Clinical trial NCT02240680
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2014-09-23; Completion date: 2017-04-25
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To investigate the efficacy, safety, and tolerability of linagliptin 5 milligrams once a day compared to placebo as as add-on therapy for 24 weeks to stable basal insulin treatment in elderly patients, 60 years of age and older, with Type 2 Diabetes Mellitus and insufficient glycaemic control.Stable background therapy of metformin and/or alpha-glucosidase inhibitors is also allowed.

In addition, this trial will assess if linagliptin reduces the risk of hypoglycaemia when added to background basal insulin therapy. The treatment duration of this trial (24 weeks) will enable assessment of the clinically relevant endpoint of a decrease in glycosylated Haemoglobin, a well-accepted measurement of chronic glycaemic control.

Detailed description:

Arms: arm 1: patient to receive a tablet of linagliptin 5 mg each day arm 2: patient to receive a tablet of placebo matching linagliptin 5 mg
Interventions: intervention 1: placebo intervention 2: linagliptin
Intervention descriptions: intervention 1: placebo matching linagliptin 5 mg intervention 2: 5 mg once a day

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02204602-03
EudraCT No.:
BI Trial No.:
2014-000904-88
1218.149
BI Investigational
Product(s):
Tradjenta®, Trajenta®, Trayenta®, Trazenta®, linagliptin
Title:
A 24 week randomized, double-blind, placebo-controlled, parallel 
group, efficacy and safety trial of once daily linagliptin, 5 milligrams 
orally, as add on to basal insulin in elderly Type 2 Diabetes Mellitus 
patients with insufficient glycaemic control
Clinical Phase:
IV
Trial Clinical 
Monitor:
, 
 
Phone: 
Fax: 
Co-ordinating 
Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 1)
Version and Date:
Version: 2.0
Date:  15 May 2014 Original Protocol
16 October 2015        Revised Protocol
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim(BI)
Name of finished product:
Tradjenta®, Trajenta®, Trayenta®, Trazenta®
Name of active ingredient:
linagliptin
Protocol date:
Trial number:
Revision date:
16 October 2015
15 May 2014
1218.149
Title of trial:
A 24 week randomized, double-blind, placebo-controlled, parallel group, efficacy and 
safety trial of once daily linagliptin, 5 milligrams orally, as add on to basal insulin in 
elderly Type 2 Diabetes Mellitus patients with insufficient glycaemic control
Co-ordinating 
Investigator:
Trial sites:
A multi-centre trial to be conducted in multiple countries
Clinical phase:
Phase IV
Objectives:
To investigate the efficacy, safety, and tolerability of linagliptin 5 milligrams (mg) 
once a day (q.d.) compared to placebo as add-on therapy for 24 weeks to stable basal 
insulin treatment in elderly (≥60 years old) patients with Type 2 Diabetes Mellitus 
(T2DM) with insufficient glycaemic control
Methodology:
Randomised, double-blind, multi-national, placebo-controlled, parallel design 
comparison as add-on therapy to a stable background of basal insulin, metformin 
(optional), and/or alpha-glucosidase inhibitors (optional) over 24 weeks.
No. of patients: 
total entered:
Entered (into the double-blind treatment period): approximately 300
each treatment:
1:1 allocation ratio per treatment arm [i.e., 150 patients assigned to linagliptin 5mg 
q.d. and 150 patients assigned to placebo matching linagliptin 5 mg q.d.]
Diagnosis:
Elderly (≥60 years old) T2DM patients with glycated (or glycosylated) haemoglobin 
(HbA1c) levels of 7.0% to 10.0% at Screen who are on a stable background 
antidiabetic therapy of basal insulin, metformin (optional), and/or alpha-glucosidase 
inhibitor (optional).
Main criteria
for inclusion:
T2DM patients who are 60 years of age or older: 

with HbA1c levels of 7.0% to 10.0% at Screen

taking stable doses of basal insulin at least 4 weeks prior to randomisation,
and metformin (optional) and/or alpha-glucosidase inhibitor (optional) at 
least 12 weeks prior to randomization

with a Body Mass Index (BMI) of less than or equal to 45 kilograms per 
meters squared (≤ 45 kg/m2 )


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim(BI)
Name of finished product:
Tradjenta®, Trajenta®, Trayenta®, Trazenta®
Name of active ingredient:
linagliptin
Protocol date:
Trial number:
Revision date:
16 October 2015
15 May 2014
1218.149
Test product(s):
linagliptin tablet 
dose:
5 mg (tablet strength)
mode of admin.:
by mouth (p.o.) each morning
Comparator products:
placebo tablet (matching linagliptin)
dose:
Not Applicable (N/A)
mode of admin.:
p.o.
Duration of treatment: A one week Screen period with no study medication, leading into a one week placebo 
Run-In period, followed by a double-blind treatment period for 24 weeks, and a one 
week post-treatment period with no study medication.
Criteria for efficacy:
The primary endpoint is the change from baseline in HbA1c after 24 weeks of 
treatment.  
Secondary endpoints are the following:

Proportion of patients experiencing at least one confirmed hypoglycaemic 
event during 24 weeks of treatment.

Proportion of patients with HbA1c on treatment <8.0% after 24 weeks of 
treatment

Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of 
treatment

Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of 
treatment

Change from baseline in Fasting Plasma Glucose (FPG) after 24 weeks of 
treatment
Criteria for safety:
Adverse events (including relevant new or worsening pre-existing conditions) and 
hypoglycaemic events
Statistical methods:
Restricted maximum likelihood estimation based on mixed-effect model for repeated
measures analysis will be used to obtain adjusted means for the treatment effects.
This model will include treatment, baseline insulin dose, and week as discrete fixed 
effects, baseline HbA1c as a continuous fixed effect, interaction between week and 
treatment, and interaction between week and baseline HbA1c. The primary treatment 
comparisons will be the contrast between treatments at Week 24.


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FLOW CHART
Screen
Run-In
Treatment
Post-Treatment
Visit
1
2
3
4
5
6
98
99
Week
-2
-1
1
6
12
18
24
25
Day 
-14
-7
1
43
85
127
169
176
Visit Duration to Next Visit (days)
7
7
42
42
42
42
7
N/A
Maximum Visit Window (in days) A
-7
-7
0
+/-7
+/-7
+/-7
+/-7
N/A
Informed Consent A
X
Patient Health Questionnaire (9 item) B
X
Mental Status Examination B
X
Medical History B
X
Demographics B
X
Inclusion/Exclusion Criteria Checks B
X
X
X
Blood Pressure and Pulse B
X
X
X
X
X
X
X
X
Height and BMI A
X
Weight A
X
X
X
Physical Examination B
X
X
12-Lead ECG C 
X
X
X
FPG D 
X
X
X
X
X
HbA1c
X
X
X
X
X
X
Laboratory Tests (urine and blood) B, F
X
X
X
X
X
X
X
X
Lipid Panel
X
X
HBGM and eDiary
X
X
X
X
X
X
X
X
Diet / Exercise Counseling I
X
X
X
X
X
X
X
Adverse Events B, J
X
X
X
X
X
X
X
X
Concomitant Therapy B
X
X
X
X
X
X
X
X
Interactive Response Technology Use K
X
X
X
X
X
X
X
X
Dispense Study Medication L
X
X
X
X
X
Randomisation 
X
Study Medication Compliance Check
X
X
X
X
X
Conclusion of Patient Participation M
X
A
The duration of the Screen Visit or Run-In Visit (each visit) must be 7 days in duration but no fewer provided that all 
evaluations, including laboratory and ECG results as well as any applicable medical information are available at the trial 
site, and the patient meets the inclusion and exclusion criteria.  The allowed visit window for the Screen Visit or Run-In 
Visit (each visit) includes an additional 1 to 7 days.  Therefore, the maximum duration of the Screen Visit or Run-In 
Visit (each visit) is a total of 14 days.  
If a visit window (+/- 7 days: i.e., 1 day to 7 days) is used after randomisation, the patient should be returned to the 
original trial schedule by the next visit (i.e., the number of visit window days used must be subtracted from the 
upcoming visit).  This procedure ensures that all patients complete: the treatment period at approximately Day 169 and 
the Post-Treatment Visit at approximately Day 176.  The visit window between Visits 98 and 99 will not be allowed 
once trial enrolment has been achieved (sufficient patients screened to randomise 300 with 100 from Japan); the 
Clinical Monitor Local (CML) will inform trial sites when trial enrolment is complete.
B
Functional reviews (Patient Health Questionnaire and Saint Louis University Mental Status Examination) will be 
completed first to assess the functional ability, mental health, and cognitive ability of potential patients.  
For the Screen Visit: the screening evaluations (except for the Patient Health Questionnaire, Saint Louis University 
Mental Status Examination, and HbA1c which must be completed in this order immediately after informed consent) may 
be completed on separate days as long as the results are obtained within the allowed days for the visit.  
C
In the event of any cardiac symptoms (i.e., suspicion of heart rhythm disorders or cardiac ischemia) at Visit 1, Visit 3 
and/or Visit 98, an additional follow-up ECG will be collected and recorded after that particular visit.
D
Fasting blood samples (no food and/or drink except for water 10 hours prior to visit) via central lab.  Starting at Visit 3,
if hyperglycaemia is noted, repeat FPG via central lab.
 
 
F
Exception: For the Screen Visit only, patients do not have to be fasting.


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H
Instruction on how to use the Home Blood Glucose Monitoring (HBGM) device will be conducted at Visit 1 and the 
device will be given to the patient.  The patient should be instructed to monitor their blood glucose 4 times daily (before 
breakfast after overnight fasting, before lunch, before dinner, and before bedtime) using the HBGM device beginning 
that day with the closest monitoring time point.  The patient will also answer meal, exercise, and symptom questions on 
the eDiary and upload their glucose values to the eDiary daily.  The patient will be instructed to monitor their blood 
glucose once or twice weekly during sleeping hours if the patient gets up.  During the trial participation, additional 
HBGM monitoring should be completed if the patient has hypo- or hyperglycaemia-related symptoms.
I
Diet and exercise counseling by a diet specialist or trained staff member.  Counseling should be based on local diet 
recommendations.  At all other visits, patients should be reminded about the importance of following the recommended 
diet and exercise plan.
J
The only adverse events that are required to be reported for patients who screen fail before Visit 2 are serious adverse 
events (SAEs).
 
 
M The criteria for discontinuing patients from the trial participation are included in Section 3.3.4.1.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 18
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................18
2.2
TRIAL OBJECTIVES.......................................................................................18
2.3
BENEFIT - RISK ASSESSMENT ...................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 21
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................21
3.1.1
Administrative structure of the trial...................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................23
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for study entry............................................................24
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Removal of patients from therapy or assessments.............................28
4.
TREATMENTS........................................................................................ 30
4.1
TREATMENTS TO BE ADMINISTERED....................................................30
4.1.1
Identity of BI investigational product and comparator product......30
4.1.2
Method of assigning patients to treatment groups ............................30
4.1.3
Selection of doses in the trial................................................................31
4.1.4
Drug assignment and administration of doses for each patient .......31
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................35
4.2.2
Restrictions............................................................................................37
4.3
TREATMENT COMPLIANCE.......................................................................38
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 39
5.1
EFFICACY - PHARMACODYNAMICS........................................................39
5.1.1
Endpoints of efficacy.............................................................................39
5.1.2
Assessment of efficacy...........................................................................40
5.2
SAFETY..............................................................................................................41
5.2.1
Endpoints of safety................................................................................41
5.2.2
Assessment of adverse events...............................................................42
5.2.3
Assessment of safety laboratory parameters......................................46
5.2.4
Electrocardiogram................................................................................48
5.2.5
Assessment of other safety parameters...............................................48
5.3
OTHER...............................................................................................................49
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................51
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................51
5.7
PHARMACODYNAMICS................................................................................52
6.
INVESTIGATIONAL PLAN.................................................................. 53
6.1
VISIT SCHEDULE............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................53
6.2.1
Screen and Run-In Periods ..................................................................53
6.2.2
Treatment period ..................................................................................54
6.2.3
End of trial and follow-up period........................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 56
7.1
STATISTICAL DESIGN - MODEL................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................56
7.3
PLANNED ANALYSES....................................................................................56
7.3.1
Primary analyses...................................................................................57


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7.3.2
Secondary analyses ...............................................................................58
7.3.3
Safety analyses.......................................................................................59
7.3.4
Interim analyses ....................................................................................60
7.3.5
Pharmacokinetic analyses ....................................................................60
7.3.6
Pharmacodynamic analyses.................................................................60
7.4
HANDLING OF MISSING DATA ..................................................................60
7.4.1
Efficacy endpoints.................................................................................60
7.4.2
Safety and other endpoints...................................................................61
7.5
RANDOMISATION ..........................................................................................61
7.6
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 63
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................65
8.3
RECORDS..........................................................................................................66
8.3.1
Source documents .................................................................................66
8.3.2
Direct access to source data and documents.......................................66
8.3.3
Storage of records .................................................................................66
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................67
8.4.1
Listedness...............................................................................................67
8.4.2
Expedited reporting to health authorities and IECs/IRBs................67
8.5
STATEMENT OF CONFIDENTIALITY.......................................................67
8.6
COMPLETION OF TRIAL..............................................................................67
8.7
PROTOCOL VIOLATIONS ............................................................................68
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................68
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
10. APPENDICES .......................................................................................... 75
10.1
INCLUSION OF ILLITERATE PATIENTS .................................................75
10.1.1 Home Blood Glucose Monitoring and eDiary ....................................75
10.1.2 Patient information and informed consent (including 
pharmacogenomics)..............................................................................75
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 77


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine aminotransferase (or SGPT)
a.m.
ante meridiem
AST
Aspartate aminotransferase (or SGOT)
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CEC
Clinical Event Committee
CI
Confidence Interval
CK
Creatine kinase
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CTP
Clinical Trial Protocol
DPP-4
Dipeptidyl-Peptidase IV
 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
e.g.
exempli gratia (for example)
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FPG
Fasting Plasma Glucose
-GT
gamma-glutamyl-transferase
GCP
Good Clinical Practice
GIP
Glucose-dependent insulinotropic peptide
GLP-1
Glucagon-like Peptide
GmbH&Co. KG Gesellschaft mit beschränkter Haftung &Company Kommanditgesellschaft
HbA1c
Glycated or glycosylated Haemoglobin


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HBGM
Home Blood Glucose Monitoring
HDL
High Density Lipoprotein
ICH
International Conference on Harmonisation
i.e.
id est (that is)
IEC
Independent Ethics Committee
Inc.
Incorporated
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
intention to treat
kg/m2
kilograms per meters squared
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
milligrams
mg/dL
milligrams per deciliter
mmol/L
millimoles per Liter
mmol/mol
millimoles per mole
MMRM
Mixed Model Repeated Measures
N/A
not applicable
NCF
Non-completer’s considered failures
NGSP
National Glycohaemoglobin Standardisation Program
OC
Observed Cases
OPU
Operating Unit
p.o.
per os (oral)
PPS
Per Protocol Set
q.d.
quaque die (once a day)
RDC
Remote Data Capture


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REP
residual effect period
SAE
Serious Adverse Event
SGLT2
sodium glucose co-transporter 2
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
STEMI
ST Elevation Myocardial Infarction
SUSAR
Serious Unexpected Suspected Adverse Reaction
T2DM
Type 2 Diabetes Mellitus
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial Master File
TS
treated set
TSAP
Trial Statistical Analysis Plan
ULN
upper limit of normal


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
T2DM accounts for 90% to 95% of all cases of diabetes and is an increasingly prevalent 
disease with over 300 million people estimated to be affected worldwide (R09-4240). The 
rate of obesity is increasing, with a parallel increase in the rate of T2DM (R14-0447).  The 
high frequency of complications leads to a significant reduction of life expectancy
(R09-4241). Because of hyperglycaemia induced microvascular complications, diabetes is 
currently the most frequent cause of adult-onset loss of vision, renal failure, and amputation 
in the Industrialised World and is additionally associated with a two to five fold increase in 
cardiovascular disease risk.
Emerging treatment for T2DM
With the chronic progression of T2DM in many patients, a declining glycaemic control over 
time can become evident despite adequate diet, exercise, and therapies with oral 
antihyperglycaemic agents.  Within a few years, treatment intensification is required because 
of a progressive loss of beta cells and the diminishing secretory capacity of the remaining 
cells, resulting in secondary drug failure and the necessity to institute insulin therapy in many 
patients.  In most cases, insulin resistance cannot be compensated by an adequately increased 
insulin secretion, ultimately leading to increased fasting and postprandial glucose 
concentrations.  Currently available antidiabetic agents are not sufficient to maintain long 
term glycaemic control.  Management of diabetes in the elderly population is complicated by 
these age-related changes (P13-00432).  
Traditional insulin secretagogues, such as the sulphonylurea drugs, increase insulin secretion 
in a non-glucose-dependent manner and carry an increased risk for hypoglycaemia.  
Additionally, it is unclear whether such a glucose independent stimulation of insulin secretion 
accelerates the loss in beta cell function.
An improved understanding of the interaction between gut related hormones and the 
endocrine system has led to the incretin concept and, based on this concept, to the 
development of a new class of antidiabetic agents.  The incretin effect is a phenomenon 
where the glucose-stimulated insulin secretion is augmented by intestinally derived peptides, 
which are released in the presence of glucose or nutrients in the gut.  Glucagon-like peptide-1 
(GLP-1) is an important member of the incretin hormone family.  Importantly, the actions of 
GLP-1 depend on the actual glucose concentration. GLP-1’s stimulation of insulin secretion 
ceases when glucose concentrations fall below 55 milligrams per deciLiter (mg/dL).  
Therefore, elevation of GLP-1 levels bears little to no risk of hypoglycaemia. 
GLP-1 is almost instantaneously inactivated by the enzyme dipeptidyl-peptidase IV (DPP-4) 
explaining its short half-life of only a few minutes.  Postprandial GLP-1 secretion has been 
reported to be attenuated in T2DM which may partially explain the increased postprandial 
glucose excursions.  Therefore, a prolongation of the half-life of GLP-1 may be seen as a 
therapy which restores the lack of GLP-secretion.  Besides its stimulatory effects on insulin 
secretion, GLP-1 has been shown to inhibit glucagon secretion, to delay gastric emptying, to 
induce satiety, and, in animal models, to maintain long-term beta cell function.  Especially 
the maintenance of beta cell function is of interest, because loss of beta cell function has been 


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identified as a major contributor to the deterioration of long term glycaemic control in 
T2DM.
DPP-4 is an enzyme widely expressed in many tissues including kidney, liver, intestine, 
lymphocytes and vascular endothelial cells.  In addition, a significant level of DPP-4 activity 
is also observed in plasma, which likely originates from multiple tissues that express the 
enzyme.  DPP-4 is thought to play an important role in the degradation of a number of 
peptides, thus regulating their half-life.  However, physiological evidence for the role of 
DPP-4 in this process is only available for a few DPP-4 substrates, e.g., GLP-1 and glucose-
dependent insulinotropic peptide (GIP), both of which exert glucose-dependent insulinotropic 
actions and thereby contribute to the maintenance of post-meal glycaemic control.  DPP-4 
knock out rodents exhibit improved glycaemic control and are resistant to diet induced 
obesity, indicating a physiological role of this enzyme in glucose homeostasis and body 
weight regulation. 
A newer class of antihyperglycaemic agent, DPP-4 inhibitors, acting on the GLP-1 axis, 
targets pancreative islet dysfunction, in particular gut-derived incretin hormones.  DPP-4 
inhibitors have some characteristics which may be of particular value in older patients.  
DPP-4 inhibitors can be taken orally, are weight neutral, well tolerated and have a lower risk 
of hypoglycaemia compared with insulin and sulphonylureas (P12-06615).  Indeed, the 
American Diabetes Association and European Association for the Study of Diabetes position 
statement specifically describe the advantage of DPP-4 inhibitors as rarely having severe side 
effects as opposed to the other treatment options (P12-05315).  In a recent observational trial 
evaluating the tolerability and safety of DPP-4 inhibitors for the treatment of older people has 
shown that patients prescribed DPP-4 inhibitors had evidence of improved glycaemic control 
in addition to a lower rate of documented hypoglycaemia (3% vs. 8%) than the non-DPP4 
inhibitor treated group (R14-0340).
A strong scientific rationale suggests that DPP-4 inhibitors can prevent or counteract 
hypoglycaemia.  This is especially important for the management of insulin-treated patients 
since the limiting factor in this population is iatrogenic hypoglycaemia.  The insulinotropic 
effects of incretins are glucose-dependent and decline as postprandial serum glucose levels 
return to normal ranges.  The incretin GIP increases glucagon levels during fasting and 
hypoglycaemic conditions, while potentiating glucose-induce insulin secretion during 
hyperglycaemia (P13-14398).  The DPP-4 inhibitors have been studied in large clinical trials, 
as add-ons to insulin.  For vildagliptin, sitagliptin and saxagliptin, an improved glycaemic 
control was shown when added to ongoing insulin therapy.  All three DPP-4 inhibitors were 
generally well tolerated in patients with T2DM (R14-0340).  The results of these trials 
suggest that concomitant treatment with DPP-4 and insulin is effective for achieving better 
glycaemic control in patients with T2DM while improving the safety and tolerability of the 
antihyperglycaemic treatment.
Management of elderly T2DM patients
T2DM is up to five times more prevalent in elderly patients (65 years of age and older) 
compared to patients who are younger (R14-0340).  Additionally, up to one in five elderly 
patients have T2DM while a similar proportion may have undiagnosed T2DM (R14-0183).  


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Furthermore, diabetes in the elderly is metabolically distinct from diabetes in middle aged 
patients (R04-1263, R09-5797).  
Glucose-lowering treatment of elderly patients with T2DM is generally deemed necessary to 
alleviate symptoms associated with hyperglycaemia and risk reduction of the long-term 
complications.  Although the general goal for patients with T2DM of a HbA1c level of 7.0% 
or less may be reasonable for some elderly patients, recent guidelines stress individualizing 
this target to balance potential benefit and risk of treatment for elderly patients at high risk of 
hypoglycaemia or complications from hypoglycaemia, as long as acutely symptomatic 
hyperglycaemia is avoided (R14-0344).  
Higher glucose levels may contribute to an increase risk of dementia through several 
potential mechanisms, including acute and chronic hyperglycaemia, insulin resistance, and 
increased microvascular disease of the central nervous system (R12-1338, R14-0250, 
R14-0436, R14-0435, R14-0434, R14-0437).  This link of hyperglycaemia to an increase risk 
of dementia may speak against generally higher targets for HbA1c in the elderly population.  
Moreover, the general concern about stricter HbA1c control is largely based on trials that used 
glucose-lowering drugs with relatively high risk of hypoglycaemia.  Thus, hypoglycaemia 
has been shown to increase the risk for dementia and is associated with increased
cardiovascular risk in patients with T2DM.  This illustrates the dilemma of poor health 
outcomes with either hyperglycaemia or hypoglycaemia in older adults with T2DM.  This 
burden may be alleviated by using pharmacotherapies that could achieve relevant 
improvements in glycaemic control with low risk of hypoglycaemia or other adverse effects.
Elderly patients with T2DM generally have a reduced ability to tolerate the adverse effects of 
medication, compared with younger patients (R09-6092).  Over time, most patients with 
T2DM experience progressive beta cell dysfunction and will require insulin therapy, usually 
in combination with oral agents, for satisfactory glycaemic control (P13-14398).  Insulin 
treatment can improve and maintain glycaemic control, preventing long-term complications 
in T2DM.  Basal insulin is becoming an important option when initiating insulin therapy in 
T2DM patients who require insulin (R14-0360).  Many elderly patients are prescribed insulin 
along with other antidiabetic medications for glycaemic control, which increases the risk of 
hypoglycaemia (P13-00432).  
Many glucose-lowering drugs have potential disadvantages for elderly patients, particularly a 
risk for hypoglycaemia (sulfonylureas, insulin), fractures (thiazolidinediones), 
contraindication, or dose adjustments for renal impairment for most oral and injectable agents 
(P13-00432).  Additionally, efficacy of glucose lowering can be affected by disease duration, 
because of deterioration over time in pancreatic beta cell function.  Therefore, safety is an 
important consideration for treatment, especially avoidance of iatrogenic hypoglycaemia, 
which occurs frequently in elderly patients and can have severe consequences. Renal 
impairment is also very common in elderly with T2DM, increasing their risk for 
hypoglycaemia and complicating treatment strategies (P13-00432, R14-0183).
Of particular importance is that hypoglycaemia had the third highest incidence of nonfatal 
complications in 70 year old and older T2DM patients, with the highest rates in patients who 
had T2DM for 10 years or more (R14-0002).  Eventually, the initiation of insulin therapy is 


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necessary in order to maintain glycaemic control.   Insulin accounts for a significant number 
of hypoglycaemic events in the elderly American population each year and SAEs, reported to 
the United States Food and Drug Administration (FDA), related to its use have been steadily 
rising in recent years (P07-11112, P11-14211).  Additionally, sulfonylureas, insulin, and 
metformin (possibly used in combination with each other or other antidiabetic medications) 
trigger a large proportion of drug-related emergency room visits and hospitalizations in the 
United States (R14-0002).  
There is a significant variation in T2DM prevalence and associated mortality rates between 
different geographic areas (P08-11948).  There is a disproportionate burden of this disease 
among some racial and ethnic populations, especially those at the low end of the 
socioeconomic spectrum and/or residing in developing countries.
Clinical trials contribute toward reducing health disparities through improved knowledge 
about treatment among diverse populations.  Minorities are significantly underrepresented in 
clinical trials, with non-participation frequently related to recruitment barriers.  The limited 
generalisability of trial results led the National Institutes of Health to develop guidelines 
ensuring that funded clinical research would generate information about the effects of the 
study intervention on both genders and diverse racial (and ethnic) groups (R13-2759).  Even 
with such guidelines in place, literature suggests significant barriers to successful recruitment 
of minority patients into clinical trials, including cultural beliefs regarding illness and disease, 
mistrust of the health care system, and differences in health beliefs and practices.  Solutions 
lie in exploring new venues to reach minority populations and to create strategies aimed at 
recruiting and retaining these patients.  Greater diversity in clinical trial samples allows for 
broader generalization of trial results, increased minority access to trials, improved standards 
of care, decreased disparities in disease treatment and outcomes, and improved external 
validity supported by a more representative sample (R13-2759).
Despite assuming a disproportional burden of disease and consumption of prescription drugs 
as well as therapies, these older patients have been vastly underrepresented in clinical trials, 
thereby restricting treatments’ generalizability, efficacy and safety (R14-0182).  A recent 
analysis has shown that only 0.6% of interventional trials in T2DM specifically targeted this 
age group, 31% excluded patients older than 65 years, and almost all excluded those older 
than 75 years (R14-0345).  In addition, elderly patients, defined as 65 years of age and older, 
by the American Geriatric Society, have frequently been excluded from those major clinical 
trials used to develop practice guidelines due to age-related complications (R10-5452).  
Based on patients’ health status and risk factors, these complications include but are not 
limited to comorbid conditions, polypharmacy, renal insufficiency, increase fall risk, visual 
impairment, and cognitive impairment and age-related decrease in pancreatic-islet function 
(P14-00552).  As noted, although there are numerous evidence-based guidelines, few 
guidelines are specifically targeted toward the needs of these patients.  
As a result of the extreme difficulty with recruiting this population, the global protocol 
amendment 1 expanded the definition of elderly population beginning at age 60 and 
reduced the lower limit of HbA1c to match the trials that were used for this trial’s 
hypothesis. 
 


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1.2
DRUG PROFILE
 
 
 
 
 
 
 
Linagliptin is a potent inhibitor of DPP-4 and prolongs the half-life of endogenous GLP-1.  
Unlike the other DPP-4 inhibitors, linagliptin, given in a once-daily, single-dose 5 mg 
regimen is excreted mainly by non-renal pathways and dose adjustment is not needed for 
renal impairment or any other factor (P12-05699).  Linagliptin also has minimal drug 
interactions (P12-05699). 
 
  
Treatment with 5 mg linagliptin, once daily, has been shown to be well-tolerated and results 
in clinically meaningful and statistically significant reductions in HbA1c, FPG, and 
postprandial glucose
  There was a consistent pattern in the 
improvement in HbA1c when linagliptin was used in patients with different background 
therapies.  Linagliptin 5 mg has also been shown to give sustained efficacy over 52 weeks in 
T2DM patients with severe renal impairment.  Additionally, linagliptin 5 mg has 
demonstrated clinically relevant efficacy for elderly and African American T2DM patients 
(P10-14001, P11-02847, P11-06845, P11-09378, P11-12477, P13-09565, 
 
 
 
 
 
  
 
  To date, 
in Phase III trials in patients with T2DM, linagliptin elicited meaningful glucose-lowering 
effects and was well tolerated with little intrinsic risk for hypoglycaemia (P10-14001, 
P11-02847, P11-06845, P11-09378, P11-12477).  
 
 


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  Overall, it has 
been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with 
T2DM.  This combination therapy was also shown to be safe and effective in vulnerable, 
elderly T2DM patients and in T2DM patients with renal impairment (P13-14398).  
Recently, in a randomised, placebo-controlled clinical trial that included 241 patients, who 
were 70 years of age and older, with inadequate glycaemic control on stable backgrounds of 
metformin and/or sulphonylurea and/or basal insulin, linagliptin was shown to be safe and 
effective in this patient population (P13-09565).  A subset from a pooled analysis of two 
Phase III trials consisting of 247 patients, 70 years of age and older, who received linagliptin 
or placebo showed adding linagliptin to basal insulin appeared to decrease the risk of 
hypoglycaemia despite significant reduction in HbA1c and no relevant reductions in insulin 
dose (P13-07824).  In summary, linagliptin has been shown to be effective and safe as an 
add-on therapy that can help patients on basal insulin to improve their blood sugar control 
without weight gain or additional risk of hypoglycaemia.
Symptoms that could be attributed to hypoglycaemia as well as plasma glucose levels will be 
closely monitored in this current trial.  Glycaemic goals in elderly patients and interventions 
to achieve such goals must take into account the clinical status of individual patients, in 
particular, avoidance of hypoglycaemia which can have a profound impact on health and 
quality of life in elderly patients.  


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The rationale for conducting this trial in an elderly population on a stable background therapy 
of basal insulin is:

to further establish the adverse event profile of linagliptin,

to achieve improved glycaemic control without increasing adverse events, 

to assess the occurrence of hypoglycaemia, and

to collect additional data in this population.
2.2
TRIAL OBJECTIVES
The objective of this trial is to investigate the efficacy, safety, and tolerability of linagliptin 
5 mg given orally once daily compared to placebo as add-on therapy for 24 weeks to stable
basal insulin treatment in elderly patients, 60 years of age and older, with T2DM with 
insufficient glycaemic control (i.e., HbA1c of 7.0% to 10%).  Stable background therapy of 
metformin and/or alpha-glucosidase inhibitors is also allowed.  
In addition, this trial will assess if linagliptin reduces the risk of hypoglycaemia when added 
to background basal insulin therapy.  The treatment duration of this trial (24 weeks) will 
enable assessment of the clinically relevant endpoint of a decrease in HbA1c, a well-accepted
measurement of chronic glycaemic control.  
For a description of the endpoints chosen and statistical analyses to assess these objectives, 
refer to Section 5 and 7.
2.3
BENEFIT - RISK ASSESSMENT
Potential general benefits for patients in this trial irrespective of the investigational 
medication received are: improvements in glycaemic control, regular diet and exercise 
counseling, as well as general medical benefit from careful and close monitoring by medical 
personnel, and HBGM during the trial.  
General risk associated with participating is related to trial specific procedures such as blood 
sampling that can be associated with bruising and pain.  The amount of blood taken during 
the whole course of the trial is not believed to be excessive and is associated with the 
standard of care for the patients.
One week Run-In Period Risk
Trial designs with a one-week placebo Run-In Period are well-established for T2DM trials.  
The patients will be maintained on stable antidiabetic therapy during the one-week Run-In 


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Period and continue regular monitoring of blood glucose with a HBGM device. Thus, the 
risk of the one-week placebo treatment in this trial is considered to be minimal. 
Background Therapy and Study Medication Specific Risk
Basal insulin is the stable background therapy in this trial.  Patients are administered basal 
insulin and not short-acting insulin because there are fewer injections, lower risk of 
hypoglycaemia, and basal insulin covers postprandial peaks.  Weight gain, hypoglycaemia, 
allergic reactions, injection site reaction, lipodystrophy, pruritus, and rash are the most 
common side effects noted with basal insulin.  All patients will have received basal insulin 
and these events mainly occur shortly after insulin initiation (at least allergic reactions).  For 
safety reasons, the basal insulin dose can always be modified by investigators.
Metformin, a typical background medication, is a drug that has been on the market for a long 
time, is widely used as a first line therapy, and therefore believed to be well characterized in 
terms of risk profile.  Metformin can however cause lactic acidosis to develop, which is 
relatively infrequent and more likely to occur in patients who have kidney or liver disease, 
excessive alcohol use, X-ray or scanning procedures that require an injectable iodinated 
contrast drug, surgery, or a serious infection (R10-5341, R10-5537).  Patients may be taking
metformin as part of their stable background therapy.  With all these conditions being 
excluded and the monitoring throughout the trial, this risk will be minimal for patients taking 
linagliptin and metformin. 
Alpha-glucosidase inhibitors (such as acarbose) may be used as background medication and 
decrease the absorption of carbohydrates from the digestive tract, thereby lowering the 
post-meal glucose levels.  Alpha-glucosidase inhibitors are used to establish greater 
glycaemic control over hyperglycaemia in T2DM, particularly with regard to postprandial 
hyperglycaemia.  Alpha-glucosidase inhibitors may be used as monotherapy in conjunction 
with an appropriate diabetic diet and exercise, or they may be used in conjunction with other 
anti-diabetic drugs.  Alpha-glucosidase inhibitors commonly are associated with 
gastrointestinal side effects such as flatulence, bloating, nausea, vomiting, and diarrhoea.
Angioedema, urticaria and rash are listed as side effects for linagliptin (with any background, 
R11-2588).  For the fixed dose combination of linagliptin plus metformin, the identified side 
effects correspond to the observed side effects of metformin (i.e., decreased appetite, 
diarrhoea, nausea, vomiting, and pruritus) plus the events for linagliptin on all backgrounds 
(nasopharyngitis, cough, hypersensitivity and pancreatitis as well as angioedema, urticaria, 
and rash).  Furthermore, longer term safety data have not shown any further safety trends to 
date. 
 
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when linagliptin is administered.  Other risks to the patients are the risks 
inherent to any clinical trial such as unexpected adverse clinical or laboratory events.  Safety 
will be ensured by monitoring the patients for adverse events (AEs) both clinically and by 
laboratory testing.  If any investigator should have a clinical concern, the safety of the 
patients will be of paramount importance.


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Approximately half of the patients participating in this trial may derive a direct benefit from 
being treated with an active compound and not a placebo.  Patients who are not adequately 
controlled (whether in the blinded placebo or active compound group), as evidenced by FPG
or blood glucose values (by HBGM device), will have adjustments to their background 
therapy or receive rescue therapy (according to Section 4.2.1) to ensure their safety.
Rescue therapy will be permitted in case of hyperglycaemia during the randomised treatment 
period if the defined criteria are met (refer to Section 4.2.1).  The choice of rescue medication 
and its dosage according to Section 4.2.1 will be left to the discretion of the investigator and 
rescue medication will be taken in accordance with the local prescribing information of that 
respective medication.  The use of rescue medication may be associated with relevant side 
effects, such as increase of hypoglycaemia risk, weight gain, etc.
Alternative Therapies for T2DM
There are several alternative therapies available for the treatment of T2DM (e.g., biguanides, 
sulphonylureas, thiazolidinediones, sodium glucose co-transporter 2 (SGLT2) inhibitors, 
metglitinides, alpha-glucosidase inhibitors, rapid acting or short acting insulin); however, 
these are not without side effects.  Side effects in the elderly population with 
thiazolidinediones include fluid retention, fracture risk, and heart failure risk.  Side effects in 
the elderly population with sulphonylureas and metglitinides include hypoglycaemia.  In the 
context of advanced age and diminished renal functions, cases of prolonged and severe 
hypoglycaemia with sulphonylurea treatment have been reported.  Side effects in the elderly 
population with alpha-glucosidase inhibitors include gastrointestinal side effects.  Side effects 
in the elderly population with rapid acting or short acting insulin include several injections 
and hypoglycaemia.
Thus, given the above considerations, the benefit-risk assessment for the use of linagliptin for 
the treatment of T2DM in elderly patients to improve glycaemic control is considered 
favourable for the conduct of this trial.  


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomised, double-blind, multi-national, placebo-controlled, parallel group trial will 
compare linagliptin 5 mg daily to placebo as add-on therapy to a stable background of basal 
insulin, metformin (optional), and/or alpha-glucosidase inhibitors (optional) over 24 weeks in 
elderly T2DM patients with insufficient glycaemic control.
In total, approximately 300 T2DM patients (100 from Japan), 60 years of age and older, 
with insufficient glycaemic control will enter (i.e., be randomised in) this trial.  The 
randomised treatment will be provided in a double-blind design within the two treatment 
arms (each patient will receive either linagliptin as active treatment or placebo matching 
linagliptin). 
Patients are enrolled into the trial once they have signed the informed consent.  The Screen 
Period is one week in length.  All patients meeting the inclusion and exclusion criteria will 
complete a one week placebo Run-In Period before randomisation.  
Patients who successfully complete the Run-In Period and still meet the inclusion and 
exclusion criteria will be randomised into the 24 week treatment period of the trial in which 
they will receive either linagliptin 5 mg or placebo.  
Run-In
(7 to 14 days duration)
Eligibility Assessment
linagliptin 5 mg
(24 weeks duration)
Post-Treatment
(7 days duration)
Screen
(7 to 14 days duration)
Eligibility Assessment
placebo
(24 weeks duration)
Randomisation
or
Figure 3.1: Trial Periods
All adverse events with an onset after the first dose of study medication up to a period of 
seven days after the last dose of study medication will be assigned to the treatment phase for 


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evaluation.  This includes adverse events that start before first study medication intake and 
deteriorate under treatment.  Other adverse events will be assigned either to the screening, 
run-in, or follow-up phase as appropriate.  All adverse events, including those persisting after 
trial completion at the Post-Treatment Visit (Visit 99), will be followed-up for up to 7 days.  
The investigative staff should confirm if continuing adverse events have resolved or have 
been sufficiently characterised.  
The end of the trial is defined as “last patient out”, i.e., last visit completed by the last patient.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG. 
BI will appoint a Trial Clinical Monitor (TCM), responsible for coordinating the activities 
required in order to manage the trial in accordance with applicable regulations and internal 
standard operating procedures (SOPs), directing the clinical trial team in the preparation, 
conduct, and reporting of the trial, order the materials as needed for the trial, ensures 
appropriate training and information of CML, Clinical Research Associates (CRAs), and 
investigators of participating countries.
Data Management and Statistical evaluation will be performed by BI according to BI SOPs.  
For these activities, a Trial Data Manager and a Trial Statistician will be appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs.  A list of responsible persons will be given in the Trial Master 
File (TMF) document.
The organisation of the trial in the participating countries will be done by the respective local 
BI organisation [Operating Unit (OPU)] or a by a Contract Research Organisation with which 
the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical trial.  In each OPU participating in this trial, a CML will be appointed 
responsible for coordinating the activities required in order to manage the trial in accordance 
with applicable regulations and internal SOPs in the countries covered by the respective BI 
OPU.
A Co-ordinating Investigator will be nominated to coordinate investigators at different trial 
sites participating in this multicentre trial.  Tasks and responsibilities for the Co-ordinating 
Investigator will be defined in a contract filed before initiation of the trial.
Documents on participating (Principal) investigators and other important participants, 
especially their curricula vitae, will be filed in the TMF. 
A BI preferred central laboratory, ECG, and IRT provider will be selected to provide services 
for laboratory sample handling and analyses, ECG interpretation, and for study medication 
logistics, respectively as required for this protocol. 
The eDiary and HBGM device will be provided by a BI preferred provider.


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Details on handling of the trial supplies including responsible institutions are given in 
Section 4 of this protocol.
The Investigator Site File (ISF) will be kept in printed version at the trial sites as far as 
required by local regulation and BI SOP.  A copy of the ISF documents will be kept as an 
electronic TMF document according to BI SOPs.
Based on the known safety profile, therapeutic window, and tolerability of linagliptin, a Data 
Monitoring Committee is not required for this trial.
Clinical Event Committees:
Independent, blinded, external committees will be managed by BI’s third party preferred 
provider and set up for adjudication of pancreatic, cerebrovascular, and cardiovascular 
events.  Details on the composition of each of the committees, their respective procedures and 
interaction will be provided in separate Clinical Event Committee (CEC) charters that will be 
filed in the TMF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
Due to its mechanism of action and the low risk for hypoglycaemia induction, DPP-4 
inhibitors like linagliptin should provide additional efficacy alongside manageable 
tolerability and safety in elderly patients when added to background antidiabetic therapy 
consisting of basal insulin, metformin (optional), and/or alpha-glucosidase inhibitors
(optional).  
Elderly patients with T2DM who have insufficient glycaemic control will enter the trial and 
receive either double-blind linagliptin or placebo.  The placebo-controlled design is 
considered ethically acceptable on the basis of the benefit and risk assessment, as defined in 
Section 2.3; appropriate criteria for patient discontinuation, ability to adjust or change 
permitted antidiabetic therapy to maintain, or obtain sufficient level of glycaemic control, as 
defined in Section 4.2.1; and relevant local and regional guidelines for optimized standard of 
care. 
The randomised treatment period is planned for 24 weeks because the primary efficacy 
endpoint of HbA1c has been shown to reflect glycaemic control over the preceding 12 weeks
and this period should allow sufficient time to demonstrate changes in the incidence of 
hypoglycaemia events.  The 1-week Post-Treatment period is considered to be sufficient, as 
previous trials with linagliptin have shown that the pharmacodynamic effect of linagliptin 
only extends to about 7 days after the last dose.
The permitted background antidiabetic therapy will not be provided as part of the clinical trial 
supplies, unless required by local laws and regulations.
The rationale for dose and dose-interval selection is described in Section 4.1.3.


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3.3
SELECTION OF TRIAL POPULATION
This is an international trial in which approximately 300 patients (100 patients from Japan)
will be randomised to treatment (150 patients to each treatment group). 
It is expected that at least 4 to 8 patients should be enrolled (or screened) at each trial site.  If 
enrolment is delayed, additional trial sites may be recruited.
The IRT system will permit each trial site to randomise up to 30 patients.  The TCM may 
allow the randomisation of additional patients after a careful assessment of potential bias due 
to the patient distribution across trial sites.  Permission for a trial site to randomise more than 
30 patients must be obtained from the TCM in writing, via the Clinical Monitor Local at BI, 
in order to increase the number of patients allowed to be randomised at the trial site.
Screening of patients for this trial is competitive (i.e., when a sufficient number of patients 
have been screened and/or randomised to study medication, screening of patients for the trial 
will end at all trial sites).  It is possible that recruitment for countries may be stopped 
while recruitment in Japan continues in order to achieve the required 100 patients 
randomized in Japan.  Investigators will be notified when a sufficient number of patients 
have been screened and of the date on which screening will finish.  The date that screening 
may end could be within a 24 hour period of time depending on enrolment numbers.  
Therefore, investigators may need to contact patients in order to cancel planned screening 
visits.  The investigators will not be allowed to recruit additional patients for this trial after 
the date that screening has ended.  Patients who have completed Screen procedures prior to 
notification of the termination of recruitment will be allowed to continue in the trial if they 
meet all entry criteria and are able to follow the visit schedule specified in this protocol.
Patient eligibility will be assessed by a complete medical history, which may be obtained by 
the investigator verbally from the patient during a trial site visit but is required to be 
documented in a source document by the investigator (including past medical records of at
least 1 year), physical examination, and laboratory tests as described in this protocol.  
Judgement of the clinical relevance of a concomitant disease is at the discretion of the 
investigator.  Conditions under therapy are always clinically relevant. 
A log of all patients included into the trial (i.e., having given informed consent) will be 
maintained in the ISF at the trial site irrespective of whether they have been treated with 
study medication or not.
3.3.1
Main diagnosis for study entry
The trial will be conducted in elderly patients with T2DM on stable basal insulin, metformin 
(optional), and/or alpha-glucosidase inhibitors (optional) with insufficient glycaemic control,
who may or may not be on a diet and exercise program per standard local clinical practice,
prior to entry.


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3.3.2
Inclusion criteria
1. Patients must sign and date an Informed Consent consistent with International 
Conference on Harmonisation (ICH) / Good Clinical Practice (GCP) guidelines and 
local regulations prior to any evaluation and participation in the trial.
2. Male and female patients with a clinical diagnosis of T2DM, at the time of Informed 
Consent, who are:
a.
60 years of age or older at informed consent or Screen Visit,
b. taking stable doses of basal or biosimilar basal insulin [strictly inclusive of: 
insulin neutral protamine Hagedorn (NPH), Humalog Basal® (a suspension 
of insulin lispro protamine), and isophane insulin; insulin degludec; insulin 
detemir; and insulin glargine] for at least 4 weeks prior to randomisation (Visit 
3) with dose adjustments up to a maximum of +/- 20% of baseline being 
allowed, 
c.
may or may not be taking metformin immediate release or extended release [if 
the patient is taking metformin, stable dose must be maintained for at least 
12 weeks without dose adjustments prior to randomisation (Visit 3)], and
d. may or may not be taking alpha-glucosidase inhibitors [acarbose, miglitol, and 
voglibose; if the patient is taking alpha-glucosidase inhibitors, stable dose 
must be maintained for at least 12 weeks without dose adjustments prior to 
randomisation (Visit 3)].
3. Patients must have an HbA1c of 7.0% [53 millimoles per mole (mmol/mol)] to 10.0% 
(86 mmol/mol) at the first visit (Screen).  
4. Patients must have a BMI of 45 kg/m2 or less at the Screen Visit.
5. In the investigator’s opinion, patients must be reliable, compliant, and agree to 
cooperate with all planned future trial evaluations as explained in detail during the 
informed consent process and to be able to perform them.
3.3.3
Exclusion criteria
Patients with, who are, who have, or who have had:
1. Impaired cognitive ability as supported by the Saint Louis University Mental Status 
Examination (R14-0995, R14-0977, R14-0992), additional assessment if necessary 
(as described below), and verified by the investigator at Screen. Saint Louis 
University Mental Status Examination scores of 21 to 26 for those patients with high 
school education or 20 to 24 for those patients who did not complete a high school 
education indicate that the patient probably has mild neurocognitive disorder and 
may be further evaluated as noted below.  


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The investigator may complete an additional assessment based on typical activities of 
daily living so that mild neurocognitive disorder can be ruled out if the investigator 
believes that a patient does not have mild neurocognitive disorder as supported by 
the score on the Saint Louis University Mental Status Examination.  Patients with 
dementia scores on this assessment of 1 to 20 with a high school education 
equivalent or 1 to 19 without a high school education equivalent must not proceed 
with further evaluations in the Screen Visit.
Note:  High school or upper secondary education (completing approximately 12 grade 
levels) equivalents may include the following examinations or certificates such as 
General Certificate of Education, Leaving Certificate, Reifezeugnis or Abitur, 
Apolyterion, Baccalaureate, Matura, Swiadectwo Dojrzalosci, Maturity,
Studentereksamen, Ylioppilastutkintotodistus or Studentbetyg, Diploma de 
Maturitate, Corso de Orientacion Universitaria, Senior High School Grad, 
Gymnasium, Higher Preparatory Examination, Higher Commercial Examination,
Higher Technical Examination, Bachillerato, University Entrance Certificate, Senior 
Certificate, National Senior Certificate, Joint Matriculation Board Certificate, 
Advanced Level Exams, National Senior Certificate or Matric examination.
2. Depressed mood as supported by a score of 10 or more on the Patient Health 
Questionnaire (R13-3779) at the Screen Visit.  
3. Type 1 Diabetes Mellitus as determined by past medical records and history.
4. Acute coronary syndrome [non-ST Elevation Myocardial Infarction (STEMI), 
STEMI, and/or unstable angina pectoris], stroke or transient ischemic attack within 
3 months prior to Screen Visit.
5. Indication of liver disease determined during Screen and/or Run-In Period, defined by 
a serum level above 3 times the upper limit of normal (ULN) in any of the following: 
alanine aminotransferase [ALT or called serum glutamic pyruvic transaminase 
(SGPT)], aspartate aminotransferase [AST or serum glutamic oxaloacetic 
transaminase (SGOT)], or alkaline phosphatase.  Gilbert-Meulengracht syndrome 
(also known as conjugated hyperbilirubinemia, constitutional hepatic dysfunction, or 
familial nonhemolytic jaundice) will be permitted.
6. Bariatric, gastric bypass, and other gastrointestinal procedures or surgeries (including 
all types of gastric banding, restriction, and/or LapBand) with the objective of 
promoting weight loss within the past two years at Screen Visit.
7. Medical history of cancer (except for resected non-invasive basal or squamous cell 
carcinoma) and/or treatment for cancer within the last 5 years.
8. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (e.g., 
malaria, babesiosis, haemolytic anaemia). 
9. Treatment with GLP-1 analogues within 3 months prior to Informed Consent.


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10. Treatment with sulphonylureas, thiazolidinediones, meglitinides, bromocriptine,
SGLT2 inhibitors, or DPP-4 inhibitors within 3 months prior to randomization (Visit 
3).
11. Treatment with rapid acting or short acting insulin and/or pre-mixed insulin
containing rapid acting or short acting insulin within 3 months prior to randomization 
(Visit 3).
12. Known hypersensitivity, allergy, or any contraindication to linagliptin or its excipients 
or the patients’ background therapy (i.e., basal insulin, metformin, or 
alpha-glucosidase inhibitors) or placebo, according to local labels. 
13. Treatment with anti-obesity drugs, including over-the-counter drugs such as Alli
(orlistat), 4 weeks prior to informed consent or any other treatment at the time of 
screening (i.e., surgery, aggressive diet regimen, etc.) leading to unstable body 
weight.
14. Current treatment with any drugs known to have significant effect on glucose 
metabolism, such as systemic steroids, at time of informed consent or change in 
dosage of thyroid hormones within 6 weeks prior to informed consent or any other 
uncontrolled endocrine disorder excluding T2DM.
15. Alcohol or drug abuse within the 3 months prior to informed consent that would 
interfere with trial participation or any ongoing condition leading to decreased 
compliance to trial procedures or study medication intake in the opinion of the 
investigator.
16. Participation in another trial with an investigational drug within 2 months prior to 
informed consent.
17. Psychological, familial, sociological, or geographical factors potentially hampering 
compliance with the protocol, visits, or trial procedures or any other clinical condition 
that would jeopardize patient safety while participating in this clinical trial in the 
opinion of the investigator.
18. Inability to commit to regular overnight fasting of at least 10 hours duration and 
attendance to trial site visits between 07:00 and 11:00 ante meridiem (a.m.).
NOTE:  No protocol waivers will be granted for any reason during the trial.  Patients who do 
not meet one or more of the entry criteria or discontinue before Visit 3 will not be 
randomised and will be screen failures.  The primary reason for the screen failure will be 
recorded on the electronic case report form (eCRF). 
If a protocol violation occurred in relation to inclusion or exclusion criteria and a patient was 
mistakenly randomized, the investigator will need to contact the CML to request permission 
for the patient to continue in the trial, document the reason for this protocol violation in the 
patient's medical records, and report the protocol violation to their Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC).


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
Screen failures
Patients who do not meet one or more of the entry criteria or discontinue before Visit 3 will 
not be randomized and will be screen failures.  The primary reason for the screen failure will 
be recorded on the eCRF. Patients who have screen failed in this trial are not permitted to be 
re-screened at a later time point.
Discontinuing or withdrawing patients from the trial
If a patient discontinues (drops out or withdraws) from this trial after randomization, the 
patient will not be replaced.
Patients have the right to withdraw from this trial at any time for any reason.  The patients 
will be asked by the investigator to provide the specific reason for their withdrawal from the 
trial (e.g., moving out of the state or country, unable to drive to trial site, etc.) and this reason 
will be recorded on the eCRF. 
Patients who discontinue from this trial are not allowed to re-enrol in this trial, including 
patients from other trial sites.
Patients will be discontinued from the trial for:

significant non-compliance (If the patient fails to comply with the protocol (e.g., 
non-compliance with study medication or evaluations), a patient may be discontinued 
after discussion between investigator and sponsor), 

concomitant drugs that interfere with the medications being given in this trial,

no longer being able to participate for other medical reasons (e.g., surgery, AEs, or other 
diseases),

persistent hyperglycaemia that is uncontrolled with rescue medication as described in 
Section 4.2.1 (In this case, the reason for discontinuation will be classified as “lack of 
efficacy”), and

occurrence of hypoglycaemia that may put the patient at risk with continued participation 
(e.g., repeated hypoglycaemic episodes).

If pancreatitis is suspected, the study medication should be stopped.
The investigator also has the right to withdraw patients from the trial because continuation of 
study medication or continuation of the follow up visits may not be in the best interest of the 
patient.
If necessary for patient safety, as determined by investigator, new antidiabetic medication 
regimen may be started the day after study medication discontinuation. The new antidiabetic 
medication must be recorded in eCRFs.


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It is understood by all concerned that an excessive rate of withdrawals can render the trial 
uninterpretable; therefore, unnecessary withdrawal of patients should be avoided.  Should a 
patient decide to discontinue, all efforts by the investigator will be made to complete and 
report the last treatment visit evaluations (i.e., Visit 98) as thoroughly as possible.
If a patient discontinues from this trial, the patient should have the Visit 98 (the final 
assessment that is considered to be on-treatment or shortly thereafter) evaluations completed 
as soon after stopping study medication as possible.  Additionally, the patient should have the 
Post-Treatment Visit (Visit 99) evaluations completed one week after Visit 98.  The 
investigator or a staff member should contact the patient (or a responsible relative or 
designee) either by telephone to determine the primary reason for withdrawal from the trial if 
the patient refuses to return to the trial site.  The primary reason for the withdrawal from the 
trial will be recorded on the Termination of Trial Medication eCRF.  If the patient is dropped 
due to an adverse event, the Termination of Trial Medication form must agree with the 
adverse event eCRF.  The reason for discontinuation will be included in the trial database and 
reported.
3.3.4.2
Discontinuation of the trial by the sponsor
BI 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. Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial and/or invalidate the earlier positive benefit-risk-assessment
3. Violation of GCP, this protocol, or the contract by a trial site or investigator, 
disturbing the appropriate conduct of the trial.
The investigator and/or 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
TREATMENTS TO BE ADMINISTERED
The study medication will be provided by Boehringer Ingelheim Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test products are below.
Substance: 
linagliptin film-coated tablet 5 mg
Pharmaceutical form: 
tablet
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength: 
5 mg
Route of administration: 
p.o., once daily
Substance: 
placebo for linagliptin film-coated tablet 5 mg
Pharmaceutical form: 
tablet
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength: 
N/A
Route of administration: 
p.o., once daily
4.1.2
Method of assigning patients to treatment groups
When a patient is qualified 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.  
Patients will be randomly assigned to linagliptin film-coated tablet 5 mg or placebo for 
linagliptin film-coated tablet 5 mg in a 1:1 ratio.  The randomisation will be stratified by 
HbA1c (< 8.5% vs. ≥ 8.5%) as determined from the blood sample taken at Visit 1 and insulin 
dose (< 40 international units total daily dose vs. ≥ 40 international units total daily dose) as 
determined at the beginning of the placebo run-in period (Visit 2).  To ensure appropriate 
representation of patients with insulin doses of < 40 international units total daily dose as 
well as ≥ 40 international units total daily dose, the trial team will monitor the proportion of 
patients being recruited into these categories.  The limitation of recruitment of a particular 
category may be arranged (on trial level and/or country level).  For further details, refer to 
Section 7.5.
Patient assignment to the treatment groups will be determined by a computer generated 
random sequence. IRT will be used to assign study medication.  IRT handling details are 
described in the manual for IRT procedures, which is available in the ISF.  Access to the 
randomisation code will be controlled and documented, for further details refer to Sections 
4.1.5.1 and 4.1.5.2.  
The assigned medication numbers will be entered in the eCRF, and the corresponding study 
medication bottle should be given to the patient.  Using this procedure, relevant parties will 


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be blinded to the treatment group assignment.  
4.1.3
Selection of doses in the trial
The dose of 5 mg linagliptin was selected based on the results from previous dose ranging 
studies (refer to Investigator's Brochure, U04-1767, current version) and represents the final 
marketed dose for linagliptin.
4.1.4
Drug assignment and administration of doses for each patient
Patients will continue with the permitted antidiabetic therapy throughout the duration of the 
trial unless a medical emergency or another plausible reason (e.g., renal impairment, lactic 
acidosis, dose intolerance, hypoglycaemia, or hyperglycaemia) necessitate changes (at the 
discretion of the investigator).  If a patient is taking antidiabetic therapy that includes 
metformin and is expected to be exposed to an iodine-containing contrast agent for a 
diagnostic or surgical procedure, metformin should be temporarily stopped before and after 
the administration of iodine-containing contrast agent according to the metformin prescribing 
information and regional or local guidelines.
Patients who qualify for double-blind treatment will be randomized to one of the dosage and 
treatment schedules described in Table 4.1.4: 1.  The study medication for this trial will be 
dispensed in a double-blind manner.  Each patient will receive a Run-In bottle at Visit 2 and 
be instructed to take placebo medication daily for one week.  At Visit 3, patients who qualify 
based on inclusion and exclusion criteria will be randomised to one of the two dosage 
regimens, either linagliptin 5 mg daily or placebo matching linagliptin daily.  
Dispensing of bottles for the double-blind treatment period will begin at Visit 3.  Dispensing 
will occur on 4 occasions over a period of 24 weeks.  For further details regarding packaging 
(e.g., number of tablets per bottle), refer to Section 4.1.6.  
Table 4.1.4: 1
Treatment group dosing schedule
Group 1: linagliptin 5 mg treatment group
Visit 
Day 
Treatment arm
Morning
Note
2
-7
placebo
〇
Run-In Period
3 to 98 1 to 169 linagliptin 5 mg 
●
Treatment Period: The last dose of study 
medication will be taken by the patient on 
the morning before Visit 98.
●: linagliptin 5 mg tablet; 〇: placebo for linagliptin 5 mg tablet
Group 2: placebo for linagliptin 5 mg tablet treatment group
Visit 
Day 
Treatment arm
Morning
Note
2
-7
placebo
〇
Run-In Period
3 to 98 1 to 169 placebo for 
linagliptin 5 mg
〇
Treatment Period: The last dose of study 
medication will be taken by the patient on 
the morning before Visit 98.
〇: placebo for linagliptin 5 mg tablet


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Administration of the study medication is once daily. Study medication can be taken with or 
without food.  At Visit 2 and each subsequent clinic visit, the investigator will open the study 
medication bottle and administer the first dose of study medication to the patient after the 
safety laboratory tests and ECG, if applicable, have been completed.
At the beginning of the placebo Run-In Period (Visit 2), patients should be instructed to take 
1 tablet with water in the morning.  To ensure a dose interval of about 24 hours, the 
medication should be taken at the same time every morning.  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.
Patients should be instructed not to take their study medication and remain fasting on the 
morning of clinic visits.  After the laboratory tests and ECG (if applicable at that particular 
visit) have been completed, the investigator will open the study medication bottle and 
administer the first dose of study medication to the patient.  Patients who fail to follow this 
procedure should have the visit rescheduled as soon as possible, ideally on the following day.  
Visits will be routinely scheduled in the morning from 07:00 a.m. to 11:00 a.m., at 
approximately the same time of day for each visit.  The actual date and time of administration 
of the study medication at the clinic visit will be recorded in the eCRF.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is a double-blind, placebo-controlled trial.  After randomisation at Visit 3, all patients, 
members of the investigative staff, sponsor’s Clinical Trial Team, and anyone involved in 
analysing or with an interest in this trial are to remain blinded to the randomisation treatment 
assignments until after the database is locked.  The randomisation treatment assignments 
(code) will be kept secret by Clinical Trial Support until database lock.
During the trial conduct, a Clinical Safety Officer or representative from BI’s Global 
Pharmacovigilance group will have access to the randomisation code for individual patients 
and would be able to unblind Serious Unexpected Suspected Adverse Reactions (SUSARs) 
for regulatory requirements to report these events.  In such cases, access to the randomisation 
treatment assignments will only be provided to authorised Clinical Safety Officers or 
representatives of Global Pharmacovigilance.  
Please refer to Section 4.1.5.2 for the procedure regarding unblinding the randomisation code 
for an individual patient in an emergency situation.
4.1.5.2
Procedures for emergency unblinding
An emergency unblinding process will allow the investigator to access an individual patient's 
treatment via IRT.  This emergency unblinding process may only be initiated in emergency 
situations when the identity of the study medication must be known to the investigator in 
order to provide appropriate medical treatment or if required to assure safety of trial 
participants.  The investigator will contact the sponsor to discuss the emergency situation as 


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soon as possible.  The reason for obtaining the emergency unblinding must be documented in 
the appropriate eCRF along with the date and the reason for unblinding the study medication.  
4.1.6
Packaging, labelling, and re-supply
Study medication will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 
The study medication will consist of bottles labeled with the trial identification and 
medication number.  After randomisation, each bottle will contain an appropriate number of 
linagliptin or placebo matching linagliptin tablets with two weeks reserve, for dosing until the 
next scheduled visit. 
Study medication will be supplied on a per visit basis.  Supply and re-supply will be managed 
by IRT.  
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
The study medication must be kept in its original packaging under the recommended storage 
conditions indicated on the label.  
Trial sites must maintain a temperature log in the location that the study medication is being 
stored. The temperature must be recorded daily with temperature range (minimum and 
maximum temperatures) being collected for the week (i.e., thermometers must record and 
retain temperatures for 7 days so that temperatures can be retrieved and recorded for holidays 
and weekends).  If the storage conditions are found to be outside the specified range, 
immediately contact the CRA and CML, as provided in the list of contacts in the ISF, in 
writing.
Following completion of the trial, all unused medication as well as bottles and containers 
must be returned to the Sponsor.  Please refer to the detailed instructions on how to return the 
study medication in Section 4 of the ISF.  Receipt, usage, and return must be documented on 
the appropriate forms.  An account must be provided for all discrepancies.
4.1.8
Drug accountability
Study medication, which will be provided by the Sponsor and/or an IRT vendor appointed by 
the Sponsor, must be kept in a secure, limited access storage area under the storage 
conditions defined by the sponsor.  A temperature log must be maintained to make certain 
that the study medication is stored at the correct temperature.
The investigator, pharmacist, or study medication storage manager will receive the study 
medications delivered by the sponsor when the following requirements are fulfilled:
•
approval of the trial protocol by the IRB or ethics committee,


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•
availability of a signed and dated clinical trial contract between the sponsor and the 
principal investigator or trial site,
•
approval/notification of the regulatory authority, e.g., competent authority (CA),
•
availability of the curriculum vitae of the principal investigator,
•
availability of a signed and dated clinical trial protocol (CTP) or immediately 
imminent signing of the CTP (in exceptional cases, medication could already be 
sent to the trial site, before its activation via IRT)
•
availability of the proof of a medical licence for the principal investigator, and
•
for the United States, availability of the FDA Form 1572.
The investigator, pharmacist, or study medication storage manager must maintain records of 
the study medication’s delivery to the trial site, the inventory at the trial site, the use by each 
patient, and the return to the sponsor or alternative disposition of unused study medication.  
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the study medication and patients in the trial.  The 
investigator, pharmacist, or study medication storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all study medication received from the Sponsor.  At the time of return to the 
Sponsor or appointed IRT vendor, the investigator, pharmacist, or study medication manager 
must verify that all unused or partially used study medication has been returned by the 
patients in the trial and that no remaining study medication is in the investigator’s possession.
The following text is only applicable for Japan:
The investigator, pharmacist, or study medication storage manager will receive the study 
medication delivered by the sponsor representative after IRB or ethics committee approval of 
the trial and completion of a clinical trial contract between the sponsor representative and 
the Head of Trial Site.
The investigator, pharmacist, or study medication storage manager should return the unused 
and collected study medication (including the empty boxes) to the sponsor after unblinding 
the trial.
In case study medication is returned before unblinding of the trial, the investigator, 
pharmacist, or study medication storage manager should seal the opened box (excluding 
empty boxes) for the patient, and before returning the unused and collected study medication 
(including the empty boxes) to the sponsor. When returning the study medication, the 
investigator, pharmacist, or study medication storage manager should exercise utmost 
caution to assure that the sponsor representative and other relevant trial staff members 
remain blinded to the patient’s name on the package (box or label) of the study medication.


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Upon completion of the trial, the investigator, pharmacist, or study medication storage 
manager submits to the sponsor representative a copy of the study medication dispensing and 
return log. When submitting the copy, the investigator, pharmacist, or study medication 
storage manager should exercise caution to assure that the sponsor representative and other 
relevant trial staff members remain blind to the patient’s name.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Patients should only take study medication and the permitted antidiabetic therapy of basal 
insulin, metformin (optional) and/or alpha-glucosidase inhibitor (optional) after 
randomisation (i.e., from Visit 3 to Visit 98) for the treatment of T2DM.
The patient’s permitted antidiabetic therapy should not be increased or decreased by > 20% 
from stable baseline during the 7 day period from the Run-In Visit to randomisation (Visit 3).
After randomisation, investigators should review the patient’s HBGM results electronically 
for hyperglycaemia and should follow the permitted antidiabetic therapy criteria noted 
below to achieve improved patient glycaemic control before taking any additional action
with rescue therapy.  Additionally, investigators should review the patient’s HBGM and 
eDiary results electronically for hypoglycaemia and should adjust or decrease the patient’s 
permitted antidiabetic therapy by electronic contact with the patient via the eDiary or 
recommend other medical advice (e.g., encouraging the patient not to skip meals, increasing 
carbohydrate intake if increasing exercise, etc.) to achieve improved or individualised patient 
glycaemic control before taking any additional action.
Criteria for Increasing, Adjusting, or Decreasing Permitted Antidiabetic Therapy 
If the following FPG criteria are met and if further supported by HBGM results during the 
same time period, investigators may increase or adjust the patient’s permitted antidiabetic 
therapy (i.e., the patient’s background therapy of stable basal insulin prior to or after 
informed consent, and if applicable metformin and/or alpha-glucosidase inhibitor) for the 
treatment of hyperglycaemia (R08-2669):
Visit 3 to Visit 5
The patient has a FPG level > 270 mg/dL [>15.0 millimoles per Liter (mmol/L)]
drawn by the study staff for the central lab after an overnight fast 
Visit 5 to Visit 98
The patient has a FPG level >240 mg/dL (>13.3 mmol/L) drawn by the study staff 
for the central lab after an overnight fast
If the above criteria are met, the investigator should increase or adjust (e.g., by changing the 
timing of administration, etc.) the patient’s permitted antidiabetic therapy to improve 
glycaemic control according to investigator’s discretion and the changes should be 
documented in the eCRF.  
If the patient is experiencing hypoglycaemia, the investigator should review the eDiary 
responses to diet and physical activity as well as the HBGM results to determine the 


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appropriate approach to reduce occurrences of hypoglycaemia (e.g., encouraging the patient 
not to skip meals, increasing carbohydrate intake if increasing exercise, decreasing or 
adjusting the patient’s permitted antidiabetic therapy).
The following permitted antidiabetic therapy will be considered to be rescue therapy:

For patients with a baseline daily insulin dose ≤10 units, any increase of basal 
insulin >50% from baseline for > 7 days duration

For patients with a baseline daily insulin dose >10 and ≤20 units, any increase of 
basal insulin >30% from baseline for > 7 days duration

For patients with a baseline daily insulin dose > 20 units, any increase of basal 
insulin >20% from baseline for > 7 days duration

Any increase in metformin and/or alpha-glucosidase inhibitors (AGI) for ≥ 1 day

Any introduction of a new antidiabetic therapy for ≥ 1 day.
Due to the elderly population and the inclusion of patients on very low daily insulin 
doses at baseline, this allows short term increases that may be required for reasons not 
associated with glycaemic control, e.g., medical procedures.
Initiating Rescue Medication (i.e., additional medications)
Rescue medication cannot be initiated during the Run-In Period and would prohibit the 
randomisation of the patient.
If increasing or adjusting the patient’s permitted antidiabetic therapy, as noted above, is 
unsuccessful in reducing the patient’s FPG to 270 mg/dL or lower (≤ 15.0 mmol/L) after an 
overnight fast following a dosage adjustment period of 6 weeks (i.e., occurring no earlier than 
Visit 4), the initiation of rescue medication is at the investigator’s discretion, based on the 
patient’s current clinical condition (e.g., ongoing illness, etc.).  
Before the initiation of rescue therapy, a sample for FPG and HbA1c will be taken using the 
central laboratory.  The HbA1c sample is not required if the HbA1c has been completed by the 
central laboratory within the last 4 weeks.
The choice of rescue medication and its dosage will be left to the discretion of the 
investigator.  However, DPP-4 inhibitors and/or a GLP-1 agonist/analogue are not allowed to 
be used as rescue medication.  
Rescue medication will not be provided as part of the clinical trial supplies, unless required 
by local laws and regulations.  The rescue medication should be taken in accordance with the 
local prescribing information of that respective medication, taking into account potential 
contraindications. 
If no further effect from the rescue medication is anticipated, in the investigator’s clinical 
opinion, and/or the patient’s hyper- or hypoglycaemia cannot be controlled, the patient should 
be discontinued from the trial as specified in Section 3.3.4.  
All concomitant (additional) and/or rescue medication will be recorded in the source 
documents and on the appropriate pages of the eCRF.  
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. 
Restrictions to additional treatment are described in Section 4.2.2.


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There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The use of the following classes of antidiabetic medications will be prohibited during the 
course of the trial: sulphonylureas, thiazolidinediones, SGLT2 inhibitors, meglitinides, 
bromocriptine, GLP-1 analogues or DPP-4 inhibitors.  The use of rescue medication for 
elevated FPG levels is noted in Section 4.2.1.  
Short-term use of rapid-acting insulin (e.g., in the event of hospitalisation) will be permitted 
based on clinical judgement of the investigator or treating physician.  Prolongation of 
rapid-acting insulin treatment over more than 2 weeks vs. treatment discontinuation should be 
discussed on a case-by-case basis between the investigator and the CML or TCM.  Refer to 
Section 3.3.3 regarding the permitted use of antidiabetic agents.
Additionally, treatment with anti-obesity drugs [including over the counter preparations such 
as Alli(orlistat)] or systemic steroids will be prohibited due to their influence on glucose 
metabolism.  However, one off or short-term use (i.e., ≤1 week 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, 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.  
No special contraindication for concomitant use with linagliptin is known based on the data 
from drug development to date (refer to Section 1.2). 
For patients who are taking metformin as background therapy: If vascular administration of 
an iodine-containing contrast agent is required, patients should be informed to discontinue 
metformin 48 hours before the contrast agent is given and not to resume metformin 
administration until 48 hours after the vascular administration.
4.2.2.2
Restrictions on diet and life style
At the first visit, patients will receive diet and exercise counseling by a diet specialist, trained 
staff member, physician, or investigator.  This diet and exercise counseling will be reviewed 
at each subsequent visit.  Documentation of diet and exercise counseling training of the 
applicable investigative staff is required to be maintained at the trial site.  The counseling will 
be based on local diet recommendations.  The patients will be reminded to follow the agreed 
diet and exercise plan at every visit.  Patients may be provided with diet and exercise 
educational material (e.g., from national diabetes associations or national health authorities) 
relevant for the country/region by the trial site. 
Patients also should not take part in another clinical trial involving an investigational 
medicinal product within the 2 months prior to Informed Consent and throughout this trial.


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4.3
TREATMENT COMPLIANCE
Patients will be asked to bring all study medication containers (with or without any remaining 
tablets) with them to each trial visit.  The tablets will be counted by the investigator or study 
coordinator and compliance will be calculated according to the formula:
%
100
period
same
in the
been taken
have
should
 which 
 tablets
of
Number 
count
t 
last table
since
aken 
actually t
 tablets
of
Number 
(%)
Compliance


During the Run-In Period, patients must have taken 80% to 120% of their prescribed study 
medication to be considered compliant.  If a patient is non-compliant during the Run-In 
Period, the investigative staff will review the patient’s correct daily dosage and counsel the 
patient on the importance of proper compliance.  Extremely non-compliant (less than or equal 
to 50% compliant) patients should not be randomised at the discretion of the investigator.
At each visit, the investigative staff will assess medication compliance by counting the tablets 
remaining.  Patients must have taken 80% to 120% of their prescribed study medication to be 
considered compliant.  If a patient is non-compliant at any visit, the investigative staff should 
determine what the cause of the non-compliance is, will review the patient’s correct daily 
dosage, and counsel the patient on the importance of proper compliance. 
Patients who do not take any study medication for 10 consecutive days should not begin 
taking study medication at the next visit or re-start study medication and should be 
discontinued from the trial.  The investigative staff should determine what the cause of the 
non-compliance is and bring the patient in for Visit 98 (last assessment considered to be 
on-treatment) as soon as possible.  The patient should return one week later to complete 
Visit 99 (Post-Treatment Visit).  Alternate antidiabetic therapy may be prescribed to patients 
being discontinued as necessary and any alternate antidiabetic therapy should be documented 
in the eCRFs.
If a patient has been non-compliant for two consecutive visits, the investigative staff should 
determine what the cause of the non-compliance is and contact the CML to discuss the 
patient’s participation in the trial.  
Patients who are extremely non-compliant (< 50% compliant) for two consecutive visits 
should be discontinued from study medication and the trial.  The investigative staff should 
determine what the cause of the non-compliance is and bring the patient in for Visit 98 (last 
assessment considered to be on treatment) as soon as possible.  The patient should return one 
week later to complete Visit 99 (Post Treatment Visit).  Alternate antidiabetic therapy may be 
prescribed to patients being discontinued as necessary and any alternate antidiabetic therapy 
should be documented in the eCRFs.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - PHARMACODYNAMICS
Refer to the Flow Chart for a schedule of each efficacy observation in the trial.
5.1.1
Endpoints of efficacy
The primary endpoint in this trial is the change from baseline in HbA1c after 24 weeks of 
treatment.  Throughout the trial protocol, the term "baseline" refers to the last observation 
prior to the administration of any randomised study medication.
Secondary endpoints are the following:

Proportion of patients experiencing at least one confirmed hypoglycaemic event 
during 24 weeks of treatment.  A confirmed hypoglycaemic event is defined as 
any symptomatic or asymptomatic event less than 54 mg/dL (< 3.0 mmol/L) as 
measured by the central laboratory (FPG) or HBGM device, any symptomatic 
event less than or equal to 70 mg/dL (3.9 mmol/L), and all events classified as 
“severe hypoglycaemia”.  
Severe hypoglycaemic episode:  an event that requires the assistance of another 
person to actively administer carbohydrates or glucagon because the patient is 
unable to take the substance on his or her own.
Note:  If another person hands the carbohydrate or glucagon to the patient without 
having to actively administer the substance because the patient is able to take the 
substance on his or her own, the hypoglycaemic episode does not qualify as 
severe.

Proportion of patients with HbA1c on treatment <8.0% after 24 weeks of treatment

Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of treatment

Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of 
treatment

Change from baseline in FPG after 24 weeks of treatment
 

 
 
 


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
 
 
 
 
 
 
5.1.2
Assessment of efficacy
HbA1c:
Blood samples for the determination of HbA1c will be taken at the trial site and processed by 
the central laboratory.  At Screen Visit, the blood sample can be taken at any time during the 
visit.  At all other visits, the blood samples should be drawn before breakfast and before study 
medication administration.  The samples will be analysed at a central laboratory or its 
affiliates having a National Glycohaemoglobin Standardisation Program (NGSP) Level I 
certificate.  Further details about sample handling, shipment, and assay procedures will be 
located in the ISF (laboratory manual).


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FPG:
Blood samples for the determination of FPG will be taken after an overnight fast (at least 
10 hours after the last meal) at the trial site and processed by central laboratory.  The samples 
should be taken before breakfast and before study medication administration.  The samples 
will be measured using validated assays by a central laboratory.  Further details about sample 
handling and shipment will be located in the ISF (laboratory manual).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2
SAFETY
5.2.1
Endpoints of safety

Incidence and intensity of Adverse Events (AEs)

Withdrawal due to AEs


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
Incidence of hypoglycaemic events:
All investigator–reported hypoglycaemic events (with or without symptoms, 
with or without measured glucose)
Severe or symptomatic hypoglycaemic events
o Severe or symptomatic events with measured glucose ≤70 mg/dL
(3.9 mmol/L)
o Severe or symptomatic events with measured glucose < 54 mg/dL
(< 3.0 mmol/L)
Severe hypoglycaemic event or hypoglycaemic events (with or without 
symptoms) with measured glucose of ≤70 mg/dL (3.9 mmol/L)
Severe hypoglycaemic event or hypoglycaemic events (with or without 
symptoms) with measured glucose of < 54 mg/dL (< 3.0 mmol/L)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A SAE is defined as any AE which results in death, is immediately life-threatening, results in 
persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is 
a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an 
important medical event when based upon 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.
For Japan: An AE which possibly leads to disability will be reported as an SAE. Every new 
occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the study medication and the occurrence of the cancer.


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Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, 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. Assessment of causal relationship should be recorded in the eCRF. 
For Japan: The reason for the decision on causal relationship needs to be provided in the 
eCRF.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
If a SAE is reported from a blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e.,
any active comparator or placebo according to the trial design).
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
AE or SAE (if SAE criteria are met) in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an AE or SAE (if SAE criteria are met) in the eCRF, if they are judged clinically 
relevant by the investigator.
Criteria for hypoglycaemic events
Every episode of FPG or blood glucose (by HBGM device) below or equal to 70 mg/dL 
(3.9 mmol/L) should be documented as a hypoglycaemic event in the eCRF with the 
respective time and date of occurrence.  
Symptomatic, severe, and hypoglycaemias with FPG or blood glucose values < 54 mg/dL 
(< 3.0 mmol/L) should be documented as an AE of "hypoglycaemic event".  Data related to 
these hypoglycaemic events [i.e., symptomatic, severe, and hypoglycaemias with FPG or 
blood glucose values < 54 mg/dL (< 3.0 mmol/L)] will be collected on a specific eCRF and 
included in the clinical trial report.


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In the case of hypoglycaemia that may put a patient at risk (for example, repeated 
symptomatic hypoglycaemia, or severe hypoglycaemia), appropriate adjustment of 
background therapy such as a dose reduction or time change should be initiated.  Patients 
should be instructed to contact the trial site if they experience symptomatic hypoglycaemia.
Adverse Events of Special Interest
The following events are considered as Adverse Events of Special Interest (AESI):

Hypersensitivity reactions such as angioedema, angioedema-like events, and 
anaphylaxis

Skin lesions such as exfoliative rash, skin necrosis, or bullous dermatitis

Hepatic events such as ≥3 fold ULN of AST and/or ALT in combination with an 
elevation of total bilirubin >2 fold ULN measured in the same blood draw 
sample, hepatitis, hepatic injury, jaundice and potential Hy’s Law cases

Renal adverse events such as acute renal failure

Pancreatitis (refer to the ISF)

Pancreatic cancer
Protocol-specified AESI (as identified by the investigator based on the above definitions 
for Adverse Events of Special Interest) can be classified as serious or non-serious but all 
these AESIs once identified by the investigator must be reported on an SAE form in an 
expedited manner similar to SAEs (within 24 hours of awareness), even if they do not 
meet any of the SAE seriousness criteria (refer to Section 5.2.2.1 for details).  Beyond of 
this, and for the purposes of ongoing pharmacovigilance activities by the sponsor, 
adverse events based on additional searches for coded preferred terms of adverse events 
captured in the trial database (such as Special MedDRA Queries and user defined 
searches) will be queried to verify with the investigator if the adverse event reported 
represent a suspected or diagnosed protocol-specified AESI.  AESIs once identified by 
the investigator must be reported on an SAE form in an expedited manner similar to 
SAEs, even if they do not meet any of the SAE seriousness criteria. 
These additional searches (summarised under the so called ‘overview of protocol-
specified AESIs and safety topics of interest ’) may change according to active 
pharmacovigilance of linagliptin.  The most up to date list of these searches will be 
included in the Remote Data Capture (RDC) system and changes will be communicated 
to all investigators. 
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the last per protocol contact) will be 
collected, documented and reported to the sponsor by the investigator on the appropriate 


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eCRFs / SAE reporting forms. Reporting will be done according to the specific definitions 
and instructions detailed in the ‘Adverse Event Reporting’ section of the ISF. 
The residual effect period (REP), defined as the period of time after the last dose of 
medication when measureable drug levels or pharmacodynamic effects are still likely to be 
present, for linagliptin is 7 days.  Therefore all events reported within 7 days of the last trial 
medication will be considered on-treatment.  The follow-up period, defined as the period 
between the last medication and the last per protocol visit, is 7 days.
Reporting will be done according to the specific definitions and instructions detailed in the 
‘Adverse Event Reporting’ section of the ISF.
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 
The investigator does not need to actively monitor patients for adverse events once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the clinical trial (including any protocol required 
REP and / or follow-up period), it should be reported by the investigator to the sponsor if 
considered relevant by the investigator.
All AEs and/or SAEs, including those persisting after trial completion, must be followed up 
until they have resolved, have been sufficiently characterized, or no further information can 
be obtained.
If not stipulated differently in the ISF, the investigator must report the following events 
immediately (within 24 hours of awareness) to the sponsor: SAEs, AESIs, and non-serious 
AEs relevant to the reported SAE or AESI.
SAEs occurring in patients after having discontinued in the study due to screening failure and 
who did not receive any study medication, should only be reported if the investigator 
considers the SAE to be related to the screening procedure.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always SAEs”, if a non-serious AE is identified 
to be serious per BI definition, a query will be raised. The investigator must verify the 
description and seriousness of the event.  If the event description is correct, the item “serious” 
needs to be ticked and an SAE has to be reported in expedited fashion following the same 
procedure as above.
The list of these always SAEs can be found in the RDC system.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs and non-serious AEs must include a causal relationship assessment made by 
the investigator.


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For Japan: This information must be also reported immediately to the head of the trial site. 
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the ISF). This immediate report is 
required irrespective of whether the investigational product has been administered or not and 
irrespective of causal relationship. It also applies if new information to existing SAEs or 
AESIs becomes available. 
5.2.3
Assessment of safety laboratory parameters
The blood sample at the Screen Visit may be taken with the patient in a fasted or non-fasted 
state.  However, after the Screen Visit, all laboratory samples must be collected after a full 
overnight fast (nothing to eat or drink except water for at least 10 hours) and before study 
medication is administered to the patient as described in the Flow Chart and Section 6.  
All laboratory tests that will be performed during the trial are listed in Tables 5.2.3: 1 and 
5.2.3: 2.  The analysis of all laboratory tests will be performed by a central laboratory.  The 
respective reference range and details regarding sample handling and shipment will be 
provided in the ISF (Laboratory Manual).
Laboratory tests and urinalysis will be performed for the visits as noted in the Flow Chart 
with the following exceptions:

For the Screen Visit, only liver transaminases, alkaline phosphatase, serum creatinine, 
and urinalysis will be performed.

The lipid panel will be performed for only Visit 3 and Visit 98
Table 5.2.3: 1
Haematology laboratory tests
Haematology
Haematocrit
Haemoglobin - Reticulocyte Count (reflex test if Haemoglobin outside normal range)
Red Blood Cells/Erythrocytes
White Blood Cells/Leukocytes
Platelet Count/Thrombocytes
Differential Automatic (relative and absolute count): 
Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes


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Table 5.2.3: 1 (Cont.) Chemistry laboratory tests 
Lipase
aspartate aminotransferase (AST, SGOT)
alanine aminotransferase (ALT, SGPT)
gamma-glutamyl-transferase (-GT)
Alkaline phosphatase
Lactic dehydrogenase (LDH)
Total bilirubin
Total Protein 
Direct bilirubin, if total bilirubin is 
elevated
Albumin 
Creatine kinase (CK)
Troponin T (reflex only for CK)
Potassium
activated partial thromboplastin time 
(aPTT)
fibrinogen

Sodium

Creatinine 

Urea (i.e., blood urea nitrogen)

Calcium

Chloride

Magnesium

Inorganic phosphorous

Uric acid

Cholesterol (total) *

High-Density Lipoprotein (HDL) 
cholesterol*

Low-Density Lipoprotein (LDL) 
cholesterol (calculated)*

Plasma triglycerides*

Glucose
* Visits 3 and 98 only
If AST and/or ALT are increased ≥3 times ULN, follow-up laboratory tests of ALT, AST, 
total bilirubin (with differentiation of bilirubin in direct and indirect), with the addition of 
alkaline phosphate, creatine kinase (CK, CK isoenzyme MB if CK is elevated), amylase, 
lipase, and International Normalized Ratio (INR) blood samples must be collected as soon as 
possible (ideally within 48 to 72 hours of the pathologic test result).  Further follow-up 
investigations shall be initiated depending on the patient's clinical course until the patient is 
recovered and/or a diagnosis was established.  
Table 5.2.3: 2
Urinalysis
Albumin, Creatinine 
(spot urine: quantitative measurement)
Protein
Glucose

Ketone

Leucocytes

Erythrocytes
Albumin/creatinine ratio will be calculated at the central laboratory.  Urine sediment will 
only be performed if there is a positive finding on the urinalysis.


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5.2.4
Electrocardiogram
Twelve-lead ECGs will be recorded according to the Flow Chart.
The 12-lead ECGs will be centrally analysed with interpretation by a cardiologist and 
assessed for pre-existing abnormalities.  Patients with any pre-existing ECG abnormalities
determined at the Screen Visit may be referred to a cardiologist and medically treated, as well 
as should be carefully monitored throughout the trial, as necessary.  ECG abnormalities
determined at the Screen Visit should be recorded on the baseline condition eCRF.  After the 
12-lead ECG is performed at the Screen Visit, any clinically relevant abnormal changes 
should be reported as AEs according to Section 5.2.2.1.
Additional ECGs may be collected by the investigator for safety reasons.  
5.2.5
Assessment of other safety parameters
Physical examination
A physical examination (e.g., evaluation of the body and its functions using inspection, 
palpation, percussion, and auscultation) will be performed by the investigator according to
the Flow Chart.  Documentation of and findings from the physical examination must be part 
of the source documents available at the trial site.
Home Blood Glucose Monitoring
All patients will receive HBGM supplies at the Screen Visit to monitor their glucose levels at 
home each day.  Instruction on the proper use of the glucometer will be provided by the study 
staff.  
Each day:  The patient should be instructed to complete 4 finger stick glucose measurements:
1. in a fasting state in the morning before breakfast (e.g., before 7 or 8 a.m.)
2. before lunch (e.g., 12 p.m.)
3. before dinner (e.g., 6 p.m.)
4. before bedtime (e.g., 8 or 9 p.m.)
It is not recommended that patients’ skip meals but approximate times of glucose measuring 
have been provided above as general guidance.
Once or twice a week during typical hours of sleep (i.e., 10 p.m. to 5 a.m.):
The patient should be instructed to complete a finger stick glucose measurement when getting 
up to use the bathroom or any other reason for being awake during typical hours of sleep.
The patient should be instructed to also contact the trial site for advice if the results of a 
HBGM test reveal blood glucose value of ≤70 mg/dL (3.9 mmol/L) after an overnight fast.  


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If the blood glucose level is <54 mg/dL (3.0 mmol/L), the patient should be instructed to eat 
and/or drink some carbohydrate containing food.  
Additional HBGM measurements should be performed in case of hypo- or hyperglycaemia 
related symptoms and if deemed necessary by the investigator or required by local 
authorities. Patients will be instructed to bring their HBGM device to visits for an additional 
measurement of fasted glucose levels. 
HBGM test results will be processed and collected by a glucometer that will transmit the 
results electronically to a small personal handheld electronic device (eDiary) each day.  The 
investigator will be able to view the patient’s HBGM data within the vendor’s database and 
should review the patient’s blood glucose results in order to determine if treatment 
adjustments need to be instituted.
The respective HBGM and eDiary procedure for illiterate patients is described in the
Appendix 10.1.1.
Assessment of meals, physical activity, and hypoglycaemic symptoms and events by eDiary
A small personal handheld electronic device will be used by the patients to record 
information regarding their blood glucose monitoring, meals, and their symptoms daily 
(eDiary).  Patients will be instructed to complete the eDiary four times every day (while 
fasting before breakfast, before lunch, before dinner, and before bedtime).  When completing 
an eDiary entry, patients will answer questions regarding their blood glucose monitoring, 
meals, physical activity or exercise, and their symptoms since their last eDiary entry.  If 
patients miss or are late with their eDiary entry, they may enter information covering a 
maximum time period of 12 hours in the past.  In addition, the patient’s HBGM values will 
be uploaded electronically to the eDiary daily.  The investigator should review the patient’s 
blood glucose and eDiary results in order to determine if treatment adjustments need to be 
instituted.
The eDiary data will be transferred to the vendor server on a daily basis.  The data will be 
transferred to the sponsor on a periodic, batch basis.  Patients will be instructed to contact the 
trial site staff if they have any problems using the eDiary.  
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor efficacy and safety aspects in an appropriate way.
The scheduled measurements are appropriate to determine relevant drug-induced changes in 
blood pressure, pulse, standard laboratory values, and ECG specific to the efficacy of 
treatment of T2DM.  The primary and secondary endpoints are standard, are widely used, and 
accepted for evaluation of safety and tolerability of oral antidiabetic drugs in respective 
pivotal Phase III trials. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
The plasma concentration and pharmacokinetic analysis of linagliptin will not be performed 
in this trial.
 
 
 
 


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5.7
PHARMACODYNAMICS
No additional pharmacodynamic parameters will be determined in this trial.
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should be routinely scheduled in the morning, at approximately the same time 
of day (07:00 AM to 11:00 AM). If a patient mistakenly takes study medication on the 
morning of a visit before attending the clinic (excluding visits starting before randomisation) 
or comes in non-fasted where a fasting condition is required (all visits except Screen), the 
visit should be rescheduled for another day as soon as possible reminding the patient about 
the expected conditions.  The rescheduled visit must take place within the allowed visit
window (i.e., in less than 7 days) so that the patient has sufficient study medication.
All patients are to adhere to the visit schedule as specified in the Flow Chart.  If any visit has 
to be rescheduled, subsequent visits should follow the original visit date schedule.  The study 
medication bottles contain sufficient medication to allow for these time windows.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screen and Run-In Periods
Screen
No trial procedures should begin until the patient has signed the informed consent for the 
trial.
Patients who have been on stable background therapy [i.e., basal insulin, metformin 
(optional), and/or alpha-glucosidase inhibitor (optional)] will have the Screen Visit 
performed.
The Screen Visit does not need to be performed fasting.
After a patient has signed the informed consent, the patient is enrolled in the trial and has 
begun screening.  The patient should be recorded on the enrolment log and be registered in 
IRT as a screened patient.
Patients who are not eligible due to inclusion and exclusion criteria should be entered as a 
screen failure in IRT.  
Run-In
Patients should be fasting (no food or drinks for at least 10 hours, only water is allowed).
Patients will be assigned and receive a placebo kit number through the IRT at this visit.
Patients who fail the Run-In Period following the Visit 2 evaluations should be entered as a 
screen failure in the IRT.  


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6.2.2
Treatment period
Patients should not take study medication at home on the morning of trial visits during the 
treatment period.
The treatment period is from Visit 3 to Visit 98.  Study medication will be dispensed to 
patients at each of these visits (except for Visit 98).  Patients will be assigned a new 
medication number through IRT at each visit.  Study medication will be administered by the 
investigator from a new bottle with the IRT-assigned medication number on the day of the 
visit.
Treatment Period (Visits 3, 4, 5, 6, 98) 
Visits should be performed fasting and as indicated in the Flow Chart, and Table 4.1.4: 1 and 
the respective protocol sections.
For Visit 98, patients will be entered in IRT as completing or discontinuing treatment.  
Premature discontinuation from the trial (between Visits 3 and 98)
If a patient prematurely discontinues from the 24-week treatment period, the patient must 
return to the trial site for both Visit 98 and Visit 99 (7 days after Visit 98), which will be 
performed. 
The investigator may initiate any additional antidiabetic therapy based on his or her 
discretion no sooner than one day after discontinuing study medication.
The scheduled Visit 98 evaluations should be performed for patients who prematurely 
discontinued from the trial including the following:
•
Blood pressure and pulse
•
Weight 
•
Physical examination
•
12-lead ECG
•
Collection of blood and urine samples for safety laboratory evaluation
•
eDiary
•
Diet and exercise counseling


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•
Study medication compliance
•
Documentation of any adverse events
•
Documentation of concomitant therapies
In addition, the patient will be instructed to return in one week for Visit 99 evaluations.
6.2.3
End of trial and follow-up period
Visits should be performed as indicated in the Flow Chart and in Table 4.1.4: 1 and the 
respective protocol sections.
For Visit 99, patients will be entered in IRT as completing or discontinuing the trial.  
Post-Treatment Period
Patients that complete the trial will take the last dose of study medication the day before 
Visit 98.  The investigator may initiate any additional antidiabetic therapy based on his or her 
discretion no sooner than one day after Visit 98.
The following Visit 99 evaluations should be performed for all patients returning for this visit 
including those patients who prematurely discontinued from the trial:

Blood pressure and pulse

Collection of blood and urine samples for safety laboratory evaluation

Return of the HBGM device for assessment of blood glucose levels

Return of the eDiary 

Documentation of any adverse events

Documentation of concomitant therapies
The end of the trial is defined as "last patient out", i.e., last visit completed by the last patient.
Premature discontinuation from the trial (between Visits 98 and 99)
If a patient discontinues after the 24-week treatment period, the patient should return to the 
trial site for Visit 99 (the Post-Treatment Visit that occurs 7 days after Visit 98), which will 
be performed as a trial visit.  
The investigator may initiate any additional antidiabetic therapy based on his or her 
discretion no sooner than one day after discontinuing study medication.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The objective of the current trial is to investigate the efficacy, safety and tolerability of 
linagliptin compared to placebo given for 24 weeks as add-on therapy to a stable background 
of basal insulin, metformin (optional), and/or alpha-glucosidase inhibitors (optional) in 
elderly patients (≥60 years of age) with T2DM and insufficient glycaemic control (i.e., 
HbA1c of 7.0% to 10%).  It is planned to show superiority of linagliptin to placebo for the 
primary endpoint, the change from baseline in HbA1c (HbA1c after 24 weeks of treatment 
minus HbA1c at baseline), followed by a decrease in the proportion of patients experiencing at 
least one confirmed hypoglycaemic event during 24 weeks of treatment, in a hierarchical 
manner.
HbA1c will be measured in the unit of percent (%) at all clinical visits.  A mixed model for 
repeated measures (MMRM) will be used to compare the change from baseline in HbA1c
after 24 weeks of the treatments.  The model will include treatment, baseline HbA1c, baseline 
insulin dose, week, week by baseline HbA1c interaction, and week by treatment interaction.
With regard to efficacy and safety endpoints, the term “baseline” refers to the last observed 
measurement prior to administration of any randomised study medication.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The superiority of treatment with linagliptin to placebo will be tested for HbA1c change from 
baseline to Week 24 at the level of α=0.05 (two-sided).
The primary hypothesis can be written as follows:
H0, 1: Mean change from baseline in HbA1c after 24 weeks of treatment with linagliptin
      = Mean change from baseline in HbA1c after 24 weeks of treatment with placebo
H1, 1: Mean change from baseline in HbA1c after 24 weeks of treatment with linagliptin
      ≠ Mean change from baseline in HbA1c after 24 weeks of treatment with placebo
This will be performed on the full analysis set (FAS).  
7.3
PLANNED ANALYSES
The primary analysis will be performed on the FAS.  The FAS will consist of all randomised 
patients who were treated with at least one dose of study medication, had a baseline and at 
least one on-treatment HbA1c measurement.
The FAS-completers set of patients is defined as all patients in the FAS who complete 24 
weeks of treatment and have an HbA1c measurement after 24 weeks of treatment.


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  A protocol violation will be considered important 
if it can be expected to have a distorting influence on the assessment of the primary endpoint.
Important protocol violations include:

Randomised study medication: incorrect study medication taken

Severe violation of treatment compliance

Severe violation of inclusion criteria 

Non-adherence to other specifications of the protocol that could bias the primary 
endpoint
Further details will be given in the Trial Statistical Analysis Plan (TSAP).
All patients treated with at least one dose of study medication (the Treated Set) will be 
included in the safety evaluation.
7.3.1
Primary analyses
The primary analysis will be performed on the FAS [observed cases (OC)]. Mean changes 
from baseline in HbA1c after 24 weeks of treatments will be analysed using a restricted 
maximum likelihood-based repeated measures approach. Analyses will include the fixed, 
categorical effects of baseline insulin dose, treatment, week, and treatment by week
interaction, as well as the continuous, fixed covariates of baseline HbA1c and baseline HbA1c
by week interaction. An unstructured (co)variance structure will be used to model the within 
patient measurements.
If this analysis fails to converge, the following covariance structures will be tested: Toeplitz, 
AR (1), and compound symmetry.  The (co)variance structure converging to the best fit, as 
determined by Akaike’s information criterion, will be used as the primary analysis. The 
Kenward-Roger approximation will be used to estimate 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 (CI)]. The residuals are assumed to have a 
multivariate normal distribution with zero means and covariance matrix as mentioned 
above. All analyses will be implemented using SAS®. The primary treatment comparisons 
will be the contrast between treatments at Week 24.  
The statistical model will be:
HbA1c change from baseline = overall mean + baseline HbA1c + baseline insulin dose 
+ treatment + week + week by baseline HbA1c interaction
+ week by treatment interaction + random error


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The primary analysis will be performed on the FAS; patients will be assigned to the treatment 
they were randomised to.
7.3.2
Secondary analyses
 
 
 
 
 
 
 
 
The additional secondary efficacy endpoints 
 will be 
analysed as follows:

Continuous endpoints (except for basal insulin dose change) with the parameter 
measured at least twice on-treatment will be analysed using a MMRM model similar 
to the primary endpoint analysis.  Descriptive summary statistics will be presented for 
each endpoint, and at each week if appropriate.

 

Binary endpoints will be tabulated (with the frequency and proportion in each 
treatment group, by week if appropriate).  Logistic regression will be applied for 


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secondary and certain other endpoints (to be specified in TSAP) to obtain the odds 
ratio between treatment groups and its 95% CI and 2-sided p-value.

 

 
 
 
 
 
 
For these analyses, patients will be assigned to the treatment they were randomised to.
The analysis of endpoints related to questionnaires will be described in the TSAP.
7.3.3
Safety analyses
All safety data will be displayed and analysed using descriptive statistical methods.  
Depending on the character of the individual safety endpoint, the most appropriate way to 
summarize the results as frequency tables for categorical data or descriptive statistics for 
continuous data will be used.  No formal inferential analysis is planned for safety 
comparison.
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA)
coding dictionary.  All events with an onset after the first dose of study medication up to a 
period of seven days after the last dose of study medication will be assigned to the treatment 
phase for evaluation.  This includes AEs that start before first study medication intake and 
deteriorate under treatment.  Other AEs will be assigned either to the screening, run-in, or 
follow-up phase as appropriate.  Safety analyses will be performed on the TS, with patients 
assigned to the treatment they were randomised to.  Additional listings based on actual 
treatment at onset of AE will be produced for patients who receive incorrect treatment at any 
point throughout the trial.
Laboratory values taken after the first dose of randomised treatment up to a period of seven 
days after the last intake of treatment will be assigned to the treatment phase for evaluation.  
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.
Changes from baseline in blood pressure and pulse rate will be summarised by treatment 
group.
Further details on the safety analysis will be specified in the TSAP.


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7.3.4
Interim analyses
No interim analysis is planned for this trial.
7.3.5
Pharmacokinetic analyses
No pharmacokinetic sampling is planned for this trial.
7.3.6
Pharmacodynamic analyses
No pharmacodynamic analysis is planned for this trial.
 
7.4
HANDLING OF MISSING DATA
7.4.1
Efficacy endpoints
In the primary analysis, if a patient misses a visit, the missing data will not be imputed. The 
mixed effect model will handle missing data based on a likelihood method under the "missing 
at random assumption". Following the intention-to-treat (ITT) principle, every randomised 
patient with at least baseline and one on-treatment measurement will be included in the
analysis.
 
 
 
If rescue therapy is initiated, HbA1c and FPG values after rescue will be set to missing and 
the missing data handled as above (OC or LOCF), according to the analysis strategy.
For the analysis of hypoglycaemia endpoints, the available data of all patients in the TS 
will be analysed (OC approach) and no imputation performed.
For binary endpoints including an HbA1c response criterion, non-completer’s considered 
failures (NCF) approach will be used, i.e., patients who discontinue from the trial 
prematurely and have no Week 24 HbA1c value will be considered as non-responders.
Methods to handle any other exceptional cases will be considered before unblinding the data 
and will be applied in a manner consistent with other trials of this type.  The evaluability of 
patients with deviations from the protocol likely to confound the treatment response will be 
decided prior to unblinding.


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7.4.2
Safety and other endpoints
With respect to safety evaluations, it is not planned to impute missing values.
The handling of missing 
 as patient reported outcome measures data will be 
specified in the TSAP or a separate health economics analysis plan, as appropriate.
7.5
RANDOMISATION
The sponsor will arrange for the randomisation as well as packaging and labelling of study 
medication.  Eligible patients will be randomly assigned to one of the two treatment groups, 
with equal allocation of treatments. The randomisation list will be generated using a 
validated system, which involves a pseudo-random number generator so that the resulting 
treatment sequence will be both reproducible and non-predictable.
The randomisation will be stratified by HbA1c (< 8.5% vs. ≥8.5%) as determined from the 
blood sample taken at Visit 1 and insulin dose (< 40 international units total daily dose vs. 
≥40 international units total daily dose) as determined at the beginning of the placebo run-in 
period (Visit 2).  To ensure appropriate representation of patients with insulin doses of 
< 40 international units total daily dose as well as ≥ 40 international units total daily dose, the 
trial team will monitor the proportion of patients being recruited into these categories.  The 
limitation of recruitment of a particular category may be arranged (on trial level and/or 
country level).  
The allocation process will be performed at Visit 3 through IRT.  However, the IRT
allocation and randomization will not increase the study medication bottles at each trial site
based on stratification.
Access to the code will be restricted to dedicated randomisation personnel and any 
exceptional access to the code (in case of an emergency) will be documented according to the 
sponsor's SOPs.
The trial will only be unblinded after all eCRF and electronic data have been entered into the 
trial database, after queries have been resolved, and after the database has been locked.  
Access to the codes will be controlled and documented by a signed confidentiality statement, 
which will be stored in the TMF.
Practical aspects of the treatment allocation process and methods to carry out blinding are 
detailed in Sections 4.1.2 and 4.1.5, respectively.
7.6
DETERMINATION OF SAMPLE SIZE
This trial will be powered to detect differences between linagliptin and placebo in HbA1c
change from baseline after 24 weeks.
A total of 300 patients will be randomised.


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Based on pooled data from the 1218.36 and 1218.63 trials
 assuming a 
standard deviation of  1.2% in both groups in the FAS with a 0.77% difference in HbA1c 
change from baseline in treatments, a number of 150 patients in each treatment arm 
will show superiority with a power >99%. This determination of power is based on a 
Student’s t-test and a two-sided significance level of 5%.
Software package nQuery version 7.0 was used to derive the sample size.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
GCP and relevant BI SOPs. Standard medical care (prophylactic, diagnostic and therapeutic 
procedures) remains in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches
of the protocol/ICH GCP.
For Japan:
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol, ICH GCP, and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
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 general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
For countries with insurance cover requirements:
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB or IEC and 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 the participating country. 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 patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML and/or CRA) or Clinical Quality Assurance auditors appointed by Boehringer 


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Ingelheim, by appropriate IRB or IEC members, and by inspectors from regulatory 
authorities.
For Japan:
The investigator must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the 
contents. The investigator 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.
The following items need to be included:
1. That the clinical trial is aimed at testing.
2. Objectives of the trial.
3. The name, title, and address of the investigator to contact.
4. Trial procedures.
5. Anticipated benefits of the investigational products and anticipated disadvantages to 
the patient.
6. Matters concerning other therapeutic measures.
7. Duration of participation in the clinical trial.
8. That the patient may withdraw from the trial at any time.
9. That patient’s refusal of or withdrawal from participation in the trial does not cause 
any disadvantage to him or her.
10. That the monitors, the auditors, and the IRB are given access to the relevant source 
documents on condition that confidentiality of the patient is fully secured.
11. That privacy of the patient is kept.
12. The office of the medical institution to contact in the event of trial-related injury.
13. That necessary treatment is available to the patient in the event of trial-related injury.
14. Matters concerning compensation in the event of any trial-related injury.
15. The type of the IRB which is used for the reviews and deliberations on the matters 
such as appropriateness of conducting the clinical trial, the matters to be reviewed 


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and deliberated by each IRB, and other matters concerning the IRBs involved in the 
clinical trial.
16. Other necessary matters concerning the clinical trial.
8.2
DATA QUALITY ASSURANCE
The trial will be conducted according to the principles of GCP and the company SOPs. 
The following steps will be taken to ensure accurate, consistent, complete, and reliable data:

Use of techniques to achieve standardisation (e.g., investigator meetings, etc.)

Use of techniques to achieve accuracy (e.g., global and local training sessions, etc.)

Use of centralised evaluations (e.g., central laboratory, centralised review of ECGs, 
etc.)

On-site monitoring and source data verification

Equipment validation and calibration

Auditing (in-house and on-site)

Coding (e.g., MedDRA)

Special data management procedures: The data management procedures to ensure the 
quality of the data are described in detail in the trial data management and analysis 
plan (TDMAP) available in the TMF.

Establishing CECs to evaluate specific events (refer to Section 3.1)

Taking steps to maintain the blind (refer to Section 4.1.5.1)

Inter-laboratory standardisation methods: The samples will be analysed at a central 
laboratory or its affiliates having a NGSP Level I certificate.
The data management procedures to ensure the quality of the data are described in detail in 
the TDMAP available in TMF.
A quality assurance audit/inspection of this trial may be conducted by the sponsor or
sponsor’s designees or by IRBs or IECs 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.


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8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, via RDC. 
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
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s trial site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs, all data must be derived from source documents.
Additionally, the following source documents must be collected and filed at the investigator’s 
trial site:

ECG results (original or copies of printouts)

Physical examinations (original documentation)

HBGM results (printout from vendor at the end of the trial)
8.3.2
Direct access to source data and documents
The investigator and/or institution will permit trial-related monitoring, audits, IRB or IEC 
review and regulatory inspection, providing direct access to all related source data / 
documents. eCRFs and all source documents, including progress notes and copies of 
laboratory and medical test results must be available at all times for review by the sponsor’s 
clinical trial monitor, auditor and inspection by health authorities (e.g. FDA). The CRA or 
on-site monitor and auditor may review all eCRFs, and written informed consents. The 
accuracy of the data will be verified by reviewing the documents described in Section 8.3.1.
8.3.3
Storage of records
For Japan:
Trial sites:
The trial sites must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and the sponsor’s SOP.


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Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the sponsor must notify the head of trial site.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For Tradjenta®, Trajenta®, Trayenta®, and Trazenta®, this is the current version of the 
Investigator’s Brochure 
. The current version of this reference document is to be 
provided in the ISF. No AEs are classified as listed for matching placebo, study design, or 
invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of SAEs, e.g. suspected unexpected serious adverse reactions (SUSARs) 
to health authorities and IECs or IRBs, will be done according to local regulatory 
requirements. Further details regarding this reporting procedure are provided in the ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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 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 or IEC and the regulatory authorities (e.g., for EU: the CA).
8.6
COMPLETION OF TRIAL
For Japan:
When the trial is completed, the investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
sponsor of the completion in writing.
For EU member states:
The EC and CA in each participating EU member state needs to be notified about the end of 
the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the CTP) or
early termination of the trial. 


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8.7
PROTOCOL VIOLATIONS
For Japan:
The investigator or sub-investigator should record all CTP violations. The investigator 
should provide and submit the sponsor and the head of the trial site the records of violations 
infringing the Japanese GCP or violations to eliminate an immediate hazard to trial subjects 
and for other medically inevitable reasons.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
For Japan:
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Schlosser A, Owens D, Taskinen MR, Prato S del, Gomis R, Patel S, et al. 
Long-term safety and efficacy of the DPP-4 inhibitor linagliptin: data from a 
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Sep 2011 Diabetologia 2011. 54(1): S108 Abstr 242.
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Gallwitz B, Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, et al. 
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P12-05699
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Inzucchi SE, Nauck M, Eynatten M von, Hehnke U, Woerle HJ, Henry R 
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the American Diabetes Association (ADA), Chicago, 21 - 25 Jun 2013 
(Poster) 2013.
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inadequately controlled with common antidiabetes treatments: a randomised, 
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insulin for patients with type 2 diabetes. Vasc Health Risk Manage 2013. 
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Fravel MA, McDanel DL, Ross MB, Moores KG, Starry MJ Special 
considerations for treatment of type 2 diabetes mellitus in the elderly. Am J 
Health Syst Pharm 2011. 68: 500-509.
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Mechanisms of the age-associated deterioration in glucose tolerance: 
contribution of alterations in insulin secretion, action, and clearance. Diabetes 
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R08-2669
Guidance for industry: diabetes mellitus: developing drugs and therapeutic 
biologics for treatment and prevention (draft guidance, February 2008). 
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Administration, Center for Drug Evaluation and Research (CDER) 2008.
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World Health Organization Diabetes. 
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R09-4241
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M Mortality from 
coronary heart disease in subjects with type 2 diabetes and in nondiabetic 
subjects with and without prior myocardial infarction. N Engl J Med 1998. 
339(4): 229-234.
R09-5797
Meneilly GS, Elliott T Metabolic alterations in middle-aged and elderly obese 
patients with type 2 diabetes. Diabetes Care 1999. 22(1): 112-118.
R09-6092
Abbatecola AM, Maggi S, Paolisso G New approaches to treating type 2 
diabetes mellitus in the elderly: role of incretin therapies. Drugs Aging 2008. 
25(11): 913-925.
R10-5341
Glucophage (metformin hydrochloride) tablets, Glucophage XR (metformin 
hydrochloride) extended-release tablets (Bristol-Myers Squibb), Rx only 
(product information, rev: January 2009). 2009.
R10-5452
CCalifornia Healthcare Foundation, American Geriatrics Society Panel on 
Improving Care for Elders with Diabetes Guidelines for improving the care of 
the older person with diabetes mellitus. J Am Geriatr Soc 2003. 51(5)(Suppl):
S265-S280.
R10-5537
Glucophage 500 mg and 850 mg film coated tablets (Merck Serono) 
(summary of product characteristics, date of revision of the text: 04/2010, last 
updated on the eMC: 17/08/10). http://www.medicines.org.uk 2010.
R11-2588
Tradjenta (linagliptin) tablets (Boehringer Ingelheim Pharmaceuticals) 
(prescribing information, revised: 5/2011). Tradjenta (linagliptin) tablets 
(Boehringer Ingelheim Pharmaceuticals) (prescribing information, revised: 
5/2011). 2011.
R12-1338
Ding J, Strachan WJ, Reynolds RM, Frier BM, Deary IJ, Fowkes FGR, et al. 
Diabetic retinopathy and cognitive decline in older people with type 2 
diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes 2010. 59: 2883-
2889.
R13-2759
NIH policy and guidelines on the inclusion of women and minorities as 
subjects in clinical research - amended, October, 2001. 
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1.htm (access date: 12 June 2013) ; Bethesda: U.S.Department of Health and 
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R13-3779
Sullivan MD, Katon WJ, Lovato LC, Miller ME, Murray AM, Horowitz KR, 
et al. Association of depression with accelerated cognitive decline among 
patients with type 2 diabetes in the ACCORD-MIND trial. JAMA Psychiatry, 
Published online August 14, 2013, doi:10.1001/jamapsychiatry.2013.1965 
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R14-0002
Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ Rates of 
complications and mortality in older patients with diabetes mellitus: the 
Diabetes and Aging study. JAMA Internal Medicine, Published online 
December 9, 2013, doi: 10.1001/jamainternmed.2013.12956 JAMA Intern 
Med 2013.
R14-0182
Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg 
AD Disparate inclusion of older adults in clinical trials: priorities and 
opportunities for policy and practice change. Am J Public Health 2010. 
100(Suppl 1): S105-S112.
R14-0183
Sinclair A, Morley JE, Rodriguez-Manas L, Paolisso G, Bayer T, Zeyfang A, 
et al. Diabetes mellitus in older people: position statement on behalf of the 
International Association of Gerontology and Geriatrics (IAGG), the European 
Diabetes Working Party for Older People (EDWPOP), and the International 
Task Force of Experts in Diabetes. . J Am Med Dir Assoc 2012. 13: 497-502.
R14-0250
Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, et al. Glucose 
levels and risk of dementia. N Engl J Med 2013. 369(6): 540-548
R14-0340
Viljoen A, Meek CL, Gadsby R, Viljoen S, Langerman H, Sinclair AJ The 
tolerability and safety of DPP-4 inhibitors for the treatment of older people 
with type 2 diabetes mellitus: an observational study. Br J Diabetes Vasc Dis 
2013. 13(4): 187-191.
R14-0344
American Diabetes Association Standards of medical care in diabetes - 2014. 
Diabetes Care 2014. 37(Suppl 1): S14-S80.
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Lakey WC, Barnard K, Batch BC, Chiswell K, Tasneem A, Green JB Are 
current clinical trials in diabetes addressing important issues in diabetes care? 
Diabetologia 2013. 56(6): 1226-1235.
R14-0360
Cryer PE Mechanisms of hypoglycemia-associated autonomic failure in 
diabetes. N Engl J Med 2013. 369(4): 362-372.
R14-0434
Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ Are amyloid-degrading 
enzymes viable therapeutic targets in Alzheimer's disease? J Neurochem 2012. 
120(Suppl 1): 167-185.
R14-0435
Bartl J, Meyer A, Brendler S, Riederer P, Gruenblatt E Different effects of 
soluble and aggregated amyloid beta42 on gene/protein expression and 
enzyme activity involved in insulin and APP pathways. J Neural Transm 2013. 
120: 113-120.
R14-0436
Pandini G, Pace V, Copani A, Squatrito S, Milardi D, Vigneri R Insulin has 
multiple antiamyloidogenic effects on human neuronal cells. Endocrinology 
2013. 154(1): 375-387.


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R14-0437
Candeias E, Duarte AI, Carvalho C, Correia SC, Cardoso S, Santos RX, et al. 
The impairment of insulin signaling in Alzheimer's disease. IUBMB Life 
2012. 64(12): 951-957.
R14-0447
Lam DW, LeRoith D The worldwide diabetes epidemic. Curr Opin Endocrinol 
Diabetes Obes 2012. 19(2): 93-96.
R14-0992
Cruz-Oliver DM, MalmstromTK, Allen CM, Tumosa N, Morley JE The 
Veterans Affairs Saint Louis University Mental Status exam (SLUMS exam) 
and the Mini-Mental Status Exam as predictors of mortality and 
institutionalization. J Nutr Health Aging 2012. 16(7): 636-641.
R14-0995
Feliciano L, Horning SM, Klebe KJ, Anderson SL, Cornwell RE, Davis HP 
Utility of the SLUMS as a cognitive screening tool among a nonveteran 
sample of older adults. Am J Geriatr Psychiatry 2013. 21(7): 623-630.
R14-0977
Tariq SH, Tumosa N, Chibnall JT, Perry MH, Morley JE Comparison of the 
Saint Louis University mental status examination and the mini-mental state 
examination for detecting dementia and mild neurocognitive disorder - a pilot 
study. Am J Geriatr Psychiatry 2006. 14(11): 900-910.
 
 
 
 
 
 
 
 
 


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10.
APPENDICES
10.1
INCLUSION OF ILLITERATE PATIENTS
10.1.1
Home Blood Glucose Monitoring and eDiary
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to HBGM as well as eDiary and documenting the results:

At Screen, the person assisting the patient with this process (e.g., the patient’s 
caregiver or relative) will attend the clinic together with the patient.

The trial site staff should confirm that this individual will be present with the patient, 
whenever he/she is likely to need to perform HBGM and answer the eDiary questions.

The trial site staff should then train both the patient and above-mentioned individual 
with respect to the correct use of the HBGM equipment during each period of the 
trial.  This will include the use of the glucose meter itself and the test strips, lancet 
device and any control solutions.  Furthermore, if whole blood referenced test strips 
are standard in the countries where illiterate patients are being recruited, the trial site
staff must ensure that both the patient and the person assisting the patient with the 
HBGM, have understood that plasma referenced test strips are used in the trial, and 
that there may be differences in the results obtained via these two methods.  A 
training letter is available to support this process.

The trial site staff should also train both the patient and the above-mentioned 
individual with respect to the completion of the eDiary questions.  
HGBM tests can be performed either by the patient him/herself, or by the person assisting the 
patient with this aspect of the trial. The person assisting the patient will need to obtain the 
answers to the eDiary questions from the patient and enter the patient’s responses into the 
eDiary.
10.1.2
Patient information and informed consent
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to patient information and informed consent: 

The designated trial site personnel performing the informed consent process will read 
the trial-approved patient information sheet and informed consent form to the patient, 
and explain the details of the trial, all in the presence of an impartial witness.

This impartial witness must be literate, and can be the patient’s relative or caregiver, 
or a member of staff employed by the clinic but not part of the immediate trial team.  
In addition, if there are any further local regulations with respect to the consent of 
illiterate patients, these should also be followed.


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
The requirements of the trial will be explained thoroughly and the patient will be 
given ample time to ask questions and consider his/her participation.  If he/she 
wishes, the patient can take the patient information sheet and informed consent form 
home for further consideration.

If patient agrees to take part in the trial, he/she would then return to the clinic for the 
consent process to be completed.  The trial site designated personnel responsible for 
this process will confirm that the patient has no further questions in the presence of 
the same impartial witness (if the patient returns on another day).  If a different 
impartial witness is present, the entire informed consent process must be repeated.

Participating patients will provide a thumb impression or make a mark (or signature if 
the patient is able to sign him/herself) on the signature section of the informed consent 
form.

The date of the patient’s signature will be left blank as the patient is illiterate.  
However, if the patient is able, he/she will date the mark/signature personally.

The impartial witness or the trial site designated personnel may write the name of the 
patient on the informed consent form.

The impartial witness should enter his/her name, sign and personally date the witness 
section of the informed consent form.  In countries where local data protection 
regulation permits it, the address or identification number of the impartial witness 
should also be entered.  The signature then attests that the content of the patient 
information sheet and informed consent form was accurately explained to the patient, 
who apparently understood and freely gave consent to participate in the trial.

The designated trial site personnel also signs and personally dates the informed 
consent form.

 


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11.
DESCRIPTION OF GLOBAL AMENDMENT
This is the original protocol.
Number of global amendment
1
Date of CTP revision
16 October 2015
EudraCT number
2014-000904-88
BI Trial number
1218.149
BI Investigational Product
Tradjenta®, Trajenta®, Trayenta®, Trazenta®, linagliptin
Title of protocol
A 24 week randomized, double-blind, placebo-controlled, 
parallel group, efficacy and safety trial of once daily 
linagliptin, 5 milligrams orally, as add on to basal insulin in 
elderly Type 2 Diabetes Mellitus patients with insufficient 
glycaemic control
To be implemented only after 
approval of the IRB or IEC
and/or Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB or IEC and/or Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB or IEC and/or Competent 
Authority approval as changes
involve logistical or 
administrative aspects only
Section to be changed
Title Page and Synopsis
Description of change
There was a change of Coordinating Investigator
and a global amendment was added.
Rationale for change
The Coordinating Investigator discontinued from 
the trial and there was an addition of a global 
amendment due to recruitment difficulties.


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Number of global amendment
1
Section to be changed
Synopsis
Description of change
Decrease of: 1.) age to 60 years old, and 2.) lower 
limit of HbA1c to 7.0%; and the secondary 
endpoint of < 7.5% HbA1c was changed to 
< 7.0%.
Rationale for change
This trial was based on the data of two trials 
(1218.36 and 1218.63), which used a lower limit 
in age for one trial and HbA1c in both trials.  As 
the inclusion criterion of HbA1c was decreased to 
7.0%, the secondary endpoint for < 7.5% HbA1c
was changed to < 7.0%.
Section to be changed
Synopsis and Flowchart
Description of change
Decrease sample size to 300 (150 per arm) based 
on the primary endpoint of HbA1c only, with 100 
patients randomized required in Japan. The key 
secondary endpoint was changed to a secondary 
endpoint. 
Rationale for change
Prescribing practices have changed in the past 5 
years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.
Section to be changed
Section 1.1
Description of change
An additional sentence was included regarding 
the rationale for the global protocol amendment.
Rationale for change
As a result of extreme difficulty with recruiting 
this population, the global protocol amendment 
expanded the definition of elderly population 
beginning at age 60.


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Number of global amendment
1
Section to be changed
Sections 2.2, 3.1, 3.3, and 3.3.2
Description of change
Decrease of: 1.) age to 60 years old, 2.) lower 
limit of HbA1c to 7.0% (53 mmol/mol), and 3.)
sample size to 300 (150 per arm) based on 
primary endpoint of HbA1c only, with 100 
patients randomized from Japan per regulatory 
requirements. 
Section 3.3: A time period ‘of at least 1 year’ has 
been added to the medical history documentation
requirement. 
Inclusion criterion 2b: The additions of 
‘biosimilar’ basal insulin and Humalog Basal® (a 
suspension of insulin lispro protamine) have been 
included in order to expand the permitted basal 
insulins.
Rationale for change
This trial was based on the data of two trials 
(1218.36 and 1218.63), which used a lower limit
of HbA1c of 7.0% and a lower limit in age for one 
trial.  Prescribing practices have changed in the 
past 5 years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.   
Section 3.3:  Medical history documentation of at 
least 1 year is needed based on required medical 
follow up of a patient being on basal insulin.  
Inclusion criterion 2b: There are two newer basal 
insulins that can be used in this trial: ‘biosimilar’ 
basal insulin and Humalog Basal® (a suspension 
of insulin lispro protamine).


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Number of global amendment
1
Section to be changed
Section 3.3.3
Description of change
Exclusion criterion number 1: Saint Louis 
University Mental Status Examination scores 
were further clarified for mild neurocognitive 
disorder.  Exclusion criterion number 4: STEMI 
and/or unstable angina pectoris were added.
Exclusion criterion number 10: The addition of 
meglitinides and bromocriptine were included 
into exclusion criterion as these were missing but 
were stated in Section 4.2.2.1 from the final 
protocol,
Rationale for change
Exclusion criterion number 1: Patients with Saint 
Louis University Mental Status Examination 
scores indicating dementia must not be evaluated 
further for the trial.  Exclusion criterion number 
4: Clarified to include STEMI and unstable 
angina pectoris for complete definition of acute 
coronary syndrome.  Exclusion criterion number 
10: The exclusion criterion must be consistent 
with Section 4.2.2.1 relating to prohibited 
concomitant medications,
Section to be changed
Section 4.2.1 - Permitted antidiabetic therapy
Description of change
3rd paragraph: After randomisation, investigators 
should review the patient’s HBGM results 
electronically for hyperglycaemia and should 
follow the permitted antidiabetic therapy criteria
noted below to achieve improved patient 
glycaemic control before taking any additional 
action with rescue therapy.
Final paragraph:  Clarification of permitted 
antidiabetic therapy that will be considered to be 
rescue therapy was included.
Rationale for change
Additions were provided to further clarify: the 
procedure for permitted antidiabetic therapy 
criteria related to the HBGM data (i.e., 
glucometer) and permitted antidiabetic therapy 
that will be considered to be rescue therapy.


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Number of global amendment
1
Section to be changed
Section 5.1.1
Description of change
The key secondary endpoint was removed and 
changed to a secondary endpoint.  As the 
inclusion criterion of HbA1c was decreased to 
7.0%, the secondary endpoint for HbA1c of 7.5% 
was changed to <7.0%.  Added the word ‘to’ 
before 70 mg/dl.
Rationale for change
Prescribing practices have changed in the past 5 
years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.  As the 
inclusion criterion of HbA1c was decreased to 
7.0%, the secondary endpoint for HbA1c of 7.5% 
was changed to <7.0%.  To further clarify 
definition of hypoglycaemia as less than or equal 
to 70 mg/dl.  
Section to be changed
Sections 5.2.1, 5.2.2.1, and 5.2.5
Description of change
Symbol of ≤ added before 70 mg/dl and the AESI 
process was changed.
Rationale for change
To further clarify definition of hypoglycaemia as 
less than or equal to 70 mg/dl and the Sponsor’s 
AESI process was updated and required 
additional clarification.
Section to be changed
Section 5.2.5 - eDiary
Description of change
The patient allowed recall period for completing a 
missed entry was changed to 12 hours.
Rationale for change
The original plan was to allow for a 24 hour recall 
period but was not possible with changes required 
for the functionality of the eDiary.


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Number of global amendment
1
Section to be changed
Section 5.3.3 – list number 1
Description of change
The pre-specified analyses will be performed at 
the end of the trial and the data will be reported 
separately from the clinical trial report.
Rationale for change
It was subsequently determined that the pre-
specified analyses data would be reported 
separately from the clinical trial report.
Section to be changed
Section 5.3.3.1 – list numbers 1 and 2
 
 
 
 
 
 
 


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Number of global amendment
1
Section to be changed
Sections 7.1, 7.2, 7.3, 7.3.1, 7.3.7, 7.4.1, and 7.6
Description of change
Decrease of age to 60 years old and lower limit of 
HbA1c to 7.0%.  Changing the key secondary 
endpoint to a secondary endpoint and decreasing 
sample size to 300 (150 per arm) based on 
primary endpoint of HbA1c only.
 
Rationale for change
This trial was based on the data of two trials 
(1218.36 and 1218.63), which used a lower limit 
in age for one trial and HbA1c in both trials.  
Prescribing practices have changed in the past 5 
years and recruitment has proved to be too 
difficult and slow to achieve the key secondary 
endpoint sample size requirement.
 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02204602
3.0
clinical-trial-protocol
A randomized, double-blind, placebo-controlled, parallel group, efficacy and safety
trial of linagliptin 5 milligrams taken once daily orally with basal insulin for 24
weeks in elderly Type 2 Diabetes Mellitus patients with insufficient glycaemic
control
Author-Trial Clinical Monitor
16 Oct 2015 23:20 CEST
Author-Trial Statistician
17 Oct 2015 00:57 CEST
Author-Trial Clinical Monitor
17 Oct 2015 03:18 CEST
Approval-Team Member Medicine
17 Oct 2015 13:36 CEST
Approval-Therapeutic Area 
19 Oct 2015 17:12 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02204602
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02873013-03
BI Trial No.:
1218.149
Title:
A 24 week randomised, double-blind, placebo-controlled, parallel 
group, efficacy and safety trial of once daily linagliptin, 5 
milligrams orally, as add on to basal insulin in elderly Type 2 
Diabetes Mellitus patients with insufficient glycaemic control.
Including Global Protocol Amendment 1 [c02204602-03]
Investigational
Product(s):
Tradjenta®, Trajenta®, Trayenta®, Trazenta®, linagliptin
Responsible trial 
statistician(s):
 
Tel: 
Fax:
Date of statistical 
analysis plan:
9 November 2016 REVISED
Version:
Final
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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 ........................................................................................10
5.1
PRIMARY ENDPOINT ....................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................10
5.2.1
Key secondary endpoints..............................................................................10
5.2.2
Secondary endpoints .....................................................................................10
..................................................................................11
.......................................................................................13
6.
GENERAL ANALYSIS DEFINITIONS...........................................14
6.1
TREATMENTS..................................................................................................14
6.1.1
Treatment regimens / study intervals..........................................................14
6.1.2
Randomised treatment..................................................................................15
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................16
6.3
PATIENT SETS ANALYSED..........................................................................23
.....................................................................................................24
6.5
POOLING OF CENTRES ................................................................................24
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................24
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................30
7.
PLANNED ANALYSIS.......................................................................33
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........33
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................33
7.3
TREATMENT COMPLIANCE .......................................................................33
7.4
PRIMARY ENDPOINT ....................................................................................34
7.4.1 
Primary efficacy analysis..............................................................................34
 
........................................................................................35
.........................................................................................37
7.5
SECONDARY ENDPOINTS............................................................................37
7.5.1
Key Secondary Endpoint..............................................................................37
7.5.2
Secondary endpoints .....................................................................................37
..................................................................................39
 
....................................................................39
7.7
EXTENT OF EXPOSURE................................................................................44
7.8
SAFETY ANALYSIS.........................................................................................45
7.8.1
Adverse events ...............................................................................................45
7.8.2
Laboratory data.............................................................................................50
7.8.3
Vital signs.......................................................................................................51
7.8.4
ECG ................................................................................................................51


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7.8.5
Others .............................................................................................................51
8.
REFERENCES.....................................................................................52
................................................................53
 
........................................................................53
 
 
...................................................................................................53
10.
HISTORY TABLE...............................................................................56


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LIST OF TABLES
 
 
............................................................................................13
Table 6.1.1: 1 Treatment regimens / study intervals (Analno 1).............................................15
Table 6.2: 1
Important protocol violations...........................................................................17
Table 6.3: 1 
Patient sets analysed.........................................................................................23
Table 6.6: 1
Summary of imputation methods for efficacy endpoints.................................27
Table 6.7: 1 
Time windows for on-treatment HbA1c and FPG measurements scheduled 
for each on-treatment visit – Week 24 .............................................................31
 
 
...........................................................................55
Table 10: 1
History table .....................................................................................................56


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP 
Term
Definition / description
ADS
Analysis data sets
AE
Adverse event
AGI
Alpha-glucosidase inhibitors
ALT
Alanine transaminase
AST
Aspartate transaminase
BIcMQ
Boehringer Ingelheim customized MedDRA Query
BMI
Body Mass Index
BRPM
Blinded report planning meeting
CI
Confidence Interval
CT
Concomitant therapies
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
(e)CRF
(Electronic) Case Report Form
DBL
Database Lock
ECG
Electro-cardiogram
EMA
European Medicines Agency
EoT
End of treatment
FAS
Full analysis set
FPG
Fasting Plasma Glucose
GPSP
Good Post-Marketing Study Practice
GVP
Good Vigilance Practice
HbA1c
Glycosylated Haemoglobin
HBGM
Home blood glucose monitoring
HLT
Higher Level Term


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Term
Definition / description
ICH
International Conference on Harmonisation
ITT
Intention-to-Treat
IRT
Interactive Response Technology
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
MMRM
Mixed model repeated measures
O*C
Oracle Clinical
OC
Observed Cases
PHQ
Patient Health Questionnaire
PK
Pharmacokinetics
PPS
Per protocol set
PSTAT
Project Statistician
PT
Preferred term
PV
Protocol violation
Q-Q
Quantile-Quantile
ROC
Rescue observed cases
SD
Standard deviation
SLUMS
Saint Louis University Mental Status exam
SMQ
Standardised MedDRA query
SOC
System organ class
TCM
Trial Clinical Monitor
TOC
Table of contents
TMW
Trial Medical Writer
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal


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3.
INTRODUCTION
As per ICH E9, 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 Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in 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 and randomisation.
SAS® Version 9.4 or later version will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The following modifications regarding the analysis of trial data are implemented:
Analysis specified in CTP
Adjusted Analysis specified in TSAP
Primary endpoint: Baseline insulin is fixed 
categorical effect.
Primary endpoint: Baseline basal insulin is 
linear continuous covariate.
 
 
 
 
 
 


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Due to an alignment of terminology on project level, it was necessary to re-phrase some 
endpoints in the TSAP. 
Analysis: Text in CTP
Analysis: Adjusted text in TSAP
Secondary endpoint: Proportion of patients 
experiencing at least one confirmed 
hypoglycaemic event during 24 weeks of 
treatment.
Proportions of patients experiencing at least 
one hypoglycaemia accompanied by a 
glucose value during 24 weeks of treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint in this study is the change from baseline in HbA1c (%) after 24 weeks 
of randomised treatment.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
There are no key secondary endpoints in this trial.
5.2.2
Secondary endpoints
Secondary endpoints are the following:

Proportion of patients experiencing at least one hypoglycaemia accompanied by a 
glucose value during 24 weeks of treatment.  Hypoglycaemia accompanied by a 
glucose value is defined as
o
any investigator reported asymptomatic hypoglycaemic event or AE with a 
reported blood glucose measurement less than 54 mg/dL (<3.0mmol/L)
[AE.SYMI=0 and ((AE.GLUCOSE <54 and AE.LABU=232) or 
(AE.GLUCOSE <3.0 and AE.LABU=301))
or
(HYPOASYM.GLUCOSE <54 and HYPOASYM.LABU=232) or 
(HYPOASYM.GLUCOSE <3.0 and HYPOASYM.LABU=301)]
or
o
any investigator reported symptomatic hypoglycaemic AE confirmed by a 
reported blood glucose measurement less than or equal to 70 mg/dL 
(≤ 3.9 mmol/L)
[AE.SYMI=1 and ((AE.GLUCOSE ≤70 and AE.LABU=232) or 
(AE.GLUCOSE ≤3.9 and AE.LABU=301))]
or
o
a severe hypoglycaemic AE, i.e.,., an event that requires the assistance of 
another person to actively administer carbohydrates or glucagon because the 
patient is unable to take the substance on his or her own. 
[AE.ASSIST=1]
Note:  If another person hands the carbohydrate or glucagon to the patient 
without having to actively administer the substance because the patient is able 
to take the substance on his or her own, the hypoglycaemic AE does not 
qualify as severe.


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Note:
(i)
Hypoglycaemias are counted only once, i.e., a severe episode that has also 
symptoms indicated on the CRF is counted only once.
(ii) If AE.SYMI is missing and ((AE.GLUCOSE <54 and AE.LABU=232) or 
(AE.GLUCOSE <3.0 and AE.LABU=301) and AE.ASSIST<>1, then the patient 
is considered for this analysis.
If AE.SYMI is missing and [ ((AE.GLUCOSE >=54 and AE.LABU=232) or 
(AE.GLUCOSE >=3.0 and AE.LABU=301) or AE.ASSIST<>1 ], then the patient 
is not considered for this analysis.

Proportion of patients with HbA1c on treatment <8.0% after 24 weeks of treatment.

Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of treatment.

Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of 
treatment.

Change from baseline in FPG (mg/dL) after 24 weeks of treatment.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In this section, the treatment set-up (treatment regimens/study intervals and randomised 
treatment) is defined.
6.1.1
Treatment regimens / study intervals
There will be five treatment phases in this trial: screening, placebo run-in, treatment, 
post-treatment and post-trial.
The purpose of the table below is to describe all the different trial/treatment intervals, in 
which a patient can lie during the course of the trial. Note that the term “treatment regimen” 
can also cover time periods with no active treatment.


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Table 6.1.1: 1 
Treatment regimens / study intervals (Analno 1)
Short label
Interval
Sort order
Start date / 
Start time 
(HH:MM)
End date / 
End time
(HH:MM)
Screening
Screening
1
Date of informed 
consent / 00:00
Date of first 
administration 
of run-in 
medication / 
00:00
Run-in
Run-in
2
Date of first 
administration of
run-in medication / 
00:00
Date and time 
of first 
administration 
of study 
medication
Placebo / 
Lina 5mg
On-treatment
3 / 4
Date of first 
administration of 
study medication / 
Time of first 
administration of 
trial medication –
if missing: 12:00 
noon
Last day of 
trial 
medication
intake + 1day, 
00:00 
Post treat
Post-treatment
5
last day of trial 
medication intake 
+1day, 00:00
Date of V99 
+1day, 00:00
Post-trial
Post-trial
6
Date of V99 
+1day, 00:00
For purposes of the analysis, the residual period for assigning measurements to the on-
treatment period is dependent on the endpoint and therefore the analysis is based on visit 
windows as opposed to treatment regimens. Visit windows are further defined in Section 6.7.
6.1.2
Randomised treatment
Patients who receive an incorrect treatment at any visit (one which they were not randomised 
to) will be analysed for both efficacy and safety under the treatment which they were 
randomised to, for the entire trial period.
A special listing of Adverse Events only for patients that took a wrong treatment between 
visits within the course of the trial will be created.


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6.2
IMPORTANT PROTOCOL VIOLATIONS
There are two aspects that qualify a violation of the protocol to be important. 
First, there are protocol violations (PVs) that potentially affect the rights or safety of  patients
in the trial. In this case, the sponsor needs to react immediately to such PVs to prevent 
recurrence. In most cases, these PVs do not have an impact on whether a patient can be 
included in an analysis, but they need to be reported. 
Second, a PV can potentially influence the primary outcome measure for the respective 
patients in a way that is neither negligible nor in accordance with the study objectives. 
Therefore, such PVs potentially affect the main study results and conclusions. This second 
category of important protocol violations (IPVs) forms the basis for the decision (during the 
database lock [DBL] meeting) of whether a patient should be excluded from an analysis set.
The decision regarding whether such patients are to be excluded or not from an analysis set 
will made the treatment blind is broken.
As the primary endpoint is analysed at 24 weeks, PVs related to efficacy and satisfying the 
criteria for IPVs that occur in Japan between day 176 and the end of the trial (Week 52) will 
not lead to exclusion from analysis sets. 
All other PVs, i.e. those discussed and assessed during MQRMS, are of minor importance 
and it is not necessary to describe or list these PVs in the integrated clinical trial report 
(CTR).
The following table defines the different categories of IPVs. The final column describes 
which PVs will be used to exclude patients from the Per Protocol analysis set (PPS).


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Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded 
from
T+
A
Entrance criteria not met
A1
Target indication not met
A1.1
No type 2 diabetes
PPS
E
A1.2
Antidiabetic background therapy 
not as required
Inclusion criteria 2b, 2c or 2d not met as 
specified in the protocol
or 
Basal insulin [insulin neutral protamine 
Hagedorn (NPH) and isophane insulin; 
Humalog Basal®, insulin degludec; insulin 
detemir; and insulin glargine] not recorded 
on electronic case report form (eCRF)
or
Basal Insulin dose changed >20% within 4 
weeks prior to randomisation (8 weeks for 
Germany) or metformin/AGI dose changed 
within 12 weeks prior to randomisation if 
applicable.
PPS
E
A2
Inclusion criteria violated
A2.1
HbA1c out of range at start of 
placebo run-in period
Inclusion criteria 3 not met 
and/or 
HbA1c <7.5% if version 1 of informed 
consent signed, <7.0% if version 2 of 
informed consent signed or >10.0% at Visit 
1 (>9.0% for Germany).
PPS
E
A2.2
Age out of range at screening
Inclusion criteria 2a not met 
and/or
age <70 years if version 1 of informed 
consent signed or <60 years if version 2 of 
informed consent signed at Visit 1.
PPS
E
A2.3
Body mass index out of range at 
screening
Inclusion criteria 4 not met
and/or
Body mass index (BMI) >45kg/m2 at 
Visit 1.
PPS
E
A3, 
A4, 
A5
Exclusion criteria violated
A3.1
Relevant concomitant diagnoses
Exclusion criteria 4 checked
and/or
Acute coronary syndrome, stroke or TIA 
recorded on concomitant diagnoses eCRF 
within 3 months prior to Visit 1.
None
S


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Example/Comment
Excluded 
from
T+
A3.2
Impaired hepatic function
Exclusion criteria 5 checked 
and/or
Alanine Transaminase (ALT) or Aspartate 
Transaminase (AST) or alkaline phosphatase 
> 3x upper limit of normal (ULN) during 
screening and/or run-in [Gilbert-
Meulengracht syndrome is permitted].
None
S
A3.3
Known hypersensitivity to any 
of the drugs in the study regimen
Exclusion criteria 12 checked.
PPS
E
S
A3.4
Treatment with protocol 
excluded antidiabetic drugs
Exclusion criteria 9 or 10 or 11 checked
and/or
Treatment with GLP-1 analogues within 3 
months prior to informed consent (Visit 1)
and/or
Treatment with sulphonylureas, 
thiazolidinediones, SGLT2 inhibitors, or 
DPP-4 inhibitors within 3 months prior to 
randomisation (Visit 3)
and/or
Treatment with rapid acting or short acting 
insulin and/or pre-mixed insulin containing 
rapid acting or short acting insulin within 3 
months prior to randomisation (Visit 3).
PPS
E
A3.5
Treatment with protocol 
excluded anti-obesity drugs
Exclusion criteria 13 checked
and/or
Intake of any of the excluded drugs reported 
on the eCRF within the time prior to 
informed consent specified in the exclusion 
criteria.
PPS
E
A3.6
Diagnosis of Type 1 Diabetes 
Mellitus
Exclusion criteria 3 checked
and/or
Type 1 Diabetes Mellitus on concomitant 
diagnoses eCRF.
PPS
E
A4.1
Treatment with any drugs that 
have significant effect on 
glucose metabolism, protocol 
excluded systemic steroids or 
change in thyroid hormone dose
Exclusion criteria 14 checked
and/or
Intake of any of the excluded drugs reported 
on the eCRF within the time prior to 
informed consent specified in the exclusion 
criteria.
PPS
E


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Example/Comment
Excluded 
from
T+
A4.2
Alcohol or drug abuse that may 
interfere with study participation
Exclusion criteria 15 checked.
PPS
E
A4.3
Participation in another trial 
with an investigational drug 
within 2 months prior to 
informed consent
Exclusion criteria 16 checked
Final decision at the DBL meeting (medical 
judgment), depending on the type of drug 
given in the prior trial (only if investigational 
drug interferes with glucose metabolism).
PPS
E
A4.4
Patient has undergone bariatric 
surgery within 2 years prior to 
informed consent
Exclusion criteria 6 checked
and/or
Evidence of surgery reported on eCRF.
None
E
A4.5
Medical history of cancer 
(except basal cell carcinoma) 
within 5 years prior to informed 
consent
Exclusion criteria 7 checked.
None
S
A4.6
Unstable Red Blood Cells
Exclusion criteria 8 checked
and/or
Diagnosis of blood dyscrasias or any 
disorder causing hemolysis or unstable red 
blood cells (e.g., malaria, babesiosis, 
haemolytic anaemia) listed on concomitant 
diagnoses page of eCRF.
None
E
A4.7
Psychological, familial, 
sociological, or geographical 
factors potentially hampering 
compliance with the protocol, 
visits, or trial procedures or any 
other clinical condition that 
would jeopardize patient safety 
while participating in this 
clinical trial in the opinion of 
the investigator
Exclusion criteria 17 checked.
None
S
A4.8
Inability to commit to regular 
overnight fasting of at least 10 
hours duration and attendance to 
trial site visits between 07:00 
and 11:00am
Exclusion criteria 18 checked.
PPS
S


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Example/Comment
Excluded 
from
T+
A5.1
Impaired cognitive ability
Exclusion criteria 1 violated
and/or
Saint Louis University Mental Status 
(SLUMS) score of 21-26 (high school 
education) or 20-24 (no high school 
education) and no confirmation from 
investigator to rule out cognitive 
impairment.
and/or 
SLUMS score of 20 or less (high school 
education) or 19 or less (no high school 
education) indicating dementia.
Note: The first version of the eCRF 
contained the following statement:
Saint Louis University Mental Status 
(SLUMS) Examination scores of 25 or less 
for those patients with high school education 
or 23 or less for those patients who did not 
complete a high school education indicate 
that the patient probably have impaired 
cognitive ability.
[CONDT.PROTAM = 1.0 or 2.0]
None
S
A5.2
Depressed mood
Exclusion criteria 2 checked
and/or
Patient Health Questionnaire (PHQ) score 
≥10 at Visit 1.
None
S
A5.3
Acute pancreatitis or Chronic 
pancreatitis
Germany only.
Exclusion criteria 19 checked
and/or
Diagnosis of acute pancreatitis within 3 
months of screening
and/or
Medical history of chronic pancreatitis.
None
S
B
Informed consent
B1
Informed consent not 
available/not done
Inclusion criteria 1 not met
and/or
Date of informed consent for the study 
missing
and/or
No signature on patient’s “Declaration of 
Informed Consent”
Patient’s data will not be used at all.
All
R


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Example/Comment
Excluded 
from
T+
B
Informed consent
B2
Informed consent too late
Date of informed consent for the study not 
obtained prior to any study related procedure 
or re-consent with new version of informed 
consent too late.
Minimum requirement for initial informed 
consent <= date of Visit 1/date of any study 
procedure.
None
S
B3
Informed consent for sub-study 
not available
No separate informed consent for DNA 
banking (unspecified DNA sample).
Note: Pre-specified DNA and RNA samples 
are covered by the trial informed consent 
and therefore no additional informed consent 
is required. 
In Australia and the UK pre-specified DNA 
sample is forbidden according to local 
amendment.
Patient’s unspecified DNA sample will not 
be retained or analysed. For Australia and 
UK, the pre-specified DNA will not be 
retained or analysed.
None
S
C
Trial medication and 
randomisation
C1
Incorrect trial medication 
taken
C1.1
No trial medication taken
Patient randomised but no trial medication 
taken.
TS, FAS 
and PPS
E
C1.2
Incorrect trial medication taken
Wrong medication taken (different 
medication than the patient was randomised 
to taken at any visit, i.e. drug kit recorded in 
eCRF from different treatment group than 
drug kit assigned by the interactive response 
technology (IRT)
and/or
Gross misuse of trial medication (e.g. 
unacceptable dose of trial medication).
Can only be finally judged after DBL since 
unblinding information is required.
PPS
E
C2
Randomisation not followed
C2.1
Treated without randomisation
Patient treated according to eCRF, but not 
randomised according to IRT.
RS, FAS 
and PPS
E


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Example/Comment
Excluded 
from
T+
C3
Non-compliance
C3.1
Non-compliance with drug 
intake
Gross non-compliance issues only – based 
on compliance section of eCRF (at least two 
times on treatment compliance was outside 
80-120% according to eCRF)
Final decision at the DBL meeting (medical 
judgment).
PPS
E
C3
Non-compliance
C3.2
Non-compliance with criteria 
for removal from trial
Criteria for removing a patient from the trial 
not adhered to.
Final decision at the DBL meeting (medical 
judgment).
None
E
C3.3
Treatment interruption for more 
than 10 consecutive days
Documented treatment interruption for 11 
consecutive days or more.
PPS
E
C3.4
Non-compliance with HBGM 
data collection
Compliance with completing HBGM < 50% 
and/or
No tests performed for 5 consecutive days.
None
E
C4
Medication code broken
C4.1
Medication code broken without 
just cause
Medication code broken for no valid reason.
Final decision at the DBL meeting (medical 
judgment).
PPS
E
D
Concomitant medication
D2
Prohibited medication use
D2.1
Rescue medication taken 
without just cause
Use of rescue medication (as defined in 
Section 4.2.1 in CTP) with FPG prior to 
rescue therapy ≤240 mg/dL for Visit 3 to 
Visit 4 or ≤200 mg/dL for Visit 5 to Visit 98 
and/or
Review of eCRF for use of rescue 
medication without 6 week dose adjustment 
period (i.e. prior to Visit 4).
PPS
E
D2.2
Antidiabetic drug taken that is 
not a protocol defined rescue 
medication and criterion to 
administer rescue medication 
not fulfilled
Antidiabetic drug other than protocol 
defined rescue medication taken and 
criterion for rescue therapy as in D2.1 not 
fulfilled.
PPS
E
* IPVs will be checked programmatically, including double programming checks for inclusion/exclusion criteria, where 
possible. IPVs where inclusion/exclusion criteria possibly need to be confirmed manually with respect to time A3.1, A3.4, 
A3.5, A4.1, A4.4, A4.5, A5.1, A5.3  and D2.3. For A1.2 dose changes may need to be checked manually. IPVs which can 
only be identified manually are A4.2, A4.3, A4.7, A4.8 and C3.2.
+ IPV-type: ‘E’ refers to efficacy IPV, ‘S’ refers to safety IPV and ‘R’ refers to general (regulatory) IPV.


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6.3
PATIENT SETS ANALYSED

Randomised set (RS):
This patient set includes all randomised patients, whether treated or not.

Treated set (TS):
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment. 

Full analysis set (FAS):
This patient set includes all patients randomised in the TS who have a baseline and at 
least one on-treatment HbA1c value.

FAS-completers-24 (FASC24):
This patient set includes all patients in the FAS who complete a minimum treatment 
duration of 149 days, did not prematurely discontinue the trial and have an available 
HbA1c measurement within the time window for the Week 24 visit (Visit 98 for non-
Japanese and Visit 7 for Japanese patients up to day 176). This analysis set is not 
required for the analysis at Week 52. See Table 6.7: 1.

Per protocol set (PPS):
This patient set includes all patients in the FAS who do not have any IPVs relating to 
efficacy, cf. Table 6.2: 1.
Table 6.3: 1 
Patient sets analysed
Patient set
Class of endpoint
TS
FAS
PPS
FASC24
Primary endpoint 
Primary 
analysis
Sensitivity 
analysis
Sensitivity 
analysis
Secondary and 
further endpoints 
X
Safety endpoints 
X
Demographics
X
Baseline efficacy 
variables
X


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6.5
POOLING OF CENTRES
This section is not applicable as no analysis by centre will be performed.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Patients may drop out of the trial before they reach the planned observation time. In particular,
patients with a lack of efficacy can be expected to drop out with a higher probability than 
patients showing a good response. Therefore various methods will be used to assess the 


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impact of missing data on the efficacy endpoints of the trial. The following paragraphs give a 
general description of the various approaches.
Original Results (OR) analysis
For some of the efficacy endpoints, analysis will be done directly on the observed data, 
without any derivation performed on them. OR analysis is relevant in cases rescue therapy 
was taken.
Observed cases (OC)
One general approach that is possible for all endpoints is to analyse only the available data 
that were observed while patients were on treatment, i.e. excluding the missing data. Missing 
data in this analysis will not be replaced.
For all efficacy endpoints using OC, this OC-technique will be adapted by setting any values 
taken after rescue medication to missing. In addition values after the addition of a new anti-
diabetic therapy or an increase in metformin and/or AGI dose as specified in Section 5.3 will 
be set to missing.
It should be noted that this method provides unbiased estimates only under the assumption 
that the data are missing at random; and so, this method is likely to lead to non-conservative 
estimates of the treatment effects in case of data missing due to patients dropping – out
because of lack of efficacy of the study medication under treatment.
Observed cases – Rescue observed cases (OC-ROC)
In this case, values taken after rescue medication are neither set to missing nor are imputed 
otherwise but taken as measured.
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. This method
tends to result in more conservative estimates than an OC-analysis.
The last observation on-treatment must not necessarily be a value selected as a visit value as
described in Section 6.7. If multiple measurements were performed within a time window for
a visit, 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 date of last drug administration or the 
first value observed in the time window.
Baseline values will not be carried forward in general, but can be used for interpolation. Only
for patients with rescue medication before the first on-treatment HbA1c measurement,
baseline HbA1c values will be used to replace values after the start of rescue medication.


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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 (cf. Section 
6.7) to be used in the descriptive analysis by visit. Replacement of missing values will only 
be performed for visits up to the planned visit to be reached by all randomised patients in the 
trial.
Interpolation will be done according to the formula described below:
Let:
 = date of a visit with a missing endpoint value;
= date of the next-visit (with end-point value non-missing) after the visit with 
missing endpoint;
 = date of a previous-visit (with end-point value non-missing) before the visit with 
missing endpoint;
	 = endpoint value for visits 	 for 
 = −1, 0, 1.
Then the missing endpoint value can be interpolated as:
 =  + ( −) ×  −
 −
.
Multiple imputation (MI)
A multiple imputation approach will be used as a sensitivity analysis for the primary endpoint. 
Further details can be found in Section 7.4.2.
Non-completers considered failure (NCF)
For binary endpoints like a treat to target response of HbA1c <7.0% a conservative method to
replace missing values is to consider them as “failures”. Missing data due to early
discontinuation will be replaced as “failure” (e.g. HbA1c ≥7.0%) up to the planned final visit
to be reached by all patients. Similarly, values obtained after the start of rescue therapy will
be considered “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. based on
imputation as described for HbA1c).


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Table 6.6: 1
Summary of imputation methods for efficacy endpoints
Imputation 
method
Endpoint
Handling of missing values
Handling of values after 
rescue therapy
OR
Continuous, binary, 
time to event and 
count
No imputation
All data included as 
measured. Multiple 
measurements per visit 
possible.
OC
Continuous
No imputation
Excluded – considered   
missing. One picked value 
per visit (cf. Section 6.7).
OC-ROC
Continuous, binary, 
time to event and 
count
No imputation
Included as measured. One 
picked value per visit (cf.
Section 6.7).
LOCF
HbA1c (at each visit 
and change from 
baseline)
Missing values at the end of 
the trial are replaced by the 
last on-treatment value. 
Missing values with 
subsequent present on-
treatment values are imputed 
by interpolation. 
Baseline values are not carried 
forward, except where rescue 
medication is taken prior to 
first on-treatment 
measurement.
Baseline values can be used in 
interpolation.
Values after the start of 
rescue therapy are replaced 
by the last available 
measurement.
If no on-treatment HbA1c 
measurement prior to rescue 
therapy is available baseline 
values are carried forward.
MI
HbA1c
Missing values are imputed by 
a two-step approach. Firstly, a 
monotone missing pattern is 
generated in the data (MCMC 
method). Secondly, missing 
values are imputed by a 
sequential regression based 
method.
Considered missing and thus 
imputed.


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Table 6.6: 1
Summary of imputation methods for efficacy endpoints (cont.)
Imputation 
method
Endpoint
Handling of missing values
Handling of values after 
rescue therapy
NCF
Binary endpoints 
derived from 
continuous endpoints 
(e.g. HbA1c<7.0%)
Missing values after premature 
discontinuation of trial 
medication are considered 
failure (endpoint not 
achieved).
Missing values with 
subsequent present on-
treatment values will be 
imputed based on the 
interpolated values for the 
underlying continuous 
endpoint. 
Values after the start of 
rescue therapy are imputed 
as failure.
 
 
Safety and other variables
Missing safety data will not be replaced, but an analysis of the changes from baseline to the
last available value under treatment and the minimum and maximum post baseline will be
determined for quantitative safety laboratory variables. For safety analysis, as last on-
treatment value the last measurement between the first intake of randomised trial drug and 
drug-stop date + 7 days will be analysed as the last value on-treatment for non-Japanese 
patients.  If a Japanese patient stops drug intake prior or at day 175 a residual period of 7 days 
will be added for Week 24 safety analysis. If a Japanese patient does not stop drug intake 
prior day 176, no residual period is added for safety analysis.
Missing dates and times
Missing or partial date and time information for adverse events (AEs) will be replaced 
according to general Boehringer Ingelheim (BI) rules (cf. 1).
If the date of first drug administration is missing but the patient was randomised and treated, 
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. 


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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 8:00 o’clock in the morning.
As a general rule, a missing drug stop date will be imputed according to the following
principles:

If an End of Treatment (EoT) visit is documented, it should be the date of the EoT 
visit (Visit 98).

If the date is incomplete with only month and year and the EoT visit is missing, it 
should be the first day of the following month.

If the patient is lost to follow-up it should be the date of the last visit + the longest
treatment duration based on drug supply + 1 day.

All other cases need to be assessed by the trial team on an individual basis, trying to
use the points above as guidance.

After application of any of the first 3 rules, the post-treatment phase starts at the same
day as the imputed drug stop date (instead of treatment stop + 1 day).
If only the year of birth is known, the day and month of birth will be imputed as 01 January.
If month and year are known, the day of the birth will be imputed as 01.
For other incomplete date information always 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. 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.
If date and time information as well as a flag is missing for start of concomitant therapy, then 
the concomitant therapy is considered on-going at screening.
If date and time information as well as a flag is missing for end of concomitant therapy, then 
the concomitant therapy is considered on-going at end of study.
 
 


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Definition of baseline
With regard to efficacy and safety endpoints, the term "baseline" generally refers to the last 
observed measurement prior to administration of any randomised study medication. Baseline 
daily basal insulin dose is derived from eCRF and is equal to the daily basal insulin dose at 
day of first study medication intake. If patients are treated by a combination of a fast-acting 
and basal insulin, only the proportion of basal insulin is used for deriving the baseline daily 
basal insulin dose. If that proportion cannot be derived, baseline daily basal insulin is set to 
missing.
If patients are treated with an intermediate type if insulin, than this dose is completely 
considered for daily basal dose.
Also, for metformin and AGI, baseline doses refer to the dose at day of first study medication 
intake.
Measurements taken prior to the first intake of randomised trial medication will be 
considered pre-treatment values. These pre-treatment values will be assigned to a visit 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory. 
The date and clock time of the first study medication administration will be used to separate 
pre-treatment from on-treatment values. 
The definition of screening for the analysis of concomitant therapies (CTs) is the time period 
from informed consent up to the first dose of trial medication.
Definition of on-treatment for analyses
Measurements taken after the first intake of randomised study medication will be considered 
on-treatment values if they have been obtained up to 7 days after study medication stop
(inclusive) – this also holds for hypoglycaemia (efficacy endpoints) and hypoglycaemic 
adverse events (safety endpoints). The only exceptions are FPG
 for which 
will be up to 1 day after drug stop (inclusive) due to reacting quicker. All on-treatment 
measurements will be assigned to the randomised trial medication for analyses.
Measurements taken after the end of the follow-up period after the last intake of trial 
medication will be considered post-trial values.
Visit windows for efficacy variables
On-treatment efficacy 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 (this is at Visit 3).


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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 (7 days after last intake for 
all variables except FPG
 which are 1 day).
Table 6.7: 1 
Time windows for on-treatment HbA1c and FPG measurements
scheduled for each on-treatment visit – Week 24
Visit 
number
Visit label
Planned days 
after 
randomisation
Planned days 
on treatment
Time window (actual 
days on treatment)
Start
EndA
3
Baseline
0
1
NA
1B
98C
Week 24
168
169
149
Trial medication
stop date + xD
days
For Japanese Patients Only
7
Week 24
168
169
149
176
A  In case of premature discontinuation of the trial medication a Visit 98 (end of treatment) has to be performed. If such a 
Visit 98 falls into the time window of a previous visit, measurements will be assigned to this previous visit. In this case 
the time window for the visit that includes Visit 98 will end x days after the trial medication stop date, including day x. 
The definition of x is endpoint specific, cf. Table 5.3: 1
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. 
C   Only for non-Japanese patients.
D    cf. Table 5.3: 1.
For examinations that are not planned at every on-treatment visit, the time windows will be 
defined according to the same algorithm, based on the midpoint between the planned visit 
day of such an examination.
Repeated and unscheduled efficacy measurements will be assigned to the nominal visits and 
listed in the subject data listings according to the time windows described above. Only one 
observation per time window (visit value / picked value) will be selected for analysis at an 
on-treatment visit – the value will be selected which is closest to the protocol planned visit 
day; except for last study drug intake. In case of last study drug intake, the value which is 
closest to the date of last study drug intake is chosen. 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 earliest value will be used. If an observation is available on the last day of 
treatment, this observation will be preferably selected over any later observation that is still 
within the time window. If there are multiple values within the time window of the last visit, 


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including a value on the last day of drug intake, the value on the last day of drug intake is 
used as the value of the last visit.
Note: For LOCF imputation, the last observed on-treatment value will be carried forward, 
whether or not it was selected in the previous time window. Also for interpolation any valid 
values can be used, regardless of whether they were selected as visit values. For more details 
on LOCF refer to Section 6.6.
For daily basal insulin the value at the visit will be determined as the last prescribed dose 
prior to the picked HbA1c value of the visit.
Visit windows will not be applied to hypoglycaemia or use of rescue therapy and events will 
not be assigned to visits. All on-treatment events will be considered in the analysis. 
Visit windows for safety variables
Safety measurements will be assigned to the nominal visit as recorded on the eCRF or as 
provided by the laboratory. In general, visit windows will not be applied. However, for the 
Week 24 analysis, if a Japanese patient stops drug intake prior or at day 175 a residual period 
of 7 days will be added for safety analysis. If a Japanese patient does not stop drug intake 
prior day 176, no residual period is added for safety analysis at Week 24.


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7.
PLANNED ANALYSIS
For End-Of-Text tables, the set of summary statistics is: N / Mean / SD / Min / Median / 
Max. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum
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 (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
For baseline eGFR calculations (MDRD) the following rules are to be applied regarding 
multiple race categories and Japanese patients:

eGFR for patients with multiple race category Black & White will be calculated as 
eGFR for patients with race category Black

eGFR for patients with multiple race category American Indian/Alaska Native & 
White will be calculated as eGFR for patients with race category White 

eGFR for patients with race Asian outside the region Asian will calculated as eGFR 
for Japanese patients.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Concomitant medication 
table will additionally be produced at Week 52 for Japanese patients only.
7.3
TREATMENT COMPLIANCE
Compliance with trial medication intake will be calculated by the investigator as a percentage 
of the number of pills taken relative to the number of pills that were planned to be taken since 
the last visit. On the eCRF only the information whether this calculated compliance was 
within the range of 80% to 120% since the previous visit is recorded. Treatment interruptions 
of greater than 7 consecutive days will be recorded in the eCRF.
Only descriptive statistics are planned for this section of the report.


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7.4
PRIMARY ENDPOINT
7.4.1 
Primary efficacy analysis
The primary analysis will be performed on the FAS (OC); patients will be assigned to the 
treatment they were randomised to and analysed according to the stratum to which they 
belong (regardless of any incorrect assignment to treatment based on identification of wrong 
stratum).
Mean changes from baseline in HbA1c after 24 weeks of treatments will be analysed using a 
restricted maximum likelihood-based repeated measures approach (mixed model repeated 
measures [MMRM]). 
Analyses will include the fixed, categorical effects of treatment, week, and treatment by week
interaction – accounting for the respective sources of variation. The model also includes the 
continuous, fixed linear covariates of baseline HbA1c, baseline daily basal insulin dose and 
baseline HbA1c by week interaction that control the treatment and week effects for possible 
impact from these underlying factors. An unstructured (co)variance structure will be used to 
model the within patient measurements.
If this analysis fails to converge, the following covariance structures will be tested: Toeplitz,
AR (1), and compound symmetry. The (co)variance structure converging to the best fit, as
determined by Akaike’s information criterion, will be used as the primary analysis.
The Kenward-Roger approximation will be used to estimate 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 (CI)]. The residuals are assumed to have a multivariate normal 
distribution with zero means and covariance matrix as specified above. All analyses will be 
implemented using SAS®. The primary treatment comparisons will be the contrast between 
treatments at Week 24.
The statistical model will be:
HbA1c change from baseline = overall mean + treatment + week 
+ treatment by week interaction 
+ baseline HbA1c + baseline daily basal insulin dose 
+ baseline HbA1c by week interaction
+ random error.
The model’s random error is assumed to follow a normal distribution.
For Week 24 analysis, all levels for factor week up to Week 24 are to be considered in the 
model, 
In addition, descriptive statistics for HbA1c (in %) over time are presented for FAS(OC), 
FAS(OC-ROC) and FAS(LOCF).


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7.5
SECONDARY ENDPOINTS
7.5.1
Key Secondary Endpoint
Not Applicable.
7.5.2
Secondary endpoints
Proportion of patients with at least one hypoglycaemia accompanied by a glucose value
during 24 weeks of treatment
Logistic regression for the proportion of patients experiencing at least one hypoglycaemia
after 24 weeks will be performed on the FAS (OC); all on-treatment hypoglycaemias will be 
considered:

up to drug stop date if a patient prematurely discontinues (Japanese patients that 
prematurely discontinue prior or at day 175)


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
up to trial medication stop date – 1 if a non-Japanese patient does not prematurely 
discontinue 

up to day 175 if a Japanese patient does not prematurely discontinue prior day 176.
The model will include treatment as fixed effect and baseline HbA1c and baseline daily basal
insulin dose as linear covariates. 
Frequencies regarding the number and percentage of patients experiencing at least one 
hypoglycaemia accompanied by a glucose value during 24 weeks in each treatment group 
will also be presented based on FAS(OC) .
Proportion of patients with HbA1c on treatment <8.0% after 24 weeks of treatment
Logistic regression for the patients achieving HbA1c <8.0% at Week 24 will be performed on 
FAS (NCF); patients who do not complete 24 weeks of treatment will be considered non-
responders. The model will include treatment as fixed effect and baseline HbA1c and baseline 
daily basal insulin dose as linear covariates. Patients with baseline HbA1c <8.0% will be 
excluded from the analysis.
A frequency table with the number and percentage of patients with HbA1c <8.0% at Week 24 
in each treatment group will be also be presented based on FAS (NCF).
Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of treatment
Logistic regression for the patients achieving HbA1c <7.0% at Week 24 will be performed on 
FAS (NCF); patients who do not complete 24 weeks of treatment will be considered non-
responders. The model will include treatment as fixed effect and baseline HbA1c and baseline 
daily basal insulin dose as linear covariates. Patients with baseline HbA1c <7.0% will be 
excluded from the analysis.
Frequencies regarding the number and percentage of patients with HbA1c <7.0% at Week 24 
in each treatment group will be also be presented based on FAS (NCF).
Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of treatment
Logistic regression for the patients achieving lowering of HbA1c by at least 0.5% from 
baseline at Week 24 will be performed on FAS (NCF); patients who do not complete 24 
weeks of treatment will be considered non-responders. The model will include treatment as 
fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates . 
Frequencies regarding the number and percentage of patients with lowering of HbA1c by at 
least 0.5% from baseline at Week 24 in each treatment group will be also be presented based 
on FAS (NCF).


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Change from baseline in FPG after 24 weeks of treatment
Analysis of change from baseline in FPG will follow the strategy for the primary endpoint.
MMRM will be used to analyse the mean changes from baseline in FPG after 24 weeks of 
treatments.
FPG change from baseline = overall mean + treatment + week 
+ treatment by week interaction 
+ baseline HbA1c + baseline daily basal insulin dose 
+ baseline FPG
+ baseline FPG by week interaction
+ random error.
The analysis will include the fixed, categorical effects of treatment, week and treatment by 
week interaction, as well as the continuous, fixed covariates of baseline FPG, baseline daily 
basal insulin dose, baseline HbA1c and baseline FPG by week. An unstructured (co)variance 
structure will be used to model the within patient measurements. This analysis will be 
performed on FAS (OC).


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7.7
EXTENT OF EXPOSURE
Exposure to trial medication will be calculated in days as (trial medication stop date – trial 
medication start date +1) and will be tabulated as a frequency table with categorised 
treatment duration. In addition, median exposure and the number of patient years of exposure 
will be given per treatment (calculated as the sum of days over all patients per treatment 
group divided by 365.25). This table will additionally be produced at Week 52 for Japanese 
patients.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
The analysis will be based on data collected up 24 weeks at DBL. For non-Japanese patients 
an additional residual period of 7 days is added to the drug stop data.
For Japanese patients, all AEs up to and including day 175 are considered. An additional 
residual period of 7 days is added for Japanese patients that prematurely discontinue prior or 
at day 175.
Any data up to day 176 inclusive that is updated or entered after DBL will be summarised in 
the analysis including data up to 52 weeks only.
7.8.1
Adverse events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE 
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies:

The same MedDRA lowest level term was reported for the occurrences.

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).

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
For further details on summarisation of AE data, please refer to the guideline 'Handling and 
summarization of AE data for clinical trial reports and integrated summaries' (2).
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between first drug intake until 7 days after last drug intake will be 
assigned to the randomised treatment; in these cases the date and time of the AE onset are 
used. All AEs occurring before first drug intake will be assigned to ‘screening’ and all 
adverse events occurring after last drug intake + 7 days will be assigned to ‘post-treatment’ 
(for listings only). For details on the treatment definition, see Section 6.1. Japanese patients 
who did not prematurely discontinue prior or at day 175 do not have a post-treatment period 
for Week 24 analysis.
According to International Conference on Harmonisation (ICH) E3 (3) AEs classified as 
‘other significant’ will include those non-serious adverse events with 

‘action taken = discontinuation’ or ‘action taken = reduced’, or


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
marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Blinded Report 
Planning Meeting. 
An overall summary of AEs will be presented. In addition, the frequency of patients with 
adverse events will be summarised by treatment, primary system organ class and preferred 
term. Separate tables will be provided for patients with other significant adverse events 
according to ICH E3 (3) for patients with serious adverse events, AELDs, AEs by severity, 
and AEs by outcome.
The frequency of patients with adverse events will also be summarised by subgroups 

Age (in years: <70, ≥70 to <75,.  ≥75)

Gender

Background therapy (Insulin+/-AGI, Insulin+Metformin+/-AGI, 
Insulin+Metformin+SU) 

Renal Function (in units mL/min/1.73m2: <60, ≥60 and <30, ≥30 to <60, ≥60 to <90, 
≥90)

Race.
In addition, frequencies of patients with post-treatment AEs will be displayed.
The system organ classes and preferred terms will be sorted alphabetically.
Analysis of investigator defined hypoglycaemic adverse events
The investigator will record for each AE whether it represents a hypoglycaemic AE and if so, 
record additional information to assess the intensity of the hypoglycaemic AE. On the basis 
of this information the hypoglycaemic AE will be classified as:

investigator defined hypoglycaemic AE with 
o
confirmed plasma glucose level of ≤70mg/dL (≤3.9mmol/L) or severe 
hypoglycaemic AE
o
confirmed plasma glucose level of <54mg/dL (<3.0mmol/L) or severe 
hypoglycaemic AE
o
severe hypoglycaemic AE

investigator defined symptomatic hypoglycaemic adverse event or any severe 
hypoglycaemic AE with 
o
confirmed plasma glucose level of ≤70mg/dL (≤3.9mmol/L) or severe 
hypoglycaemic AE
o
confirmed plasma glucose level of <54mg/dL (<3.0mmol/L) or severe 
hypoglycaemic AE
o
severe hypoglycaemic AE.
A frequency table will be provided for the number of patients per treatment group that 
experienced any investigator defined hypoglycaemic AE as defined above.


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Asymptomatic hypoglycaemia events which do not represent an AE will also be collected on 
a separate CRF page. No symptoms are recorded for these events, only plasma glucose levels. 
An overview table with frequency of patients who experienced any hypoglycaemia – reported 
as investigator defined AE or as asymptomatic hypoglycaemia (not as AE) will be presented. 
Also frequencies for asymptomatic hypoglycaemic events (reported as AE or non-AE) will be 
shown. The number of patients with hypoglycaemic events (as AE or non-AE) will be 
tabulated by treatment group.
The impact of the occurrence of investigator defined hypoglycaemic AEs will be explored 
using logistic regression; the model will include treatment, continuous baseline HbA1c and 
baseline daily basal insulin dose. Time to first onset of the first investigator defined 
hypoglycaemic AE will be analysed by Kaplan-Meier estimates if enough events occur.
 
 
 
 
 
 
 
Adverse events of special interest
Adverse Events of Special Interest (AESI) are topics under close surveillance in all clinical 
trials including linagliptin. At the time of finalisation of this protocol, the AESI categories 
and types of events include:

Hypersensitivity reactions such as angioedema, angioedema-like events, and 
anaphylaxis (narrow SMQ Hypersensitivity)

Skin lesions such as exfoliative rash, skin necrosis, or bullous dermatitis (narrow 
SMQ SCAR)

Hepatic events such as ≥3 fold upper limit of normal (ULN) of AST and/or ALT, 
hepatitis, hepatic injury, jaundice and potential Hy’s Law cases
o
AEs based  – Table based on following (sub) SMQs 

Drug related hepatic disorders - severe events only (SMQ)

Liver related investigations, signs and symptoms (SMQ)

Cholestasis and jaundice of hepatic origin (SMQ)


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o
Lab based: DILI evaluation listing (potential Hy’s Law cases) – listing of all 
patients that have at least one AST/ALT value greater or equal than 3 times 
ULN or one Total bilirubin case greater or equal 2 times ULN

Renal adverse events such as acute renal failure (Narrow SMQ acute renal failure)

Pancreatitis (Pancreatic event tables)

Pancreatic cancer (will be captured in pancreatic event tables and proposed 
malignancy table)
The categories and events included as AESIs may change according to the active 
pharmacovigilance of linagliptin and are expected to be updated on a periodic basis. 
Definitions, including Standardised MedDRA Queries (SMQs) for the AESIs will be 
maintained on project level and presented in Section 16.2.7.
AESIs will be summarised by preferred term.
Events qualifying for external adjudication by the Clinical Event Committee (CEC)
An independent external CEC regularly reviews cardiovascular and neurovascular events and
evaluates whether pre-specified criteria for these adjudicated endpoints are met. Details on
composition of the CEC, responsibilities and clinical event definitions are provided in a
separate CEC Charter. Events qualifying for adjudication will be selected based on the SMQs
(as detailed in the latest CEC charter version):

Ischemic heart disease (excluding selected PTs as listed in the CEC charter)

Cardiac failure (excluding selected PTs as listed in the CEC charter)

Torsade de pointes / QT prolongation

Central nervous system vascular disorders (excluding selected PTs as listed in the 
CEC charter)

Further simple preferred terms and

All fatal cases
The CEC will be provided with additional, specified background material on the patients with
these events and will perform an adjudication of the events.
Adjudication will be incorporated to the database and will include the following
adjudication endpoints:

Cardiovascular death, including presumed cardiovascular death and other 
cardiovascular death, fatal stroke, fatal myocardial infarction, sudden death, 
worsening of heart failure, cardiogenic shock

Myocardial infarction (non-fatal)

Stroke (non-fatal)

Hospitalisation for unstable angina pectoris


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
Stent thrombosis

Heart failure requiring hospitalisation

Coronary revascularisation procedures (Coronary Artery Bypass Grafting (CABG) or 
Percutaneous Coronary Intervention (PCI))

Transient ischemic attack (TIA)
Additionally, a separate independent, blinded, external committee will regularly review
pancreatic events. The adjudication process for these events is clarified in a separate CEC
charter.
This independent and external CEC will regularly review events suspect of acute
pancreatitis, chronic pancreatitis, asymptomatic pancreatic hyper-enzymemia and pancreatic
malignancy and will evaluate whether pre-specified criteria for these adjudication events are
met. Details on composition of the CEC, responsibilities and clinical event definitions are
provided in the charter. Events qualifying for adjudication will be selected based on the latest
CEC charter version:

SMQs acute pancreatitis (excluding selected PTs as listed in the CEC charter)

Trigger events of acute pancreatitis

Trigger events of chronic pancreatitis

Trigger events pancreatic malignancy
A list of amylase and lipase laboratory values that are ≥ 3 times the upper limit of normal
(ULN) and not reported as AE, but considered for adjudication by Team
Member medicine (TMM) or Team Member Drug Safety (TMDS).
The CEC will be provided with additional, specified background material on the patients with
these events and will perform an assessment of the events.
Adjudication assessments will be incorporated to the database and will include the following
adjudication endpoints:

Acute pancreatitis (with organ failure)

Acute pancreatitis (without organ failure)

Chronic pancreatitis (with organ failure)

Asymptomatic pancreatic hyper-enzymemia

Pancreatic malignancy
Frequency tables by treatment group will be provided for the adjudicated endpoints
(cardiovascular and pancreatic events, respectively) and for the preferred terms in the
specified SMQs of events.
Tables will be provided for cardiovascular and pancreatic events respectively that were
confirmed or non-assessable
o
Frequency [N (%)] of patients with adverse events qualifying for CECP 
adjudication by treatment, system organ class and preferred term − TS


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o
Adjudication results: Frequency [N(%)] of patients with CECP confirmed 
pancreatic adverse events by treatment – TS.
Other selected safety topics
Other selected safety topics are topics that are under close surveillance in trials with
linagliptin. At the time of finalisation of this protocol, the following safety topic was included

Malignancy.
Frequencies of patients in each treatment group will be provided by user-defined AE category 
and preferred term. The SMQ “Malignant or unspecified tumours” is to be applied.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (4).
Laboratory values taken after the first dose of randomised treatment up to a period of 7 days 
after the last dose of study medication will be assigned to the treatment period for evaluation.
Descriptive statistics for baseline, last value on treatment and difference from baseline will be 
presented. Laboratory values will be compared to their reference ranges and a frequency table 
will be provided for the number of patients with transitions relative to reference ranges at 
baseline. A frequency table of patients with possible clinically significant abnormalities will 
also be presented. 
In order to support screening for highly increased amylase and/or lipase values with respect 
to upper limit of normal (ULN), a specific transition table will be provided. The table lists the 
number and frequency of patients with last value or maximum value on treatment 

less than or equal ULN

greater than ULN

greater than 2 ULN

greater than 3 ULN
for baseline categories

less than LLN

greater than or equal LLN and less than or equal ULN

greater than ULN and less than or equal 3ULN

greater than 3ULN
All analyses will be based on the treated set (TS).


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7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. The following parameters 
are analysed: pulse, systolic blood pressure, diastolic blood pressure.
7.8.4
ECG
12-lead ECG measurements will be taken at baseline (Visit 3) and after 24 weeks (Visit 98 
[EoT] for non-Japanese patients, Visit 7 for Japanese patients) and additionally at Week 36 
and 52 (EoT) for Japanese patients. ECG-findings before randomisation will be considered as 
baseline conditions. Any clinically significant new findings in the ECG-measurement after 
the first screening ECG will be considered AEs and analysed as planned in Section 7.8.1.
7.8.5
Others
Physical Examination will be taken at screening (Visit 1), and at the end of the treatment 
(Visit 98). Findings in the physical examination at screening will be considered a baseline 
condition. Any clinically significant new findings in the Physical Examination during the 
course of the trial will be considered AEs and analysed as planned in Section 7.8.1.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
3
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.
4
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
12-Oct-16
None
This is the final TSAP without any 
modification
Revised
09-Nov-2016
6.2
Table 6.2: 1 additional column defining 
the type of the IPV,
FPG limits adjusted
footnote added
 
6.8
section omitted from TSAP, will move 
to ADS plan
7.8.1
age, renal function and background 
therapy subgroups for AE and 
hypoglycaemic AE analyses adjusted,