Clinical trial NCT02897349
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2016-09-30; Completion date: 2019-01-18
Enrollment: 206 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of linagliptin compared to placebo when added on to insulin therapy alone or in combination with metformin in Chinese patients with type 2 diabetes mellitus with insufficient glycaemic control

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: placebo intervention 2: linagliptin intervention 3: background therapy
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: insulin with or without metformin

Protocol documents:
Prot_002.pdf: 
abcd
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11679959-03
BI Trial No.:
1218.102
BI Investigational 
Product:
Linagliptin (Trajenta)
Title:
A phase III,  randomised, double-blind, placebo-controlled, 
parallel group, efficacy and safety study of linagliptin, 
administered orally once daily, in combination with insulin 
therapy for 24 weeks in Chinese type 2 diabetes mellitus patients 
with insufficient glycaemic control
Lay Title:
Linagliptin Add-on to Insulin Background Therapy
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone: 
Fax:
Coordinating 
Investigator:
Phone: 
Fax:
Status:
Final Protocol (Revised Protocol (based on amendment 02))
Version and Date:
Version: 3.0
Date: 28 Nov 2017
Page 1 of 70
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Linagliptin (Trajenta)
Name of active ingredient:
Linagliptin (Trajenta)
Protocol date:
04 Feb 2016
Trial number:
1218.102
Revision date:
28 Nov 2017
Title of trial:
A phase III, randomised, double-blind, placebo-controlled, parallel 
group, efficacy and safety study of linagliptin, administered orally 
once daily, in combination with insulin therapy for 24 weeks in 
Chinese type 2 diabetes mellitus patients with insufficient glycaemic 
control
Coordinating 
Investigator:
Trial site:
Multi-centre trial conducted in China
Clinical phase:
Phase III
Objectives:
To evaluate the efficacy and safety of  linagliptin 5 mg once a day 
(q.d.) compared to placebo when added on to insulin therapy alone or 
in combination with metformin in Chinese patients with type 2 
diabetes mellitus with insufficient glycaemic control
Methodology:
A randomised, double-blind, placebo-controlled, parallel group
design comparison, as add-on therapy to a stable background of 
insulin (basal insulin, premixed insulin) and metformin (optional) 
over 24 weeks
No. of patients: 
total entered:
206 patients
each treatment:
103 patients
Diagnosis :
Type 2 diabetes mellitus
Main criteria
for inclusion:
Patients ≥18 years with type 2 diabetes mellitus
Insufficient glycaemic control (HbA1C ≥ 7.5 to ≤10.0%)
Background therapy with subcutaneous insulin alone (basal insulin, 
premixed insulin) or in combination with metformin
Test product:
Linagliptin


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Linagliptin (Trajenta)
Name of active ingredient:
Linagliptin (Trajenta)
Protocol date:
04 Feb 2016
Trial number:
1218.102
Revision date:
28 Nov 2017
dose:
5mg once daily 
mode of 
administration:
Tablets per os 
Comparator products:
Placebo
dose:
Not applicable
mode of 
administration:
Tablets per os
Duration of treatment:
2-week placebo run-in
24 week double-blind treatment with either linagliptin 5 mg or 
placebo
1 week follow-up 
Endpoints
The primary endpoint is the change from baseline in HbA1c after 24 
weeks of treatment.
Secondary efficacy endpoints are the following:

Change from baseline in fasting plasma glucose (FPG) after 
24 weeks of treatment

Change from baseline in 2-hour postprandial plasma glucose 
(PPG) after 24 weeks of treatment

Proportion of patients with HbA1c on treatment <7.0% after 24 
weeks of treatment

Proportion of patients with HbA1c on treatment <6.5% after 24 
weeks of treatment

Proportion of patients with HbA1c lowering by at least 0.5% after 
24 weeks of treatment
Secondary safety endpoints are:

Incidence of investigator–reported hypoglycaemic events 
confirmed by a measured blood glucose ≤70 mg/dL 


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Linagliptin (Trajenta)
Name of active ingredient:
Linagliptin (Trajenta)
Protocol date:
04 Feb 2016
Trial number:
1218.102
Revision date:
28 Nov 2017
(≤3.9 mmol/L)

Incidence of severe hypoglycaemic events (requiring active 
assistance by another person, or fatal)
Safety criteria:
Adverse events (including relevant new or worsening pre-existing 
conditions) and AEs of Special Interest (AESI)
Statistical methods:
The primary analysis using a restricted maximum likelihood-based 
mixed model repeated measures approach is applied to compare the 
change in HbA1c from baseline between treatments after 24 weeks of 
treatment. The statistical model will include ‘treatment’, ‘type of 
insulin’ and ‘week’ as fixed, categorical effects, ‘baseline HbA1c’ as a 
continuous covariate, ‘week by treatment interaction’ and ‘baseline 
HbA1c by week interaction’. 


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FLOW CHART
Trial Period
Screening
Placebo 
run-in 
period
Randomised treatment period
Follow
-up 
period
Visit
1A
2
3
4
5
6
7
8(EOT)
9B
Study week
-3
-2
0
4
8
12
18
24
25
Study day
-21
-14
1
29
57
85
127
169
176
Visit window (in days)
+/-7
-7
NA
+/-7
+/-7
+/-7 +/-7
+7
+7
Informed Consent
X
Medical history / 
concomitant diagnoses
X 
Demographics
XK
X
In-/Exclusion criteria
X
X
X
Physical examination
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
Waist circumference
X
X
Diet and exercise 
counselling C
X
X
X
X
X
X
X
12-lead ECGD
X
X
Pregnancy test E
X
X
X
X
Glomerular filtration 
rate M
X
X
X
X
Safety lab tests F
(urine and blood)
XG
X
X
X
X
X
FPG 
X
X
X
X
X
X
X
X
2-hour PPG test 
X
X
MTT test
X
X
HbA1c
X
X
X
X
X
X
X
Lipid lab panel
X
X
Home Blood Glucose 
Monitoring H
X
X
X
X
X
X
X
X


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Trial Period
Screening
Placebo 
run-in 
period
Randomised treatment period
Follow
-up 
period
Visit
1A
2
3
4
5
6
7
8(EOT)
9B
Study week
-3
-2
0
4
8
12
18
24
25
Adverse events
X
XJ
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
Dispense placebo run-
in medication I
X
Randomisation (via 
IRT)
X
Dispense double-blind 
study medication I
X
X
X
X
X
Medication 
compliance check
X
X
X
X
X
X
A
The screening procedures can be done on different days within the time window after inform consent signed.
B 
Visit 9 (Follow-up visit) is required as following: 
(a) for patients that regularly completed treatment phase: phone visit to obtain adverse event information 
(b) for prematurely discontinued patients: trial site visit to obtain vital signs, safety lab and adverse events etc.
C
Diligent diet and exercise counselling by a diet specialist or delegated staff member at visit 2. Counselling is based on 
local diet recommendations. At all visits, patients should be reminded about the importance to follow the 
recommended diet and exercise plan.
D
In addition to the visits indicated, ECG should be recorded in case of respective cardiac symptoms (indicating rhythm 
disorders or cardiac ischaemia)
E 
For female patients (local urine pregnancy test in women of child bearing potential)
F
Fasting blood samples (full overnight fast (nothing to eat or drink except water for at least 10 hours))
G
For the screening Visit 1, laboratory only includes liver transaminases, alkaline phosphatase, and serum creatinine. 
Patients do not have to be fasting.
H
Instruction and training of the patient to use the device at Visit 2. Daily measurements during Run-in and Follow-up. 
During the treatment period a weekly test is recommended. During the whole trial participation, additional 
measurements should be done in case of hypo- or hyperglycaemia related symptoms.  
I
At all visits, the respective kit number has to be allocated to the patient via IRT.
J
For patients that screen fail before Visit 2, only serious adverse events need to be reported
K
Only screening relevant demographics (gender, date of birth, race and ethnicity) at visit 1. Smoking and alcohol status 
could be collected at visit 2.
M
Calculated based on MDRD formula (Section 5.3.3)


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................12
MEDICAL BACKGROUND.............................................................................12
1.1
DRUG PROFILE................................................................................................12
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....15
RATIONALE FOR PERFORMING THE TRIAL.........................................15
2.1
TRIAL OBJECTIVES........................................................................................15
2.2
BENEFIT - RISK ASSESSMENT.....................................................................15
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................17
OVERALL TRIAL DESIGN AND PLAN .......................................................17
3.1
3.1.1
Administrative structure of the trial .................................................................18
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................19
SELECTION OF TRIAL POPULATION .......................................................19
3.3
3.3.1
Main diagnosis for trial entry ............................................................................20
3.3.2
Inclusion criteria .................................................................................................20
3.3.3
Exclusion criteria ................................................................................................21
3.3.4
Removal of patients from therapy or assessments...........................................22
Removal of individual patients .............................................................................22
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................23
3.3.4.2
4.
TREATMENTS...................................................................................................24
INVESTIGATIONAL TREATMENTS ...........................................................24
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................24
4.1.2
Selection of doses in the trial..............................................................................24
4.1.3
Method of assigning patients to treatment groups...........................................24
4.1.4
Drug assignment and administration of doses for each patient......................25
4.1.5
Blinding and procedures for unblinding...........................................................25
Blinding.................................................................................................................25
4.1.5.1
Unblinding and breaking the code ........................................................................26
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................26
4.1.7
Storage conditions...............................................................................................26
4.1.8
Drug accountability.............................................................................................27
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................27
4.2.1
Other treatments and emergency procedures..................................................27


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4.2.2
Restrictions ..........................................................................................................29
Restrictions regarding concomitant treatment ......................................................29
4.2.2.1
Restrictions on diet and life style..........................................................................30
4.2.2.2
Restrictions regarding women of childbearing potential......................................30
4.2.2.3
TREATMENT COMPLIANCE........................................................................30
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................32
TRIAL ENDPOINTS..........................................................................................32
5.1
5.1.1
Primary Endpoint ...............................................................................................32
5.1.2
Secondary Endpoints..........................................................................................32
ASSESSMENT OF EFFICACY........................................................................33
5.2
ASSESSMENT OF SAFETY.............................................................................34
5.3
5.3.1
Physical examination ..........................................................................................34
5.3.2
Vital Signs............................................................................................................34
5.3.3
Safety laboratory parameters ............................................................................34
5.3.4
Electrocardiogram ..............................................................................................36
5.3.5
Other safety parameters.....................................................................................36
5.3.6
Assessment of adverse events.............................................................................37
Definitions of AEs ................................................................................................37
5.3.6.1
Adverse event collection and reporting ................................................................40
5.3.6.2
5.3.7
Criteria for hypoglycaemic events.....................................................................42
APPROPRIATENESS OF MEASUREMENTS..............................................43
5.7
6.
INVESTIGATIONAL PLAN.............................................................................45
VISIT SCHEDULE.............................................................................................45
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................45
6.2
6.2.1
Screening and run-in period ..............................................................................45
6.2.2
Treatment period ................................................................................................46
6.2.3
Follow Up Period and Trial Completion...........................................................47
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................48
STATISTICAL DESIGN - MODEL.................................................................48
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................48
7.2
PLANNED ANALYSES.....................................................................................48
7.3
7.3.1
Primary endpoint analyses.................................................................................49
7.3.2
Secondary endpoint analyses .............................................................................50


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7.3.4
Safety analyses.....................................................................................................51
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................51
INTERIM ANALYSES ......................................................................................51
7.4
HANDLING OF MISSING DATA ...................................................................52
7.5
RANDOMISATION ...........................................................................................52
7.6
DETERMINATION OF SAMPLE SIZE .........................................................53
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................54
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................54
DATA QUALITY ASSURANCE ......................................................................55
8.2
RECORDS...........................................................................................................55
8.3
8.3.1
Source documents ...............................................................................................55
8.3.2
Direct access to source data and documents.....................................................56
8.3.3
Storage period of records ...................................................................................56
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................56
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........57
8.5
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................57
TRIAL MILESTONES.......................................................................................57
8.6
9.
REFERENCES....................................................................................................58
PUBLISHED REFERENCES............................................................................58
9.1
UNPUBLISHED REFERENCES......................................................................59
9.2
10.
APPENDICES.....................................................................................................60
11.
DESCRIPTION OF GLOBAL AMENDMENT..............................................61


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Events of Special Interest
ADA
American Diabetes Association
ALT
Alanine aminotransferase (or SGPT)
AMP
Auxiliary Medicinal Product
ANCOVA
Analysis of Covariance
AST
Aspartate aminotransferase (or SGOT)
BI
Boehringer Ingelheim
BIcMQs
Boehringer Ingelheim customized MedDRA Queries 
BMI
Body Mass Index
BP
Blood Pressure
CA
Competent Authority
CEC
Clinical Event Committee
CI
Confidence Interval
CK
Creatine kinase
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF/eCRF
Case Report Form/electronic Case Report Form
CRO
Clinical Research Organisation
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DEDP
Drug exposure during pregnancy
DPP-4
Dipeptidyl-peptidase IV
EASD
European Association for the Study of Diabetes
ECG
Electrocardiogram
EOT
End of treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
FPG
Fasting plasma glucose
FPI
Fasting plasma insulin
FC
Flow chart
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GIP
Glucose-dependent insulinotropic peptide
GLP-1
Glucagon like peptide-1
HBA1c
Glycosylated haemoglobin A1c
HBGM
Home Blood Glucose Monitoring
HDL
High Density Lipoprotein
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
ICH
International Conference on Harmonisation
IPV
important protocol violation


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ISF
Investigator Site File
i.v.
intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intention To Treat
LDH
Lactic dehydrogenase
LDL
Low Density Lipoprotein
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTT
Meal Tolerance Test
NGSP
National Glycohemoglobin Standardization Program 
NOAEL
OPU
No Observed Adverse Effect Level
Operative Unit
OC
observed case
PK
Pharmacokinetics
p.o.
per os (oral)
PPG
Post-prandial glucose
PPS
Per Protocol Set
q.d.
quaque die (once a day)
REP
Residual Effect Period
RDC
Remote Data Capture
SAE
Serious Adverse Event
s.c.
SFDA
Subcutaneous
State Food and Drug Administration
SGLT2
sodium glucose co-transporter 2
SMQs
Special MedDRA Queries
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
STEMI
ST Segment Elevation Myocardial Infarction
SUSAR
Serious Unexpected Suspected Adverse Reaction
TCM
Trial Clinical Monitor
TDMAP
T2DM
Trial Data Management and Analysis Plan
Type 2 diabetes mellitus
TIA
Transient ischemic attack
TS 
Treated set
t.i.d.
ter in die (3 times a day)
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
ULN
upper limit of normal
WOCBP
women of childbearing potential


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Type 2 diabetes mellitus (T2DM) accounts for 90 to 95% of all cases of diabetes and is an 
increasingly prevalent disease with an estimated 180 million affected people worldwide. Its 
incidence is expected to double during the next 20 years. Complications induced by 
hyperglycaemia are currently the most frequent cause of adult-onset loss of vision, renal 
failure, and amputation in the Industrialized World. Diabetes is also associated with 
macrovascular complications with a 2- to 5-fold increase in cardiovascular disease risk. The 
high frequency of complications leads to a significant reduction of life expectancy.
Although several antidiabetic compounds have been developed to improve glucose control 
and attenuate the metabolic derangements that accompany uncontrolled T2DM, none of these 
compounds has been able to maintain long-term glycaemic control.
The improved understanding of the incretin effect has contributed to the development of a 
new class of antidiabetic agents. The incretin effect results from glucagon like peptide-1
(GLP-1) and glucose dependent insulinotropic peptide (GIP), two intestinal peptides, that are 
released in the presence of glucose or nutrients in the gut. GLP-1 stimulates insulin secretion, 
thereby augmenting glucose-stimulated insulin release. However, there is little risk of 
hypoglycaemia due to GLP-1 because GLP-1 activity decreases when glucose concentrations 
fall below 55 mg/dL. Normally, GLP-1 is almost instantaneously inactivated by the enzyme 
Dipeptidyl-peptidase IV (DPP-4) that is widely expressed in many tissues including kidney, 
liver, intestine, lymphocytes and vascular endothelial cells. Therefore, inhibiting DPP-4 
would prolong the activity of GLP-1 for stimulating insulin secretion. 
DRUG PROFILE
1.2
Linagliptin is a potent inhibitor of DPP-4 activity and prolongs the half-life of GLP-1. This 
has been shown in vitro, in various animal models, and in clinical trials. Linagliptin is an 
orally available compound with a low risk for hypoglycaemic episodes.
Linagliptin (BI 1356, Tradjenta®, Trayenta®, Trazenta®, Trajenta®), received its first 
worldwide marketing approval on 02 May 2011. Marketing approval in the meantime has 
been received in over 90 countries worldwide including Europe, US, China and other regions. 
Linagliptin is marketed as 5 mg film-coated tablets.
Clinical Pharmacokinetics
In earlier PK trials, linagliptin showed nonlinear PK in the therapeutic dose range, with a less 
than dose proportional increase in plasma concentrations. Clearance, volume of distribution, 
and amount excreted unchanged in urine increased with increasing doses, possibly due to 
nonlinear protein binding. Linagliptin was predominantly excreted unchanged in faeces. 
Renal excretion was considered to be a minor elimination pathway. No dose adjustment of 
linagliptin based on hepatic impairment, renal impairment, age, body mass index (BMI), 


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weight, gender, or race is considered necessary. Linagliptin showed no clinically relevant 
interaction with metformin, pioglitazone, glyburide or empagliflozin.
Clinical efficacy and safety
Treatment with 5 mg linagliptin qd has resulted in clinically meaningful and statistically 
significant reductions in HbA1c, FPG, and postprandial glucose. There is a consistent pattern 
in the improvement in HbA1c levels when linagliptin was used in patients with different 
background therapies. These findings demonstrate efficacy for up to 18 to 24 weeks duration 
for different background therapies and are further supported by trials of longer duration up to 
104 weeks.
Overall, in phase III studies the overall incidence of adverse events (AEs), drug related AEs, 
AEs of severe intensity, AEs leading to discontinuation, and serious AEs (Serious Adverse 
Event, SAEs) were very similar across studies, with linagliptin being mostly comparable with 
placebo. For description of side effects of linagliptin refer to the current Investigator’s 
Brochure (IB) [c01838725-16] and the local prescribing information of Trajenta® [R15-
6052].
The growing safety evidence base for linagliptin, including completed Phase III and IV 
clinical trials, comprises patients treated with background therapies of metformin, 
sulphonylurea, empagliflozin, and insulin. 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]. 
The limited intrinsic risk for hypoglycaemia makes linagliptin especially interesting as an 
add-on to insulin. So far, the combination of linagliptin and insulin has been tested in three 
major clinical trials in different populations. 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.
An analysis of two independent phase III studies, linagliptin monotherapy was shown to have 
a similar dose–exposure–response relationship in Japanese, Asian (non-Japanese) and White 
patients. Linagliptin treatment resulted in clinically relevant improvements in glycemic 


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control in all groups although the effect on HbA1c is more pronounced in Japanese and Asian 
(non-Japanese) patients. Overall, linagliptin 5 mg is a safe and effective treatment option in 
patients with type 2 diabetes regardless of race or ethnic backgrounds [P16-00852].
For a more detailed description of the linagliptin profile please refer to the current 
Investigator’s Brochure (IB) [c01838725-16].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
The rationale for conducting this trial in Chinese patients with T2DM on a stable background 
therapy of insulin is:
-
to achieve improved glycaemic control,
-
to assess the occurrence of hypoglycaemia, and
-
to collect further data on efficacy and safety in patients treated with linagliptin in this 
population
TRIAL OBJECTIVES
2.2
The objective is to investigate the efficacy and safety of linagliptin (5 mg / once daily) 
compared to placebo for 24 weeks in Chinese patients with T2DM with insufficient 
glycaemic control (i.e., HbA1c of 7.5% to 10%) on stable background therapy with insulin 
alone or in combination with metformin.
For a description of the endpoints chosen and statistical analyses to assess these objectives,
refer to Section 5 and 7.
BENEFIT - RISK ASSESSMENT
2.3
Potential general benefits for patients in this trial irrespective of the investigational
medication received are: improvements in glycaemic control, regular diet and exercise 
counselling, as well as general medical benefit from careful and close monitoring by
medical personnel, and Home Blood Glucose Monitoring (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.
Two weeks Run-In Period Risk
Trial designs with a two-week placebo Run-In Period are well-established for T2DM trials.
The patients will be maintained on stable antidiabetic therapy during the two-week Run-In 
Period and continue regular monitoring of blood glucose with a HBGM device.  Thus, the
risk of the two-week placebo treatment in this trial is considered to be minimal.
Background Therapy and Study Medication Specific Risk
Insulin is the stable background therapy in this trial.  Patients are administered basal insulin 
or pre-mixed insulin and not short-acting insulin because there are fewer injections, lower 
risk of hypoglycaemia, and both kinds of insulin covers postprandial peaks. Weight gain, 


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hypoglycaemia, allergic reactions, injection site reaction, lipodystrophy, pruritus, and rash 
are the most common side effects noted with insulin.  All patients will have received insulin 
and these events mainly occur shortly after insulin initiation (at least allergic reactions).  For 
safety reasons, the insulin dose can always be modified by investigators.
For linagliptin, nasopharyngitis, cough, hypersensitivity and pancreatitis are listed side effects 
(independently of background therapy). For a background therapy of insulin in addition 
constipation is a listed ADR for linagliptin. In addition, based on post marketing experience, 
angioedema, urticaria and rash are listed as side effects for linagliptin [R15-6052].  
Furthermore, longer term safety data have not shown any further safety trends to date.  For 
additional information (on any further side effects of linagliptin beyond of the above 
described at time of protocol finalization) and for additional details, refer to the linagliptin 
Investigator Brochure [c01838725-16, current version] and the current version of the local 
prescribing information of Trajenta®.
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 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.
Patients who exceed the predefined limits for hyperglycaemia as determined by blood 
glucose values (section 4.2.1) during the randomised period will receive rescue therapy 
(according to Section 4.2.1) or have adjustments in their background therapy.
Alternative Therapies for T2DM
There are several alternative therapies available for the treatment of T2DM (e.g.,
sulphonylureas, thiazolidinediones, sodium glucose co-transporter 2 (SGLT2) inhibitors, 
meglitinides, alpha-glucosidase inhibitors, rapid acting or short acting insulin); however, 
these are not without side effects as described in local prescribing information for products 
in China.
Thus, given the above considerations, the benefit-risk assessment for the use of linagliptin for
treatment of T2DM in Chinese 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
OVERALL TRIAL DESIGN AND PLAN
3.1
This randomised, double-blind, multi-centre, and placebo-controlled, parallel group study 
compares linagliptin (5 mg) to placebo as add-on therapy to stable insulin alone (basal 
insulin, premixed insulin) or in combination with metformin. 
In total, 206 patients with T2DM who meet the entry criteria are planned for inclusion in this 
trial. The randomised treatment will be double-blind between linagliptin and placebo, i.e. 
each patient will receive either active treatment or placebo matching linagliptin.
Patients pre-treated with insulin alone or insulin in combination with metformin are included 
in the study once they have signed the informed consent. Acceptable basal insulins could be 
insulin glargin, insulin detemir or NPH (neutral protamin hagedorn) insulin with duration of 
action up to 24 h; Furtheron, patients on pre-mixed insulins may be included up to a certain 
limit in accordance with the defined randomisation criteria (ref. to section 7.6 and the 
Investigator Site File (ISF) for further details). Acceptable pre-mixed insulins could be 
preparations with 25/75 or 30/70 ratio, with once or twice daily posology only. All patients 
suitable after screening will undergo a 2-week placebo run-in period before randomisation. 
Patients who successfully complete this period and who still meet the inclusion/exclusion 
criteria will be randomised (with an allocation of 1:1 and refer to section 7.6) to the 24 week 
randomised treatment period of the study in which they will receive either 5mg linagliptin or 
placebo. During the 24-week randomised treatment period, the background therapy described 
above should remain unchanged if at all possible.
The end of treatment (EOT) visit will be performed for all patients upon completion of 24-
week treatment and for those who prematurely discontinue trial medication. The follow-up 
visit will be performed one week after EOT.
The patient participation is concluded when they have undergone last planned visit.
The time period for which AEs will still be considered on-treatment is 7 days following last 
intake of trial medication. After trial completion all AEs, including those persisting are 
followed-up for up to 30 days and it should be confirmed if they have resolved or sufficiently 
characterised.
The end of the trial is defined as “last patient out”, i.e. last visit completed by last patient.
Figure 3.1:1 Treatment periods and treatment groups in the trial design
R
24 weeks stable 
background medication
24-week treatment
EOT                 FU
Run-in
2 weeks
Visit 1 


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities are defined in a contract.
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in ISF.
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedure (SOPs),
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service and an interactive response technology (IRT) vendor will be used 
in this trial. Details will be provided in IRT Manual and Central Laboratory Manual, 
available in ISF.
The HBGM device will be provided by a BI preferred provider.
Clinical Event Committee 
The study is set up with prospective centralized blinded adjudication of all 
cardio/cerebrovascular trigger events. The prospectively defined adjudication process will 
assess cardiac and neurological vascular events through an independent, blinded, external 
Clinical Event Committee (CEC). Details on the composition of the committee, its 
procedures and interactions are provided in a separate CEC charter.
Additionally, a separate independent, blinded, external committee will be set up for 
adjudication of pancreatic events. The adjudication process for pancreatic events will be 
clarified in a separate CEC charter.


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
According to current guidelines (ADA, EASD), insulin therapy should be initiated 
immediately in patients newly diagnosed with T2DM with an HbA1c >8.5% and as a second 
step in patients with insufficient glycaemic control despite treatment with oral antidiabetic 
agents [R10-5741]. Therefore, patients with current insulin therapy alone or combined with 
metformin represent an important proportion of the patient population with T2DM.
Due to its mechanism of action and the low risk for hypoglycaemia induction, DPP-4 
inhibitors like linagliptin should provide additional efficacy in combination with the planned 
background therapy, especially in postprandial glucose control. The patients enter the study 
on the basis of insufficient glycaemic control despite standard treatment with insulin alone or 
combined with metformin. The placebo-controlled design is considered ethically acceptable 
on the basis of appropriate criteria for patient discontinuation and criteria for rescue therapy 
as defined in the relevant guidelines (e.g. FDA Guidance for Industry for developing drugs in 
diabetes [R08-2669]).
The study duration with stable background therapy is planned for 24 weeks because HbA1c as 
the primary endpoint has been demonstrated to be a reflection of the glycaemic control over 
the preceding 12 weeks and a stable effect could be shown at 24 weeks [P13-12370]. The one 
week follow-up period is considered to be sufficient, as previous studies with linagliptin have 
shown that the pharmacodynamic effect of linagliptin only extends to about 7 days after the 
last dose.
SELECTION OF TRIAL POPULATION
3.3
Up to 400 patients will be screened for the trial in 20-30 investigational sites in China to 
ensure that 206 Chinese patients are randomised to trial treatment (103 to each treatment 
group) and complete the trial.
It is planned to have at least 90 randomised patients on both background of pre-mixed insulin 
and basal insulin, which will be handled through IRT and refer to section 7.6.
If the patient’s background type distribution is not balanced as expected, the impact on the 
study conduct should be carefully considered. The sponsor should further monitor the 
recruitment of the trial with regard to the type of patient’s background treatment.
The intent is to obtain a balanced mix of patients pre-treated with premixed insulin or basal 
insulin. As such the sponsor may cap specific patient populations.
It is expected that at least 5 patients should be randomised at each trial centre. Investigators 
who fail to screen at least one patient within the first 6 weeks of the site initiation may be 
excluded from further participation. If enrolment is delayed, additional centres may be 
recruited.


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Permission to randomise more than 20 patients per site must be obtained from the Trial 
Clinical Monitor at Boehringer Ingelheim. 
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
centres when such a number of patients has been screened that it is anticipated that a 
sufficient number of patients will be randomised to trial treatment. Investigators will be 
notified when the appropriate number of patients has been screened and screening is 
complete, and will not be allowed to recruit additional patients for this study. Patients who 
have completed Visit 1 procedures prior to notification of the termination of recruitment will 
be allowed to continue in the study, if they meet all entry criteria and they are able to follow 
the visit schedule specified in this protocol.
The check for patient eligibility will be based upon a complete medical history including a 
physical examination and clinical laboratory tests. 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 enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in Chinese patients with T2DM who have insufficient glycaemic
control despite diet and exercise and receiving insulin alone or in combination with 
metformin.
3.3.2
Inclusion criteria
1.
Diagnosis of type 2 diabetes mellitus prior to informed consent. 
2.
Chinese male or female patients who are pre-treated with insulin alone or in 
combination with metformin:
-
With maximum insulin dose of ≤1 unit/kg/day. Acceptable basal insulins could 
be insulin glargin, insulin detemir or NPH (neutral protamin hagedorn) insulin 
with duration of action up to 24 h; acceptable pre-mixed insulins could be 
preparations with 25/75 or 30/70 ratio, with once or twice daily posology only. 
The total insulin dose should not be changed by more than 10% of the baseline 
value within the 12 weeks prior to randomisation (Visit 3). Both human insulin & 
insulin analogue are accepted.
-
If the patient is taking metformin, stable dose (at least 1500 mg daily) must be 
maintained for at least 12 weeks without dose adjustments prior to randomisation 
(Visit 3).
3.
HbA1c fulfills the following criteria: ≥7.5 % to ≤10.0 % at Visit 1.


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4.
Age ≥18 years at Visit 1.
5.
BMI ≤45 kg/m2 (Body Mass Index) at Visit 1.
6.
Women of childbearing potential must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 
1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient information.
-
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. 
-
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy.
7.
Signed and dated written informed consent by date of Visit 1 in accordance with ICH-
GCP and local legislation
3.3.3
Exclusion criteria
1.
Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after 
an overnight fast during placebo run-in and confirmed by a second measurement (not 
on the same day).
2.
Any other antidiabetic drug within 3 months prior to informed consent except those 
defined as background treatment via inclusion criterion 2.
3.
Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke 
or TIA within 3 months prior to informed consent.
4.
Indication of liver disease, defined by serum levels of either ALT (SGPT), AST 
(SGOT), or alkaline phosphatase above 3 × upper limit of normal (ULN) as 
determined during screening and/or run-in phase.
5.
Any contraindications to metformin according to the local label for those patients that 
enter the study with metformin therapy as provided in ISF. 
6.
Bariatric surgery within the past two years and other gastrointestinal surgeries that 
induce chronic malabsorption.
7.
Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer 
within the last 5 years.
8.
Blood dyscrasias or any disorders causing hemolysis or unstable Red Blood Cell (e.g. 
malaria, babesiosis, haemolytic anemia).
9.
Known hypersensitivity or allergy to the investigational product or its recipients.
10. Treatment with anti-obesity drugs 3 months 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. 
11. Current treatment with 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 except T2DM.
12. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.


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13. Alcohol or drug abuse within the 3 months prior to informed consent that would 
interfere with trial participation or any ongoing condition leading to a decreased 
compliance to study procedures or study drug intake in the opinion of the investigator.
14. Participation in another trial with an investigational drug within 2 months prior to 
informed consent or previous enrolment in this trial.
15. Any other clinical condition that would jeopardize patient’s safety while participating 
in this clinical trial in the opinion of the investigator.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for trial treatment or trial participation, without the 
need to justify the decision.

The patient needs to take concomitant drugs that interfere with the investigational 
product or other study medications.

The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy).

Introduction of rescue therapy due to hyperglycaemia as described in section 4.2.1
does not lead to sufficient treatment efficacy (rescue criteria still met). In this case, the 
reason for discontinuation will be classified as “lack of efficacy”. 

Occurrence of hypoglycaemia that may put the patient at risk with continued 
participation (e.g. repeated hypoglycaemic episodes).

If a patient becomes pregnant during the trial the investigational drug will be stopped, 
the patient will be discontinued from the trial and the patient will be followed up until 
birth or otherwise termination of the pregnancy.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to stick to the trial requirements in the future. 
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and section 6.2.3.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the CRF 
(case report form). These data will be included in the trial database and reported.


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A patient can be discontinued after discussion between sponsor and investigator if eligibility 
criteria are being violated, or if the patient fails to comply with the protocol (e.g. non-
attendance at study assessments).
Patients who drop out during the screening phase prior to randomisation (Visit 3) will be 
considered a screening failure. They have to be recorded as screening failure in eCRFs and no 
further follow-up is required. 
Patients who discontinue or withdraw from the study after randomisation (Visit 3) will be 
considered as “early discontinuations” and the reason for premature discontinuation must be 
recorded in the eCRFs. The data will be included in the trial database and will be reported. If 
determined by investigator as necessary for patient safety, new antidiabetic medication 
regimen can be started immediately after discontinuation and must be recorded in eCRFs.
Patients who withdraw or discontinue from the trial after randomisation will not be replaced.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS 
4.1
The study medication will be provided by Boehringer Ingelheim Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are below.
•
Substance: linagliptin
•
Pharmaceutical form: tablet
•
Source: Boehringer Ingelheim Pharma GmbH & Co. KG
•
Unit Strength: 5 mg
•
Route of administration: p.o., once daily
The characteristics of the reference product are below.
•
Substance: placebo matching linagliptin 5 mg
•
Pharmaceutical form: tablet
•
Source: Boehringer Ingelheim Pharma GmbH & Co. KG
•
Unit Strength: NA
•
Route of administration: p.o., once daily
4.1.2
Selection of doses in the trial
The doses of 5 mg linagliptin was selected based on the results from previous dose finding 
studies (please refer to the actual version of the Investigator's Brochure, [c01838725-16]) and 
represents the final to be marketed dose for linagliptin.
4.1.3
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. This will involve the use of interactive response technology (IRT). To facilitate the 
use of the IRT, the Investigator will receive an IRT manual including all necessary 
instructions for using the IRT. A copy of the manual will be available in the ISF.
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 
type (basal insulin vs pre-mixed insulin). For further details please refer to Section 7.6.    
Patient assignment to the treatment groups will be determined by a computer generated 
random sequence. Access to the randomisation code will be controlled and documented – for 


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further details please refer to Sections 4.1.5.1 and 4.1.5.2.
The assigned medication number will be entered in the eCRF, and the corresponding 
medication kit should be given to the patient. Using this procedure, relevant parties will be 
blinded to the treatment group assignment.
4.1.4
Drug assignment and administration of doses for each patient
Patients who qualify will be randomised to linagliptin 5 mg or placebo. Medication will be 
dispensed in a double-blind manner.
Patients will be assigned a placebo run-in kit at the beginning of the placebo run-in period 
(Visit 2), and dispensing will occur just once.  Dispensing of kits for the double-blind 
treatment period will begin at Visit 3.  Dispensing will occur on 5 occasions over a period of 
24 weeks.  For further details regarding packaging (e.g. number of tablets per pack) please 
refer to Section 4.1.6.  
From the start of the placebo run-in period (Visit 2), patients should be instructed to take their 
trial medication once daily with water. To ensure a dose interval of about 24 hours, the 
medication should be taken at the same time every day. If a dose is missed by more than 12 
hours, that dose should be skipped and the next dose should be taken as scheduled. No double 
doses should be taken, and dose reductions are not permitted. Linagliptin can be taken with or 
without food.
Patients should be instructed not to take their trial medication on the morning of study visits 
as they will be dosed whilst in the trial site. Patients who fail to do so should have the visit 
rescheduled as soon as possible, ideally on the following day.  Visits should be routinely 
scheduled in the morning, at approximately the same time of day (07:00 AM to 11:00 AM) 
for each visit.  The actual date and time of administration of the medication at the trial visit 
will be recorded in the eCRF.
Patients will continue with their standard insulin with or without concomitant metformin 
therapy throughout the entire study.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, Investigators and everyone involved in trial conduct or analysis or with any other 
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after database lock.
The randomisation code will be kept secret by Clinical Trial Support at BI up to database 
lock. Please refer to Section 4.1.5.2 for the rules regarding breaking the code for an 
individual or for all patients in emergency situations.


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Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’ s 
Pharmacovigilance group to access the randomisation code for individual patients during trial 
conduct. The access to the code will only be given to authorised Pharmacovigilance 
representatives and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP).
The study medication will consist of packs labelled with the trial identification and 
medication kit number.  Each pack will contain an appropriate number of linagliptin tablets 
or matching linagliptin placebo with some reserve (see below), for dosing until the next 
scheduled visit. 
The placebo run-in kit, assigned to all patients successfully completing Visit 2, will contain 
21 tablets (i.e. sufficient supply for 2 weeks, with 1 week in reserve).  Each double-blind 
treatment period kit will contain 42 tablets (i.e sufficient supply for 4 weeks, with 2 weeks in 
reserve). At Visit 3, 4 and 5, the patient will receive 1 treatment kit. At Visit 6 and 7, the 
patient will receive 2 treatment kits.
Re-supply to the sites will be managed via an IRT system, which will also monitor expiry 
dates of supplies available at the sites
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
The minimum/maximum storage temperature must be measured and documented by the 
Investigator / pharmacist / investigational drug storage manager in accordance with BI (or 
designated CRO) SOPs. 


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4.1.8
Drug accountability
The Investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:
-
approval of the study protocol by the Institutional Review Board (IRB) / 
ethics committee
-
availability of a signed and dated clinical trial contract between the sponsor 
and the head of the investigational site
-
approval / notification of the regulatory authority, e.g. competent authority
-
availability of the curriculum vitae of the Principal Investigator
-
availability of a signed and dated clinical trial protocol
-
if applicable, availability of the proof of a medical licence for the Principal 
Investigator
The Investigator < and/or > Pharmacist < and/or > investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution centre will maintain records of the disposal.
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor / appointed CRO, the Investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Throughout the duration of the trial, patients should continue to take insulin alone or in 
combination with metformin as background therapy. 
Acceptable basal insulins could be insulin glargin, insulin detemir or NPH (neutral protamin 
hagedorn) insulin with duration of action up to 24 h; acceptable pre-mixed insulins could be 
preparations with 25/75 or 30/70 ratio, with once or twice daily posology only. The 
background medication of metformin should remain unchanged throughout the study. The
total prescribed insulin dose should not be changed by more than 10% of the baseline value in 
the 24 weeks after randomisation. The background medication will not be provided as part of 
the clinical trial supplies.


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The patients can take their background medication as they are used to, where it is suggested 
that basal insulin is always given in the evening. Morning dose of metformin/any permitted 
pre-mixed insulin and study medication should be taken after the visits blood sample taken, 
and the patients should have the same habits of dosing throughout the trial.
Hyperglycaemia
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 insulin prior to or after informed 
consent, and if applicable metformin) for the treatment of hyperglycaemia [R08-2669]:
Week
Visit
FPG level
Week 1-12
up to visit 6
>240 mg/dl (>13.3 mmol/l) after overnight fast
Week 12-24
after visit 6 until Visit 8
>200 mg/dl (>11.1 mmol/l) after overnight fast
To confirm the above results, meaning that there is a minimum of two measurements, at least 
one of which should be performed after an overnight fast at the investigational site, and on a 
different day to the initial measurement.  
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.
The first choice of rescue therapy should be the adjustment of insulin therapy. Its dosage will 
be left to the discretion of the investigator. In very rare cases, adjustment of background 
therapy or addition of another oral anti-diabetic medication would be appropriate. Such cases 
should be discussed with the local clinical monitor or the Trial Clinical Monitor (TCM). 
Rescue therapy should be taken in accordance with the local prescribing information of the 
respective drug, taking into account potential contraindications.
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 insulin 
>50% from baseline for > 7 days duration
-
For patients with a baseline daily insulin dose >10 and ≤20 units, any increase of 
insulin >30% from baseline for > 7 days duration
-
For patients with a baseline daily insulin dose > 20 units, any increase of insulin 
>20% from baseline for > 7 days duration
-
Any increase in metformin for ≥ 1 day
-
Any introduction of a new antidiabetic therapy for ≥ 1 day.
A FPG, HbA1c sample should be taken before initiation of rescue therapy and sent to central 
lab for analysis. The HbA1c sample is not required if a sample has been taken and sent to the 
central lab for analysis within the last 4 weeks.


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Hypoglycaemia
If the patient is experiencing hypoglycaemia (criteria see section 5.3.7), the investigator 
should review the diary responses to diet and physical activity as well as the HBGM results to 
determine the 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).
In the case of hypoglycaemia that may put patient on risk (e.g. repeated symptomatic 
hypoglycaemia or severe hypoglycaemia), appropriate adjustment of anti-diabetic therapy 
such as a dose reduction / discontinuation of ongoing rescue medication or existing 
background therapy should be initiated. Reduction or discontinuation of ongoing rescue 
medication should be considered before a reduction in the dose of existing background 
therapy.
If, in the Investigator’s clinical opinion, no further effect from the rescue medication is 
anticipated, and the patient’s hyper- or hypoglycaemia cannot be controlled, the patient 
should be discontinued from the trial as specified in Section 3.3.4.  
Any rescue medication will be recorded in the source documents and on the appropriate 
pages of the eCRF.  
Rescue medication will not be provided as part of the clinical trial supplies.
Any additional treatment, that does not qualify as a rescue medication, and is considered 
necessary for the patient's welfare may be given at the discretion of the Investigator. 
Exceptions to this are the restrictions described in Section 4.2.2.
In this trial, the background therapy (i.e. insulin alone or in the combination with metformin) 
and the chosen rescue medications are considered as Auxiliary Medicinal Product (AMP).  
This means that in the event of SAEs, the Investigator will assess the causal relationship of 
the SAE to the AMPs.  Further details regarding SAE reporting can be found in Section 5.3.6.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Short-term use of additional prandial/intravenous insulin will be permitted (only in the event 
of an emergency situation and/or hospitalisation) based on clinical judgement of the 
Investigator or treating physician. Prolongation of additional prandial/intravenous 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/TCM.  Please also refer to Section 
3.3.3 regarding the permitted use of antidiabetic agents pre-trial.    
Additionally, treatment with anti-obesity drugs, herbal medications with antidiabetic effects
or systemic steroids will be prohibited due to their influence on glucose metabolism.  
However, one off or short-term use (i.e. ≤1 week’s duration) of systemic steroids will be 


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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.  
For patients receiving metformin, in case a vascular administration of iodine containing 
contrast agent is required, metformin should be temporarily discontinued at the time of or 
before the contrast agent is given and resumed not earlier than 48 hours after administration.
Restrictions on diet and life style
4.2.2.2
At the beginning of the Run-in period, patients will receive diet and exercise counselling by a 
diet specialist or delegated staff member. The counselling will be based on local diet 
recommendations. The patients will be reminded to follow the agreed diet and exercise plan 
at every visit.
Patients also should not take part in another clinical trial involving an investigational 
medicinal product within 2 months prior to informed consent.
Restrictions regarding women of childbearing potential 
4.2.2.3
Women of childbearing potential must use the contraception methods described in the patient 
information.
TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits. The tablets will be counted by the investigator or 
designee and compliance will be calculated in a worksheet, which must be kept as a source 
document.
Based on tablets counts, treatment compliance will be calculated as the number of tablets 
taken, divided by the number of tablets which should have been taken according to the 
scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorised by the sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken
Compliance during the placebo run-in period should be between 80% and 120%.  If 
compliance is outside this range, the patient should be carefully interviewed and, if necessary, 
re-informed about the purpose and the conduct of the trial. Unreliable patients should not be 
randomised at the discretion of the Investigator.


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Compliance during the double-blind treatment period should also be between 80% and 120%. 
Patients who are not compliant according to this definition should be carefully interviewed 
and re-informed about the purpose and the conduct of the trial.


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint in this study is the change from baseline in HbA1c after 24 weeks of 
treatment. Throughout the study protocol, the term "baseline" refers to the last observation 
prior to the randomised period.
5.1.2
Secondary Endpoints
Secondary efficacy endpoints are:

Change from baseline in FPG after 24 weeks of treatment;

Change from baseline in 2-hour PPG after 24 weeks of treatment

Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of treatment

Proportion of patients with HbA1c on treatment <6.5% after 24 weeks of treatment

Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of treatment
Secondary safety endpoints are:

Incidence of investigator–reported hypoglycaemic events confirmed by a measured blood 
glucose ≤70 mg/dL (≤3.9 mmol/L)

Incidence of severe hypoglycaemic events (requiring active assistance by another person, 
or fatal)


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ASSESSMENT OF EFFICACY
5.2
HbA1c
Blood samples for the determination of HbA1c will be taken at all visits except Visit 2. The 
blood sample can be taken at any time during the visit. For the determination of HbA1c, 3 mL 
of blood will be collected. The samples will be analysed at a central laboratory or its affiliates 
having a National Glycohemoglobin Standardization Program (NGSP) Level I certificate. 
Further details about sample handling, shipment, and assay procedures can be found in the 
Investigator’s Site File (Lab manual).
Fasting plasma glucose (FPG)
Blood samples for the determination of FPG at the central laboratory will be taken after an 
overnight fast. The samples should be taken before breakfast and before trial drug 
administration. The samples will be measured at a central laboratory using validated assays. 
Further details about sample handling and shipment can be found in the ISF (Lab manual).
Meal Tolerance Test (MTT) 
Meal Tolerance Test (MTT) will be performed using a standardised breakfast. MTT at Visit 3 
would be performed before randomisation, i.e. without intake of trial medication during the 
MTT.
At Visit 3, after blood sample of FPG drawing, patients would have a standardised breakfast 
and intake metformin and/ or accepted pre-mixed insulin (if applicable), finished within 15 
min, and PPG blood samples would be collected at time points 60 ±10 min and 120 ±10 min 
after the start of standardised breakfast. Study medication would only be taken after last PPG 
blood samples drawing, i.e. following randomisation. 
At Visit 8, 30 min after blood sample of FPG drawing and administration of study 
medication, patients would have a standardised breakfast and intake metformin and/ or 
accepted pre-mixed insulin (if applicable), finished within 15 min, and PPG blood samples 
would be collected at time points 60 ±10 min and 120 ±10 min after the start of standardised 
breakfast.
Weight and Waist circumference
Weight measurements should always be done on the same scales for one patient. In order to 
get comparable body weight values, it should be performed in the following way:

fasting (except for the screening visit), 


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
after the urine sampling (weight after bladder voiding), 

shoes and coat/jackets should be taken off 

pockets should be emptied of heavy objects (i.e. keys, coins etc)
Waist circumference measurements should be made around a patient’s bare midriff, after the 
patient exhales while standing without shoes and with both feet touching and arms hanging 
freely.  The measuring tape should be made of a material that is not easily stretched, such as 
fibreglass.  The tape should be placed perpendicular to the long axis of the body and 
horizontal to the floor and applied with sufficient tension to conform to the measurement 
surface.  
Waist circumference should be determined by measuring the midpoint between the lowest rib 
and the iliac crest.
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
At start of run-in and end of treatment, a complete physical examination will be performed by 
the investigator (see Flow chart). Documentation of, and findings from the physical 
examination, must be part of the source documents available at the site.
5.3.2
Vital Signs
Systolic and diastolic blood pressure as well as pulse rate (electronically or by palpation, 
count for 1 minute) will be measured after 5 minutes of rest in the seated position. All 
recordings should be made using the same blood pressure recording instrument on the same 
arm (see Flow chart).
5.3.3
Safety laboratory parameters
All safety laboratory samples (except at Visit 1) will be collected after a full overnight fast 
(nothing to eat or drink except water for at least 10 hours) and before background anti-
diabetic therapies and investigational drug as described in the Flow Chart and Section 6. The 
blood sample at Visit 1 (screening visit) can be taken with the patient in a fasted or non-
fasted state. 
All parameters that will be determined during the trial conduct are listed in table 5.3.3: 1 and 
5.3.3: 2. The analysis will be performed by a central laboratory. The respective reference 
range and details about sample handling and shipment will be provided in the ISF (Lab 
Manual).
Reduced safety lab panels excluding urinalysis are planned for the following visits:
- For the screening Visit 1, laboratory only includes liver transaminases, alkaline 
phosphatase, and serum creatinine.


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- Lipid fractions will only be determined at baseline (V3) and end of treatment (V8)
Table 5.3.3: 1
Safety laboratory parameters – Haematology
•
Haematocrit
•
Haemoglobin
•
Red Blood Cells (RBC)/Erythrocytes
•
WBC/Leukocytes
•
Platelet Count/Thrombocytes
•
Differential Automatic (relative and absolute count): 
•
Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes
Table 5.3.3: 2
Safety laboratory parameters – Clinical Chemistry

Amylase

Lipase

AST (aspartate transaminase, 
SGOT)

ALT (alanine transaminase, 
SGPT)

-GT (gamma-glutamyl-
transferase)

Alkaline phosphatase

Lactic dehydrogenase (LDH)

Total bilirubin

Direct bilirubin, if total bilirubin 
is elevated

Total Protein 

Albumin 

Creatine kinase (CK)

CK-MB, if CK is elevated

Potassium

Sodium

Creatinine

Urea

Calcium

Inorganic phosphorous

Uric acid

Cholesterol (total) *

HDL cholesterol*

LDL cholesterol*

Triglycerides*

Glucose
* Visits 3,8 only
Table 5.3.3:3
Safety laboratory parameters – urine

Albumin, Creatinine (spot urine 
–quantitative measurement)

Protein

Glucose

Ketone

Leucocytes

Erythrocytes
The albumine/creatinine ratio will be calculated at the central lab. Urine sediment will only 
be done if there is a positive finding on the urinalysis.


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The glomerular filtration rate (GFR) will be derived from serum creatinine
* values based on 
the standard MDRD formula:
eGFR (ml/min/1.73 m2) = 175 x [Screatinine (umol/L)/88.4]-1.154 x [age]-0.203 x [0.742 if 
patient is female] x [1.212 if patient is of African origin]
*: creatinine methods calibrated to an IDMS reference method
Pregnancy testing (urine) will be performed in female patients of child bearing potential only 
according to the timepoints indicated in the Flow chart.
5.3.4
Electrocardiogram
Printed paper traces from 12 lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected 
at baseline (visit 3) and at the end of the trial (visit 8) for all patients. In the event of any 
cardiac symptoms (i.e. suspicion of heart rhythm disorders or cardiac ischemia), an additional 
ECG will be recorded. All ECGs will be evaluated, (signed, dated and commented upon) by 
the treating physician/investigator and stored locally. 
Any clinically relevant changes in the ECG will be reported as AEs. Any ECG abnormalities 
will be carefully monitored and if necessary the patient will be removed from the trial and 
medically treated.
5.3.5
Other safety parameters
Home Blood Glucose Monitoring
All patients will be provided with HBGM equipment and supplies for use at home during the 
2-week Run-In periods. Instruction on the proper use of the HBGM will be provided by the 
study staff. The patient will be asked to record the results of the HBGM test on a HBGM 
Testing Log that will be included in the patients source document file. Only in the case of 
linked adverse events or of hypoglycaemia, the single HBGM values will be recorded in the 
CRF. 
During Run-In and Follow-up, HBGM testing should be performed once daily in the fasted
state and at any time the patient is symptomatic, i.e., experiences signs/symptoms of hyper-
or hypoglycaemia. If during Run-in, results of a HBGM test reveal blood glucose 
>240 mg/dL (13.3 mmol/L) after an overnight fast, the patient should contact the site. The 
investigator should then decide about start of the randomised period or further patient 
participation in the trial based on fasted plasma glucose determinations according to the 
inclusion and exclusion criteria as outlined in Section 3.3.
During the randomised treatment period, HBGM testing is recommended to be done once 
weekly (more frequently if required by local authorities) and at any time the patient is 
symptomatic, i.e., experiences signs/symptoms of hyper- or hypoglycaemia. If during this 
period, results of a fasting HBGM test reveal blood glucose levels meeting rescue criteria 
(see Section 4.2.1), the patient should contact the site and the investigator should follow the 
instructions given in Section 4.2.1.


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5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

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 judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.


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AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC)
system. These events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs:

Hypersensitivity reactions such as angioedema, angioedema-like events, and 
anaphylaxis

Skin lesions such as exfoliative rash, skin necrosis, or bullous dermatitis

*Hepatic injury as defined by the following alterations of hepatic laboratory 
parameters: ≥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
*These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided via RDC. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy,
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Protocol-specified AESIs (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, even if they do not meet any of the SAE seriousness criteria.
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 (SMQs), and user defined 


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searches (Boehringer Ingelheim customized MedDRA Queries (BicMQs)) 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 defined 
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 ISF/ RDC
system and changes will be communicated to all investigators.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of signs or symptoms that 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 AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
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. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 


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of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Adverse event collection and reporting
5.3.6.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF by the Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual patient’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
However, if an individual patient discontinues trial medication prematurely but stays in 
the trial (i.e. if further visits incl. telephone visits, or vital status assessments are planned) 
from then on and until the individual patient’s end of the trial the Investigator must report 
related SAEs and related AESIs. 
•
After the individual patient’s end of trial: 
the Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become aware of.
Figure 5.3.6.2: 1
Types of AEs to be reported according to the trial period
The REP is defined as 7 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 


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treatment, please see section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication and any possible interactions between the investigational drug and an 
AMP.
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 


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is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3.7
Criteria for hypoglycaemic events 
Every episode of plasma glucose ≤70 mg/dl (≤3.9mmol/l) should be documented in the 
eCRF with the respective time and date of occurrence. Such hypoglycaemic events should be 
documented in the eCRF according to the following criteria:
-
Asymptomatic hypoglycaemia: event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration ≤70 mg/dl (3.9 
mmol/l)
-
Documented symptomatic hypoglycaemia with glucose concentration ≥54 mg/dl and 
≤70 mg/dl (≥3.0 mmol/l and ≤3.9 mmol/l): event accompanied by typical symptoms 
of hypoglycaemia
-
Documented symptomatic hypoglycaemia with glucose concentration < 54 mg/dl (< 3.0 
mmol/l): event accompanied by typical symptoms of hypoglycaemia 
-
Severe hypoglycaemic episode: Event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions.
Note for severe hypoglycemia: 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.
Any hypoglycaemia with glucose values < 54 mg/dl (< 3.0 mmol/l) and all symptomatic or 
severe hypoglycaemia events should be documented as an adverse event of hypoglycemia. 
Further details on documentation of hypoglycemia are provided on the respective eCRF 
pages.


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APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects in an appropriate way. 
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values, biomarkers specific to efficacy of treatment of T2DM, and ECG. 
The primary and secondary endpoints are standard and accepted for evaluation of safety and 
tolerability of an oral antidiabetic drug, and they are widely used in respective pivotal phase 
III studies. 


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Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
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 trial medication on the 
morning of a visit before attending the trial site (excluding visits starting before 
randomisation) or comes in non-fasted where a fasting condition is required (all visits except 
screening), 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 in a short enough 
time-frame so that the patient has sufficient trial medication available.
All patients are to adhere to the visit schedule as specified in the Flow Chart. If any visit has 
to be rescheduled, subsequent visits should follow the original visit date schedule. The trial 
medication packs contain sufficient medication to allow for these time windows.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in period
Screening Period
The screening visit is the only visit in this study that does not need to be done fasting.
No trial procedures should be done unless the patient has consented to taking part in the trial.
Once patients have consented, the patient is considered to be enrolled in the trial and have 
started screening.  The patient should be recorded on the enrolment log and be registered in 
the IRT as a screened patient.
Patients who fail screening following Visit 1 procedures should be registered as a screen 
failure in the IRT (refer to IRT user manual). 
Run-in Period 
From this visit on, patients should be fasting (no food or drinks, water only for at least 10 
hours) prior to each visit.
Patients who fail the run-in period following Visit 2 procedures should be registered as a 
screen failure in the IRT (refer to IRT user manual).
The patients can take their background medication as they are used to, where it is suggested 
that basal insulin is always given in the evening. Morning dose of metformin/any permitted
pre-mixed insulin and study medication should be taken after the visits blood sample 
collection, and the patients should have the same habits of dosing throughout the trial.


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Monitor adverse events, document in the patients file (source data) and eCRF. For patients 
that fail on screening before or at this visit, only serious AE’s that took place between 
screening and this Visit 2 must be recorded in the eCRF and the SAE form.
Instruct patients on the correct use of HBGM for glucose testing during the 2 week Run-In 
Period

Patients should use the HBGM equipment/supplies to test glucose levels in a fasting 
state. During the Run-in period patients should test once a day before breakfast (i.e. 
after an overnight fast). Additionally, patients should test their glucose levels if they 
experience signs/symptoms of hypo- or hyperglycaemia. Test results should be 
documented on the HBGM testing log. More frequent HBGM testing is permitted at
the Investigator’s and/or patient’s discretion.

If the HBGM test reveals an overnight fasted blood glucose of >240 mg/dl 
(>13.3mol/l), the patient should contact the study site for a visit at the next day. The 
investigator will then draw a new blood sample (overnight fasted samples for FPG 
determination) to confirm the hyperglycaemia, document the AE if appropriate and 
decide about the possible exclusion from randomisation (screening failure).
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding T2DM) will be reported on the Baseline Condition eCRF page.
Medical History
Medical history will be collected and reported in the Medical History eCRF page. 
6.2.2
Treatment period
The treatment period is from Visit 3 to Visit 8.  Patients will be dispensed medication at each 
of these visits (except for Visit 8). Medication number of each occasion will be allocated by 
IRT (refer to IRT user manual).
Patients should not take study medication at home on the morning of trial visits during the
treatment period.
Randomisation visit (Visit 3)
Visits should be performed fasting and as indicated in the Flow Chart and the respective 
protocol sections.
Randomisation/treatment allocation and dispensing of study medication should be the last 
activity at this visit.
Visits 4-8
Visits should be performed as mentioned in the Flow Chart and the respective protocol 
sections.  


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If a patient prematurely discontinues from the 24-week treatment period, the patient must
return to the trial site for both Visit 8 (within 7 days of stopping study treatment) and Visit 9 
(7 days after Visit 8), which will be performed.
The investigator may initiate any additional antidiabetic therapy for the patient, based on his 
or her discretion, no sooner than one day after discontinuing study medication or after Visit 8.
6.2.3
Follow Up Period and Trial Completion
For all patients completing the study according to protocol a follow-up contact (Visit 9) with 
the patient (preferably by phone) should be done by the investigator at the end of the follow-
up period of 7 days.
In case of premature discontinuation from the 24 week treatment period however, an End of 
Trial Visit (V9) should be performed and the patient should return to Visit 9 (7 days after 
Visit 8/end of treatment). The following examinations should be performed at Visit 9:
•
Vital signs
•
Collection of blood and urine samples for safety laboratory evaluation
•
Documentation of any adverse events
•
Documentation of concomitant therapies


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
The objective of this randomised, double-blind, placebo-controlled study is to investigate the 
efficacy and safety of linagliptin compared to placebo given for 24 weeks as add-on therapy 
to insulin alone or in combination with metformin in Chinese patients with T2DM and 
insufficient glycemic control. The primary endpoint in this study is the change in HbA1c from 
baseline after 24 weeks of treatment. HbA1c will be measured in the unit of % at all clinical 
visits. It is planned to show superiority of linagliptin to placebo.
The primary analysis is a restricted maximum likelihood (REML) -based mixed model 
repeated measures (MMRM) approach. The statistical model will include fixed classification 
effects for treatment, type of insulin, week, the linear covariate baseline HbA1c, treatment by 
week interaction, and baseline HbA1c by week 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.
NULL AND ALTERNATIVE HYPOTHESES
7.2
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: 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: 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
PLANNED ANALYSES
7.3
The statistical analysis will be based on the following populations.
Treated Set 
The treated set (TS) will consist of all patients who were randomised and treated with at least 
one dose of study drug.  
Full Analysis Set 


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The full analysis set (FAS) will consist of all patients in the TS who had a baseline and at 
least one on-treatment HbA1c measurement. 
7.3.1
Primary endpoint analyses
The primary analysis will be performed on the FAS and patients will be assigned to the 
treatment they were randomised to. A REML-based MMRM approach is applied to compare 
the change in HbA1c from baseline after 24 weeks of treatment (Section 7.2). 
The statistical model will be 
HbA1c change from baseline = overall mean + baseline HbA1c + treatment + type of insulin    
   + week+ week by treatment interaction
   + baseline HbA1c by week interaction 
   + random error
This model includes effects accounting for the following sources of variation: ‘baseline 
HbA1c’, ‘treatment’, ‘type of insulin (basal insulin or any permitted pre-mixed insulin) ’, 
‘week’, ‘week by treatment interaction’ and ‘baseline HbA1c by week interaction’. 
‘Treatment’, ‘type of insulin’, ‘week’ and ‘week by treatment interaction’ are fixed, 
categorical effects, and ‘baseline HbA1c’ and ‘baseline HbA1c by week interaction’ are 
continuous, linear covariates. For each patient, the error terms from the on-treatment visits 
represent the within-patient variability, and are assumed to follow a multivariate normal 
distribution with an unstructured covariance matrix.
If the model fails to converge, further covariance structures will be tested, details will be 
provided in the TSAP. The first model to converge will be used as the primary analysis. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
Significance tests will be based on least squares means using a two-sided α= 0.05 (two sided 
95% confidence intervals). 
Only the available data which were observed whilst patients were on treatment will be 
included in the analysis. Missing data are handled implicitly by the above statistical model, 


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rather than by using any imputation. This approach, referred to as observed case (OC), will 
additionally set to missing all values measured after rescue medication use.
Superiority will be tested using the p-value of the treatment effect and a two-sided 95% 
confidence interval for the treatment difference. 
7.3.2
Secondary endpoint analyses
The analyses for the secondary endpoints will be based on FAS and patients will be assigned 
to the treatment they were randomised. These analyses are exploratory in nature and the p-
values provided by these analyses will only be nominal.

In general, continuous endpoints will be analysed using a MMRM model similar to 
the primary endpoint analysis with the respective baseline parameter as an additional 
linear covariate. However for the endpoints with only one on-treatment measurement,  
an ANCOVA model similar to that used for the HbA1c sensitivity analysis (refer to 
Section 7.3.1) will be applied with the respective baseline parameter as an additional 
linear covariate. In addition, descriptive statistics will be presented for each endpoint, 
and at each week if appropriate. 

Binary endpoints will be tabulated (with frequency and proportion in each treatment 
group, by week if appropriate). Logistic regression will be used to obtain odds ratios 
and their corresponding 95% confidence intervals and p-values.

The analysis for safety endpoint is specified in Section 7.3.4.


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7.3.4
Safety analyses
Safety analysis will be performed on TS, with patients assigned to the treatment they were 
randomised. In general, safety analyses will be descriptive in nature and will be based on BI 
standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of REP will be considered 
‘treatment-emergent’. The REP is defined as a period of seven days after the last dose of trial 
medication. AEs that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’. Frequency, severity, and causal relationship of AEs will
be tabulated by system organ class and preferred term after coding according to the current 
version of the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
No pharmacokinetic and pharmacodynamic analyses are planned for this trial.
INTERIM ANALYSES
7.4
No interim analysis is planned for this trial.


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HANDLING OF MISSING DATA
7.5
In the primary analysis, missing data will not be imputed (OC approach). The mixed effect 
model will handle missing data based on a likelihood method under the “missing at random” 
assumption.
 If 
rescue therapy is initiated, HbA1c and FPG values after rescue medication will be set to 
missing and the missing data will be handled as above (OC 
), according to the 
analysis strategy. For the analysis of secondary endpoints using ANCOVA, missing values 
will not be imputed (OC approach).
For binary endpoints including an HbA1c response criterion, non-completers’ considered 
failure (NCF) will be applied, i.e., patients who discontinued from the trial prematurely and 
have no HbA1c measurement at Week 24 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.
With respect to safety evaluations, it is not planned to impute missing values. The handling of 
missing biomarkers will be specified in the TSAP.
RANDOMISATION
7.6
The sponsor will arrange for the randomisation as well as for packaging and labelling of trial 
medication. The trial will be performed as a double-blind design with respect to the two 
blinded treatment arms. Eligible patients will be randomly assigned to one of the two 
treatment groups, linagliptin and placebo, with an allocation of 1:1. 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 block size will be documented in the CTR. Access to the codes will be 
controlled and documented.
The randomisation will be stratified on the basis of patients belonging to any of the categories 
below at the beginning of the placebo run-in period:
1. HbA1c value: HbA1c < 8.5% or 8.5%. 
2. Type of insulin: basal insulin or pre-mixed insulin (at least 90 randomised patients 
for each)
The allocation process will be performed on Visit 3 through IRT. 


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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 study will only be unblinded after all CRF / 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.
DETERMINATION OF SAMPLE SIZE
7.7
In order to be in line with local regulatory requirements, 100 patients per treatment group for 
primary analysis (i.e. FAS) are required. To compensate for the anticipated dropout rate 
(about 2.2% in global trial 1218.36 [P13-12370]), 206 patients (approximate 103 patients per 
treatment arm) will need to be randomised. 
Assuming a standard deviation of 1.1% for HbA1c change from baseline at 24 weeks, a 
sample of size 100 patients per treatment group is sufficient to detect a 0.55% difference 
between the treatment groups with a power of  94% and a two-sided type-I error of 5%. See 
Table 7.7: 1 for sample size calculation for different scenarios. The software ADDPLAN 
6.0.4 is used to estimate the sample size.
Table 7.7:1
Sample size calculation based on two group t-test of equal means 
(equal N's)
Parameters
Calculation of N for primary analysis 
Test significance level, 
0.05
0.05
0.05
0.05
0.05
0.05
1 or 2 sided test?
2
2
2
2
2
2
Difference in means, 1 - 2
0.55
0.55
0.55
0.55
0.55
0.55
Common standard deviation, 
1.2
1.2
1.1
1.1
1.1
1.1
Power ( % )
80
90
80
90
94
95
N
76
101
64
86
100
103


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and 
other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor 
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is 
stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of 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 Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The Investigator 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 


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places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (CRF) for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)


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
Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy 
of the data will be verified by direct comparison with the source documents described in 
section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.


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STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
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 / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual Investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPDD at their site. Early termination of the 
trial is defined as the premature termination of the trial due to any reason before the end of 
the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P10-14001
Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, 
Woerle HJ. Safety and efficacy of linagliptin as add-on therapy to metformin 
in patients with type 2 diabetes: a randomised, double-blind, placebocontrolled 
study. Diabetes Obes Metab 2011. 13(1): 65-74.
P11-02847
Prato S del, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. 
Effect of linagliptin monotherapy on glycaemic control and markers of betacell 
function in patients with inadequately controlled type 2 diabetes: a randomised
controlled trial. Diabetes Obes Metab 2011. 13(3): 258-267.
P11-06845
Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA Efficacy and safety of 
initial combination therapy with linagliptin and pioglitazone in patients with 
inadequately controlled type 2 diabetes: a randomised, double-blind, 
placebocontrolled study. Diabetes Obes Metab 2011. 13(7): 653-661.
P11-09378
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 
large 2-year study in subjects with type 2 diabetes mellitus. 47th Ann Mtg of 
the European Association for the Study of Diabetes (EASD), Lisbon, 12 – 16 
Sep 2011 Diabetologia 2011. 54(1): S108 Abstr 242.
P11-12477
Gallwitz B, Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, et al. 
Efficacy and safety of linagliptin in with metformin monotherapy inadequately 
controlled type 2 diabetes. 46th Ann Mtg of the German Society of Diabetes, 
Leipzig, 1 - 4 Jun 2011 Diabetologie 2011. 6(Suppl 1): S19 Abstr FV44.
P11-14211
Budnitz DS, Lovegrove MC, Shehab N, Richards CL Emergency 
hospitalizations for adverse drug events in older Americans. N Engl J Med 
2011. 365(21): 2002-2012.
P13-07824
Inzucchi SE, Nauck M, Eynatten M von, Hehnke U, Woerle HJ, Henry R 
Lower risk of hypoglycaemia in elderly type 2 diabetes patients when 
linagliptin is added to basal insulin: an exploratory analysis. 73rd Sci Sess of 
the American Diabetes Association (ADA), Chicago, 21 - 25 Jun 2013 (Poster) 
2013.
P13-09565
Barnett AH, Huisman H, Jones R, Eynatten M von, Patel S, Woerle HJ 
Linagliptin for patients aged 70 years or older with type 2 diabetes 
inadequately controlled with common antidiabetes treatments: a randomised, 
double-blind, placebo-controlled trial. Lancet, Published Online August 13, 
2013, doi: 10.1016/S0140-6736(13)61500-7 Lancet 2013. 382(9902): 1413-
1423.


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P13-12370 
Yki-Jarvinen H, Rosenstock J, Duran-Garcia S, Pinnetti S, Bhattacharya S, 
Thiemann S, Patel S, Woerle HJ. Effects of adding linagliptin to basal insulin 
regimen for inadequately controlled type 2 diabetes: a >/= 52-week 
randomised, double-blind study. Diabetes Care, Publish Ahead of Print, 
published online September 23, 2013, doi: 10.2337/dc12-2718 Diabetes Care 
2013. 36:3875-3881.
P13-14398
Websky K von, Reichetzeder C, Hocher B Linagliptin as add-on therapy to 
insulin for patients with type 2 diabetes. Vasc Health Risk Manage 2013. 9: 
681-694. 
P16-00852
Sarashina A. Comparable pharmacodynamics, efficacy and safety of
linagliptin 5 mg among Japanese, Asian and White patients with type 2
diabetes. Journal of Diabetes Investigation, accepted article, Accepted 
manuscript online: 12 JAN 2016, doi: 10.1111/jdi.12482 J Diabetes Invest 
2016
R07-1029
Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. 
Diabetes Care 2004. 27(6):1487-1495.
R08-2669 
Guidance for industry: diabetes mellitus: developing drugs and therapeutic
biologics for treatment and prevention (draft guidance, February 2008).
Rockville: U.S.Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER) 2008.
R09-2151
FDA Guidance for Industry - Diabetes Mellitus - Evaluating Cardiovascular 
Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes 
R10-5741
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, 
Zinman B. Medical management of hyperglycaemia in type 2 diabetes 
mellitus: a consensus algorithm for the initiation and adjustment of therapy: a 
consensus statement from the American Diabetes Association and the 
European Association for the Study of Diabetes. Diabetologia 2009. 52:17-30.
R15-6052
Tradjenta (linagliptin) tablets (Boehringer Ingelheim) (China prescribing 
information, revised: 6/2014). 2015
R15-6053  
Glucophage 500 mg (metformin hydrochloride) tablets, (Bristol-Myers 
Squibb) (China prescribing information, rev.Aug 2010). 2010  
UNPUBLISHED REFERENCES
9.2
c01838725-16
 
Investigator's Brochure. Current version.


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10.
APPENDICES
Not applicable


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11.
DESCRIPTION OF GLOBAL AMENDMENT
Number of global 
amendment
1.0
Date of CTP revision
14 Oct 2016
BI Trial number
1218.102
BI Investigational 
Product
Linagliptin (Trajenta)
Title of protocol
A phase III,  randomised, double-blind, placebo-controlled, 
parallel group, efficacy and safety study of linagliptin, 
administered orally once daily, in combination with insulin 
therapy for 24 weeks in Chinese type 2 diabetes mellitus 
patients with insufficient glycaemic control
To be implemented 
only after approval of 
the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified 
of change with request 
for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects 
only
Section to be changed
FLOW CHART note L
Description of change
Previous text:
L
At visit 3, AFTER blood sample of FPG drawing, 
patients will have a standardised breakfast, finished 
within 15 minutes, and PPG blood samples will be 
collected at time points 60 ±10 min and 120 ±10 min 
after the start of standardised breakfast. Study 
medication would be in-taken after PPG blood samples 
drawing. At visit 8, 30 min after blood sample of FPG 
drawing and administration of study medication, patients 
will have a standardised breakfast, finished within 15 
min, and PPG blood samples would be collected at time 
points 60 ±10 minutes and 120 ±10 min after the start of 


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standardised breakfast. (All patients at all sites should 
participate) 
Was changed to:
L
At visit 3, AFTER blood sample of FPG drawing, 
patients will have a standardised breakfast and intake 
metformin and/ or accepted pre-mixed insulin (if 
applicable), finished within 15 minutes, and PPG blood 
samples will be collected at time points 60 ±10 min and 
120 ±10 min after the start of standardised breakfast. 
Study medication would be in-taken after PPG blood 
samples drawing. At visit 8, 30 min after blood sample 
of FPG drawing and administration of study medication, 
patients will have a standardised breakfast and intake 
metformin and/ or accepted pre-mixed insulin (if 
applicable), finished within 15 min, and PPG blood 
samples would be collected at time points 60 ±10 
minutes and 120 ±10 min after the start of standardised 
breakfast. (All patients at all sites should participate) 
Rationale for change
Clarification for the intake time of permitted pre-mixed 
insulin.
Section to be changed
ABBREVIATIONS
Description of change
Add “WOCBP women of childbearing potential”
Rationale for change
Add new abbreviation
Section to be changed
1.2
DRUG PROFILE
Description of change
Previous text:
The favourable effects regarding the counteraction of 
hypoglycaemic make linagliptin especially interesting as an 
add-on to insulin.
Was changed to:
The limited intrinsic risk for hypoglycaemia makes linagliptin 
especially interesting as an add-on to insulin.
Rationale for change
For consistency of wording to the above paragraph.
Section to be changed
3.3.2
Inclusion criteria
Description of change
Previous text: 
2. Chinese male or female patients who are pre-treated with 
insulin alone or in combination with metformin:
-
With maximum insulin dose of ≤1 unit/kg/day. 
Acceptable basal insulins could be insulin glargin, 
insulin detemir or NPH (neutral protamin hagedorn) 
insulin with duration of action up to 24 h; acceptable 
pre-mixed insulins (permitted for a pre-defined subset 


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of patients) could be preparations with 25/75 or 30/70 
ratio, with once or twice daily posology only. The total 
insulin dose should not be changed by more than 10% 
of the baseline value within the 12 weeks prior to 
randomisation (Visit 3). 
Was changed to:
2. Chinese male or female patients who are pre-treated with 
insulin alone or in combination with metformin:
-
With maximum insulin dose of ≤1 unit/kg/day. 
Acceptable basal insulins could be insulin glargin, 
insulin detemir or NPH (neutral protamin hagedorn) 
insulin with duration of action up to 24 h; acceptable 
pre-mixed insulins could be preparations with 25/75 or 
30/70 ratio, with once or twice daily posology only. The 
total insulin dose should not be changed by more than
10% of the baseline value within the 12 weeks prior to 
randomisation (Visit 3). Both human insulin & insulin 
analogue are accepted.
Rationale for change
Pre-defined subset for pre-mixed insulin has been specified in 
protocol sections 3.3 and 7.6. Classification for the type of 
insulin.
Section to be changed
3.3.2
Inclusion criteria
Description of change
Previous text: 
6.
Women of childbearing potential must be ready and 
able to use highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in the 
patient information.
Women of childbearing potential are defined as:
-
having experienced menarche and 
-
not postmenopausal (12 months with no menses 
without an alternative medical cause) and 
-
not permanently sterilised (e.g., tubal occlusion, 
hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy).
Was changed to:
6.
Women of childbearing potential must be ready and 
able to use highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in the 
patient information.


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-
A woman is considered of childbearing potential 
(WOCBP), i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. 
-
Permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy.
Rationale for change
Tubal occlusion is considered as a method of highly effective 
birth control, but NOT a method of permanent sterilisation 
according to BI updated Contraception Guidance.
Section to be changed
4.2.1
Other treatments and emergency procedures
Description of change
Previous text: 
Morning dose of metformin and study medication should be 
taken after the visits blood sample collection, and the patients 
should have the same habits of dosing throughout the trial.
Was changed to:
Morning dose of metformin/any permitted pre-mixed insulin 
and study medication should be taken after the fasting visits 
blood sample collection, and the patients should have the same 
habits of dosing throughout the trial.
Rationale for change
Clarification for the intake time of permitted pre-mixed 
insulin.
Section to be changed
4.2.1 Other treatments and emergency procedures
Description of change
Previous text:
Hyperglycaemic:
Week
Visit
FPG level
Week 1-12
up to visit 6
>270 mg/dl (>15.0 mmol/l) 
after overnight fast
Week 12-24 after visit 6
until Visit 8
>240 mg/dl (>13.3 mmol/l) 
after overnight fast
Was changed to:
Hyperglycaemia:
Week
Visit
FPG level
Week 1-12
up to visit 6
>240 mg/dl (>13.3 mmol/l) 
after overnight fast
Week 12-24 after visit 6
until Visit 8
>200 mg/dl (>11.1 mmol/l) 
after overnight fast
Rationale for change
Keep consistency with Chinese medical practice.


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Section to be changed
5.2 ASSESSMENT OF EFFICACY
Description of change
Previous text:
At Visit 3, after blood sample of FPG drawing, patients would 
have a standardised breakfast, finished within 15 min, and 
PPG blood samples would be collected at time points 60 ±10 
min and 120 ±10 min after the start of standardised breakfast. 
Study medication would only be taken after last PPG blood 
samples drawing, i.e. following randomisation. 
At Visit 8, 30 min after blood sample of FPG drawing and 
administration of study medication, patients would have a 
standardised breakfast, finished within 15 min, and PPG blood 
samples would be collected at time points 60 ±10 min and 
120 ±10 min after the start of standardised breakfast
Was changed to:
At Visit 3, after blood sample of FPG drawing, patients would 
have a standardised breakfast and intake metformin and/ or
accepted pre-mixed insulin (if applicable), finished within 15 
min, and PPG blood samples would be collected at time points 
60 ±10 min and 120 ±10 min after the start of standardised 
breakfast. Study medication would only be taken after last 
PPG blood samples drawing, i.e. following randomisation. 
At Visit 8, 30 min after blood sample of FPG drawing and 
administration of study medication, patients would have a 
standardised breakfast and intake metformin and/ or accepted 
pre-mixed insulin (if applicable), finished within 15 min, and 
PPG blood samples would be collected at time points 60 ±10 
min and 120 ±10 min after the start of standardised breakfast.
Rationale for change
Clarification for the intake time of permitted pre-mixed 
insulin.
Section to be changed
5.3.7
Criteria for hypoglycaemic events
Description of change
Previous text:
Every episode of plasma glucose ≤70 mg/dl (≤3.9mmol/l) 
should be documented in the eCRF with the respective time 
and date of occurrence. 
Any hypoglycaemic with glucose values < 54 mg/dl (< 3.0 
mmol/l) and all symptomatic and severe hypoglycaemics 
should be documented as an AE "hypoglycaemic event".
-
For the analysis, all hypoglycaemic events will be 
classified according to the criteria described in the Trial 


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Statistical Analysis Plan. 
-
All investigator defined hypoglycaemic events (i.e. those 
reported as AE) will be analysed in further detail 
depending on symptoms, severity and reported blood 
glucose measurements at time of occurrence of the 
reported hypoglycaemic event. This will include 
evaluation of confirmed hypoglycaemic events, i.e. those 
with a measured plasma glucose concentration ≤70 mg/dl 
(≤3.9 mmol/l) or being severe hypoglycaemic events (i.e. 
those requiring the assistance of another person to actively 
administer carbohydrate, glucagon or other resuscitative 
actions).
Was changed to:
Every episode of plasma glucose ≤70 mg/dl (≤3.9mmol/l) 
should be documented in the eCRF with the respective time 
and date of occurrence. Such hypoglycaemic events should be 
documented in the eCRF according to the following criteria:
-
Asymptomatic hypoglycaemia: event not accompanied by 
typical symptoms of hypoglycaemia but with a measured 
plasma glucose concentration ≤70 mg/dl (3.9 mmol/l)
-
Documented symptomatic hypoglycaemia with glucose 
concentration ≥54 mg/dl and ≤70 mg/dl (≥3.0 mmol/l 
and ≤3.9 mmol/l): event accompanied by typical 
symptoms of hypoglycaemia
-
Documented symptomatic hypoglycaemia with glucose 
concentration < 54 mg/dl (< 3.0 mmol/l): event 
accompanied by typical symptoms of hypoglycaemia 
-
Severe hypoglycaemic episode: Event requiring the 
assistance of another person to actively administer 
carbohydrate, glucagon or other resuscitative actions
Note for severe hypoglycemia: 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.
Any hypoglycaemia with glucose values < 54 mg/dl (< 3.0 
mmol/l) and all symptomatic or severe hypoglycaemia events 
should be documented as an adverse event of hypoglycemia. 
Further details on documentation of hypoglycemia are 
provided on the respective eCRF pages.
Rationale for change
Clarification for hypoglycaemic events.


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Section to be changed
6.2.1
Screening and run-in period
3rd paragraph of run-in period.
Description of change
Previous text: 
Morning dose of metformin and study medication should be 
taken after the visits blood sample collection, and the patients 
should have the same habits of dosing throughout the trial.
Was changed to:
Morning dose of metformin/any permitted pre-mixed insulin
and study medication should be taken after the visits blood 
sample collection, and the patients should have the same habits 
of dosing throughout the trial.
Rationale for change
Clarification for the intake time of pre-mixed insulin.
Section to be changed
6.2.2
Treatment period
Visits 4-8
Description of change
Previous text:
If a patient prematurely discontinues from the 24-week 
treatment period, the patient must return to the trial site for 
both Visit 8 and Visit 9 (7 days after Visit 8), which will be 
performed.
Was changed to:
If a patient prematurely discontinues from the 24-week 
treatment period, the patient must return to the trial site for 
both Visit 8 (within 7 days of stopping study treatment) and 
Visit 9 (7 days after Visit 8), which will be performed.
Rationale for change
Clarification.
Section to be changed
8.3.2
Direct access to source data and documents
Description of change
Duplicated paragraphs were removed as below:
An adaptive approach to clinical trial monitoring will be 
utilised. The sponsor will perform a risk assessment of the trial 
to determine the extent and nature of monitoring required in 
order to ensure the reliability and robustness of the results. 
Regular review of risk reports will provide sponsor oversight 
during trial conduct and direct monitoring activities to the 
areas of greatest risk which have the most potential impact to 
subject safety and data quality.
The Investigator /institution will allow on-site trial-related 
monitoring, audits, IRB / IEC review and regulatory 
inspections. Direct access should be granted to all source 
documents (paper and e-records) including progress notes, 
copies of laboratory and medical test results. The CRA and 
auditor may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with 


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the source documents described in section 8.3.1. The sponsor 
will also monitor compliance with the protocol and ICH GCP.
An adaptive approach to clinical trial monitoring   will be 
utilised. This is initiated by an assessment of the risk 
associated with the trial combined with identification of 
critical data and processes. An Integrated Quality and Risk 
Management Plan   documents the strategies involved with the 
implementation of onsite, offsite and central monitoring   
activities in order to direct focus to the areas of greatest risk 
which have the most potential impact to subject safety and data 
quality. Trial oversight is achieved by regular review of a 
report of risk which then influences any monitoring 
adaptations. 
The Investigator /institution will allow on-site trial-related 
monitoring, audits, IRB/IEC review and regulatory 
inspections. Direct access should be granted to all source 
documents (paper and e-records) including progress notes, 
copies of laboratory and medical test results The CRA and 
auditor may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with 
the source documents described in section 8.3.1. The sponsor 
will also monitor compliance with the protocol and ICH GCP.
Rationale for change
Delete duplicated content.
Section to be changed
Throughout protocol
Description of change
Typo correction for hypoglycaemia and hyperglycaemia.
Rationale for change
Typo correction.
Number of global 
amendment
2.0
Date of CTP revision
28 Nov 2017
BI Trial number
1218.102
BI Investigational 
Product
Linagliptin (Trajenta)
Title of protocol
A phase III,  randomised, double-blind, placebo-controlled, 
parallel group, efficacy and safety study of linagliptin, 
administered orally once daily, in combination with insulin 
therapy for 24 weeks in Chinese type 2 diabetes mellitus 
patients with insufficient glycaemic control
To be implemented 
only after approval of 
the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –


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IRB / IEC / Competent 
Authority to be notified 
of change with request 
for approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects 
only
Section to be changed
3.3
SELECTION OF TRIAL POPULATION
Description of change
Previous text:
It is planned to have not more than 25% of the overall 
randomised patients on background of pre-mixed insulin, 
which will be handled through IRT and refer to section 7.6.
Was changed to:
It is planned to have at least 90 randomised patients on both 
background of pre-mixed insulin and basal insulin, which will 
be handled through IRT and refer to section 7.6.
If the patient’s background type distribution is not balanced as 
expected, the impact on the study conduct should be carefully 
considered. The sponsor should further monitor the 
recruitment of the trial with regard to the type of patient’s 
background treatment.
The intent is to obtain a balanced mix of patients pre-treated 
with premixed insulin or basal insulin. As such the sponsor 
may cap specific patient populations.
Rationale for change
Keep consistency with Chinese medical practice.
Section to be changed
7.6 RANDOMISATION
Description of change
Previous text: 
The randomisation will be stratified on the basis of patients 
belonging to any of the categories below at the beginning of 
the placebo run-in period:
1.
HbA1c value: HbA1c < 8.5% or 8.5%. 
2.
Type of insulin: basal insulin or pre-mixed insulin (no 
more than 25% of the overall randomised patients to be 
on background of pre-mixed insulin)
The allocation process will be performed on Visit 3 through 
IRT. 
Was changed to:


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The randomisation will be stratified on the basis of patients 
belonging to any of the categories below at the beginning of 
the placebo run-in period:
1.
HbA1c value: HbA1c < 8.5% or 8.5%. 
2.
Type of insulin: basal insulin or pre-mixed insulin (at 
least 90 randomised patients for each) 
The allocation process will be performed on Visit 3 through 
IRT.
Rationale for change
For consistency of wording to the above paragraph.


 
 
 
 
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c11679959
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clinical-trial-protocol-revision-02
A phase III, randomised, double-blind, placebo-controlled, parallel group, efficacy
and safety study of linagliptin, administered orally once daily, in combination with
insulin therapy for 24 weeks in Chinese type 2 diabetes mellitus patients  with
insufficient glycaemic control
Approval-Biostatistics
29 Nov 2017 08:35 CET
Approval-Trial Clinical Monitor
29 Nov 2017 09:08 CET
Approval-Team Member Medicine
29 Nov 2017 10:10 CET
Approval-Therapeutic Area 
30 Nov 2017 10:28 CET


Boehringer Ingelheim 
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SAP_001.pdf: 
1
2
16.1.9 Documentation of statistical methods...........................................................
8-01-tsap ..............................................................................................................
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TITLE PAGE
Trial Statistical Analysis Plan
C10222465-03
BI Trial No.:
1218.102
Title:
A phase III, randomised, double-blind, placebo-controlled, parallel 
group, efficacy and safety study of linagliptin, administered orally 
once daily, in combination with insulin therapy for 24 weeks in 
Chinese type 2 diabetes mellitus patients with insufficient 
glycaemic control
Investigational
Product(s):
Linagliptin (Trajenta)
Responsible trial 
statistician(s):
Address: 
 
Phone:
, Fax: 
Date of statistical 
analysis plan:
14 FEB 2019 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.
ENDPOINT(S).......................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
(Other) Secondary endpoint(s) ............................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................14
6.1
TREATMENT(S)................................................................................................14
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................14
6.3
PATIENT SETS ANALYSED...........................................................................19
6.5
POOLING OF CENTRES .................................................................................22
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................22
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................27
7.
PLANNED ANALYSIS......................................................................................31
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........31
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................32
7.3
TREATMENT COMPLIANCE........................................................................32
7.4
PRIMARY ENDPOINT(S) ................................................................................32
7.4.1
Primary efficacy analysis....................................................................................32
7.5
SECONDARY ENDPOINT(S) ..........................................................................34
7.5.1
Key secondary endpoint(s).................................................................................34
7.5.2
(Other) Secondary endpoint(s) ..........................................................................34
7.7
EXTENT OF EXPOSURE.................................................................................38
7.8
SAFETY ANALYSIS..........................................................................................38
7.8.1
Adverse events.....................................................................................................38
7.8.2
Laboratory data ..................................................................................................41
7.8.3
Vital signs.............................................................................................................43
7.8.4
ECG......................................................................................................................44
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7.8.5
Others...................................................................................................................44
8.
REFERENCES....................................................................................................45
10.
HISTORY TABLE..............................................................................................47
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LIST OF TABLES
Table 6.1: 1 
Treatment regimens / study intervals................................................................14
Table 6.2: 1
Important protocol violations ...........................................................................15
Table 6.3: 1 
Check-box for data set to be used for which class of endpoints.......................19
 
Table 6.6: 1 
Summary of imputation methods for efficacy endpoints .................................25
Table 6.7: 1 
Endpoint specific follow-up period for the assignment to active treatment.....28
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for each 
on-treatment visit..............................................................................................29
Table 7.8.2: 1 MDRD staging..................................................................................................43
Table 10: 1
History table .....................................................................................................47
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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase (or SGPT)
ANCOVA
Analysis of Covariance
ANTE(1)
First-order Ante-dependence
AR(1)
First-order Autoregressive
ARH(1)
Heterogeneous First-order Autoregressive
AST
Aspartate Aminotransferase (or SGOT)
AUC
Area Under the Curve
BIcMQ
Boehringer Ingelheim Customised MedDRA Query
BMI
Body Mass Index
BRPM
Blinded Report Planning Meeting
CEC
Clinical Event Committee
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DMG
Dictionary Maintenance Group
DI
Disposition Index
DRA
Drug Regulatory Affairs
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EMEA
European Agency for the Evaluation of Medicinal Products
EoT
End-of-Trial
FAS
Full Analysis Set
FPG
Fasting Plasma Glucose
FPI
Fasting Plasma Insulin
GFR
Glomerular Filtration Rate
HbA1c
Glycosylated Haemoglobin A1c
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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
MMRM
Mixed Model Repeated Measures
MQRM
Medical Quality Review Meeting
MTT
Meal Tolerance Test
NCF
Non-Completers Considered as Failure
O*C
Oracle Clinical
OC
Observed Cases
PK
Pharmacokinetics
PPG
Post-prandial Glucose
PPS
Per Protocol Set
PSTAT
Project Statistician
PT
Preferred Term
PV
Protocol Violation
Q1
Lower Quartile
Q3
Upper Quartile
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
RS
Randomised Set
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3.
INTRODUCTION
As per International Conference on Harmonisation (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 trial statistical analysis plan (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 randomization.
SAS® Version 9.4 or later version will be used for all analysis.
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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Due to an alignment of terminology and analysis of hypoglycaemic events on project level,
the new definition and analyses were applied in the TSAP, including investigator defined 
hypoglycaemic AE and severe hypoglycaemic AE.
The definitions of treated set and full analysis set were updated to be more accurate.
Text in CTP
Adjusted text in TSAP
TS - Treated Set 
The treated set (TS) will consist of all 
patients who were randomised and treated 
with at least one dose of study drug.
TS - Treated Set 
It consists of all patients treated with at least 
one dose of study drug. The TS is the basis 
for safety analyses.
FAS - Full Analysis Set
The full analysis set (FAS) will consist of all 
patients in the TS who had a baseline HbA1c
value and at least one on-treatment HbA1c
value.
FAS - Full Analysis Set
It consists of all patients randomised in the 
TS who had a baseline HbA1c value and at 
least one on-treatment HbA1c value. The 
FAS is the basis for the intention-to-treat 
(ITT) analysis.
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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint in this study is the change from baseline in HbA1c after 24 weeks of 
treatment (HbA1c after 24 weeks of treatment minus HbA1c at baseline), where “baseline”
refers to the last observation prior to the start of randomised study drug, including the 
observation prior to the placebo run-in. HbA1c will be measured in the unit of % at all clinical 
visits. No transformation (e.g. logarithmic) of the change from baseline in HbA1c values will 
be done.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable in this trial.
5.2.2
(Other) Secondary endpoint(s)
Secondary efficacy endpoints are:

Change from baseline in FPG after 24 weeks of treatment

Change from baseline in 2-hour PPG after 24 weeks of treatment

Proportion of patients with HbA1c on treatment <7.0% after 24 weeks of treatment

Proportion of patients with HbA1c on treatment <6.5% after 24 weeks of treatment

Proportion of patients with HbA1c lowering by at least 0.5% after 24 weeks of treatment
The secondary safety endpoints defined in CTP regarding investigator defined hypoglycaemic 
AE and severe hypoglycaemic AE were included in Section 7.8 Safety Analyses.
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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
There will be 5 treatment phases in this trial: screening period, placebo run-in period, 
double-blind treatment period (with either BI drug or matching placebo), post-treatment and 
post-study.
Table 6.1: 1 
Treatment regimens / study intervals
Label
Interval
Start date
Start time
Screening
Screening period
Date of informed consent
00:00
Run-in 
Placebo
Placebo run-in
period
Date of first administration of 
run-in medication
00:00
Lina 5 mg / 
Placebo
Double-blind 
treatment period
Date of first administration of study 
medication for double-blind 
treatment period
Time of first 
administration of 
study medication, 
12:00 if missing
Post-treatment
Post-treatment
Date of last drug intake + X* + 1
00:00
Post-study
Post-study
Date of last contact + 1
00:00
* The endpoint specific follow-up period for the assignment to active treatment are presented in detail in Section 6.7.
The purpose of the definition in the above is to describe all the different study/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.
The efficacy and safety analyses will follow the intention-to-treat (ITT) principle in assigning 
patients to treatment groups, i.e. patients will be analysed as randomised.
If a patient erroneously receives the wrong trial drug, the patient will be analysed ‘as
randomised’. Additionally, the AEs with an onset during the time of the incorrect study
treatment will also be listed separately.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Table 6.2: 1 defines the different categories of important protocol violations (IPVs) to be 
considered for evaluability of efficacy (E) or for patients’ right and safety (S). IPVs marked 
with an ‘S’ only will not lead to exclusion of a patient from the per-protocol-set (PPS). Only 
the IPVs marked with ‘E’ will lead to exclusion from the PPS.
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Table 6.2: 1 Important protocol violations 
PV Category / 
Code
Description
Criterion to check for PV 
(Comments)
Efficacy (E) 
or Safety (S)
PV 
Leading to 
Exclusion 
from PPS
A
Entrance criteria 
not met
A1
Target indication 
not met
A1.1
No type 2 diabetes
Inclusion criterion #1 checked NO
E
Yes
A1.2
Antidiabetic 
background 
therapy not as 
required
Inclusion criterion #2 checked NO 
or required antidiabetic background 
not recorded on eCRF
E
Yes
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 at Visit 1 out of range for 
inclusion by >0.2% (i.e., <7.3% or 
>10.2%)
E
Yes
A2.2
Age out of range at 
screening
Inclusion criteria #4 not met and/or
Age < 18 years
E
Yes
A2.3
Body mass index 
(BMI) out of range 
at screening
Inclusion criteria #5 not met and/or
BMI > 45 kg/m2
E
Yes
A3
Exclusion criteria 
violated
A3.1
Treatment with 
protocol excluded 
antidiabetic drugs
Exclusion criterion #2, #5 checked 
Or
Intake of any of the excluded drugs 
reported on the eCRF within the 
time prior to informed consent 
specified in the exclusion criteria
E
Yes
A3.2
Relevant 
concomitant 
diagnoses
Exclusion criterion #3 checked
Or
acute coronary syndrome 
(non-STEMI, STEMI and unstable 
angina pectoris), stroke or TIA 
recorded on concomitant diagnoses 
eCRF within previous 3 months
S
No
A3.3
Impaired hepatic 
function
Exclusion criterion #4 checked
Or
ALT (SGPT) or AST (SGOT) or 
alkaline phosphatase > 3xULN at 
screening / run-in phase
S
No
A3.4
Gastrointestinal 
surgery
Exclusion criterion #6 checked
E
Yes
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Table 6.2: 1 (continued)
Important protocol violations
PV Category / 
Code
Description
Criterion to check for PV 
(Comments)
Efficacy (E) 
or Safety (S)
PV 
Leading to 
Exclusion 
from PPS
A3.5
Medical history of 
cancer (except for 
basal cell 
carcinoma) and/or 
treatment for 
cancer within the 
last 5 years
Exclusion criterion #7 checked
S
No
A3.6
Blood dyscrasias 
or relevant 
disorders
Exclusion criterion #8 checked
S
No
A3.7
Known 
hypersensitivity to 
any of the drugs in 
the study regimen
Exclusion criterion #9 checked
E
Yes
A3.8
Treatment with 
protocol excluded 
anti-obesity drugs
Exclusion criterion #10 checked
Or
intake of any of the excluded drugs 
reported on the eCRF within the 
time prior to informed consent
specified in the exclusion criterion
E
Yes
A3.9
Treatment with 
protocol excluded 
systemic steroids 
or change in 
thyroid hormone 
dose
Exclusion criterion #11 checked
Or
intake of any of excluded drugs 
reported on the eCRF within the 
time prior to informed consent 
specified in the exclusion criteria
E
Yes
A3.10
Specific exclusion 
criterion for 
pre-menopausal 
women violated
Exclusion criterion #12 checked
S
No
A3.11
Alcohol or drug 
abuse that may 
interfere with study 
participation
Exclusion criterion #13 checked
E
Yes
A3.12
Participation in 
another trial with 
an investigational 
drug within 2 
months prior to 
informed consent
Exclusion criterion #14 checked
Final decision at the DBL meeting 
(medical judgement), depending on 
the type of drug given in the prior 
trial (only if investigational drug 
interferes with glucose 
metabolism).
E
Yes
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Table 6.2: 1 (continued)
Important protocol violations
PV Category / 
Code
Description
Criterion to check for PV 
(Comments)
Efficacy (E) 
or Safety (S)
PV 
Leading to 
Exclusion 
from PPS
B
Informed consent
B1
Informed consent 
not available
Date of informed consent missing
Or
No signature on patient’s 
“Declaration of Informed Consent”
Patient’s data will not be used at 
all.
S/E
Yes
B2
Informed consent 
too late
Date of informed consent 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
S
No
C
Trial medication 
and 
randomisation
C1
Incorrect trial 
medication taken
C1.1
No study 
medication taken
Patient randomised but no study 
medication taken.
Exclude also from FAS and TS.
E
Yes
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 IVRS)
Can only be finally judged after 
DBL since unblinding information 
is required.
E
Yes
C2
Randomisation not 
followed
C2.1
Treated without 
randomisation
Patient treated according to eCRF 
but not randomised by IVRS.
Exclude also from FAS and RS.
E
Yes
C3
Non-compliance
C3.1
Non-compliance
with drug intake
Gross non-compliance issues only –
based on compliance section of 
CRF (at least two times on 
treatment compliance was outside 
80-120% according to eCRF)
Final decision at the DBL meeting. 
(medical judgement)
E
Yes
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Table 6.2: 1 (continued)
Important protocol violations
PV Category / 
Code
Description
Criterion to check for PV 
(Comments)
Efficacy (E) 
or Safety (S)
PV 
Leading to 
Exclusion 
from PPS
C3.2
Non-compliance 
with criteria for 
removal from the 
trial
Criteria for removing a patient from 
the trial not adhered to.
Final decision at the DBL meeting. 
(medical judgement)
E
Yes
C3.3
Treatment 
interruption for 
more than 10 
consecutive days
Documented treatment interruption 
for 11 consecutive days or more.
E
Yes
C4
Medication code 
broken
C4.1
Medication code 
broken without just 
cause
Medication code was broken for no 
valid reason.
Final decision at the DBL meeting. 
(medical judgement)
E
Yes
D
Concomitant 
medication
D1
Prohibited 
medication use
D1.1
Rescue medication 
taken without just 
cause
Review of eCRF for use of rescue 
medication within the 24 weeks and 
fasting plasma glucose prior to 
rescue therapy < 90% of protocol 
requirement for rescue medication 
(if threshold is 240, FPG<216 
mg/dL or <12 mmol/L prior to 
rescue medication) and no 
documented hyperglycaemia.
E
Yes
D1.2
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 D1.1 not fulfilled.
E
Yes
D1.3
Use of 
contraindicated 
drugs
Review of eCRF for 
contraindicated drugs.
Final decision at the BRPM 
meeting. (medical judgement)
E
Yes
Note : Missing visits, evaluations, and tests will be considered missing data, not protocol 
deviations.
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6.3
PATIENT SETS ANALYSED
SCR - Screened Patients Set
It consists of all patients screened for the trial, with informed consent given and who 
completed at least some screening procedures at Visit 1.
RS - Randomised set
It consists of all patients from the screened set who were randomised to study drug, regardless 
of whether any study drug was taken.
TS - Treated Set 
It consists of all patients treated with at least one dose of study drug. The TS is the basis for 
safety analyses.  
FAS - Full Analysis Set 
It consists of all patients randomised in the TS who had a baseline HbA1c value and at least 
one on-treatment HbA1c value. The FAS is the basis for the intention-to-treat (ITT) analysis.
FAS - Completers
It consists of all patients in the FAS with treatment duration no less than 149 days and did not 
prematurely discontinue the trial. The date of last intake of study drug should be on or after 
the start of the time window of the last on-treatment visit, and an HbA1c value should be 
available within the time window for this visit.
PPS - Per Protocol Set
It consists all patients in the FAS without important PVs for efficacy.
MTT-set - Meal Tolerance Test set
It consists all patients of the FAS with a valid MTT at baseline and at the end of the study. An 
MTT is considered valid if it has a valid FPG and a valid 2 hour PPG value.
Table 6.3: 1 
Check-box for data set to be used for which class of endpoints
Class of endpoint 
TS
FAS 
MTT-set
Primary endpoint –primary 
analysis
X
Primary endpoint –sensitivity 
analysis
Other efficacy endpoints
X
MTT endpoints
X
Safety endpoints
X
Demographics
X
Baseline for efficacy
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
Based on the different reasons of patients’ data missing for different endpoints, various 
methods will be used to assess the impact of missing data on the efficacy endpoints of this
trial, depending upon the type of the endpoint. A description of the various approached are 
given in the following:
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, this OC-technique will be adapted by setting any values taken after 
rescue medication to missing. The definition of rescue therapy please refers to section 5.3.
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 anti-conservative
estimates of the treatment effects in case of data missing due to patients dropping-out because 
of the lack of efficacy of the drug under study. However, since it can be expected that the 
drop-out rate due to lack of efficacy and the rate of patients with rescue therapy is higher in 
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the placebo group, this approach will lead to a conservative estimates of the placebo-adjusted 
treatment effect of linagliptin.
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Non-completers considered as failure (NCF)
For binary endpoints like a treat to target response of HbA1c < 7% a conservative method to 
replace missing values is to consider them as “failure”. Missing data due to early 
discontinuation will be replaced as “failure” (e.g. HbA1c 7%) 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 values of 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
OC
Continuous and 
binary endpoints
No imputation
Excluded (considered 
missing). One picked 
value per visit.
NCF
Binary endpoints 
derived from 
continuous 
endpoints (e.g. 
HbA1c<7.0%)
Missing values after 
premature discontinuation 
of study drug 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 change from baseline to the 
last available value under treatment and the minimum and maximum post baseline will be 
determined for quantitative safety laboratory variables. In general, the last measurement taken 
between the first intake of randomised trial drug and drug-stop date + 7 days will be analysed 
as the last value on-treatment.
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Missing dates and times
Missing or partial date and time information for AEs will be replaced according to general BI 
rules (2).
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 randomization. If the date of 
first administration is partially missing with the month and year present, the day will be set to 
the date of randomization if randomisation was in the same month. If randomization was in 
the month prior to the first drug administration the missing day will be imputed as the first 
day of the month. A missing time of first drug administration will be imputed as 12:00 
o’clock noon, missing administration times at on-treatment visits will be imputed by 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.

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.
Additional rules for the treatment set-up in O*C:

Since usually no times are available for the start of the screening, placebo run-in period 
will be considered to start at 0:00 o’clock (midnight).

Also the start of the post-treatment period will be considered at 0:00 o’clock (midnight) 
on the day after the study drug stop date.

The post study period on the date after the follow-up visit, starting at 0:00 o’clock 
midnight.

In general, the start if the post-treatment period is defined as date of last drug 
administration + 1 day. If the drug stop date is incomplete with only month and year 
present, the post-treatment period starts on the first day of the following month (i.e. at 
the same day as the imputed drug stop date).

The post study period start is intended to start on the date of last contact + 1 day and 
the date of last contact is assumed to be after the date of last drug administration. In 
patients who discontinue the study, it can happen that the date of last contact is before 
date of last drug administration. To account for such cases the start of the post-study 
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period is defined as the maximum of the last contact date + 1 day, the date of the last 
visit + 1 day and the start of the post-treatment period + 1 day.
Only the year of birth will be collected in the eCRF, and the day and month of birth will be 
imputed as 01 January. 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. 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.
Missing dates for meal tolerance test in the eCRF should be replaced based on the dates of the 
according lab samples. Missing times for the start and end of a meal will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
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. For daily 
insulin dose the baseline will be derived from the eCRF and is equal to the daily insulin dose 
at day of first study medication intake. Also, for metformin, baseline dose refers to the dose at 
day of first study medication intake.
Measurements taken prior to the first intake of randomised study drug will be considered 
pre-treatment values. The 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 drug administration will be used to separate pre-treatment 
from on-treatment values. Measurements taken after the first intake of randomised study drug 
will be considered on-treatment values if they have been obtained up to end of the parameter 
specific follow-up period as defined in Table 6.7: 1 below and will be assigned to the 
randomised study drug for analyse.
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Table 6.7: 1 
Endpoint specific follow-up period for the assignment to active treatment 
Endpoint
Last day of assignment to treatment phase
(days after study drug stop date)
Efficacy
HbA1c
7
FPG
1
PPG, 
0
Body weight
7
Waist circumference
7
Rescue medication (new antidiabetic treatment, 
increases of background antidiabetic treatment)
If patient did not prematurely discontinue from 
trial medication
-1
If patient prematurely discontinued from trial 
medication (any reason)
0
Safety
Adverse events
7
Safety laboratory measurements
7
Vital signs
7
Measurements taken after the end of the follow-up period after the last intake of study drug 
will be considered post-treatment values.
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 study drug (usually this is at Visit 3). Reasons to base 
the time widows on the actual treatment start date rather than the randomisation date are:

If first intake of study drug shows a large delay by e.g. more than one week after the 
date of randomisation, a measurement taken four weeks after randomisation rather 
reflects the drug effect after three weeks than after four weeks and thus may 
underestimate the treatment effect at this visit.

With large delays of the introduction of study drug after the randomization, the time 
window for the first on-treatment visit could include times the patients was not yet on 
study drug.
The time window for the first visit after randomization starts on the day after the first intake 
of study drug. This maximises the number of measurements used in by visit analyses and 
provides consistency with the planned last observation carried forward (LOCF) approach, but 
may lead to an underestimation of the treatment effect at the first visit form parameters that 
react slowly on treatment.
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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 (cf. Table 6.7: 1).
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for each 
on-treatment visit
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
4
Week 4
28
29
2
43
5
Week 8
56
57
44
71
6
Week 12
84
85
72
106
7
Week 18
126
127
107
148
8
Week 24/EoT
168
169
149
Study drug 
stop date + 
X days
A  In case of premature discontinuation of the study drug a Visit 8 (EoT) has to be performed. If such a Visit 
8 falls into the time window of a previous visit, measurements will be assigned to this previous visit and 
the visit value will be determined as described below. In this case the time window for the visit that 
includes Visit 8 will end X days after the study drug stop date, including Day X. The definition of X is 
endpoint specific, cf. Table 6.7: 1.
B  Only values taken prior to the start of treatment with randomised study drug can be considered baseline 
values. Time windows will be used for assignment of measurements to scheduled visits. 
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 will be selected for analysis at an on-treatment visit – the value 
will be selected which is closest to the protocol planned day. If there are two observations 
which have the same difference in days to the planned day or if there are two observations on 
the same day, the 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, 
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.
Safety measurements will be assigned to the nominal visit as recorded on the eCRF or as 
provided by the laboratory.
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7.
PLANNED ANALYSIS
Disposition of the patient population participating in the trial will be analysed by treatment 
groups and presented in the clinical trial report (CTR) as a frequency-distribution. The 
number of patients participating in the study by centre will also be analysed by treatment
group and presented as a frequency distribution.
A frequency of patients with important PVs, also summarised by whether the IPV led to 
exclusion from the PPS, will be presented by treatment group for the treated set. The 
frequency of patients in different analysis sets and primary reason for exclusion will also be 
analysed for each treatment group on randomised set.
For in-text tables presenting descriptive analysis of the end-points and other variables, the set 
of summary statistics is: N (number of patient with non-missing values), mean, standard 
deviation (SD).
For the respective end-of-text tables, the set of summary statistics is: N / Mean / SD / Min / 
Median / Max. 
For appendix tables, the set of summary statistics is: N / Mean / SD / Min / Q1 (lower quartile) 
/ Median / Q3 (upper quartile) / Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
Missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive analysis of the following demographic variables measured at baseline will be 
presented on the TS population:
Gender, age (in years), age-groups, weight (kg), weight categories, BMI (kg/m2), BMI 
categories, eGFR (ml/min/1.73m2), eGFR categories, Metformin dose, baseline daily insulin 
dose, daily insulin dose per body weight (IU/kg), type of insulin, height (cm), waist 
circumference (cm), smoking-status and alcohol status. Categories for demographic and 
baseline characteristics are defined in Section 6.4.
Descriptive analysis of the following baseline efficacy variables will be presented on the FAS 
population:
HbA1c, HbA1c categories, FPG (mg/dL), FPG categories, 
 
 
 time since diagnosis of diabetes.
A summary of the number of patients in each randomisation stratum per treatment will also be 
shown. This will be based upon the data received from the IRT provider.
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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency distribution of patients with different concomitant diseases and medications
(including the anti-diabetic therapies at screening) will be presented.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. Frequency distribution of 
patients whether with compliance-level between 80% and 120% will be presented by visit
(Week 0 to 4, Week 4 to 8, Week 8 to 12, Week 12 to 18 and Week 18 to 24).
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary efficacy analysis
The primary analysis will be performed on the FAS (OC) and patients will be assigned to the 
treatment they were randomised to. A REML-based MMRM approach is applied to compare 
the change in HbA1c from baseline after 24 weeks of treatment.
The statistical model will be 
HbA1c change from baseline = overall mean + baseline HbA1c + treatment + type of insulin
+ week+ week by treatment interaction
+ baseline HbA1c by week interaction 
+ random error
This model includes effects accounting for the following sources of variation: ‘baseline 
HbA1c’, ‘treatment’, ‘type of insulin (basal insulin or any permitted pre-mixed insulin) ’, 
‘week’, ‘week by treatment interaction’ and ‘baseline HbA1c by week interaction’. 
‘Treatment’, ‘type of insulin’, ‘week’ and ‘week by treatment interaction’ are fixed, 
categorical effects, and ‘baseline HbA1c’ and ‘baseline HbA1c by week interaction’ are 
continuous, linear covariates. For each patient, the error terms from the on-treatment visits 
represent the within-patient variability, and are assumed to follow a multivariate normal 
distribution with an unstructured covariance matrix.
If the model fails to converge, the following covariance structures will be tested in order: 
ANTE(1)ARH(1)AR(1). The first model to converge will be used as the primary analysis. 
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. Significance tests will be based on least squares means using a two-sided α= 0.05 
(two sided 95% confidence intervals). 
Only the available data which were observed whilst patients were on treatment will be 
included in the analysis. Missing data are handled implicitly by the above statistical model, 
rather than by using any imputation. 
Superiority will be tested using the p-value of the treatment effect and a two-sided 95% 
confidence interval for the treatment difference.
For Week 24 analysis, all levels for factor week up to Week 24 are to be considered in the 
model, i.e. Week 4, 8 12, 18 and 24.
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In addition, descriptive statistics for HbA1c over time are presented for FAS (OC), 
 
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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
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 change from baseline in FPG after 24 weeks of 
treatment.
FPG change from baseline = overall mean + baseline HbA1c + treatment + type of insulin
+ week+ week by treatment interaction
+ baseline FPG
+ baseline FPG by week interaction
+ random error
The analysis will include the fixed categorical effects of treatment, type of insulin, week and 
treatment by week interaction, as well as the continuous, fixed covariates of baseline FPG, 
baseline HbA1c and baseline FPG by week. An unstructured (co)variance structure will be 
used to model the within patients measurements. This analysis will be performed on FAS 
(OC).
Change from baseline in 2-hour PPG after 24 weeks of treatment
Change from baseline is calculated as the on-treatment value minus the baseline values. The 
descriptive statistics will be displayed based on MTT-set (OC).
As 2-hour PPG is only collected once on-treatment, an ANCOVA model will be fitted on the 
MTT-set (OC). The analysis will use the ANCOVA model used in the strategy for the 
sensitivity analysis of HbA1c, with additional baseline 2-hour PPG as a continuous covariate.
2-hour PPG change from baseline = overall mean + baseline HbA1c + treatment 
+ type of insulin + baseline 2-hour PPG
+ random error
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, continuous baseline HbA1c and type of 
insulin. Patients with baseline HbA1c < 7.0% will be excluded from the analysis.
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A frequency table with the number and percentage of patients with HbA1c < 7.0% at Week 
24 in each treatment group will also be presented based on FAS (NCF).
Proportion of patients with HbA1c on treatment < 6.5% after 24 weeks of treatment
Logistic regression for the patients achieving HbA1c < 6.5% 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, continuous baseline HbA1c and type of 
insulin. Patients with baseline HbA1c < 6.5% will be excluded from the analysis.
A frequency table with the number and percentage of patients with HbA1c < 6.5% at week 24 
in each treatment group will 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,
continuous baseline HbA1c and type of insulin.
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).
The analyses for further safety endpoints are specified in Section 7.8.1.
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7.7
EXTENT OF EXPOSURE
Exposure to study drug will be calculated in days as (study drug stop date – study drug start 
date + 1) and will be tabulated as a frequency table with categorized 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).
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. All safety data will be displayed and 
analysed using descriptive statistical methods. No formal inferential analysis is planned for 
safety comparison.
7.8.1
Adverse events
The analysis of AEs will be descriptive in nature. All analysis of AEs will be based on the 
number of patients with AEs (not the number of AEs) according to the BI standards (3). For 
this purpose, AE data will be combined in a 2-step procedure into AE records.
Processing of individual AE information
In a first step, for analysis multiple AE occurrence data on the CRF will be collapsed into an 
AE provided that all of the following applies:

The same lowest level term is reported for the occurrences.

The occurrences are time-overlapping or time-adjacent (time-adjacency of 2 occurrences 
was given if the second occurrence started on the same day or on the day after the end of 
the first occurrence).

Treatment does not change between the onset of the occurrence OR treatment changes 
between the onset of the occurrences, but no deterioration is observed for the later 
occurrence.
Assignment of AEs to treatments
In a second step, AE episodes will be condensed into AE records provided that the episodes 
are reported with the same term on the respective MedDRA level and that the episodes are
assigned to the same treatment.
The analysis of AEs will be based on the concept of treatment emergent AEs. To this end, all 
AEs occurring between start of treatment and end of REP will be considered 
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‘treatment-emergent’. The REP is defined as a period of 7 days after the last dose of trial 
medication. That means that all AEs occurring between first drug intake till last drug intake + 
residual effect period (REP) will be assigned to the randomised treatment. All AEs occurring
before first drug intake will be assigned to ‘screening’ and all AEs occurring after the REP 
will be assigned to ‘post-treatment’ (for listing only). For details on the treatment definition, 
see Section 6.1.
In general, in-text AE tables will only present AEs assigned to the randomised treatments. 
End-of-text tables will display in addition AEs observed ‘pre-treatment’ (including AEs 
observed during screening and placebo run-in regardless of treatment group) and AEs 
observed during post-treatment regardless of treatment group.
Analysis of other significant AEs
According to ICH E3 (1), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant AEs with
(i)
‘action taken = discontinuation’ or ‘action taken = reduced’ or
(ii)
marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor / Investigator at a Medical Quality 
Review Meeting (MQRM).
AE summaries
An overall summary of AEs will be presented.
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class (SOC) and preferred term (PT). Separate tables will be provided for 
patients with other significant adverse events according to ICH E3 (1), for patients with AESI, 
for patients with AEs leading to discontinuation, for patients with drug-related AEs and for 
patients with serious adverse event (SAE).The system organ classes will be sorted 
alphabetically, and preferred terms will be sorted by frequency (within SOC).
The frequency of patients with AEs will also be summarised by subgroups, including age, 
gender, background therapy and renal function. The details of the subgroups can be found in 
Table 6.4: 1.
Additional AE analyses
Analysis of hypoglycaemic events
The investigator will record for each AE whether it represents a hypoglycaemic event and if 
so, record additional information to assess the intensity of the hypoglycaemic event. On the 
basis of this information the hypoglycaemic event will be classified as:

investigator defined hypoglycaemic AE

hypoglycaemic AE with PG <= 70 mg/dL (<= 3.9 mmol/L) or severe hypoglycaemic 
AE (= confirmed hypoglycaemic AE)
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
hypoglycaemic AE with PG < 54 mg/Dl (<= 3.0 mmol/L) or severe hypoglycaemic 
AE

severe hypoglycaemic AE

investigator defined symptomatic hypoglycaemic AE or severe hypoglycaemic AE

symptomatic hypoglycaemic AE with PG <= 70 mg/dL (<= 3.9 mmol/L) or severe 
hypoglycaemic AE

symptomatic hypoglycaemic AE with PG < 54 mg/dL (<= 3.9 mmol/L) or severe 
hypoglycaemic AE

severe hypoglycaemic AE
Asymptomatic hypoglycaemic events which are not considered to be an adverse events by the 
investigator and which have plasma glucose concentration >= 3.0 mmol/L and <= 3.9 mmol/L 
(>= 54mg/dL and <= 70 mg/dL) will be recorded by the investigator on a separate eCRF 
page.
Based on the above definition, different tables will be shown for (i) patients with investigator 
defined hypoglycaemic AEs, (ii) patients with any hypoglycaemia (investigator defined 
hypoglycaemic AE or asymptomatic hypoglycaemia not reported as AE), (iii) patients with 
any asymptomatic hypoglycaemia (investigator defined asymptomatic hypoglycaemic AE or 
asymptomatic hypoglycaemia not reported as AE).Each table will include total number of 
hypoglycaemic events, number of episodes per patient, minimum glucose level of worst 
episode, and time to onset of first episode. 
Furthermore, patients with investigator defined hypoglycaemic AEs and confirmed
hypoglycaemic AE will be tabulated by treatment group. A subgroup analysis with respect to 
age and rescue therapy will be performed.
The impact of treatment on the occurrence of patients with investigator defined 
hypoglycaemic AEs will also be explored using a logistic model involving treatment,
continuous baseline HbA1c, and type of insulin. Time to the onset of the first investigator 
defined hypoglycaemic AE will be analysed by Kaplan-Meier estimates.
Analysis of protocol specified AEs (=events of special interest)
As defined in protocol, 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 injury as defined by the following alterations of hepatic laboratory parameters: 
≥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
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
Renal adverse events such as acute renal failure

Pancreatitis (refer to the ISF)

Pancreatic cancer
The categories and events included as AESIs may change over time. The definitions, 
including SMQs for the AESIs will be maintained on project level. All AESIs defined in the 
CTP are presented in the CTR. If further AESIs have been defined, they will also be included 
into the CTR.
For each AESI, the frequency of patients with the respective AESI will be summarised by 
treatment, user-defined AE category and preferred term.
Cardiovascular and neurological events qualifying for external adjudication by the Clinical 
Event Committee (CEC)
An independent external CEC regularly reviews events suspect of stroke, myocardial 
ischemia (incl. myocardial infraction), cardiovascular death and evaluates whether 
pre-specified criteria for these adjudication endpoints are met. Details on composition of the 
CEC, responsibilities and clinical event definitions are provided in a separate CEC Charter.
The CEC will be provided with additional, specified background material on the patients with 
these events and perform an assessment of the events.
Frequency tables will be provided for the preferred terms in the specified SMQs of events and 
for the adjudication endpoints.
Pancreatic events qualifying for external adjudication by the Clinical Event Committee 
(CEC)
An independent external CEC regularly reviews events suspect of acute pancreatitis, chronic 
pancreatitis, Asymptomatic Pancreatic Hyperenzymemia and Pancreatitis Malignancy and 
evaluates whether pre-specified criteria for these adjudication events are met. Details on 
composition of the CEC, responsibilities and clinical events definitions are provided in a 
separate CEC charter.
The CEC will be provided with additional, specified background material on the patients with 
these events and perform an assessment of the events.
Frequency tables will be provided for the preferred terms in the specified SMQs of events and 
for the adjudication endpoints.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(4). All analyses will be based on TS.
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Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised study drug. Laboratory values taken up to 7 days after the last 
administration of randomised study drug will be considered as on-treatment. 
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range at baseline and the 
last measurement on treatment. Descriptive statistics will be provided by treatment group for 
baseline, on-treatment values and for changes from baseline. Frequency tables will summarise 
the number of patients with potentially clinically significant abnormalities. 
Specific considerations for hepatic parameters
To support analyses of liver related adverse drug effects, Potential Hy’s law cases are defined 
by the combination of the following events within a time span of 30 days:

Any on-treatment value of ALT or AST (or both) >= 3 times upper limit of normal (ULN) 
with

Total bilirubin >= 2 x ULN and

Alkaline phosphatase <= 2 x ULN
The start of the 30 day time span is triggered by each liver tranaminase elevation above the 
defined thresholds.
Patients who fulfil one or two of the criteria for ALT/AST or total bilirubin elevation above 
for a potential Hy’s law case and has no information available for the remaining parameter(s) 
at the same timepoint or within the 30 day time windows will be considered for presentation 
of potential Hy’s law lab constellation as well.
All calculations for the grading will be based on the originally measured laboratory values 
and the ULNs given by the laboratory, not on normalised values with BI standard reference 
ranges.
Specific considerations for amylase and lipase
In order to support screening for highly increase amylase and/or lipase values in regards to the 
ULN, specific transition tables are defined. These transition tables check for erased values, 
values above the twofold ULN and values above the threefold ULN either at the end of 
treatment or at the peak value on treatment.
All calculations for the underlying grading will be based on the originally measured 
laboratory values and the ULNs given by the laboratory, not on normalised values with BI 
standard reference ranges.
Specific renal endpoints
The glomerular filtration rate (GFR) will be derived from serum creatinine* values based on 
the standard MDRD formula:
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eGFR (ml/min/1.73 m2) = 175 x [Screatinine (µmol/L)/88.4]-1.154 x [age]-0.203 x [0.742 if 
patient is female] x [1.212 if patient is of African origin]
*: creatinine methods calibrated to an IDMS reference method
Calculation of age in the determination of eGFR will be done by:
Age = (laboratory assessment date – date of birth + 1) / 365.25.
To support analysis of renal function, eGFR throughout the trial will be categorised according 
to the following MDRD staging:
Table 7.8.2: 1
MDRD staging
Stage
eGFR (mL/min/1.73m²)
Description
Label for displays
1
>=90
Normal renal function 
≥90 (normal)
2
60 to <90
Mild renal impairment
60 to <90 (mild)
3
45 to <60 
Moderate renal impairment A
45 to <60 (moderate A)
4
30 to <45
Moderate renal impairment B
30 to <45 (moderate B)
5
<30
Sever renal impairment or 
endstage renal disease
<30 (end stage)
Fasting plasma glucose will be included in the safety analyses with respect to the reference 
range and in the analysis of possible clinically significant abnormalities. Descriptive statistics 
over time and further statistical analyses will be part of the efficacy analysis.
Urine albumin and urine creatinine do not have a reference range and are determined to 
calculate the albumin / creatinine ratio. Only the albumin /creatinine ratio will be analysed as 
for albumin and creatinine no normalised values can be derived. In cases where urine albumin
values are reported to be below the quantification limits (e.g. < 3 mg/L) the albumin / 
creatinine ratio is determined as missing and will not be replaced by estimated values.
Reported original negative quantitative safety laboratory values will be excluded from 
analyses (consistently from all tables and listings). (This does not apply to normalised values, 
which will be used.)
7.8.3
Vital signs
Vital signs observed throughout the whole trial will be assessed with regard to possible 
changes compared to findings before start of treatment. Only descriptive statistics by 
treatment group at each on-treatment visit are planned for this section.
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7.8.4
ECG
12-lead ECG measurements will be taken at Visit 3 and at the end-of-trial (Visit 8). Any 
clinically significant new findings in the ECG-measurement at the EoT compared to that from 
the first measurement will be considered as AEs.
7.8.5
Others
7.8.5.1 Physical examination
Physical Examination will be taken during placebo run-in period (Visit 2), and at the EoT. 
Findings in the physical examination at placebo run-in period will be considered as 
baseline-condition. Any clinically significant new findings in the Physical Examination at the
EoT will be considered as AEs.
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8.
REFERENCES 
[1] CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
[2] 001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
[3] 001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
[4] 001-MCG-157: "Handling, 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
Initial
13-SEP-16
None
This is the initial TSAP with necessary
information for trial conduct.
Final
26-SEP-17
Sections 
empty in 
initial 
version
Added as it is the final TSAP.
6.2

“Uncontrolled hyperglycaemic”
category deleted

“Background antidiabetic therapy 
not taken as specified in the 
protocol” deleted
6.3

TS and FAS rephrased

MTT-set added
7.1

Variables showed in demographic 
and baseline adjusted
7.8.1

Analysis of hypoglycaemic events 
updated based on project update

“Safety topic of interest” section 
deleted
Revised
14-FEB-2019
7.8.2

eGFR categories updated
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