Clinical trial NCT04531462
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2020-10-05; Completion date: 2022-08-26
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is to assess the efficacy of empagliflozin 10 mg after 52 weeks compared to placebo in elderly patients with Type 2 diabetes mellitus (T2DM) and to explore if empagliflozin has any impact on patient physical condition compared to placebo in elderly patients with T2DM.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Empagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Empagliflozin intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
25 May 2020
Revision date
N/A
BI trial number
1245-0218
Title of trial
A randomised, double-blind, placebo-controlled, parallel group, 52 weeks phase IV 
trial to evaluate efficacy and safety of oral, once daily empagliflozin in elderly
Japanese patients with type 2 diabetes mellitus and insufficient glycaemic control
Coordinating 
Investigator
Phone: 
 FAX: 
Trial site(s)
Multi-center trial conducted in Japan
Clinical phase
IV
Trial rationale
Japan’s population is aging, and it is reported that more than 50% of patients with 
type 2 diabetes mellitus (T2DM) are currently of advanced age (≥60 years old). 
However, efficacy data is limited in the elderly population (especially those aged 
≥75 years), who tends to have a low body mass index (BMI). It is well known that 
ageing process itself can lead to unfavourable changes related to deteriorations of 
physical status. There is increasing interest in sarcopenia in elderly patients with 
T2DM. Poor glycemic control in patients with diabetes may be associated with low 
muscle mass.The aim of this study is to evaluate efficacy and safety over 52 weeks 
of empagliflozin therapy in elderly Japanese with T2DM patients whose glycaemia
is insufficiently controlled despite of with or without other oral antidiabetic drugs as 
background treatment.
Trial objective(s)
The main objective of this study is to assess the efficacy of empagliflozin 10 mg 
after 52 weeks compared to placebo in elderly patients with T2DM.
Secondary objectives are to explore if empagliflozin has any impact on patient 
physical condition compared to placebo in elderly patients with T2DM.
Trial endpoints
The primary endpoint is: 
•
Change from baseline in glycosylated haemoglobin A1c (HbA1c) after 
52 weeks of treatment (HbA1c will be measured in the units of % and 
mmol/mol at all clinical visits; the primary endpoint will use units of %).
Secondary endpoints are:
•
Change of muscle mass from baseline to Week 52
•
Change of body fat measurement from baseline to Week 52
•
Change of lean body mass from baseline to Week 52
•
Change of total body water from baseline to Week 52
•
Change of bone mineral content from baseline to Week 52
•
Change of skeletal muscle index from baseline to Week 52
•
Change of grip strength from baseline to Week 52
•
Change of time in the 5-time chair stand test from baseline to Week 52
Trial design
Randomised, double-blind, multi-center, placebo-controlled, parallel group trial
Total number of patients
randomised
128
Number of patients on 
each treatment
64
Diagnosis
The trial will be performed in the elderly Japanese patients (65 years or older) with 
T2DM. Two populations will be recruited; patients who are treatment naïve and 
have insufficient glycaemic control, and patients who have insufficient glycaemic 
control despite of stable antidiabetic treatment.


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Main in- and exclusion 
criteria
Inclusion criteria
•
Japanese patients with diagnosis of T2DM prior to informed consent
•
HbA1c ≥7.0% and ≤10.0% for patients at Visit 1 (screening)
•
If the patient is on treatment with oral antidiabetic drug(s) potentially 
associated with severe hypoglycaemia (e.g., sulfonylurea or glinides), the 
following HbA1c value is used as criterion
1)
HbA1c ≥7.5% and ≤10.0% for age ≥65 and <75
2)
HbA1c ≥8.0% and ≤10.0% for age ≥75
•
Patients on diet and exercise regimen who are drug-naïve or on treatment 
with any oral antidiabetic drug(s) other than glucagon-like peptide-1 
(GLP-1) agonists and SGLT-2 inhibitor. Antidiabetic therapy has to be 
unchanged for 12 weeks prior to randomisation (any thiazolidinedione 
therapy has to be unchanged for at least 18 weeks prior to informed 
consent). 
•
Age ≥65 years at informed consent
•
BMI ≥22 kg/m2 at Visit 1 (screening)
•
Male or post-menopausal female patients
Exclusion criteria
•
Uncontrolled hyperglycaemia with a fasting glucose level >200 mg/dL
(>11.1 mmol/L) during run-in period
•
Treatment with insulin within 12 weeks prior to informed consent
•
Impaired cognitive ability as supported by Mini Mental State Examination
(MMSE)-J (defined as ≤23) and verified by the investigator at screening
•
Acute coronary syndrome (ST-elevation myocardial infarction [STEMI], 
non-STEMI, and unstable angina pectoris), stroke or transient ischemic 
attack within 12 weeks prior to informed consent
•
Indication of liver disease, defined by serum levels of either alanine 
aminotransferase (ALT [SGPT]), aspartate aminotransferase (AST 
[SGOT]), or alkaline phosphatase (ALP) above 3 x upper limit of normal 
(ULN) as determined during screening and run-in period
•
Impaired renal function, defined as estimated glomerular filtration rate
(eGFR) <45 mL/min/1.73 m2 (severe renal impairment, Modification of 
Diet in Renal Disease [MDRD] formula) as determined during screening 
and run-in period
•
Low grip strength defined as <28 kg for male or as <18 kg for female at 
screening
•
Short length of calf circumference defined as <34 cm for male or 33 cm 
for female at screening
•
Already confirmed diagnose of sarcopenia (based on AWGS algorithm 
2019)
•
Known history of diabetic ketoacidosis
•
Known contraindications to empagliflozin according to the Japanese label
•
Disorders causing haemolysis or unstable red blood cells
•
Treatment with anti-obesity drugs  within 12 weeks prior to informed 
consent or any other treatment at the time of screening (i.e., surgery, 
aggressive diet regimen (e.g., low- carbohydrate diet), etc.) leading to 
unstable body weight
•
Current treatment with systemic steroids (other than inhaled or topical 
steroids) at informed consent or change in dosage of thyroid hormones 
within 6 weeks prior to informed consent or any other uncontrolled
endocrine disorder except T2DM
Test product(s)
empagliflozin
dose
10 mg daily
mode of 
administration
oral


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Comparator product(s)
placebo
dose
Not applicable
mode of
administration
oral
Duration of treatment
52 weeks
Statistical methods
The primary analysis is a restricted maximum likelihood (REML)-based mixed 
model repeated measures (MMRM) comparing the change from baseline in HbA1c 
(in units of %) after 52 weeks of double-blind treatment. The statistical model will 
include fixed classification effects for treatment, gender, baseline renal function, 
visit and visit-by-treatment interaction, and a linear covariate for baseline HbA1c 
and age. An unstructured covariance structure will be used to model the within-
patient errors.
Descriptive statistics will be used to analyse the safety endpoints.






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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
1.1
MEDICAL BACKGROUND.............................................................................13
1.2
DRUG PROFILE................................................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................16
1.4
BENEFIT - RISK ASSESSMENT.....................................................................16
1.4.1
Benefits.................................................................................................................17
1.4.2
Risks .....................................................................................................................17
1.4.3
Discussion.............................................................................................................21
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................23
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........23
2.1.1
Main objectives....................................................................................................23
2.1.2
Primary endpoint(s)............................................................................................23
2.1.3
Secondary endpoint(s) ........................................................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................25
3.1
OVERALL TRIAL DESIGN.............................................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from treatment or assessments..................................28
3.3.4.1
Discontinuation of trial treatment .........................................................................28
3.3.4.2
Withdrawal of consent to trial participation .........................................................30
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................30
4.
TREATMENTS...................................................................................................31
4.1
INVESTIGATIONAL TREATMENTS ...........................................................31
4.1.1
Identity of the Investigational Medicinal Products..........................................31
4.1.2
Selection of doses in the trial and dose modifications......................................32
4.1.3
Method of assigning patients to treatment groups...........................................32
4.1.4
Drug assignment and administration of doses for each patient......................32




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5.5
BIOBANKING ....................................................................................................50
5.6
OTHER ASSESSMENTS...................................................................................50
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................50
6.
INVESTIGATIONAL PLAN.............................................................................51
6.1
VISIT SCHEDULE.............................................................................................51
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................51
6.2.1
Screening and run-in period ..............................................................................51
6.2.2
Treatment period ................................................................................................53
6.2.3
Follow-up period and trial completion..............................................................54
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................55
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................55
7.2
PLANNED ANALYSES.....................................................................................55
7.2.1
General considerations .......................................................................................55
7.2.2
Primary endpoint analyses.................................................................................55
7.2.3
Secondary endpoint analyses .............................................................................56
7.2.5
Safety analyses.....................................................................................................56
7.2.6
Other Analyses ....................................................................................................57
7.2.7
Interim Analyses .................................................................................................57
7.3
HANDLING OF MISSING DATA ...................................................................57
7.4
RANDOMISATION ...........................................................................................57
7.5
DETERMINATION OF SAMPLE SIZE .........................................................58
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION,
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........59
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................59
8.2
DATA QUALITY ASSURANCE ......................................................................60
8.3
RECORDS...........................................................................................................60
8.3.1
Source documents ...............................................................................................60
8.3.2
Direct access to source data and documents.....................................................61
8.3.3
Storage period of records ...................................................................................62
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................62
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........62
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................62
8.6
TRIAL MILESTONES.......................................................................................62
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................63
9.
REFERENCES....................................................................................................65
9.1
PUBLISHED REFERENCES............................................................................65
9.2
UNPUBLISHED REFERENCES......................................................................66
10.
APPENDICES.....................................................................................................67
10.1
GRIP STRENGTH .............................................................................................67




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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BIA
Bioelectrical impedance analysis
BMI
Body mass index
CA
Competent Authority
CEC
Clinical event committee
CI
Confidence Interval
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
DBL
Database Lock
DILI
Drug Induced Liver Injury
DKA
Diabetic ketoacidosis
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FPG
Fasting plasma glucose
GCP
Good Clinical Practice
GLP-1
Glucagon-Like Peptide-1
GMP
Good Manufacturing Practice
GPSP
Good Post-Marketing Study Practice
GVP
Good Vigilance Practice
IB
Investigator’s Brochure


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IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMSE
Mini mental state examination
OAD
Oral antidiabetic drug
OPU
Operative Unit
PRO
Patient reported outcomes
REP
Residual Effect Period
SAE
Serious Adverse Event
SGLT-2
Sodium-glucose cotransporter 2
SMBG
Self-monitoring blood glucose
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
ULN
Upper Level of Normal
UTI
Urinary tract infection


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Type 2 diabetes mellitus (T2DM) accounts for 90 to 95% of all cases of diabetes. T2DM is a 
progressive disease with high morbidity and mortality. Recent estimates suggest that the
number of people worldwide with T2DM is currently 382 million and is expected to reach at 
least 592 million in 2035 [R14-1408].
In Japan, approximately 10 million people are strongly suspected to be affected by T2DM 
and a further 10 million people have a confirmed diagnosis of T2DM. In total 20 million 
people are suffering from either T2DM or pre-diabeties [R17-3735].
According to the Japanese Diabetes Society guideline [R17-1515], it is recommended to 
achieve the glycaemic goal of HbA1c to <7.0%, while less stringent HbA1c goal (<8.0%) is 
recommended in cases where intensive therapy is not feasible due to side effects such as 
hypoglycaemia or for other reasons, taking into consideration the age, duration of disease, 
organ damage, support structure etc..
Diet and exercise therapy should be initiated in T2DM patients. If a patient does not achieve
the glycaemic control target after continuing diet and exercise therapy for several months, 
medication therapy should be initiated. Antidiabetic medications are selected considering age, 
degree of obesity, degree of complications, liver function, renal function, insulin-distributing 
ability, and insulin resistance.
Sodium-glucose cotransporter 2 (SGLT-2) is a member of a larger group of sodium substrate 
co-transporters, the sodium-glucose co-transport 5 gene family [R05-0939]. Under 
normoglycemia, glucose is almost completely reabsorbed by SGLTs in the kidney, whereas 
the reuptake capacity of the kidney is saturated at plasma glucose concentrations higher than 
approximately 10-11 mmol/L, resulting in increasing glycosuria typically seen in patients 
with diabetes mellitus. The capacity to reabsorb glucose can be decreased by inhibition of 
SGLT-2. In humans, empagliflozin very selectively blocks glucose transport via SGLT-2 
(IC50 1.3 nmol/l), with a 5000-fold selectivity over SGLT-1 (IC50 6278 nmol/l).
Recently, the prevention of sarcopenia, a dysnutrition state accompanying aging or obesity in 
patients with diabetes, has become a new target of diabetes treatment. Sarcopenia, a 
recognised geriatric syndrome, is characterised by age-related decline of skeletal muscle plus 
low muscle strength and/or physical performance [R20-0528]. It is becoming clear that the 
risk of some symptoms/diseases such as falling, the need for nursing care, the frequency of 
complications, and death increases when the amount of muscle mass decreases beyond a 
certain level in elderly people. 
For the definition and diagnostic criteria of sarcopenia, consensus by the European Working 
Group on Sarcopenia in Older People was announced in 2010. The body composition of an 
average Asian person is apparently different from that of a European person; hence, the 
diagnostic criteria of sarcopenia for Asian people should be independently developed. With 
this perspective, consensus by the Asian Working Group on Sarcopenia in Older People was 


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subsequently announced in 2014 [R20-0528] and updated the criteria to assess and evaluate 
sarcopenia in 2019 [R20-0617].
In addition to age-related or primary sarcopenia, dysnutrition based on metabolic syndrome 
with visceral fat accumulation and decreased muscle mass, regardless of age, has been 
recognized as secondary sarcopenia. It has been shown that patients with poorly controlled 
glycaemia of diabetes have significantly less muscle volume. Furthermore, the possibility that 
this muscle loss might be exacerbated even by diabetes treatment has been indicated when 
measured as total lean mass. It has been recently clarified that sodium–glucose cotransporter 
2 (SGLT-2) inhibitors show excellent effects in treating T2DM not only by correcting 
hyperglycemia and reducing the risk of cardiovascular events, but also by reducing the body
fat mass, including visceral fat. Symptoms based on insulin resistance should be therefore 
further alleviated by this decrease in visceral fat mass. The mechanism for such a reduction in 
fat mass with the use of SGLT-2 inhibitor is believed to be a result of lipolysis in the adipose 
tissue due to activation of gluconeogenesis. There is a concern, however, that the activation 
of the gluconeogenic system should induce not only lipolysis in the adipose tissue, but also 
proteolysis in the skeletal muscle that supplies amino acids to the liver as a substrate and can 
therefore lead to sarcopenia. To address this issue, it was carried out a clinical study using 
luseogliflozin, and SGLT-2 inhibitor, for Japanese patients with T2DM. Luseogliflozin 
treatment brought about favorable changes in body composition and metabolism of 
moderately obese Japanese patients with T2DM, accompanied by body fat reduction, and 
minimal muscle and bone mineral content reduction [R19-1405]. A report on the other study 
with canagliflozin, another SGLT-2 inhibitor, was also made in which skeletal muscle mass
index also showed similar trends [P13-08159].
1.2
DRUG PROFILE
Empagliflozin received its first marketing approval in April 2014 in Australia and is 
approved for the treatment as an adjunct to diet and exercise to improve glycaemic control in 
adult patients with T2DM in more than 100 countries. In Japan, empagliflozin has received 
marketing approval on 26 Dec 2014. The preferred trade name is Jardiance®.
Based on a dedicated cardiovascular outcome trial (EMPA-REG OUTCOME®), a separate 
indication, reduction of the risk of cardiovascular death in patients with T2DM and 
established cardiovascular disease, was approved in more than 40 countries including the US, 
Canada and Australia. In over 50 countries including the EU, the indication was modified 
and/or the results included in the clinical trial section acknowledging the positive results of 
the cardiovascular outcome study. In Japan, the indication was not modified and the result is
not yet included in the local prescribing information of Jardiance® [R20-0462].
There have been no marketing withdrawals or suspensions, no failures to obtain marketing 
authorisation renewal, no restrictions placed on the distribution of the product and no clinical 
trial suspensions for any product containing empagliflozin.
Mode of action
Empagliflozin, an orally available potent selective SGLT-2 inhibitor, has been studied as part 
of a global development program including more than 15000 patients with type 2 diabetes 


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treated in clinical studies, of which more than 10000 patients were treated with 
empagliflozin, either alone or in combination with metformin, a sulfonylurea, a Peroxisome 
Proliferator-Activated Receptor γ agonist, dipeptidyl peptidase-4 inhibitors, or insulin. This 
agent lowers both the saturation threshold and the transport maximum of SGLT-2 for 
glucose, resulting in increased glycosuria, insulin-independent reduction of plasma glucose 
levels with a low risk of hypoglycaemia, and negative energy balance with weight reduction.
Key pharmacokinetic characteristics
Empagliflozin showed mainly linear pharmacokinetics in humans reaching peak levels at 
approximately 1.5 hours with a biphasic decline and a terminal elimination half-life of 
12.4 hours. Following oral administration of [14C]-empagliflozin, approximately 41.2% and 
54.4% of drug-related radioactivity was excreted in faeces and urine, respectively. None of 
the detected metabolites were major. Empagliflozin tablets can be administered with or 
without food.
Drug interactions
Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest 
that the primary route of metabolism of empagliflozin in humans is glucuronidation by the 
uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. 
Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. At 
therapeutic doses, the potential for empagliflozin to reversibly inhibit or inactivate the major 
CYP450 isoforms and UGT1 isoforms is remote. Drug-drug interactions involving the major 
CYP450 isoforms and UGT1 isoforms with empagliflozin and concomitantly administered 
substrates of these enzymes are therefore considered unlikely.
No clinically meaningful interactions were observed when empagliflozin was coadministered 
with other commonly used medicinal products. Based on results of pharmacokinetic studies 
no dose adjustment of empagliflozin is recommended when co-administered with commonly 
prescribed medicinal products.
Empagliflozin pharmacokinetics was similar with and without co-administration of 
metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, 
and simvastatin, in healthy volunteers, with or without co-administration of torasemide and 
hydrochlorothiazide in patients with T2DM. Increases in overall exposure (area under the 
curve) of empagliflozin were seen following co-administration with gemfibrozil (59%), 
rifampicin (35%), or probenecid (53%). These changes were not considered to be clinically 
meaningful.
Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, 
glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, 
hydrochlorothiazide, torasemide and oral contraceptives when co-administered in healthy 
volunteers.


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Residual Effect Period
The Residual Effect Period (REP) of empagliflozin is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamics effects still likely to be present.
Data from non-clinical studies
A comprehensive package of safety pharmacology, general toxicology, genetic toxicology, 
carcinogenicity, reproductive and developmental toxicology studies were conducted in mice, 
rats, rabbits and dogs to support the chronic administration of empagliflozin to humans. In 
addition, combination studies have been completed in rats with empagliflozin plus metformin 
or empagliflozin plus linagliptin. With the exception of the dose range finding and selected 
safety pharmacology studies, all studies were completed under good laboratory practice 
conditions.
Data from clinical studies
Empagliflozin was well tolerated in both healthy subjects and patients with T2DM up to 
maximum treatment duration of 208 weeks in completed T2DM studies Treatment with 
empagliflozin resulted in a similar percentage of overall AEs, severe AEs, and serious AEs 
compared to placebo and/or active comparators.
For a more detailed description of the empagliflozin profile, please refer to the current 
investigator’s brochure (IB) [c01678844] and Japanese package insert [R20-0462].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Japan’s population is aging, and the proportion of elderly people (≥65 years) is approximately 
30% of the total Japanese population [R20-0461]. It is reported that approximately 50% of 
patients with T2DM are currently of advanced age (≥60 years) [R20-0463].
There is no label restriction for age to use empagliflozin in Japan. However, efficacy data are
limited in the elderly population (especially ≥75 years), who tends to have a low body mass 
index (BMI).
It is well known that ageing process itself can lead to unfavourable changes related to 
deteriorations of physical status. In Japan there is increasing interest in sarcopenia in elderly 
patients with T2DM. 
Poor glycemic control in patients with diabetes may be associated with low muscle mass. 
Conversely, adequate glycemic control may increase muscle mass [R19-3669].
This study will investigate the efficacy of empagliflozin in elderly Japanese patients with 
T2DM. In addition, it will explore how it changes by treatment with empagliflozin on 
physical performance including grip strength and muscle mass.
1.4
BENEFIT - RISK ASSESSMENT
Empagliflozin is currently indicated for T2DM.


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In completed clinical studies, empagliflozin was well tolerated in non-diabetic healthy 
volunteers and patients with T2DM up to maximal treatment duration of 208 weeks. The 
frequency of overall adverse events (AEs), AEs leading to discontinuation and serious
adverse events (SAEs) were similar to placebo [c01678844].
1.4.1
Benefits
Treatment with empagliflozin 10 mg has been shown to result in clinically meaningful and 
statistically significant reductions in HbA1c, fasting plasma glucose (FPG), and in body 
weight in patients with T2DM. 
All patients taking part in the trial may derive general medical benefit from careful and close 
monitoring by medical personnel during the trial. Safety will be ensured by monitoring the 
patients for AEs both clinically and by laboratory testing, and for hypo/hyperglycaemia by 
self-monitoring blood glucose (SMBG).
1.4.2
Risks
Table 1.4.2: 1 displays the anticipated side effects of the study drugs, based on the 
mechanism of action, on the observed clinical data from ongoing studies, and on published 
clinical data.
Table 1.4.2:1 Known and potential risks of clinical relevance for the study population
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: empagliflozin
Hypoglycaemia
The risk of hypoglycaemia is 
considered to be low. 
However, when empagliflozin 
is used concomitantly with 
sulfonylurea and/or glinides, 
possibly increasing the risk of 
hypoglycaemia.
Patients in treatment with 
insulin are excluded from 
the study.
Guidance for the 
investigator provided in the 
IB [c01678844].
Blood glucose will be 
monitored with SMBG.
Volume depletion
Empagliflozin may selectively 
reduce interstitial volume with 
minimal change in 
intravascular volume
Polyuria and consequent 
dehydration and hypotension 
were identified as risks in
Guidance for the 
investigator provided in the 
IB [c01678844].
Information and 
recommendations for the 
patients provided in the 
informed consent form 
(ICF).


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Table 1.4.2:1 Known and potential risks of clinical relevance for the study population (cont.)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale for 
the risk
Mitigation strategy
patients treated with 
empagliflozin, especially in 
patients with known 
cardiovascular disease, history 
of hypotension, taking 
diuretics or other 
antihypertensive drugs, or 
elderly patients aged 75 years
and older [P19-02151].
Diabetic ketoacidosis
（DKA）
Rare cases of DKA, including 
fatal cases, were reported in 
patients treated with SGLT2-
inhibitors. In patients treated 
with SGLT2-inhibitors DKA 
may occur with lower than 
usual glucose values. The risk 
of DKA is increased in patients 
with lower than needed insulin 
intake, type 1 diabetes mellitus
(T1DM), low carbohydrate 
intake, acute illness, major 
trauma, operation, severe 
dehydration or alcohol use.
Patients with T1DM are 
excluded from the study.
Patients in treatment with 
insulin are excluded from 
the study.
Guidance for the 
investigator provided in the 
IB [c01678844].
Training will be provided to 
the investigators during 
investigator meeting. 
Information and 
recommendations for the 
patients provided in the 
ICF.
DKA is an adverse event of 
special interest (AESI). 
Cases reported as DKA or 
metabolic acidosis are 
adjudicated. (See Sections 
4.2.1 and 8.7 details are 
also described in the 
adjudication charter).
Complicated urinary 
tract infections (UTI)
Cases of complicated UTI, 
including pyelonephritis and
urosepsis were reported in
Guidance for the 
investigator provided in the 
IB [c01678844].


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Table 1.4.2:1 Known and potential risks of clinical relevance for the study population (cont.)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale for 
the risk
Mitigation strategy
patients treated with 
empagliflozin.
Information and 
recommendations for the 
patients provided in the 
ICF.
Necrotizing fasciitis of 
perineum (Fournier’s 
gangrene)
Rare cases of Fournier’s 
gangrene, including fatal cases, 
were reported in patients 
treated with SGLT2-inhibitors.
Guidance for the 
investigator provided in the 
IB [c01678844]. 
Information and 
recommendations for the 
patients provided in the 
ICF.
Hypersensitivity
The risks of allergic skin 
reactions (e.g., rash, urticaria) 
and angioedema were 
identified for empagliflozin 
based on post-marketing 
experience.
As with all drugs, the risk of 
severe and unexpected allergic 
reactions cannot be excluded.
Patients with 
hypersensitivity to 
empagliflozin are excluded 
from trial participation.
Drug-induced liver 
injury (DILI)
No risk of DILI was identified 
for empagliflozin. However, 
DILI generally can be severe 
and lead to fatal outcome or 
need of liver transplant. 
Therefore, careful monitoring 
and assessment of patients for 
potential DILI are needed.
Parameters for potential 
liver injury are included in 
the safety laboratory.
Cases of liver impairment 
are defined as an AESI. 
Severe cases of liver 
impairment are adjudicated. 
(See Sections 5.2.3, 
5.2.6.1.4 and 8.7; details 
are also described in the 
adjudication charter).
Renal safety
In clinical trials in patients 
with DM, the incidence of 
renal impairment was similar 
to placebo. An initial decrease 
of estimated glomerular 
Parameters for potential 
renal impairment are 
included in the safety 
laboratory.


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Table 1.4.2:1 Known and potential risks of clinical relevance for the study population (cont.)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale for 
the risk
Mitigation strategy
filtration rate (eGFR) was seen 
in patients treated with 
empagliflozin, which improved 
during continuous treatment or 
discontinuation of 
empagliflozin.
Cases of renal impairment, 
including those requiring 
dialysis, were reported in 
patients using SGLT2-
inhibitors. Due to the renal 
mode of action and risk of 
volume depletion, the renal 
safety should be monitored.
Cases of renal impairment 
are defined as an AESI (see 
Sections 5.2.3 and 
5.2.6.1.4).
Trial procedures
The patients who take 
placebo have a higher 
probability of treatment 
failure, i.e., of increase 
in HbA1c.
50% of patients will receive 
placebo.
This study will have criteria 
for rescue therapy (refer to 
Section 4.2.2) and patient
discontinuation from study 
medication to ensure an 
adequate treatment in case 
of any clinical concern 
(refer to Section 3.3.4).
Hyperglycaemia
50% of patients will receive 
placebo and these patients thus 
have a higher probability of 
treatment failure, i.e., of 
increase in FPG and HbA1c.
Blood glucose will be 
monitored with SMBG.
Appropriate 
inclusion/exclusion criteria 
of HbA1c and FPG values,
as well as criteria for rescue 
therapy and patient 
discontinuation will ensure 
an adequate treatment in 
case of any clinical 
concern.


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Table 1.4.2:1 Known and potential risks of clinical relevance for the study population (cont.)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Bruising and pain 
commonly experienced 
in association with 
blood sampling
The frequency of blood 
sampling during the whole 
course of the trial is not 
excessive.
Other risks
Administration of 
Placebo
If the patient is randomised to 
receive a placebo, patients may 
not be able to control their 
blood glucose sufficiently 
during the course of the trial.
If the rescue criteria are 
met, rescue therapy will be 
initiated at the
investigator’s discretion. If 
the rescue criterion is met
and/or investigator judges
necessary, the patient will 
receive rescue therapy.
Known and potential risks in healthy volunteers and patients with T2DM:
For the main risks, please refer to Table 1.4.2:1.
In general there was a small increase in frequency of urinary tract infection (UTI) compared 
to placebo. There was an increase in frequency of genital infections with the use of 
empagliflozin. There was a small increase in total cholesterol, low-density lipoprotein 
cholesterol and high-density lipoprotein cholesterol and no significant changes in 
triglycerides. No clinically relevant changes in electrolytes were observed with empagliflozin 
[c01678844].
Other risks to the patients are the risks inherent to any clinical trial such as unexpected 
adverse clinical or laboratory events.
For more information about clinical efficacy data and adverse drug reactions of empagliflozin
reference is made to the current version of the empagliflozin IB [c01678844] and the local 
prescribing information of Jardiance® [R20-0462].
1.4.3
Discussion
All patients taking part in the trial may derive general medical benefit from careful and close 
monitoring by medical personnel during the study. Safety will be ensured by monitoring the 
patients for AEs both clinically, by laboratory testing, and for hypo/hyperglycaemia by 
SMBG.


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Patients who are randomised to placebo group will not benefit from efficacy of 
investigational drug, but they will continue to receive their standard of care that has been 
provided before participating in the trial.
During the study, in case blood glucose level meets rescue criteria, patient will receive rescue 
therapy to ensure their safety (see Section 4.2.1). 
Given the safety profile of empagliflozin established in patients with T2DM, the careful 
monitoring to be conducted during the study visits, and the blood glucose monitoring to be 
performed by the patients at home during the study, the sponsor considers the risks for the 
participating patients will be minimised and justified when compared with the potential 
benefits from this trial.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this study is to assess the efficacy of empagliflozin 10 mg after 
52 weeks compared to placebo in elderly patients with T2DM.
Secondary objectives are to explore if empagliflozin has any impact on patient physical 
condition compared to placebo in elderly patients with T2DM.
2.1.2
Primary endpoint(s)
The primary endpoint in this study is the change in HbA1c from baseline after 52 weeks of 
treatment. HbA1c will be measured in the units of % and mmol/mol at all clinical visits; the 
primary endpoint will use units of %.
2.1.3
Secondary endpoint(s)
Secondary endpoints are the following safety endpoints:
•
Change of muscle mass from baseline to Week 52
•
Change of body fat measurement from baseline to Week 52
•
Change of lean body mass from baseline to Week 52
•
Change of total body water from baseline to Week 52
•
Change of bone mineral content from baseline to Week 52
•
Change of skeletal muscle index from baseline to Week 52
•
Change of grip strength from baseline to Week 52
•
Change of time in the 5-time chair stand test from baseline to Week 52
Please refer to Section 5.1.2, 5.1.3, and 5.1.4, and Appendix 10.1, 10.2, and 10.3 how each 
item will be measured and evaluated.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a randomised, double-blind, placebo-controlled, multi-centre trial. The trial design is 
illustrated in Figure 3.1: 1.
Approximately 128 male and female eligible patients with T2DM will be randomised (1:1) in 
the study in Japan. 
Each randomised patient will be treated with oral empagliflozin or placebo daily in addition to
standard of care. Patients will receive the trial medication for 52 weeks. An End of study 
(EOS) visit will be performed 7 days after the End of Treatment Visit (EOT).
EOT: end of treatment, EOS: end of study
Figure 3.1: 1 Overall study design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Since efficacy data is limited in the elderly population (especially ≥75 years) compare to 
placebo and there are no studies that have thoroughly investigated how empagliflozin affects 
muscle mass, grip strength, lower limb function, and physical activity in the elderly patient 
compared to placebo, the trial design that compare empagliflozin to placebo is appropriate.
As the patients who participate in the study will continue to receive stable standard of care 
that has been provided prior to screening, and will receive rescue medication if indicated, a 
placebo-controlled trial is justified. Since patients will continue their baseline treatment, the 
risk of significant hyperglycaemia is low during the 52 weeks. Additionally, rescue therapies 
can be applied during this time frame to assure patient safety.


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The intention of the run-in period is to ensure central laboratory data availability for 
randomisation, to assess the compliance of the trial medication administration, to ensure 
fasting glucose level is stable by a regular monitoring of blood glucose with a SMBG, and to 
ensure that the patient can continue diet and exercise and background medication according 
to investigator’s instructions.
A double-blind design is adopted in order to minimise bias to evaluate the efficacy and safety 
of empagliflozin in comparison to placebo. The randomised treatment period is planned for 
52 weeks which is considered a relevant observation time for the investigation of the defined 
endpoints of efficacy and safety, including the variation of physical activity, in special 
physical activity and grip strength in patients over 75 years of age, in elderly patients in long-
term treatment with empagliflozin, .
The one-week follow-up period, after treatment, is considered to be sufficient as the REP of
empagliflozin is 7 days.
3.3
SELECTION OF TRIAL POPULATION
Approximately 128 patients are planned to be randomised in Japan and participation of 
approximately 20 sites is planned. Screening of patients for this trial is competitive, i.e., 
screening for the trial will stop at all sites at the same time once a sufficient number of 
patients has been screened. Investigators will be notified about screening completion and will 
then not be allowed to screen additional patients for this trial.
A log of all patients enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the clinical trial manager (CT Manager) should 
be contacted immediately.
3.3.1
Main diagnosis for trial entry
The trial will be performed in the elderly Japanese patients with T2DM. Two populations will 
be recruited; patients who are treatment naïve and have insufficient glycaemic control, and 
patients who have insufficient glycaemic control despite of stable antidiabetic treatment for 
12 weeks (any thiazolidinedione therapy has to be unchanged for 18 weeks).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Japanese1 patients with diagnosis of T2DM prior to informed consent
                                                
1 Japanese is defined as patient has parents who are Japanese.


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2. HbA1c ≥7.0% and ≤10.0% for patients at Visit 1 (screening)
If the patient is on treatment with oral antidiabetic drug(s) potentially associated with
severe hypoglycaemia (e.g., sulfonylurea or glinides), the following HbA1c value is used
as criterion
1) HbA1c ≥7.5% and ≤10.0% for age ≥65 and <75
2) HbA1c ≥8.0% and ≤10.0% for age ≥75
3. Patients on diet and exercise regimen who are drug-naïve2 or on treatment with any oral
antidiabetic drug (OAD) other than Glucagon-Like Peptide-1 (GLP-1) agonists and
SGLT-2 inhibitor. Antidiabetic therapy has to be unchanged for 12 weeks prior to
randomisation (any thiazolidinedione therapy has to be unchanged for at least 18 weeks
prior to informed consent).
4. Age ≥65 years at informed consent
5. BMI ≥22 kg/m2 at Visit 1 (screening)
6. Male or post-menopausal3 female patients
7. Patient signed and dated written informed consent in accordance with ICH-GCP and local
legislation prior to admission to the trial
3.3.3
Exclusion criteria
1. Uncontrolled hyperglycaemia with a fasting glucose level >200 mg/dL (>11.1 mmol/L)
during run-in period
2. Treatment with insulin within 12 weeks prior to informed consent
3. Impaired cognitive ability as supported by MMSE-J (defined as ≤23) and verified by the
investigator at screening
4. Acute coronary syndrome (ST-elevation myocardial infarction [STEMI], non-STEMI,
and unstable angina pectoris), stroke or transient ischemic attack within 12 weeks prior to
informed consent
5. Indication of liver disease, defined by serum levels of either alanine aminotransferase
(ALT [SGPT]), aspartate aminotransferase (AST [SGOT]), or alkaline phosphatase
(ALP) above 3 x upper limit of normal (ULN) as determined during screening and run-in
period
6. Impaired renal function, defined as eGFR <45 mL/min/1.73 m2 (severe renal impairment,
Modification of Diet in Renal Disease [MDRD] formula) as determined during screening
and run-in period
7. Low grip strength defined as <28 kg for male or as <18 kg for female at screening
8. Short length of calf circumference defined as <34 cm for male or 33 cm for female at
screening
9. Inability to perform 5 times chair stand test according trial protocol
10. Already confirmed diagnose of sarcopenia (based on AWGS algorithm 2019)
2 drug-naïve is defined as no antidiabetic drugs for at least 12 weeks prior to informed consent.
3 Menopause is a point in time 12 months after a woman's last period.


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11. Known history of diabetic ketoacidosis
12. Known contraindications to empagliflozin according to the Japanese label
13. Disorders causing haemolysis or unstable red blood cells
14. Any previous (within 2 years prior to informed consent) or planned bariatric surgery (or 
any other weight loss surgery) or other gastrointestinal surgery that induce chronic 
malabsorption
15. Medical history of cancer (except for resected non-invasive basal cell or squamous 
carcinoma) and/or treatment for cancer within the last 5 years
16. Treatment with anti-obesity drugs within 12 weeks prior to informed consent or any other 
treatment at the time of screening (i.e., surgery, aggressive diet regimen (e.g., low-
carbohydrate diet), etc.) leading to unstable body weight
17. Current treatment with systemic steroids (other than inhaled or topical steroids) at 
informed consent or change in dosage of thyroid hormones within 6 weeks prior to 
informed consent or any other uncontrolled endocrine disorder except T2DM
18. Known or suspected allergy or hypersensitivity to trial products or related products (e.g.,
SGLT-2 inhibitors)
19. Alcohol or drug abuse prior to informed consent that would interfere with trial 
participation or any ongoing condition leading to a decreased compliance to trial 
procedures or trial drug intake, in the opinion of the investigator
20. Intake of an investigational drug in another trial within 30 days prior to Visit 1 or 
participation in the follow-up period of another trial (participation in observational studies 
is permitted)
21. Any other clinical condition that, in the opinion of the investigator, would jeopardise 
patient’s safety while participating in this clinical trial
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and electronic case report form (eCRF). If 
applicable, consider the requirements for adverse event collection reporting (please see 
Sections 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:


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∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures
and, in the opinion of both, the investigator and sponsor representative, is not willing or
able to adhere to the trial requirements in the future.
∀
The patient needs to take concomitant medication that interferes with the investigational
medicinal product. Please refer to Sections 4.2.1 and 4.2.2
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery,
adverse events, or other diseases).
∀
Introduction of rescue therapy due to hyperglycaemia as described in Section 4.2.1 does
not lead to sufficient treatment efficacy (rescue criteria still met). In this case, the reason
for discontinuation will be classified as “lack of efficacy”
∀
Occurrence of hypoglycaemia that may put the patient at risk with continued participation
(e.g., repeated hypoglycaemic episodes)
∀
Medically significant events that may put the patient at risk with continued participation
(i.e., DKA, severe UTI including urosepsis, Fournier’s gangrene).
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see Section 4.1.4.
Patients who discontinue treatment prematurely will be followed up until the end of the trial 
as outlined in the flowchart and Section 6.2.2.
A patient can be discontinued from the trial after discussion between the sponsor and the 
investigator if the eligibility criteria are being violated.
Patients who discontinue or withdraw from the study during placebo run-in period and before 
being randomised at Visit 3 will be considered a run-in failure. They have to be recorded as 
in eCRFs and no further follow-up is required (except for AEs, if needed).
Patients who are discontinued from the study after randomisation (Visit 3) and before 
completing 52 weeks of treatment will be considered as early discontinuations and the reason 
for the discontinuation must be recorded in the eCRFs. The reason will be included in the 
trial database and reported. If determined by the investigator as necessary for the patient’s 
safety, a new antidiabetic medication regimen can be started immediately after 
discontinuation and must be recorded in the eCRFs. In this case, EOT visit must be 
performed before taking any new antidiabetic drug. If new efficacy/safety information 
becomes available, Boehringer Ingelheim will review the benefit-risk-assessment and, if 
needed, pause or discontinue the trial treatment for all patients or take any other appropriate 
action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the flowchart and Section 6.2.3.


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3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, and explain the scientific relevance of their data 
even if he/she discontinue the trial treatment as well as explain the options for continued 
planned visit up to follow-up after trial treatment discontinuation, please see Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.
3. Deviations from Good Clinical Practice (GCP), the trial protocol, or the contract 
impairing the appropriate conduct of the trial.
Further follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The trial medication will be provided by Boehringer Ingelheim Pharma GmbH & Co.KG.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1
Empagliflozin
Substance:
Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim GmbH & Co.KG
Unit strength:
10 mg
Posology:
1 tablet once daily
Mode of administration:
Oral
Table 4.1.1: 2
Placebo to empagliflozin
Substance:
Placebo to empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim GmbH & Co.KG
Unit strength:
-
Posology:
1 tablet once daily
Method and route of administration:
Oral
Standard of care will not be provided as part of the clinical trial supplies.


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4.1.2
Selection of doses in the trial and dose modifications
Empagliflozin 10 mg and 25 mg are approved in Japan for the treatment of T2DM.
In the ongoing Japanese post-marketing study, approximately 97% of patients who started 
treatment at 10 mg continue treatment with empagliflozin 10 mg for over a year without 
uptitration. Therefore, only empagliflozin 10 mg will be given in this study [c15144621]. 
4.1.3
Method of assigning patients to treatment groups
When a patient is confirmed eligible for entry into the randomised double-blind treatment 
period, treatment assignment will be by means of a third-party phone/web-based 
randomisation at Visit 3. This will involve the use of interactive response technology (IRT). 
To facilitate the use of the IRT, the investigator will receive an IRT manual including all 
necessary instructions for using the IRT. IRT manual will be available in the ISF. 
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to treatment groups of empagliflozin 10 mg or placebo to empagliflozin according to a 
randomisation plan in a 1:1 ratio at visit 3 via IRT. The randomisation will be stratified by 
HbA1c (<8.5% vs. ≥8.5%) as determined from the blood sample taken at Visit 1 and age 
(≥65 to <75 years vs. ≥75 years) at Visit 1. For further details please refer to Section 7.4.
Note that the medication number is different from the patient number (the latter is generated 
during screening via the IRT System). The assigned medication number will be entered in the 
eCRF, and the corresponding medication kit should be given to the patient. Using this 
procedure, relevant parties will be blinded to the treatment group assignment.
4.1.4
Drug assignment and administration of doses for each patient
Eligible patients will be randomised to empagliflozin 10 mg or placebo. Medication will be 
dispensed in a double-blind manner. The empagliflozin dosing is described in Table 4.1.4:1.
Patients will be assigned a placebo run-in kit at the beginning of the placebo run-in period 
(Visit 2), and this kit will contain sufficient medication for the run-in period within visit 
window. Dispensing of kits for the double-blind treatment period will begin at Visit 3 and 
occur on 5 occasions over a period of 52 weeks. 
From the start of the placebo run-in period (Visit 2), patients should be instructed to take their 
trial medication, 1 tablet with water, once daily in the morning. To ensure a dose interval of 
about 24 hours, the medication should be taken at the same time each day. If a dose is missed 
by more than 12 hours, that dose should be skipped and the next dose should be taken as 
scheduled. No double doses should be taken, and dose reductions are not permitted. 
Empagliflozin can be taken with or without food.
Patients should be instructed not to take their trial medication on the morning of study visits 
as they will be dosed while patient is in the trial site. Patients who fail to do so should have 
the visit rescheduled as soon as possible, ideally on the following day. Visits should be 
routinely scheduled in the morning, at approximately the same time of day for each visit. The 


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actual date and time of administration of the medication at the trial visit will be recorded in 
the eCRF.
Patients will continue with their standard of care throughout the entire study.
Table 4.1.4: 1
Empagliflozin dose administration schedule 
Total units per dose
Timing
Placebo run-in period (open-label)
All patients
matching placebo
1 tablet
once daily, 
morning
Randomised treatment period (double-blind)
10 mg
active drug
1 tablet
once daily, 
morning
or
Placebo
matching placebo
1 tablet
once daily, 
morning
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis
or with any other interest in this double-blind trial will remain blinded with regard to the 
randomised treatment assignments until after database lock.
The access to the randomisation code will be kept restricted until its release for analysis.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the principal investigator via IRT. It must only be 
used in an emergency situation when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants. The reason for unblinding must be documented in the source documents and
appropriate eCRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s pharmacovigilance (PV) group 
to access the randomisation code for individual patients during trial conduct. The access to 
the code will only be given to authorised PV representatives for processing in the PV 
database system and will not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated contract 
research organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed 
via an IRT system, which will also monitor expiry dates of supplies available at the sites.


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For details of packaging and the description of the label, refer to the ISF.
The study medication will consist of packs labelled with the trial identification and 
medication kit number. Each pack will contain an appropriate number of empagliflozin 
tablets or placebo to empagliflozin with some reserve (see below) for dosing until the next 
scheduled visit.
The kit for placebo run-in period, assigned to all patients successfully completing Visit 2, will 
contain 21 tablets (i.e., sufficient supply for 2 weeks, with 1 week in reserve). Each kit for 
double-blind treatment period will contain 35 tablets (i.e., sufficient supply for 4 weeks, with
1 week in reserve). 
At Visit 3, the patient will receive 1 kit for double-blind treatment period. The patient will 
receive 2 kits at Visit 4, 3 kits at Visit 5 and 6, and 4 kits at Visit 7.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the clinical research 
associate (CRA) or CT Manager (as provided in the list of contacts) must be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the institutional review board (IRB)
∀
Availability of a signed and dated clinical trial contract between the sponsor and the
investigational site,
∀
Notification to the Pharmaceuticals and Medical Devices Agency,
∀
Availability of the curriculum vitae of the principal investigator,
∀
Availability of a signed and dated clinical trial protocol,
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial


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patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the clinical trial protocol and reconcile all 
investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Throughout the duration of the trial, patients should continue to take their previous 
antidiabetic therapy as permitted by trial protocol, including acceptable OADs with the 
exception of SGLT-2 inhibitors (treatment with insulin and GLP-1 agonists is excluded as 
well, see Section 4.2.2). This background medication of OADs should remain unchanged 
throughout the study. The background medication will not be provided as part of the clinical 
trial supplies.
The patients can take their background medication as they are used to and should have the 
same habits of dosing throughout the trial. Morning dose of OADs and study medication 
should be taken after the visits blood samples are taken.
Hyperglycaemia
Rescue medication can be given if the criterion below is met during the run-in period at the
investigator’s discretion. Patients who need rescue medication prior to Visit 3 are not eligible 
for randomisation. Please see Section 3.3.4.1:
-
The patient has a glucose level >200 mg/dL (>11.1 mmol/L) after an overnight fast
Rescue medication, for the treatment of hyperglycaemia, can be initiated during the double-
blind treatment period of the trial (i.e., from Visit 3 to Visit 8) at the investigator’s discretion 
if the criterion below is met:
-
The patient has a glucose level >200 mg/dL (>11.1 mmol/L) after an overnight fast
The above results should be confirmed, meaning that there is a minimum of two 
measurements, at least second measurement should be performed at the investigational site
after an overnight fast (central or local laboratory testing is allowed), and on a different day 
to the initial measurement.
In order to expedite the rescue medication initiation decision, the investigator may confirm 
the results (second measurement) at the local or commonly used laboratory. This procedure 
with its results should be documented in the patient’s medical chart. Before initiation of 
rescue therapy a FPG sample should be drawn and sent to the central lab for analysis.


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If the above criteria are met, the initiation of rescue medication is at the Investigator’s 
discretion, based on the patients’ current clinical condition (e.g., ongoing illness etc.). If dose 
of standard of care increase, it should be recognised as rescue medication.
Rescue medication can be used from when it is initiated until the end of the trial. The choice 
of rescue medication and its dosage will be left to the discretion of the investigator excluding 
SGLT-2 inhibitors. Regardless of the choice made, rescue medication should be taken in 
accordance with the prescribing information of that respective medication, taking into 
account potential contraindications.
In the case of hypoglycaemic event that may put patient on risk (e.g., repeated symptomatic 
hypoglycaemic events or severe hypoglycaemic event), appropriate adjustment of oral 
antidiabetic therapy such as a dose reduction/discontinuation of ongoing rescue medication
should be initiated.
If, in the investigator’s clinical opinion, no further effect from the rescue medication is 
anticipated, and the patient’s hyper- or hypoglycaemia cannot be controlled, the patient 
should be discontinued from the trial as specified in Section 3.3.4.
Any rescue medications should be recorded in the source documents and on the appropriate 
pages of the eCRF.
Rescue medication will not be provided as part of the clinical trial supplies.
Special attention must be paid to the prevention of DKA. All patients must be made aware of 
this risk and need to be instructed to contact the investigator or other healthcare professional 
in case of symptoms of DKA. 
In case of a suspected DKA the investigator should ensure that appropriate tests are 
performed at the earliest opportunity according to guidelines in Japan, such as a blood gas 
test (i.e., pH, bicarbonate, anion gap, potassium, blood glucose, etc; the results will be 
collected on the relevant page of the eCRF) and that the patient is appropriately treated (i.e., 
hospitalised or referred to emergency treatment) according to treatment guidelines in Japan.
Any additional treatment, that does not qualify as a rescue medication, and is considered 
necessary for the patient's welfare may be given at the discretion of the investigator.
Exceptions to this are the restrictions described in Section 4.2.2. 
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Patient can continue any standard of care if patient used it before participating in the trial.
Antidiabetic therapy has to be unchanged for 12 weeks prior to randomisation (for 
thiazolidinedione, therapy has to be unchanged for at least 18 weeks prior to informed 
consent). 
SGLT-2 inhibitors (other than blinded study medication), Insulin, GLP-1 agonists, and any 
other diabetes drugs other than standard of care will be prohibited during the course of the 
trial.


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Treatment with anti-obesity drugs or systemic steroids will be prohibited due to their 
influence on glucose metabolism and muscle mass. However, intermittent or short-term use 
(i.e., ≤2 weeks duration) of systemic steroids will be permitted as well as therapy with non-
systemic steroids such as inhaled or local steroids. Furthermore, for patients taking thyroid 
hormones and testosterone, any change in the dose should be avoided. If dose changes do 
occur, then they should be recorded in the source documents and in the eCRF.
4.2.2.2
Restrictions on diet and life style
Through the clinical trial, patients will receive diet and exercise counselling by a diet 
specialist or trained trial staff. The counselling will be based on the diet and exercise 
recommendations of The Japanese Diabetes Society. The patients will be reminded to follow 
the agreed diet and exercise plan. 
To avoid DKA, extreme diets (e.g., ketogenic diets) have to be avoided.
Through the double-blind treatment period, the investigator and trial staff will instruct the 
patient to drink appropriate volume of water every day. and it must be ensured particularly in 
the beginning of use of investigational drug, and caution must be continued during use.
Herbal or nutritional supplements with effect on blood glucose are prohibited throughout 
trial. Patients using/requiring these supplements should be discontinued from the trial, see 
Section 3.3.4.1.
Patients also should not take investigational drug in another trial within 30 days prior to 
Visit 1 in this trial. Furthermore, patients should not participate in another trial (involving an 
investigational drug) after discontinuing medication in this trial for the remaining trial period.
There are no other restrictions on diet and lifestyle.
4.2.2.3
Contraception requirements
Only male and post-menopausal female participate in this trial. Therefore, there are no 
special contraception requirements to be followed.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor.
Treatment compliance (%) =
Number of tablet actually taken # 100
     Number of tablet which should have been taken as 
directed by the investigator


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If the compliance is smaller than 80% or larger than 120%, site staff will explain a reason in 
eCRF and remind to the patient the importance of treatment compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
HbA1c
HbA1c is considered appropriate to evaluate the efficacy as primary endpoint because HbA1c 
is an internationally accepted endpoint of stable glycaemic control.
Blood samples for the determination of HbA1c at the central laboratory will be taken at all 
the visits except Visit 2, the blood sample can be taken at any time during the visit. For the 
determination of HbA1c, 3 mL of blood will be collected. The samples will be analysed at a 
central laboratory having a National Glycohaemoglobin Standardisation Program (NGSP) 
Level I certificate. Further details about sample handling, shipment, and assay procedures can 
be found in the ISF (Lab manual).
5.1.2
Grip strength
Grip strength is an important function of upper extremities for elderly population, and it is 
used for the assessment of sarcopenia in AWGS 2019 [R20-0617]. The Sarcopenia Frail 
Society of Japan recommends to use this criterion of AWGS. Therefore, grip strength is a 
parameter to evaluate physical condition and assess sarcopenia. 
The procedure to measure grip strength is described in Appendix 10.1.
5.1.3
Lower limb function
Lower limb function for elderly population is an important function, and it is used for the 
assessment of sarcopenia in AWGS 2019 [R20-0617]. The Sarcopenia Frail Society of Japan
recommends to use this criterion of AWGS. As same as grip strength, time of chair stand test 
is a parameter to evaluate physical condition and assess sarcopenia.
The procedure to implement chair stand test is described in Appendix 10.2.
5.1.4
Body composition
Body composition assessment is being increasingly recognised as an important tool in the 
evaluation of nutritional status in a variety of clinical conditions and for fitness assessment in 
both research and clinical settings and muscle mass is an important parameter for diagnosing 
sarcopenia in AWGS 2019 [R20-0617].
Bioelectrical impedance analysis (BIA) is a commonly used method for estimating body 
composition and it assesses body composition by passing a very small current through the 
body and assessing differences in impedance caused by the fact that fat and lean tissues have 
different electrical properties. Since all lean tissue in the limbs is either bone or muscle use of 
segmental BIA can provide a good proxy for skeletal muscle mass by assessing the 
composition of limbs alone. BIA is a valid tool for the assessments of total body and 


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segmental body composition in the general middle-aged population, particularly for the 
quantification of body lean mass [R20-0698].
The body composition planned to be measured by using BIA includes muscle mass (kg), 
body fat percentage (%), body fat mass (kg), lean body mass (fat-free mass) (kg), total body 
water (kg), and bone mineral content (estimated bone mass) (kg). Skeletal muscle index is 
calculated by dividing the limb muscle mass (kg) by the square of the height (m2). The 
procedure to measure body composition is described in Appendix 10.3 and instruction in ISF.


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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
Targeted physical examination will include evaluation of organ systems associated with 
AE(s) symptoms or laboratory abnormalities.
Measurement of height calf circumference, and body weight will be performed at the time 
points specified in the flowchart. For calf circumference, the maximum non-dominant calf 
circumference is measured.
The results must be included in the source documents available at the site. 


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5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling. Clinically relevant abnormal findings as judged by the investigator will be reported 
as AE (see Section 5.2.6).
Vital signs include systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must be 
included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1, 5.2.3: 2 and 5.2.3: 3.
For the sampling time points please see the flowchart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Safety laboratory samples (except screening) will be collected after a full overnight fast 
(nothing to eat or drink except water for at least 10 hours) and before administration of 
background antidiabetic therapies and investigational drug as described in the flowchart and 
Section 6. The blood sample at Visit 1 (screening visit) can be taken with the patient in a 
fasted or nonfasted state.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the ISF (lab manual). 
It is the responsibility of the investigator to evaluate the laboratory reports. Clinically relevant 
abnormal findings as judged by the investigator will be reported as AE (please refer to 
Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (see Section 5.2.6.1 and the DILI checklist provided in the ISF). The amount of 
blood taken from the patient concerned will be increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.2.3: 1
Safety laboratory tests – Haematology
Visit
1
2
3
4
5
6
7
8
EOT
9
EOS
Study week
-3
-2
0
4
12
24
36
52
53*
Haematocrit
X
X
X
X
X
X
X
Haemoglobin
X
X
X
X
X
X
X
Red Blood Cells 
(RBC)/Erythrocytes
X
X
X
X
X
X
X
WBC/Leukocytes
X
X
Platelet 
Count/Thrombocytes
X
X
Differential Automatic 
(relative and absolute 
count): Neutrophils, 
Eosinophils, Basophils, 
Monocytes, Lymphocytes
X
X
* EOS should be done 1 week after Visit 8 or EOT
Table 5.2.3: 2
Safety laboratory parameters – Clinical Chemistry
Visit
1
2
3
4
5
6
7
8
EOT
9
EOS
Study week
-3
-2
0
4
12
24
36
52
53*
Glucose (fasted)
X
X
X
X
X
X
X
X
Lipase
X
X
X
X
X
X
X
AST  (aspartate 
transaminase, SGOT)
X
X
X
X
X
X
X
ALT (alanine transaminase, 
SGPT)
X
X
X
X
X
X
X
Alkaline phosphatase
X
X
X
X
X
X
X
Bilirubin total
X
X
X
X
X
X
X
Direct bilirubin, if bilirubin 
total increased
X
X
X
X
X
X
X
Total Protein
X
X
X
X
X
X
X
Albumin
X
X
X
X
X
X
X
Potassium
X
X
X
X
X
X
X
Sodium
X
X
X
X
X
X
X
Bicarbonate
X
X
X
X
X
X
X
Creatinine
X
X
X
X
X
X
X
Blood urea nitrogen
X
X
X
X
X
X
X
Calcium
X
X
X
Inorganic phosphorous
X
X
Uric acid
X
X
X
Cholesterol (total)
X
X
HDL cholesterol
X
X
LDL cholesterol
X
X
Triglycerides
X
X
Thyroid stimulation 
hormone
X
* EOS should be done 1 week after Visit 8 or EOT


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Table 5.2.3: 3
Safety laboratory parameters – urine
Visit
1
2
3
4
5
6
7
8
EOT
9
EOS
Study week
-3
-2
0
4
12
24
36
52
53*
Protein
X
X
X
X
X
X
X
Ketone
X
X
X
X
X
X
X
Leucocytes
X
X
X
X
X
X
X
Erythrocytes
X
X
X
X
X
X
X
* EOS should be done 1 week after Visit 8 or EOT
If the investigator needs safety lab (e.g., to follow an ongoing AE), he/she can perform it in 
the local lab. The results will not be captured in the eCRF. Clinically significant lab 
abnormalities will be reported as AE (see Section 5.2.6).
Estimate glomerular filtration rate
The estimated glomerular filtration rate (eGFR) will be derived from serum creatinine* 
values based on the standard MDRD formula:
eGFR (ml/min/1.73 m2) = 175 x [Screatinine (umol/L)/88.4]-1.154 x [age]-0.203 x [0.742 if 
patient is female] x [1.212 if patient is of African origin]
*: creatinine methods calibrated to an IDMS reference method
NT-proBNP will be measured at screening as part of baseline examinations to characterise 
the patient population in the trial.
5.2.4
Electrocardiogram
The 12-lead electrocardiogram (ECG) must be administered by a qualified technologist and 
results will be recorded as scheduled in the flowchart. The investigator or a designee will 
evaluate whether the ECG is normal or abnormal and assess clinical relevance. ECGs may be 
repeated for quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.5
Other safety parameters
Self-monitoring of blood glucose
All patients will be provided at Visit 2 with SMBG equipment and supplies for use at home 
throughout trial participation. Instruction on the proper use of the SMBG equipment will be 
provided by the trial staff. The patient will be asked to record the results of the SMBG test on 
a SMBG test log and will submit it to site staff at every visit. The log will be included in the 


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patients source document file. Clinically relevant abnormal findings as judged by the 
investigator will be reported as AE (see Section 5.2.6). Only in the case of linked AEs or of 
hypoglycaemia events, the single SMBG values will be recorded in the eCRF. 
During the run-in period, SMBG test is recommended to be done daily in the fasted state
(before breakfast, i.e., after an overnight fast) and at any time the patient is symptomatic, i.e., 
experiences signs/symptoms of hyper- or hypoglycaemia. If during this period, results of a 
fasting SMBG test reveal blood glucose levels meeting rescue criteria (see Section 4.2.1), the 
patient should contact the site and the investigator should follow the instructions given in 
Section 4.2.1. During the double-blind treatment period, SMBG test is recommended to be 
done daily but be performed at least once a week in the same way as in the run-in period.
For the 1 week follow-up period, after the Visit 8 (EOT) up to a time period as judged by the 
investigator, SMBG test should be performed at least once daily in the fasted state and any 
time the patient is symptomatic, i.e., experiences signs/symptoms of hyper- or 
hypoglycaemia. If result of SMBG test reveals blood glucose of >200 mg/dL (11.1 mmol/L) 
after an overnight fast the patient should contact the site to assess if a change in his/her 
T2DM treatment is required.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀Changes in vital signs, ECG, physical examination, data on SMBG log and laboratory 
test results, if they are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,


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-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
AEs which possibly lead to disability will be reported as SAEs as “deemed serious for any 
other reason”.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture system. A 
copy of the latest list of “Always Serious AEs” will be provided upon request. These events 
should always be reported as SAEs as described in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.6.1.4
Adverse events of special interest
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g., the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s PV Department within the same timeframe that 
applies to SAEs, please see Section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 


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∀
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold
ULN measured in the same blood draw sample, or
∀
aminotransferase (ALT, and/or AST) elevations ≥5 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Diabetic ketoacidosis (DKA)
The risk of DKA must be considered in the event of non-specific symptoms such as nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, difficulty in breathing, confusion, and 
unusual fatigue or sleepiness.
In case of a suspected DKA, the investigator should ensure that appropriate tests are 
performed at the earliest opportunity according to Treatment Guide for Diabetes [R17-1515], 
such as blood tests (glucose, blood urea nitrogen/creatinine, and ketone) and blood gas test 
(pH, bicarbonate, anion gap). The results will be collected on the relevant page of the eCRF.
Investigators should also differentiate deteriorating ketosis/DKA from any mild to moderate 
increase of ketones which may be seen due to the mechanism of action of empagliflozin, 
especially in the fasted state (e.g., in the morning). 
Due to its mechanism of action, empagliflozin may potentially modify the clinical
presentation of DKA which may occur at lower plasma glucose levels in patients with DM. 
The diagnosis of DKA in these patients can be based on arterial pH ≤7.30, serum bicarbonate 
levels <15 and measurement of serum betahydroxybutrate levels. Other diagnostic criteria 
which can support the diagnosis of DKA are urine ketones and anion gap >10.
Investigators should note that not all criteria mentioned above need to apply for the diagnosis 
of DKA, and clinical judgment should also be taken into consideration.
Decreased renal function
Decreased renal function is defined by a creatinine value showing a ≥2 fold increase from 
baseline and is above the ULN.
For the AESI “decreased renal function” the patient needs to be followed-up appropriately 
based on local clinical guidance.


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Events leading to lower limb amputation
Any event leading to a lower limb procedure of amputation, auto-amputation or 
disarticulation as defined below is considered as an AESI.
Amputation is a resection of a limb through a bone. Disarticulation is a resection of a limb 
through a joint. Auto-amputation is a spontaneous separation of non-viable portion of the 
lower limb.
Not included in this definition are debridement (removal of callus or dead tissue), procedures 
on a stump (like stump revision, drainage of an abscess, wound revision etc.) and other 
procedures (e.g., nail resection or removal) without a concomitant resection of a limb 
(amputation or disarticulation). (International Working Group of Diabetic Foot, 2015).
Each lower limb amputation, disarticulation, or auto-amputation should be reported 
separately. The SAE report should include the date of the procedure, the level of amputation 
or disarticulation, the medical condition(s) leading to the procedure and if the patient had 
some of the known risk factor(s) for lower limb amputation.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g., pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not
exposed to drugs (e.g., Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e., greater effect size if the dose is increased,
smaller effect size if dose is reduced).


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of
drug administration; an allergic reaction weeks after discontinuation of the drug
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g., after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g.,
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of study
(EOS):
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial:
the investigator does not need to actively monitor the patient for new AEs but should only
report any occurrence of cancer and trial treatment related SAEs and trial treatment
related AESIs of which the investigator may become aware of by any means of
communication, e.g., phone call. Those AEs should be reported on the BI SAE form (see
Section 5.2.6.2.2), but not on the eCRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form (within 24 hours) to the sponsor’s unique entry 
point (country specific contact details will be provided in the ISF). The same timeline applies 
if follow-up information becomes available. In specific occasions, the investigator could 
inform the sponsor upfront via telephone. This does not replace the requirement to complete 
and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 


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be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
Pregnancy is unlikely to occur as the trial includes only post menopausal women.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable.
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits except for screening (Visit 1) should take place in the morning. If a patient 
mistakenly takes trial medication in the morning of a visit before attending the clinic or 
comes in fed condition where a fasting condition is required, the visit should be rescheduled 
for another day as soon as possible reminding the patient of the expected conditions. The 
rescheduled visit must take place in a short enough time-frame so that the patient has 
sufficient trial medication available.
All patients are to adhere to the visit schedule as specified in the flowchart. If any visit has to 
be rescheduled, subsequent visits should follow the original visit date schedule. The trial 
medication kits contain sufficient medication to allow for these time windows. The run-in 
period must be 14 to 21 days long prior to randomisation.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Trial procedures to be performed at each visit are listed in the flowchart and the respective 
protocol sections. Explanations of procedures are provided in section 5. Additional details 
regarding visit procedures are provided below. Please also reference the instructions provided 
in the ISF for clarification on eCRF issues.
All visits except Visit 1 must be performed in fasted state (at least 10 hours with nothing to 
eat or drink except water).
At the end of every visit from Visit 2 to 8 the patient must be reminded to bring SMBG test 
log and the dispensed medication kit at the next scheduled visit. Preferably, a phone call to 
remind the patient must take place one or two days before the patient's next visit.
Patient reported outcomes (PROs) 
should be 
completed by the patient on his/her own in a pre-specified order in a quiet area/room before 
any other visit assessments or treatments, and, if possible, before any interaction with the 
investigator or other trial staff.
6.2.1
Screening and run-in period
Screening Period
No trial procedures should be done unless the patient has consented to taking part in the trial. 
Once they have consented, the patient is considered to be enrolled in the trial and should then 
be recorded in the enrolment log, and screening will be started. The patient should be 
registered in the IRT and recorded in the eCRF as a screened patient at Visit 1.
Visit 2 should be done no more than 7 days after screening (Visit 1). If needed (e.g., in case 
of national holiday), the time window for Visit 1 may be extended at the discretion of the CT 
Manager in conjunction with the clinical trial leader (CT Leader) on a case by case basis.


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Demographics:
Informed consent date, age on the day of informed consent (in years), sex (in order to 
describe the subject`s sex at birth), gender identity (in order to describe how the subject self-
identifies regardless of their genotypic or phenotypic sex), ethnicity and race will be collected 
and reported in the eCRF.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding T2DM) will be reported on the baseline condition eCRF page.
Medical History
Medical history will be collected and reported in the medical history eCRF page. Information 
on clinically significant previous and concomitant illnesses, other than T2DM, or any 
clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical history at screening on the baseline 
condition page in the eCRF.
Run-in Period
From this visit on, patients should be fasting (no food or drinks, water only for at least 
10 hours) prior to each visit.
Patients who fail the run-in period following Visit 2 procedures should be registered in the 
IRT (refer to IRT user manual). It is considered as a run-in failure.
For standard of care, details please see Section 4.2.1.
Investigator should monitor adverse events, document it in the medical record and eCRF. 
Investigator and site staff instruct patients on the correct use of SMBG for glucose testing 
during the run-in period.
•
Patients should use the SMBG equipment/supplies to test glucose levels in a fasting state.
During the run-in period patients should test once a day before breakfast (i.e., after an
overnight fast). Additionally, patients should test their glucose levels if they experience
signs/symptoms of hypo- or hyperglycaemia. Test results should be documented on the
SMBG testing log. More frequent SMBG testing is permitted at the Investigator’s and/or
patient’s discretion.
•
If the SMBG test reveals an overnight fasted blood glucose of >200 mg/dl (>11.1 mol/l),
the patient should contact the study site for a visit at the next day. The investigator will
then draw a new blood sample (overnight fasted samples for FPG determination) to
confirm the hyperglycaemia, document the AE if appropriate and decide about the
possible exclusion from randomisation (it is considered as run-in failure).






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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The eligible patients for this trial will be randomised to one of two treatment groups 
(empagliflozin or placebo) in a 1:1 ratio, stratified according to HbA1c (<8.5% or ≥8.5% at 
screening), and age (≥65 to <75 years old or ≥75 years old at screening).
7.1
NULL AND ALTERNATIVE HYPOTHESES
The effect of empagliflozin 10 mg will be tested against placebo at a two-sided α = 0.05 level 
of significance.
H0: Mean change from baseline in HbA1c after 52 weeks of treatment with empagliflozin 
10 mg = mean change from baseline in HbA1c after 52 weeks of treatment with placebo
against
H1: Mean change from baseline in HbA1c after 52 weeks of treatment with empagliflozin 
10 mg ≠mean change from baseline in HbA1c after 52 weeks of treatment with placebo.
The primary endpoint will use HbA1c units of %.
Secondary endpoints and further endpoints will be evaluated in an exploratory manner.
7.2
PLANNED ANALYSES
7.2.1
General considerations
With regard to each efficacy and safety endpoint during the randomised 52 weeks treatment 
period, the term "baseline" refers to the last observed measurement prior to the administration 
of any randomised trial medication.
The statistical analysis will be based on the following populations.
The treated set (TS) will consist of all patients who were randomised and treated with at least
one dose of trial drug.
The full analysis set (FAS) will consist of all patients in the TS who had a baseline HbA1c
assessment and at least one on-treatment HbA1c assessment during the 52 week double-blind
part of the trial.
Per protocol set (PPS) will consist of all patients in FAS who were without important 
protocol violations (IPVs) for efficacy. The definition of IPVs will be specified in the TSAP.
7.2.2
Primary endpoint analyses
For primary endpoint, refer to Section 2.1.2. The primary analysis will be performed on the 
FAS with treatment assignment as randomised.


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The primary analysis is a restricted maximum likelihood (REML)-based mixed model 
repeated measures (MMRM) comparing the change in HbA1c (in units of %) from baseline 
after 52 weeks of double-blind treatment.
The statistical model will include fixed classification effects for treatment, gender, baseline 
renal function, visit and visit-by-treatment interaction, and a linear covariate for baseline 
HbA1c and age. An unstructured covariance structure will be used to model the within-
patient errors. If this unstructured covariance structure fails to converge, the following 
structures will be tested: compound symmetry, variance components and Toeplitz. The 
covariance structure converging to the best fit, as determined by Akaike’s information 
criterion, will be used.
The Kenward-Roger approximation will be used to estimate the denominator degrees of
freedom.
Only the available data that were observed while patients were on treatment will be included
in the analysis. Missing data are handled implicitly by the above statistical model, rather than
using any imputation. This approach, referred to as observed case (OC), will additionally set
all values measured after rescue medication taken to missing.
Sensitivity analyses of the primary endpoint will be performed. Such sensitivity analyses will 
be specified in the TSAP.
7.2.3
Secondary endpoint analyses
For secondary endpoints, refer to Section 2.1.3. A more detailed description will be provided 
in the TSAP.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of double-blind treatment and end of the REP, a period of 7 days
after the last dose of trial medication, will be assigned to the on-treatment period for 
evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of double-blind treatment and 
end of the REP. Adverse events that start before first double-blind drug intake and deteriorate 
under treatment will also be considered as ‘treatment-emergent’.


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA
at database lock. Adverse events of special interest (AESI) will also be summarised.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Further details on the safety analysis will be specified in the TSAP.
7.2.6
Other Analyses
Not required.
7.2.7
Interim Analyses
No interim analysis is planned for this trial.
7.3
HANDLING OF MISSING DATA
As defined for the primary endpoint analysis, missing data are handled implicitly by the
statistical model, rather than by using any imputation. This approach will additionally set all 
values measured after rescue medication taken to missing. Further details will be described in 
the TSAP.
With respect to safety evaluations, it is not planned to impute missing values.
7.4
RANDOMISATION
The trial will be performed as a double-blind design with respect to the two blinded treatment
groups. Randomisation to the two treatment groups of empagliflozin 10 mg and placebo will 
be 1:1 and will be stratified by following 2 factors: 

HbA1c (<8.5 or ≥8.5%) at Visit 1

Age (≥65 to <75 or ≥75 years) at Visit 1
The randomisation of patients to the treatment groups will be performed via an IRT system. 
BI will arrange for the randomisation and the packaging and labelling of trial medication. 
The randomisation list will be generated using a validated system, which involves a pseudo-
random number generator and a supplied seed number so that the resulting allocation of


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treatment will be both reproducible and non-predictable. The block size will be documented 
in the clinical trial report. Access to the radomisation codes will be controlled and 
documented.
7.5
DETERMINATION OF SAMPLE SIZE
Based upon previous experiences with these compounds, the difference in HbA1c change 
from baseline after 52 weeks between the treatment groups can be assumed to be 0.5% with a 
standard deviation of 0.85%. With a randomisation ratio of 1:1, it is assumed that the sample 
size of each group (empagliflozin 10 mg and placebo) is 62 patients. Assuming that 
approximately 3% of patients will not be eligible for inclusion into FAS due to the absence of 
a post-baseline primary endpoint value, 64 patients for the empagliflozin 10 mg group and 64 
patients for the placebo group need to be randomised. With this sample size, a power of 90%
for a two-sided test at level α=5% for the primary endpoint will be achieved.
Calculations were performed using nQuery Advisor® 6.1 statistical package by 
 
.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonised Guideline for GCP,
relevant BI Standard Operating Procedures (SOPs), the Japanese GCP regulations (Ministry 
of Health and Welfare Ordinance No. 28, March 27, 1997), Good Post-Marketing Study 
Practice (GPSP), Good Vigilance Practice (GVP) and other relevant regulations. Investigators 
and site staff must adhere to these principles. Deviation from the protocol, the principles of 
ICH GCP or applicable regulations will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol , of ICH GCP, or of Japanese GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the clinical trial report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/independent ethics committee (IEC) and competent authority 
(CA) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of Japan. Each signature must be personally dated by each 
signatory and the informed consent and any additional patient-information form retained by 
the investigator as part of the trial records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 


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informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An integrated quality and risk management 
plan documents the rationale and strategies for risk management during trial conduct 
including monitoring approaches, vendor management and other processes focusing on areas 
of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 


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retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Before providing any copy of patient´s source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted from any copy of the patients’
source documents.
If the patient is not compliant with the protocol, any corrective action e.g., re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper
documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature
discontinuation document the reason for it)
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be
documented evidence in the source data (e.g., medical records) that the trial participant
meets all inclusion criteria and does not meet any exclusion criteria. The absence of
records (either medical records, verbal documented feedback of the patient or testing
conducted specific for a protocol) to support inclusion/exclusion criteria does not make
the patient eligible for the clinical trial
∀
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB/IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g., FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.


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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Not applicable.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site. Early termination of the trial is 


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defined as the premature termination of the trial due to any reason before the end of the trial
as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim.
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
An independent external clinical event committee (CEC) will be established to adjudicate 
centrally and in a blinded fashion events suspected of DKA (for further details see Section 
5.2.6.1.4) and hepatic events. The CEC will evaluate whether pre-specified criteria for 
adjudication endpoints are met. For qualifying events, study sites will be asked to provide 
relevant source documents generated from any medical evaluations of these events will be 
requested including laboratory values, histological analysis, results of ultrasound, computed 
tomography, magnetic resonance imaging, scintigraphy, hospital discharge letters, and 
medical reports from other physicians. All evaluations will be performed in a blinded fashion. 
The assessments will be analysed based on empagliflozin data combined from multiple trials 
(i.e., on project level). The tasks and responsibilities of the CEC will be specified in a charter. 
The CEC will maintain the adjudication results in writing.
Relevant documentation on the participating (principal) investigators (e.g., their curricula 
vitae) will be filed in the ISF.
The investigators and trial staff will have access to the BI web portal Clinergize to access 
documents provided by the sponsor.
BI has appointed a CT Leader, responsible for coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of CT Managers, CRAs, and investigators
of Japan.
The organisation of the trial in Japan will be performed by the respective local or regional BI-
organisation (Operating Unit, OPU) in accordance with applicable regulations and BI SOPs,
or by a CRO with which the responsibilities and tasks will have been agreed and a written 
contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.


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A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT manual and Lab manual, available in the ISF.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.






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10.
APPENDICES
10.1
GRIP STRENGTH
A Smedley-type dynamometer is used to measure grip strength.
The site staff instructs the patient to adjust the grip width so that the second joint of the index 
finger is approximately 90 degrees (almost right angle).
The site staff asks the patient to be careful not to touch the body or clothes with hand while 
keeping arms down naturally. The site staff makes sure that the patient does not wave the grip 
dynamometer.
Grip strength is measured twice alternately left and right. Records are rounded down to the 
nearest kilogram and averaged for the better of the left and right.
10.2
CHAIR STAND TEST
Patients fold their arms across their chest and try to stand up once from a chair. If patients can 
stand from a chair, they repeat same action five times. It is measured the time required to 
perform five rise from a chair to an upright position as fast as possible without the use of 
arms.
10.3
BODY COMPOSITION
Body composition is measured by using BIA (MC-780A-N, TANITA). The patient barefoot 
stands on the bench evenly on the toe and heel electrodes and holds the grip on each hand.
Note: do not move during the measurement.
It is recommended that urination and defecation is completed before measurement. For a
patient who has dehydration, hypothermia, swelling or fever, the visit to measure body 
composition has to be rescheduled as soon as possible.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Description of change
Rationale for change
11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Description of change
Rationale for change


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12.
REFERENCES FOR CTP AUTHORS
Not applicable.


APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
Title: 
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
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Boehringer Ingelheim 
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c35189692-01
BI Trial No.:
1245-0218
Title:
A randomised, double-blind, placebo-controlled, parallel group, 
52 weeks phase IV trial to evaluate efficacy and safety of oral, 
once daily empagliflozin in elderly Japanese patients with type 2 
diabetes mellitus and insufficient glycaemic control
Including protocol version 1.0 [c3096609-01]
Investigational
Product(s):
Jardiance®, empagliflozin
Responsible trial 
statistician(s):
Address: 
Tel:
Date of statistical 
analysis plan:
09 MAY 2022 SIGNED
Version:
1
Page 1 of 37
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! 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS(S) ....................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENT(S)................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.6.1 
Definition of rescue therapy for censoring .......................................................15
6.6.2 
Imputation methods............................................................................................15
6.6.2.1 
Original result (OR) analysis ................................................................................15
6.6.2.2 
Observed cases (OC) analysis...............................................................................15
6.6.2.3 
Observed cases analysis including values on rescue medication (OC-IR) ...........16
6.6.2.4 
Last observation carried forward (LOCF) ............................................................16
6.6.2.5 
Non-completers considered failure (NCF)............................................................16
6.6.3 
Safety and other variables..................................................................................17
6.6.4 
Missing dates and times......................................................................................17
 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................18
7.
PLANNED ANALYSIS......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................21
7.3
TREATMENT COMPLIANCE........................................................................22




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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals................................................................12
Table 6.3: 1
Summary of which data sets will be used for which class of endpoints ..........13
Table 6.7: 1
Endpoint specific follow-up period for the assignment to active treatment.....18
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for each 
on-treatment visit..............................................................................................19
Table 7.8.2: 1 MDRD staging..................................................................................................29
Table 11: 1
History table .....................................................................................................37


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
ALT
ANCOVA
AST
ATC
BI
BIcMQ
BMI
CEC
CRF
CT
CTP
CTR
DBL
DBP
DKA
DM&SM
ECG
EDMS
eCRF
eGFR
EMA
EOT
EOS
FAS
FPG
HbA1c
ICH
iPD
IRT
ITT
LLT
LOCF
MDRD
Adverse event of special interest
Alanine transaminase
Analysis of covariance
Aspartate transaminase
Anatomical-Therapeutic-Chemical classification
Boehringer Ingelheim
BI-customized MedDRA query
Body mass index
Clinical event committee
Case report form
Concomitant therapy
Clinical Trial Protocol
Clinical Trial Report
Database Lock
Diastolic blood pressure
Diabetic ketoacidosis
Boehringer Ingelheim Data Management and Statistics Manual
ECG Electrocardiogram
Electronic Document Management System
Electronic Case Report Form
Estimated glomerular filtration rate
European medicines agency
End of treatment
End of study
Full analysis set
Fasting plasma glucose
Glycated haemoglobin
International Conference on Harmonisation
Important protocol deviation
Interactive response technology
Intention to treat
Lowest Level Term
Last observation carried forward
Modification of diet in renal disease


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Term
Definition / description
MedDRA
MMRM
MQRM
NCF
OC
OC-IR
OR
PK
PPS
PT
PD
Q1
Q3
REML
RS
SBP
SCR
SD
SDG
SMQ
SOC
TMF
TOC
TS
TSAP
ULN
WHO
Medical Dictionary for Regulatory Activities
Mixed-effect Model Repeated Measures
Medical Quality Review Meeting
Non-completers considered failure
Observed case
Observed cases, including values after rescue
Original results
Pharmacokinetics
Per protocol set
Preferred term
Protocol deviation
Lower quartile
Upper quartile
Restricted maximum likelihood
Randomised set
Systolic blood pressure
Screened set
Standard deviation
Standardized Drug Groupings
Standardised MedDRA query
System Organ Class
Trial Master File
Table of contents
Treated set
Trial statistical analysis plan
Upper limit of normal
World Health Organisation


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP, including Protocol Amendments. In particular, 
the TSAP is based on the planned analysis specification as written in the CTP Section 7 
“Statistical Methods and Determination of Sample Size”. Therefore, TSAP readers may 
consult the CTP for more background information on the study, e.g., on study objectives, 
study design and population, treatments, definition of measurements and variables, planning 
of sample size, randomization.
SAS® Version 9.4 or a later version will be used for all analyses.




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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is defined in the CTP Section 2.1.2. 
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable. 
5.2.2
Secondary endpoint(s)
Secondary endpoints are listed in the CTP Section 2.1.3.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
There will be 5 treatment study phases in this trial: screening, placebo run-in, study treatment 
phase (with either 10 mg Empagliflozin or matching placebo), post-treatment and post-study.
The purpose of the definitions below is to describe all the different study/treatment intervals, 
in which a patient can lie during the course of the trial. 
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date 
Start time
Screening
Screening
Date of informed consent 
00: 00
Run-in
Run-in
Date of first administration of 
run-in medication
Time of first 
administration of 
run-in medication 
12:00 if missing
Placebo/Emp
agliflozin 
10mg
Treatment
Date of first administration of 
trial medication
Time of first 
administration of 
trial medication 
12:00 if missing
Post-
treatment
Post-
treatment
Date of last intake of trial 
medication + 1 day
00:00
Post-study
Post-study
Last contact date + 1 day
00:00
For efficacy and safety analyses, measurements will still be considered on-treatment during a 
follow-up period specific to each parameter. These follow-up periods are defined in Table 6.7: 
1.
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to 
treatment groups, i.e. patients will be analysed as randomised.
Safety analyses will be run on the treated set (TS). Patients will be shown under the 
randomised treatment. Safety analyses will also assign patients to the treatment group as 
randomised. In the exceptional case that a patient took the wrong treatment, adverse events 
may occur while being on the wrong treatment. Analyses of this data are described in Section 
7.8.1.7.
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important, if it affects the rights or safety of the study patients, or 
if it can potentially influence the primary outcome measurement in a non-negligible way (4).
The documentation of the iPD categories, definition and how to handle iPDs in the analysis 
are done in the DV domain and stored within the TMF in EDMS.


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6.3
SUBJECT SETS ANALYSED
The following analysis sets will be defined for this trial.
SCR - Screened patients set
All patients screened for the trial, with informed consent given and who completed at least 
one screening procedure at Visit 1.
RS - Randomised set
All patients from the screened set who were randomised to trial medication, regardless of 
whether any trial medication was taken.
TS – Treated set
All patients randomized and treated with at least one dose of trial medication. The TS is the 
basis for safety analyses.
FAS - Full analysis set 
All patients randomised, treated with at least one dose of trial medication, and with a baseline 
and at least one on-treatment HbA1c value. The FAS is the basis for the ITT analysis.
PPS - Per-protocol set
All patients in the FAS without iPD leading to exclusion.
In Table 6.3: 1 the data sets which are to be used for each category class of endpoint are 
illustrated. Note that the number of patients with available data for an endpoint may differ. 
For details, see Section 6.6 “Handling of missing data and outliers”.
Table 6.3: 1
Summary of which data sets will be used for which class of endpoints
Class of endpoint 
TS
FAS
PPS
Primary endpoint 
OC, OC-IR, 
LOCF
OC
Subgroup analyses 
of primary 
endpoint 
OC
Further endpoints 
(binary)
NCF
Further endpoints 
(continuous)
OC, OR#
Safety endpoints
OR, OC-IR^
#OR results will only be presented for time to first rescue medication and number of patients 
with rescue.
^OC-IR will be used for secondary endpoints and laboratory measurements.


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6.5
POOLING OF CENTRES
This section is not applicable, because centre is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Based on the different reasons of patients’ data missing for different endpoints, various 
methods will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint (see Table 6.3: 1).
6.6.1 Definition of rescue therapy for censoring
For some of the imputation methods defined below, values after rescue medication will be set 
to missing. In this context, the following two situations are defined as use of rescue 
medication:
∀
Additional antidiabetic medication used for ≥7 consecutive days
∀
Increased in dose of background medication for ≥7 consecutive days
This approach will be used when considering which data to exclude from the OC and LOCF 
analyses. For this definition of rescue therapy no statistical analysis will be conducted. For the 
definition of rescue therapy as a further endpoint, please refer to Section 5.3.2.
6.6.2 Imputation methods
6.6.2.1 Original result (OR) analysis
Original result analysis implies the analysis of data exactly as observed. OR analysis will be 
performed on endpoints that are either not affected by patients’ rescue medication use or if it 
is not meaningful to apply any imputation rule on them for replacing the missing values.
6.6.2.2 Observed cases (OC) analysis
For all efficacy endpoints, it is planned to analyse only the available data that were observed 
while patients were on treatment, i.e., excluding the missing data. In other words, OC analysis 
will be performed and missing data in this analysis will not be replaced. Also, all values 
measured after rescue medication will be handled as missing (rescue medication as defined in 
Section 6.6.1).
The OC-technique represents the primary data selection tool that will be used for the primary 
analysis in this trial. Subsequent handling of missing data will be performed via a likelihood 
based method, and in the case of the primary analysis, will use the MMRM model.


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6.6.2.3 Observed cases analysis including values on rescue medication (OC-IR)
For some endpoints the OC-technique will also be adapted without setting the values 
measured after rescue medication taken to missing, and using the original observed values 
instead. This is also done as a sensitivity analysis of the endpoint with OC as the imputation 
rule and will be called Observed Cases including values on rescue medication (OC-IR).
6.6.2.4 Last observation carried forward (LOCF)
An alternative method for quantitative endpoints is to replace missing values due to early 
discontinuation of a patient by her/his last observed measurement on treatment. 
The last observation on-treatment need not necessarily be a value selected as a visit value if 
multiple measurements were performed within a time window for a visit. In this case the last 
on-treatment value within the time window will be carried forward, while the visit value can 
be the value that was observed closest to the planned visit date or the first value observed in 
the time window. See Table 6.7: 2 for further details.
For example, if a patient is on rescue medication after Visit 3 and before Visit 4, then all the 
on-treatment visits will be set to missing and the HbA1c value from baseline will be carried 
forward to populate the missing on-treatment values in HbA1c.
Missing values within a course of measurements on treatment will be interpolated based on 
the last observed value before the missing visit and the first observed value after the missing 
visit. This is independent from the selection of a value as the picked visit value to be used in 
the descriptive analysis by visit.
The missing endpoint value can be interpolated as E0 = E-1 + ((E1 - E-1) x (D0 - D-1) / (D1 -
D-1)), where
D0 = date of a visit with a missing endpoint value,
D1 = date of the next-visit (with end-point value non-missing) after the visit with missing 
endpoint,
D-1 = date of a previous-visit (with end-point value non-missing) before the visit with 
missing endpoint, and
Ei = endpoint values for visits D-1, D0 and D1 for i = -1, 0 and 1.
The values measured after rescue medication was taken during the active treatment period by 
the patients will be set to missing; and these missing values will be imputed by LOCF 
technique.
Missing data will only be imputed up to the planned visit to be reached by all randomised 
patients (Week 52).
6.6.2.5 Non-completers considered failure (NCF)
For binary endpoints, like a treat to target response of HbA1c < 7.0%, a method that missing 
values are replaced as “failures” will be considered. Missing data due to early discontinuation 
per the completer definition will be replaced as “failure” (i.e., HbA1c >= 7.0%) up to the 


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planned final visit to be reached by all patients. In addition, values obtained after rescue 
medication will also be handled as “failure”.
For binary endpoints that are derived from quantitative endpoints (e.g. HbA1c), missing 
values within a course of measurements on treatment will be replaced on the basis of the 
corresponding imputed value of the underlying quantitative endpoint (e.g. interpolation for 
HbA1c).
6.6.3 Safety and other variables
Missing safety data will not be replaced. 
6.6.4 Missing dates and times
a) Missing AE dates
Missing or partial date information for AEs will be replaced according to general BI rules 
described in the BI guidance for “Handling of missing and incomplete AE dates” (5).
b) Missing drug administration dates
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. 
If the date of first administration is partially missing with the month and year present, the day 
will be set to the date of randomisation if randomisation was in the same month. If 
randomisation was in the month prior to the first drug administration the missing day will be 
imputed as the first day of the month. A missing time of first drug administration will be 
imputed as 12:00 o'clock noon, missing administration times at on-treatment visits will be 
imputed by 08:00 o'clock in the morning.
If the date of trial medication stop is partially or completely missing, use the minimum of the 
following dates:
∀
End of treatment visit date, if available
∀
Date of death
∀
Trial completion (last contact date)
∀
Longest extrapolated treatment duration (assuming 1 tablet/day)
∀
(in case for partially missing date) Last day of the year/month given as partial date
In case of a partially missing date, if the imputed date is before the first day of the month/year 
given as the partial date, the first day of the month/year will be used. All other cases need to 
be assessed by the trial team on an individual patient basis, using the points above as 
guidance.
c) Missing dates for concomitant and other antidiabetic therapies
For incomplete date information, the midpoint of the possible interval will be used. If only the 
year is present, the day and month will be imputed as 01 July, if year and month is present the 
day will be imputed as 15. If the year is missing, the date will be considered missing.


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If this leads to contradictions for the start or end date of a concomitant therapy (e.g. imputed 
end date before documented start date), a partial end date will be imputed as the end of the 
interval or a partial start date will be imputed as the start of the interval in the database to 
resolve this contradiction.
All other cases or conflicting cases resulting from these imputation rules need to be assessed 
by the trial team on an individual patient basis.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
With regard to efficacy and safety endpoints, the term “baseline” refers to the last observed 
measurement prior to administration of any randomised trial medication. Measurements taken 
prior to the first intake of randomised trial medication will be considered pre-treatment 
values. Since the protocol specifies that all measurements are taken at Visit 3 before any 
intake of trial medication, all measurements at the first day of drug intake are assumed to 
qualify as baseline assessments.
Measurements taken after the first intake of randomised trial medication will be considered 
on-treatment values if they have been obtained up to end of the parameter specific follow-up 
period as defined in Table 6.7:1 below and will be assigned to the randomised trial medication
for efficacy and safety analyses.
Measurements taken after the end of the endpoint specific follow-up period and after the last 
intake of trial medication will be considered post-treatment values. 
On-treatment efficacy, safety, health related and QoL measurements will be assigned to visits 
based on time windows around the planned visit dates. These time windows are defined based 
on the planned number of days after the date of first administration of trial medication (see 
Table 6.7: 2).
Table 6.7: 1
Endpoint specific assignment to active treatment
Endpoint 
Last day of assignment to treatment 
phase 


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(days after trial medication stop date)
Efficacy
HbA1c
7
Safety 
Adverse events
7
Safety laboratory measurements
3
Pulse rate 
1
FPG
1
Chair stand test
7
Grip strength
7
Body composition 
7
Reasons to base the time windows on the actual treatment start date rather than the 
randomisation date are:
∀
If first intake of trial medication shows a large delay by e.g. more than one week after 
the date of randomisation, a measurement taken four weeks after randomisation rather 
reflects the drug effect after three weeks than after four weeks and thus may 
underestimate the treatment effect at this visit.
∀
With large delays of the introduction of trial medication after the randomisation, the 
time window for the first on-treatment visit could include times the patient was not yet 
on trial medication.
The time window for the first visit after randomisation starts on the day after the first intake of 
trial medication. This maximises the number of measurements used in by visit analyses, but 
may lead to an underestimation of the treatment effect at the first visit for parameters that 
react slowly on treatment.
The midpoint between two on-treatment visits defines the end of a time window, with the 
midpoint being included in the time window of the preceding visit. The end of the time 
window of the last on-treatment visit (EOT) is endpoint dependent (cf. Table 6.7: 1).
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for each on-
treatment visit
Time Window (actual days on 
treatment)
Visit number 
Visit label
Planned days
Start
EndA


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3
Baseline
1
NA
1B
4
Week 4
29
2
57
5
Week 12
85
58
127
6
Week 24
169
128
211
7
Week 36
253
212
309
8
Week 52/EOT
365
310
Trial 
medication
stop date + X 
days
A. In case of premature discontinuation of the trial medication a Visit 8 has to be performed. 
If such a Visit 8 falls into the time window of a previous visit, measurements will be assigned 
to this previous visit and the visit value will be determined as described below. In this case the 
time window for the visit that includes Visit 8 will end X days after the trial medication stop 
date, including Day X. The definition of X is endpoint specific, cf. Table 6.7: 1. No time 
window for optional visit is planned.
B. Only values taken prior to the start of treatment with randomised trial medication can be 
considered baseline values. Time windows will be used for assignment of measurements to 
scheduled visits.
Only one observation per time window will be selected for analysis at an on-treatment visit -
the value will be selected which is closest to the protocol planned visit day. If there are two 
observations which have the same difference in days to the planned day or if there are two 
observations on the same day, the first value will be used. 
Note: For LOCF imputation, the last observed on-treatment value will be carried forward 
within the applicable period, whether or not it was selected in the previous time window. For 
interpolation only selected values are to be used. For more details on LOCF refer to Section 
6.6.


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7.
PLANNED ANALYSIS
Disposition of the patient population participating in the trial will be analysed by treatment 
groups and presented in the clinical trial report as a frequency-distribution.
A frequency of patients with iPDs, also summarised by whether the iPD led to exclusion from 
the PPS, will be presented by treatment group for the RS. The frequency of patients in 
different analysis sets will also be analysed for each treatment group. 
For in-text tables presenting descriptive analysis of the endpoints and other variables 
(analysed in original scale), the set of summary statistics is: N (number of patients with 
nonmissing values), mean, SD.
For end-of-text tables, the set of summary statistics is: N (number of patients with nonmissing 
values) / Mean / SD / Min / Q1) / Median / Q3 / Max.
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Standards for Reporting of Clinical Trials and Project Summaries” (6).
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or not.
In all specified statistical analyses, treatment comparisons will be made between randomised 
empagliflozin group and placebo.
Descriptive statistics on the impact of COVID-19 on study visits as well as trial medication 
intake will be provided if any.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive analysis of the following demographic variables measured at baseline will be 
presented:
Sex, age (in years), age groups, BMI (kg/m2), BMI categories, history of hypertension(Yes /
No), height (cm), duration of diabetes (categories based on years), renal impairment (eGFR 
using MDRD formula), HbA1c (%) and HbA1c categories. Categories for baseline 
characteristics are defined in Section 6.4.
Demographic and baseline characteristics tables will be presented for the FAS. A summary of 
the number of patients in each randomisation strata per treatment will also be shown. This 
will be based upon the data received from the IRT provider.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the FAS.
Concomitant medication use will be summarised by WHO ATC level 3 (ATC3) and preferred 
name. Summaries will be presented for concomitant therapies taken during randomised 


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treatment, taken at baseline and those newly introduced during ramdomised treatment. 
Separate summaries of use of acetylsalicylic acid (ASA), antihypertensives or lipid lowering 
drugs at baseline by preferred name will be presented. The following codes from the SDGs
will be used to define ASA, antihypertensives and lipid lowering drugs:
∀
ASA: 50000019
∀
Antihypertensives: 0000000049
o
Adrenergic receptor agonists: 0000000051
o
Adrenergic receptor antagonists: 0000000050
o
Angiotensin converting enzyme (ACE) inhibitors: 0000000053
o
Angiotensin II receptor antagonists: 0000000054
o
Calcium channel blockers: 0000000769
o
Renin inhibitors: 0000000095
o
Other antihypertensives: 0000000055
∀
Lipid lowering drugs: 6000000014
o
Niacin: 6000000008
o
Fibrates: 6000000009
o
Statins: 0000000096
o
Ezetimibe: 50000014
o
PCSK9: 50000011
∀
Other lipid lowering drugs: 6000000010
Concomitant diseases will be summarised by MedDRA SOC and PT. Relevant medical 
history by treatment group will also be presented. Both summaries will be presented using the 
FAS.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and 
percentage of patients with overall compliance will be reported. The sum of all reported 
compliance over the planned visits (disregarding run-in) will be divided by the total duration 
(until last visit where medication is returned) to derive the overall compliance. The FAS will 
be considered.
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary analysis will be performed on the FAS (OC). The primary analysis is an REML-
based MMRM approach comparing the change from baseline in HbA1c after 52 weeks of 
treatment. All randomised treatment groups will be included in the same analysis. 
The primary analysis model will be: HbA1c change from baseline at each on-treatment visit = 
baseline HbA1c + age + baseline renal function + sex + visit by treatment interaction + 
random error,
where ‘baseline renal function’, ‘sex’ and ‘visit by treatment interaction’ are fixed 
classification effects, and ‘baseline HbA1c’ and ‘age’ are linear covariates.


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In all modelling, the variable ‘baseline renal function’ will be defined as last eGFR value
before first intake of study treatment categorised according to the CKD staging. Note that 
baseline renal function refers to the eGFR categorization (>=60 mL/min/1.73 m2, <60 
mL/min/1.73 m2). Such categorization is applicable to the analysis of other endpoints as well.
For each patient, the error terms from all the visits represent the within-patient variability, and 
are assumed to follow a multivariate normal distribution with an unstructured covariance 
matrix. If an unstructured (co)variance structure fails to converge, the following structures 
will be tested: compound symmetry, variance components and Toeplitz. The (co)variance 
structure converging to the best fit, as determined by Akaike’s information criterion, will be 
used. This rule will also be used for other MMRM analyses unless otherwise stated.
The treatment effect will be estimated on the basis of the least square mean treatment 
difference at week 52 extracted from the primary analysis model.
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. Significance tests will be based on least-squares means using a two-sided α = 0.05 
(two-sided 95% confidence intervals).  


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
Not applicable.
7.5.2
(Other) Secondary endpoint(s)
Refer to Section 7.8.5 for the analyses of secondary endpoints.


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7.7
EXTENT OF EXPOSURE
A descriptive statistics table with mean, SD, median and range of the number of days a patient 
was on treatment will be provided for the TS. The tables will also provide the sum total of the 
time (in years) that all patients pooled together were on treatment. A separate listing will be 
created of any patients that switched treatment at any time indicating exposure to each 
treatment. A frequency table of number and percent of patients belonging to each categorical 
range of exposure weeks will be provided as well. The following are the categories of
exposure-ranges (in weeks):
0 to <4, 4 to <12, 12 to <24, 24 to <36, 36 to <51 and >=51.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse Events
AEs will be coded using the latest version of the MedDRA coding dictionary at DBL. The 
analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs (NOT the number of AEs). For analysis of multiple AE 
occurrences, data from the eCRF will be collapsed into an AE provided that all of the 
following applies:
∀
All AE attributes are identical (including LLT, intensity, action taken, therapy 
required, seriousness, reason for seriousness, relationship, outcome, AE of special 
interest and also additional information of specific AEs or AESIs.
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
For further details on summarization of AE data, please refer to the guideline “Analysis and 
Presentation of Adverse Event Data from Clinical Trials” (7).
7.8.1.1 Assignment of AEs to treatment
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. This means that all adverse events occurring between first drug intake until 7 days 
after last drug intake will be assigned to the first treatment received. All adverse events 
occurring before first drug intake will be assigned to 'pre-treatment' and all adverse events 
occurring after last drug intake + 7 days will be assigned to 'post-treatment'.
7.8.1.2 AE summaries
An overall summary of adverse events will be presented.
The frequency of patients with adverse events will be summarised by treatment, primary SOC
and PT. 
AEs will also be reported by intensity. Separate tables will be provided:
∀
for patients with adverse events of special interest (AESI), 
∀
for patients with serious adverse events, 
∀
for patients with AEs leading to discontinuation,
∀
for patients with AEs leading to death,
∀
for patients with drug-related AEs.
The SOCs will be sorted according to the standard sort order specified by EMA, and PTs will 
be sorted by frequency (within SOC).


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7.8.1.3 Analysis of hypoglycaemic events
The investigator will record for each AE whether it represents a hypoglycaemic event and, if 
so, record additional information to assess the intensity of the hypoglycaemic event. On the 
basis of this information the hypoglycaemic event will be classified as:
∀
confirmed hypoglycaemic adverse event are defined as hypoglycaemic adverse events 
that had a glucose concentration ≤ 70 mg/dL or required assistance.
∀
severe hypoglycaemia: event requiring assistance.
∀
hypoglycaemia event with blood glucose level <54 mg/dL (<3.0 mmol/L), even if 
asymptomatic.
∀
symptomatic hypoglycaemia, independent of the blood glucose value (this includes 
cases when the blood glucose was not measured during the event, but hypoglycaemia
was diagnosed based on the clinical presentation).
The number of patients with hypoglycaemia according to investigator's judgement will be 
tabulated by treatment group. A subgroup analysis of confirmed events with respect to age 
category, rescue therapy and renal function will be performed.
The impact of treatment on the occurrence of hypoglycaemia will be explored using logistic 
regression model involving treatment and continuous baseline HbA1c. Time to the onset of 
the first hypoglycaemia will be estimated by Kaplan-Meier method. The logistic regression 
and Kaplan-Meier analysis will be performed on confirmed events as for all hypoglycaemia 
tables.
Summaries of hypoglycaemic events will include total number of hypoglycaemic events, 
descriptive hypoglycaemic event rate, number of episodes per patient, severity and intensity 
of the worst episode, action taken, minimum glucose level of worst episode, and time to onset 
of first episode. Hypoglycaemic events will also be summarised by baseline eGFR using 
MDRD formula, background medication and age group.
Different tables will be shown for (i) patients with investigator defined asymptomatic or 
symptomatic hypoglycaemia reported as AE, (ii) patients with confirmed hypoglycaemic 
adverse events, i.e. hypoglycaemic adverse events that had a plasma glucose concentration ≤
70 ml/dL or required assistance, and, (iii) patients with minor, confirmed hypoglycaemic 
adverse events, defined as a hypoglycaemic event that had a plasma glucose concentration ≤ 
70 mg/dL but did not require assistance.
7.8.1.4 AEs of special interest (AESI)
The protocol defines the following adverse events that for analysis purposes will be 
considered as AESIs:
∀
Decreased renal function
∀
Hepatic injury
∀
Diabetic ketoacidosis (DKA)
∀
Events leading to lower limb amputation
Events of these AESIs are identified through the AE being flagged by the investigator as an 
AESI on the CRF.


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AE frequency tables will be created for renal and hepatic events based on narrow SMQs.
Renal:    20000003 Acute renal failure
Hepatic: 20000008 Liver related investigations, signs and symptoms (SMQ)
               20000009 Cholestasis and jaundice of hepatic origin (SMQ)
               20000010 Hepatitis, non-infectious (SMQ)
               20000013 Hepatic failure, fibrosis and cirrhosis and other liver damage-related   
conditions
The frequency of patients with DKA will be summarised based on the applicable BIcMQ at 
the time of the analysis.
The frequency of patients with events leading to lower limb amputation will be summarised.
In addition, muscle weakness will be tabulated by treatment group, which will be defined by 
the PTs of Sarcopenia, Muscular weakness, Muscle atrophy, Muscle fatigue and Myopathy. 
7.8.1.5 Events qualifying for external adjudication by the Clinical Event Committee (CEC)
An independent external CEC regularly reviews events and evaluates whether pre-specified 
criteria for these adjudication endpoints are met. Details on composition of the CEC, 
responsibilities and clinical event definitions are provided in a separate CEC Charter.
The CEC will be provided with additional, specified background material on the patients with 
these events and perform an assessment of the events.
Adjudication assessments will be incorporated to the database. Frequency tables will be 
provided for the PTs in the specified SMQs of events and for the adjudication endpoints. 
Tables will be provided for events qualifying for adjudication and then separately the events 
that were confirmed or non-assessable.
7.8.1.6 Analysis of adjudicated events 
DKA and hepatic events will be adjudicated by an external expert committee. The patients 
with adjudicated hepatic events will be summarized.
7.8.1.7 AEs while patients taking wrong medication
A listing will be provided for AEs that occurred while a patient was taking the wrong 
medication. If such a patient is identified, an additional adverse event table that assigns the 
adverse events to the actual treatment taken will be presented. A patient who took both the 
assigned treatment and at least one tablet of the wrong treatment, will be counted as at risk in 
both treatment groups for the respective relevant time. The table will include all adverse 
events by SOC and PT.


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7.8.1.8 COVID-19 related analyses
The subgroup of patients with SARS-COV-2 infection will be analysed. SARS-COV-2
infections will be defined by the narrow BIcMQ SARS-COV-2 infection. All analyses will be 
repeated using the broad instead of the narrow BIcMQ.
An overview of adverse events will be presented for this subgroup of patients. Additionally, 
the number of patients with adverse events, the number of serious AEs and AEs leading to 
discontinuation of study treatment will be presented by treatment, primary SOC and PT.
A listing will be prepared presenting all SARS-COV-2 infections.
7.8.2
Laboratory data
For continuous safety laboratory parameters, standardised and normalised values will be 
derived as well as the differences to baseline. The process of standardisation and 
normalisation as well as standard analyses for safety laboratory data are described in the BI 
guidance for the “Handling, Display and Analysis of Laboratory Data” (8). All analyses 
considering multiple of times ULN will be based on original and not normalised data.
The frequency of the number of patients with AST/ALT elevations ≥3xULN, ≥5xULN, ≥
10xULN, and ≥20xULN will be displayed.
To support analyses of liver related adverse drug effects, patients with AST and/or ALT ≥
3xULN with concomitant or subsequent TBILI ≥2xULN in a 30 day period after AST/ALT 
elevation are of special interest. 
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds. Patients who fulfil one or two of the criteria for ALT/AST or total 
bilirubin elevations above and has no information available for the remaining parameter(s) at 
the same time-point or within the 30 day time window will not be listed under “ALT and/or 
AST ≥ 3xULN with Total Bilirubin ≥ 2xULN”. 
Patients with elevations as described will be summarised and stratified by Alkaline 
phosphatase < 2xULN and ≥ 2xULN.
All calculations for the grading of renal function will be based on the originally measured 
laboratory values and the ULNs given by the laboratory, not on normalised values with BI 
standard reference ranges. The glomerular filtration rate will be estimated according to the 
MDRD formula (please see Table 6.4: 1) and stored in the trial databases.
For the analysis of eGFR and for the covariates in the statistical modelling, the values 
calculated by the MDRD formula using the serum creatinine values from the central 
laboratory will be used, not the eGFR values provided by the central laboratory. For the 
assignment of iPDs based on renal function the central laboratory values will be used.
To support analysis of renal function, eGFR throughout the trial will be categorised according 
to the MDRD staging shown in Table 7.8.2: 1.


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Table 7.8.2: 1 MDRD staging
Stage
eGFR [mL/min/1.73m2]
Description
1
≥ 90
Normal renal function
2
60 to < 90
Mild renal impairment
3A
45 to < 60
Moderate renal impairment A
3B
< 45
Moderate renal impairment B to 
end-stage renal impairment
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(see DM&SM: “Handling, Display and Analysis of Laboratory Data”) (8).
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised trial medication. Laboratory measurements taken up to 3 days after the 
last administration of randomised trial medication will be considered as on-treatment.
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range at baseline and the 
last measurement on treatment. Descriptive statistics will be provided by treatment group for 
baseline, on-treatment values and for changes from baseline. Frequency tables will summarise 
the number of patients with potentially clinically significant abnormalities. Details on patients 
with elevated liver enzymes will be listed. Summaries will also be presented for patients with 
elevated liver enzymes.
A summary will also be created representing the number of patients per treatment group that 
experienced a doubling in creatinine on treatment compared to baseline that was out of the 
normal range.
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings.
A shift table from baseline to last value on treatment for eGFR using MDRD formula will 
also be provided.
7.8.3
Vital signs
Vital signs (SBP, DBP and pulse rate) will be taken at Screening (Visit 1) through EOT (Visit 
8). Only descriptive statistics are planned for the summary of vital signs for baseline, on-
treatment and change from baseline by visit. Descriptive statistics will also be shown 
graphically for SBP and DBP.


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7.8.4
ECG
12-lead ECG measurements will be taken at baseline (Visit 3) and EOS (Visit 9). ECG-
findings before first intake of trial medication will be considered as baseline condition. Any 
clinically significant new findings in the ECG measurement after the first ECG will be 
considered as AEs and analysed as planned in Section 7.8.1.
7.8.5
Others
Time curve analysis
Descriptive statistics will be presented in tables for creatinine, eGFR, haematocrit, 
haemoglobin and weight over time by treatment. Presented values will be used to create plots 
of the parameters over time.
In addition, tables of descriptive statistics for creatinine, eGFR values will also be presented 
for age subgroups.
Secondary endpoints analyses
Secondary endpoints in this trial only provide one post-baseline assessment (no repeated 
measurements). ANCOVA will be performed to compare the change from baseline in each of 
the continuous secondary endpoints at week 52 on the TS (OC-IR).
The statistical model will be: Change from baseline in secondary endpoint after 52 weeks = 
baseline secondary endpoint + age + sex + treatment + BMI + baseline HbA1c + random 
error.
In addition, descriptive statistics will be provided by visit including actual values and change 
from baseline values in the abovementioned secondary endpoints at Week 52. Descriptive 
statistics will also be presented with boxplots in each group both at baseline and at Week 52.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be released to unblind the trial database after the last patient 
has completed their End-of-Study/Follow-up visit and all data has been entered and cleaned as 
defined in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) 
form.




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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
09-MAY-22
None
This is the final TSAP 


 
 
 
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