amendment Edition Number

DISCOVER: DISCOVERing Treatment Reality of Type 2 Diabetes in Real World
Settings

Sponsor:
AstraZeneca AB
151 85 Södertälje, Sweden

Financial Support By:

AstraZeneca

The following Amendment(s) have been made to this protocol since the date of preparation:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment

This submission /document contains trade secrets and confidential commercial information, disclosure of which
is prohibited without providing advance notice to AstraZeneca and opportunity to object.

Associated Document to 8-P-102-CV-C: T02 NIS Primary Protocol
Template Active Date: May 2014

Non Interventional Study Primary Protocol Amendment (NISP) Synopsis
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date of protocol amendment: 01 July 2015

NON-INTERVENTIONAL STUDY PRIMARY PROTOCOL SYNOPSIS

DISCOVER: DISCOVERing Treatment Reality of Type 2 Diabetes in Real
World Settings
International Co-ordinating Investigator of the Non-Interventional Study Primary
Professor Linong Ji, MD

Peking University People’s Hospital,
11 Xizhimen Nan Dajie, Xicheng District,
Beijing, China
Tel. + 86 1068358517

Scientific Committee members of the Non-Interventional Study Primary
Professor Bernard Charbonnel, MD

Department of Endocrinology,
University of Nantes,
44000 Nantes, France
Tel. + 33 (02) 40083642
Professor Marília Gomes, MD

Unit of Diabetes,

Universidade Estadual do Rio de Janeiro,
Avenida 28 de Setembro, 77, 3o andar,
CEP 20.551-030,
Rio de Janeiro, Brazil
Tel. + 55 2128688224
Professor Kamlesh Khunti, MBChB, PhD
Diabetes Research Centre

University of Leicester
Leicester General Hospital
Gwendolen Road, Leicester, United Kingdom
LE5 4P W
Tel.: + 44 116 258 4005

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Non Interventional Study Primary Protocol Amendment (NISP) Synopsis
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date of protocol amendment: 01 July 2015

Professor Antonio Nicolucci, MD

Consorzio Mario Negri Sud,
Via Nazionale 8/a, 66030 S Maria Imbaro, Italy
Tel.: + 39 0872570260
Professor Stuart Pocock, PhD
Medical Statistics Unit,
London School of Hygiene and Tropical Medicine,
Keppel Street, London, United Kingdom
WC1E 7HT

Tel. + 44 207927 2413
Professor Marina Shestakova, MD

Institute of Diabetes, Federal Scientific Centre of Endocrinology,
Dmitryia Uljanova, No. 11, 117036 Moscow, Russia.
Tel. + 7 495 124 45 00
Professor Mikhail Kosiborod, MD

Saint Luke's Mid America Heart Institute,
University of Missouri-Kansas City,
4401 Wornall Road 600
Kansas City, MO, USATel. + 1 816 931 1883

Study Site(s), number of subjects and countries planned
Approximately 9650 subjects recruited from sites in Argentina, Australia, Austria, Brazil,
Canada, China (Mainland), Colombia, Costa Rica, Czech Rep, France, Germany, India,
Indonesia, Italy, Malaysia, Mexico, Netherlands, the Nordics (Denmark, Norway and Sweden)
Panama, Poland, Russia, South Korea, Spain, Taiwan and the United Kingdom.
.
Total planned Study period
Estimated date of first subject in

Q4 2014

Estimated date of last subject in

Q4 2015

Estimated date of last subject last visit

Q4 2018

Estimated date of data base lock

Q1 2019

Medicinal Products (type, dose, mode of administration) and concomitant medication
Not applicable

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Non Interventional Study Primary Protocol Amendment (NISP) Synopsis
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date of protocol amendment: 01 July 2015

Rationale for this Non-Interventional Study (NIS) Primary
In many geographical regions, data on diabetes treatments and control is scarce and where data
sources are available these do not contain enough detail to capture the entire patient journey.
Little data has been captured and published since the launch of newer classes of therapy such
as DPP-IV inhibitors, GLP-1 agonists and most recently the SGLT2 inhibitors as compared to
the well known established oral hypoglyacemic agents sulphonylureas and metformin.
In this context, this study aims to provide data on real world second and further line antidiabetic therapy use among type 2 diabetes patients in different geographical regions. The
association of these therapies with achieving disease control and in preventing and controlling
diabetes complications will be documented. The DISCOVER program will be the largest
global study of this kind ever performed.
Objectives of this Non-Interventional Study Primary
(a)

Primary objective
The primary objective is to describe the disease management patterns and clinical
evolution over three years in type 2 diabetes mellitus patients initiating a second
line anti-diabetic treatment (add-on or switch), after a first line oral treatment with a
monotherapy, dual or triple therapy.

(b)

Main secondary objective
To describe, overall and by patient characteristics as well as second line antidiabetic medication class, treatment response in terms of changes in HbA1c, body
weight, blood pressure and lipid profile from baseline and achievement of HbA1c
target goals.
To describe treatment changes, that is initiation of third line or above add-on antidiabetic medication, initiation of insulin therapy, switching of anti-diabetic
medications or dose changes.

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Non Interventional Study Primary Protocol Amendment (NISP) Synopsis
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date of protocol amendment: 01 July 2015

To describe disease progression in terms of microvascular complications, that is,
incidence of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy or
diabetes-related peripheral revascularization and/or non-traumatic amputation.
To describe incidence of macrovascular complications, that is, cardiovascular death,
heart failure, myocardial infarction and stroke.
To describe hypoglycemic events and/or hospitalizations for hypoglycemia.
To describe patient reported Quality of Life.
To describe healthcare resource use.
To describe risk factors (disease, patient, treatment and setting characteristics at
baseline: e.g. age, gender, duration of diabetes, second line anti-diabetic medication
class, presence of co-morbidities, socioeconomic status, quality of care) associated
with microvascular complications, macrovascular complications, hypoglycemic
events, quality of life and healthcare resource use during follow-up.
To describe factors associated with treatment choice at baseline.
Study design
This study is a multi-country, multicenter, observational, prospective, longitudinal cohort
study. The countries patients will be recruited from are: Argentina, Australia, Austria, Brazil,
Canada, China (Mainland), Colombia, Costa Rica, Czech Rep, France, Germany, India,
Indonesia, Italy, Malaysia, Mexico, Netherlands, the Nordics (Denmark, Norway and Sweden)
Panama, Poland, Russia, South Korea, Spain, Taiwan and the United Kingdom.
.
It is estimated that approximately 9650 patients will be enrolled in total with each patient
followed up for 3 years.
In France, Germany, the Nordics and the United Kingdom, the observational, prospective
design will be enhanced with integration of retrospective data collected in electronic medical

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Non Interventional Study Primary Protocol Amendment (NISP) Synopsis
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date of protocol amendment: 01 July 2015

records, patient registers or disease registers. In the remaining countries, AstraZeneca and its
study partners will pursue the establishment of data networks at the sites to allow for
extraction of additional clinical information and from electronic medical records with linkage
to the NIS, in accordance with the country specific privacy laws.
Target subject population
Patients with type 2 diabetes initiating their second line anti-diabetic therapy after first line
diabetic therapy.
Study variable(s):
Primary variable
• Class of diabetic medication/s initiated as second-line anti-diabetic therapy and
associated clinical evolution (through HbA1c, body weight, blood pressure,
hypoglycemic events, micro- and macro-vascular complications).
Secondary variables
• Site characteristics.
• Physician speciality.
• Patient demographics.
• Vital signs and lab tests.
• Medical history of T2DM, including presence of risk factors.
• Co-morbidities and co-medications.
• Changes in diabetes treatments during follow-up and reasons.
• Number of major hypoglycemic events, occurrence of minor hypoglycemic events.
• Microvascular complications (nephropathy, retinopathy, neuropathy and amputation)
and macrovascular complications.
• All-cause death.
• Patient reported outcomes: Quality of Life: SF-36, HFS-II, lifestyle and healthcare
avoidance due to costs. The specific PROs to be used in each country will depend on
the availability of versions in the official language/s.

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Non Interventional Study Primary Protocol Amendment (NISP) Synopsis
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date of protocol amendment: 01 July 2015

• Healthcare resource use.
Statistical methods
Statistical methods appropriate for descriptive purposes in epidemiological studies will be
used for the analysis of collected data. Interim analysis might be performed at baseline after
the last subject is recruited and then 1 and 2 years after last subject in.
It is therefore proposed to include an overall sample size of 9650 patients. This will guarantee
that, for any second line compound class given to ≥ 1.5% of patients (i.e., 201 patients),
sufficiently precise and meaningful data will be obtained.

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Non Interventional Study Primary Protocol Amendment
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date: 01 July 2015

TABLE OF CONTENTS

PAGE

TITLE PAGE............................................................................................................................1
NON-INTERVENTIONAL STUDY PRIMARY PROTOCOL SYNOPSIS..........................2
Primary variable .......................................................................................................................6
Secondary variables ..................................................................................................................6
TABLE OF CONTENTS .........................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...........................................11
1.

INTRODUCTION .................................................................................................12

1.1

Background ............................................................................................................12

1.2

Rationale for conducting this NIS Primary............................................................13

2.

NIS OBJECTIVES.................................................................................................14

2.1

Primary objective ...................................................................................................14

2.2

Secondary objectives .............................................................................................14

3.

STUDY PLAN AND PROCEDURES ..................................................................15

3.1

Overall study design and flow chart ......................................................................16

DATA COLLECTION AT ENROLMENT AND FOLLOW-UP .........................................18
Enrolment procedures.............................................................................................................18
4.

SELECTION OF SUBJECT POPULATION........................................................22

4.1

Investigators ...........................................................................................................22

4.2

Inclusion criteria ....................................................................................................23

4.3

Exclusion criteria ...................................................................................................23

5.

DISCONTINUATION OF SUBJECTS ................................................................24

5.1

Criteria for Discontinuation ...................................................................................24

5.2

Procedures for discontinuation ..............................................................................24

6.

THERAPEUTIC STRATEGY ..............................................................................24

6.1

Therapeutic strategy of a Non-Interventional Study..............................................24

7.

STUDY CONDUCT ..............................................................................................24

7.1

Restrictions during the study (if applicable) ..........................................................24

8.

MEASUREMENTS OF STUDY VARIABLES AND DEFINITIONS OF
OUTCOME VARIABLES ....................................................................................24
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8.1

Primary variable .....................................................................................................24

8.2

Variables to be collected during follow-up:...........................................................26

8.3
8.3.1
8.3.2
8.3.3
8.3.4
8.3.5

Patient Reported Outcomes (PRO) ........................................................................26
SF-36 ......................................................................................................................26
Hypoglycemia Fear Survey (HFS-II).....................................................................27
Lifestyle score ........................................................................................................27
Healthcare avoidance due to costs .........................................................................28
Administration of PRO questionnaires ..................................................................28

8.4

Health Economic measurements and variables (if applicable) ..............................28

9.

SAFETY REPORTING .........................................................................................29

9.1
9.1.1
9.1.2
9.1.3

Definitions..............................................................................................................29
Definition of Adverse Event (AE) .........................................................................29
Definition of Serious Adverse Event (SAE) ..........................................................29
Definition of Adverse Drug Reactions (ADR) ......................................................29

9.2

Adverse Event Reporting .......................................................................................29

10.

ETHICAL CONDUCT OF THE NON-INTERVENTIONAL STUDY ...............30

10.1

Ethics review..........................................................................................................30

10.2

Subject Informed consent ......................................................................................30

10.3

Subject data protection...........................................................................................31

11.

STUDY MANAGEMENT BY ASTRAZENECA ................................................32

11.1

Monitoring, Quality Control and Archiving ..........................................................32

11.2

Training of study site personnel.............................................................................33

11.3

NIS timetable and end of study..............................................................................33

12.

DATA MANAGEMENT.......................................................................................34

12.1

Collection, monitoring, processing of data and archiving .....................................34

12.2

Reporting and publication of data ..........................................................................35

13.

STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............36

13.1

Statistical evaluation – general aspects ..................................................................36

13.2

Description of analysis sets....................................................................................36

13.3

Method of statistical analysis .................................................................................36

13.4

Determination of sample size.................................................................................38

14.

LIST OF REFERENCES .......................................................................................39

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LIST OF TABLES
Table 1

Study Plan.................................................................................................22

Table 2. Precision of estimated proportions per class of products for a sample size of
200. 500 or 1000 patients (2-sided 95% Confidence Interval).................38

LIST OF FIGURES
Figure 1

Study Flow Chart......................................................................................21

LIST OF APPENDICES
Appendix A

Signatures

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Non Interventional Study Primary Protocol Amendment
NIS D-code: DISCOVER D1690R00002
Edition Number: 1
Date: 01 July 2015

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this NIS Protocol.
Abbreviation or
special term

Explanation

AE

Adverse event

ADR

Adverse Drug Reaction

Assessment

An observation made on a variable involving a subjective judgement
(assessment)

AZ

AstraZeneca

CRF

Case Report Form (electronic/paper)

CRO

Clinical Research Organisation

ePRO

Electronic Patient Reported Outcome

National Coordinator

The National Coordinator is the main line of contact to coordinate the
submissions and responses of the Leading Ethics Committee and of the
Ethics Committees related to the other participating sites (Non-Leading
Ethics Committees).

NIS

Non-Interventional Study

NISA

Non-Interventional Study Agreement

NISP

Non-Interventional Study Protocol

NISR

Non Interventional Study Report

EC

Ethics Committee, synonymous to Institutional Review Board (IRB) and
Independent Ethics Committee (IEC)

GCP

Good Clinical Practice

ICH

International Conference on Harmonisation

PI

Principal Investigator responsible for the conduct of a NIS at a site

PRO

Patient Reported Outcomes

Variable

A characteristic of a property of a subject that may vary eg, from time to
time or between subjects

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Edition Number: 1
Date: 01 July 2015

1.

INTRODUCTION

1.1

Background

382 million people have diabetes in 2013; by 2035 this is estimated to rise to 592 million
according to the IDF Atlas 6th edition. The number of people with type 2 diabetes is
increasing in every country. If poorly managed, diabetes can lead to serious and costly
complications.
Management of type 2 diabetes involves individualized and optimal control of factors that
cause complications, of which blood glucose is an important one of many others. Clear
guidelines for good glycaemic control have been developed recommending a glycated
haemoglobin (HbA1c) goal of