Clinical trial NCT03429543
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim
Start date: 2018-03-20; Completion date: 2023-05-31
Enrollment: 175 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to evaluate the efficacy and safety of an empagliflozin dosing regimen and one dose of linagliptin in patients with type 2 diabetes who are aged 10 to below 18 years and are currently taking metformin, insulin or both drugs (DINAMO TM) or who are treatment naïve or not on active treatment after metformin withdrawal (DINAMO TM MONO) .

Empagliflozin and linagliptin are both approved for use in adult patients with type 2 diabetes. This study will assess how well empagliflozin and linagliptin work by finding out how these treatments affect blood glucose (sugar) levels compared to placebo (a pill that contains no active drug), in children and adolescents. Empagliflozin and linagliptin are considered investigational products in this study since while they have been approved for use in adults, they have not been approved for children and adolescents due to lack of clinical studies in this specific population.

Patients with type 2 diabetes have higher levels of blood glucose (sugar) than patients who do not have this disease. The high level of sugar in the blood can lead to serious short-term and long-term medical problems. The main goal of treating diabetic patients is to lower blood glucose to a normal level. Lowering and controlling blood glucose help prevent or delay complications of diabetes such as heart disease, kidney, eye and nerve diseases, and the possibility of amputation.

Empagliflozin is a drug that helps to reduce blood glucose (sugar) levels by causing glucose to be excreted in the urines.

Linagliptin works by increasing the production of insulin (a hormone that controls the level of blood glucose) after meals when blood glucose (sugar) levels are too high. This helps to lower blood sugar levels.

The subject will either receive one of the active study drugs or a placebo. This study will be double blind; this means that neither the subject, nor the study doctor will know which treatment the subject will receive.

Which treatment the subject receives is decided by a computer, purely by chance; this is called a "random assignment".

For this study, there will first be a screening visit, followed by a 2-week placebo run-in period (all subjects will take placebo once daily). This run-in period is designed to ensure subjects are able to take the study drugs as described in the study protocol. Thereafter there will be a 26-week treatment phase (week 1-week 26) and a 26-week safety extension period (week 27-week 52). Following this there will be a follow-up visit at week 55.

On Day 1 after the placebo run-in phase, the subject will be randomly assigned to receive one of the 3 treatments: empagliflozin 10 mg, linagliptin 5 mg or placebo in a blinded manner. This treatment will continue up to week 14. Then after week 14, the subject will be assigned to receive one of the following 4 treatments: empagliflozin 10 mg, empagliflozin 25 mg, linagliptin 5 mg or placebo in a blinded manner. The drugs assigned after week 14 will be the same drugs as on Day 1 but some subjects will receive a higher dose of empagliflozin.

After the completion of the 26-week treatment period, the subject will enter a 26-week safety extension period. The same active treatment that the subject had been assigned to at week 14 visit will be continued. Subjects assigned to placebo on Day 1 will be randomly assigned to receive one of the 3 active treatments: empagliflozin 10 mg, empagliflozin 25 mg or linagliptin 5 mg in a blinded manner. This safety extension period is primarily designed to provide additional information on how well empagliflozin and linagliptin are tolerated.

Following the treatment phases, there will be a follow-up visit at week 55

Intervention model description:

Eligible subjects with HbA1c of 6.5% to 10.5% at screening will be randomized in a 1:1:1 ratio to receive empagliflozin 10 mg, linagliptin 5 mg or placebo. HbA1c assessment will be performed at Week 12. All subjects with Week 12 HbA1c \< 7% will remain on previously assigned randomized treatment. Subjects taking empagliflozin with Week 12 HbA1c \>= 7% will be re-randomized in a 1:1 ratio to continue on the low dose treatment (empagliflozin 10 mg) or up-titrate to the high dose treatment (empagliflozin 25 mg). Subjects taking linagliptin or placebo with Week 12 HbA1c \>= 7% will remain on previously assigned treatment. All subjects will get new medication kits dispensed at Week 14 to maintain the blinding.

At Week 26, all subjects previously assigned to placebo will be re-randomized in a 1:1:1: ratio to receive one of the active treatments: empagliflozin 10 mg, empagliflozin 25 mg or linagliptin 5 mg. All subjects will get new medication kits dispensed at Week 14 to maintain the blinding.

Detailed description:

Arms: arm 1: Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily, until end of treatment. arm 2: Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily, until end of treatment. arm 3: Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. At week 26, patients were re-randomised to receive 10 milligram (mg) empagliflozin, taken once daily, until end of treatment. arm 4: Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. At week 26, patients were re-randomised to receive 25 milligram (mg) empagliflozin, taken once daily, until end of treatment. arm 5: Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 5 milligram (mg) Linagliptin once daily, until end of treatment. arm 6: Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily, until Week 14. Responder patients were not re-randomised at week 14 and continued 10 mg empagliflozin, taken once daily, until end of treatment. Non responder patients were re-randomised at Week 14 to receive 10 mg empagliflozin, taken once daily, until end of treatment. arm 7: Patients treated with metformin and/or insulin or patients who do not tolerate metformin or treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily until Week 14. Non responder patients were re-randomised at Week 14 to receive 25 mg empagliflozin, taken once daily, until end of treatment.
Interventions: intervention 1: Metformin intervention 2: Insulin intervention 3: Placebo intervention 4: Linagliptin intervention 5: Empagliflozin
Intervention descriptions: intervention 1: At least 1000 mg/day or up to a maximal tolerated dose. intervention 2: Basal or multiple dose injection. intervention 3: 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily. intervention 4: 1 film-coated tablet Linagliptin once daily, until end of treatment. intervention 5: 1 film-coated tablet of Empagliflozin once daily, until end of treatment.

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
Title of trial:
A double-blind, randomised, placebo-controlled, parallel group trial 
to evaluate the efficacy and safety of empagliflozin and linagliptin 
over 26 weeks, with a double-blind active treatment safety extension 
period up to 52 weeks, in children and adolescents with type 2 
diabetes mellitus
Coordinating
Investigator:
Trial site(s):
Multi-centre trial conducted in approximately 15-20 countries
Clinical phase:
III
Rationale:
DINAMOTM (main study)
The trial is planned to be conducted in children and adolescents 
treated with diet and exercise and metformin and/or insulin 
background. Patients not tolerating metformin and treated with diet 
and exercise only have an unmet medical need for oral antidiabetic 
drugs beside metformin and are expected to highly benefit from 
inclusion into this trial.
DINAMOTM Mono:
The TODAY study has shown that the majority of youth with 
T2DM can be effectively treated with metformin monotherapy 
during the first 12 months of the disease. However, the TODAY 
study also demonstrated that metformin monotherapy fails to 
maintain HbA1c < 8.0% in most adolescents during the second year 
of treatment, even in the face of substantial residual endogenous 
insulin. Therefore, studies are warranted to assess whether oral 
antidiabetic medications can either replace metformin as initial 
therapy or whether a patients can switch from metformin 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
monotherapy in case of metformin failure to another oral 
antidiabetic medication instead of initiation of insulin therapy. 
Objective(s):
DINAMOTM (main study)
The objective of this study is to assess the efficacy and safety of an 
empagliflozin dosing regimen and one dose of linagliptin versus 
placebo after 26 weeks of treatment in children and adolescents with 
type 2 diabetes mellitus treated with metformin and/or insulin or 
who are not tolerating metformin. In addition, this study will assess 
long term safety of empagliflozin and linagliptin after 52 weeks of 
treatment.
DINAMOTM Mono (ancillary study)
The objective of this study is to explore the effect of an 
empagliflozin dosing regimen and one dose of linagliptin as 
Monotherapy in children and adolescents with type 2 diabetes 
mellitus.
Methodology:
Multicentre, randomised, double-blind, placebo-controlled and 
parallel group design of 3 treatment arms (placebo, linagliptin 5 mg, 
empagliflozin 10 mg) over 26 weeks with a possible dose increase 
of empagliflozin 10 mg to 25 mg at Week 14 in patients not 
achieving HbA1c < 7.0% at Week 12 and a double-blind active 
treatment safety extension period up to 52 weeks. 
Patients on placebo will be re-randomised at Week 26 to receive 
either linagliptin or one of the empagliflozin doses (empagliflozin 
10 mg or 25 mg). Since patients and investigators will stay blinded, 
investigators will have to perform an IRT call for all patients at 
Week 14 and Week 26 in order to get new trial medication kits 
assigned.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
No. of patients: 
~ 170 (150 patients in DINAMOTM and ~ 20 patients in 
DINAMOTM Mono)
total entered:
DINAMOTM:
At least 150 patients treated with metformin and/or insulin or 
patients who are not tolerating metformin.
DINAMOTM Mono:
Approximately 20 drug-naïve patients or patients who are not on 
active treatment.
each treatment:
DINAMOTM: at least 50 patients
DINAMOTM Mono: approximately 6 patients
Diagnosis :
Type 2 diabetes mellitus
Main criteria
for inclusion:
Main inclusion criteria:
∀
Patients from 10 to 17 years of age (inclusive) at the time of 
randomisation (Visit 2)
∀
Documented diagnosis of T2DM at Visit 1A:
o
DINAMOTM: Documented diagnosis of T2DM for at 
least 8 weeks at Visit 1A.
o
DINAMOTM Mono: Confirmation of T2DM at Visit 
1A.
∀
Insufficient glycaemic control as measured by the central 
laboratory at Visit 1A:
o
DINAMOTM: HbA1c ≥ 6.5% and ≤ 10.5%
o
DINAMOTM Mono: HbA1c ≥ 6.5% and ≤ 9.0%


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
∀
DINAMOTM: Patients treated with diet and exercise plus 
metformin at least 1000 mg/day (or up to a maximal 
tolerated dose) at a stable dose for 8 weeks prior to 
randomisation and/or stable insulin therapy (basal or MDI) 
for 8 weeks prior to randomisation (stable insulin therapy is 
defined as a weekly average variation of the basal insulin 
dose ≤ 0.1 IU/kg over 8 weeks prior to randomisation)
∀
Patients not tolerating metformin and treated with diet and 
exercise only are also eligible for inclusion
∀
DINAMOTM Mono: Drug-naïve patients or patients not on 
active treatment (including discontinuation of metformin due 
to intolerance [or previous discontinuation for other reasons] 
and/or discontinuation of insulin [insulin use must be 8 
weeks or less] at investigator’s discretion) prior to or at Visit 
1A
∀
BMI ≥ 85th percentile for age and sex according to WHO 
references at Visit 1B
∀
Negative for both islet cell antigen auto-antibodies (IA-2) 
and glutamic acid decarboxylase (GAD) auto-antibodies as 
measured by the central laboratory at Visit 1A
∀
Non-fasting serum C-peptide levels ≥ 0.6 ng/ml or > 0.199 
nmol/L as measured by the central laboratory at Visit 1A


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
Main exclusion criteria:
∀
History of acute metabolic decompensation such as diabetic 
ketoacidosis within 8 weeks prior to Visit 1A and up to 
randomisation 
∀
Diagnosis of monogenic diabetes (e.g. MODY)
∀
Impaired renal function defined as estimated Glomerular 
Filtration Rate (eGFR) < 60 ml/min/1.73m² (according to 
Zappitelli formula) as measured by the central laboratory at 
Visit 1A.
Test products:
Linagliptin
Empagliflozin
dose:
Linagliptin, 5 mg daily
Empagliflozin, 10 mg daily
Empagliflozin, 25 mg daily (after Week 14)
mode of 
administration:
p.o.
Comparator products:
Placebo
dose:
Not applicable
mode of 
administration:
p.o.
Duration of treatment:
Two-week placebo run in; 26-week treatment period and 26-week 
safety extension period.
For patients on insulin, the insulin therapy will be kept unchanged 
except for adjustments because of safety reasons.
Endpoints
DINAMOTM:
Primary endpoint:
∀
The primary efficacy endpoint will be the change in HbA1c 
(%) from baseline to the end of 26 weeks


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
Secondary endpoints:
∀
Change in fasting plasma glucose (FPG, mg/dL) from 
baseline to the end of 26 weeks
∀
Change in body weight (kg) from baseline to the end of 26 
weeks
∀
Change in systolic blood pressure (SBP, mmHg) from 
baseline to the end of 26 weeks
∀
Change in diastolic blood pressure (DBP, mmHg) from
baseline to the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 6.5% at the 
end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 7.0% at the 
end of 26 weeks
DINAMOTM Mono:
Primary endpoint:
∀
The primary efficacy endpoint will be the occurrence of 
treatment failure up to or at Week 26 as a binary endpoint, 
defined as meeting at least one of the following criteria:
o
Use of rescue medication at any time up to Week 26
o
Increase from baseline in HbA1c by 0.5% at Week 26
o
Increase from baseline in HbA1c to above 7.0% at 
Week 26 in patients with baseline HbA1c < 7.0%


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
Secondary endpoints:
∀
Time to treatment failure
∀
Change in HbA1c (%) from baseline to the end of 26 weeks
∀
Change in fasting plasma glucose (FPG, mg/dL) from 
baseline to the end of 26 weeks
∀
Change in body weight (kg) from baseline to the end of 26 
weeks
∀
Change in systolic blood pressure (SBP, mmHg) from 
baseline to the end of 26 weeks
∀
Change in diastolic blood pressure (DBP, mmHg) from 
baseline to the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 6.5% at the 
end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 7.0% at the 
end of 26 weeks
Safety criteria:
DINAMOTM and DINAMOTM Mono:
∀
Adverse events after 26 and 52 weeks, including adverse 
events of special interest (see section 5.3.6.1), genital tract 
infections, bone fracture, urinary tract infections, arthralgia, 
bullous pemphigoid, adverse events related to reduced 
intravascular volume, and ketone measurements reported as 
AE
∀
Percentage of patients with reported hypoglycaemia after 26 
and 52 weeks
∀
Vital signs and heart rate after 26 and 52 weeks
∀
Change from baseline in Tanner staging after 26 and 52 
weeks


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
∀
Change from baseline in serum electrolytes, hematology, 
biochemistry, lipids, IGF-1 and IGF-BP3 and markers of 
mineral and bone metabolism after 26 and 52 weeks
∀
Growth velocity (cm/year) after 26 and 52 weeks
Statistical methods:
DINAMOTM:
The primary endpoint will be analysed using an effectiveness
“wash-out” approach.
The “wash-out” approach will be based on an analysis of covariance 
(ANCOVA) model with baseline HbA1c as a continuous covariate, 
and with categorical covariates for treatment and age. The effect of 
linagliptin and of empagliflozin will be compared to placebo at the 
overall alpha level of 5% using the Hochberg method to account for 
multiple testing. The analysis will be based on all randomised
patients who are treated with at least one dose of study drug and 
have a baseline HbA1c value. All available HbA1c measurements 
up to Week 26 will be included regardless of adherence to treatment 
or the use of rescue medication. Patients will be assigned to the 
treatment they were randomised to at the initial randomisation.
After achieving statistically significant results for both comparisons 
in the “wash-out” approach, a secondary family of hypotheses 
comparing the individual empagliflozin doses versus placebo will be 
tested using “ inverse probability weighting” approach. The first 
analysis is the comparison of empagliflozin versus placebo in a 
regimen starting on empagliflozin 10 mg and either having a dose 
increase in patients who are not at glycaemic target at Week 12 to 
empagliflozin 25 mg, or continue with empagliflozin 10 mg who are 
at glycaemic target at Week 12 and the second analysis is the 
comparison of empagliflozin versus placebo using only 
empagliflozin 10 mg regardless whether the patients are responder 
or non-responder at Week 12. These analyses will be hierarchically
tested in a confirmatory setting.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
The secondary endpoint of change in FPG from baseline to the end 
of 26 weeks will be analysed using an ANCOVA model including 
treatment as a fixed classification effect, baseline FPG as a linear 
covariate, and age as a categorical covariate.
The other secondary endpoints will be analysed based on a restricted 
maximum likelihood (REML) approach using mixed effects model 
for repeated measurements (MMRM). The analyses will include the 
fixed categorical effects of treatment, visit, and treatment by visit 
interaction, as well as the categorical covariate age and the 
continuous, fixed covariates of baseline and baseline by visit 
interaction. An unstructured covariance structure will be used to 
model the within-patient measurements. The analysis will be based 
on all randomised patients who are treated with at least one dose of 
study drug and have a baseline HbA1c value. 
The proportion of patients who achieve HbA1c < 7.0% and < 6.5% 
at the end of 26 weeks will be determined per treatment group and 
the risk difference of active treatments versus placebo will be 
determined and assessed by an exact 2-sided 95% confidence 
interval.
DINAMOTM Mono:
The primary endpoint analysis will be a comparison of the treatment 
failure rates of linagliptin 5 mg, pooled empagliflozin and placebo. 
The risk difference of active treatments versus placebo will be 
determined and assessed by an exact 2-sided 90% confidence 
interval based on the method of Chan and Zhang. Patients will be 
assigned to the treatment they were randomised to at the initial 
randomisation.
The secondary endpoint of time to treatment failure will be analysed 
and graphically described by Kaplan-Meier estimates up to the


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Trajenta®
Jardiance®
Name of active ingredient:
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Protocol date:
11 Oct 2017
Trial number:
1218-0091
Revision date:
23 May 2022
planned end of the study. A descriptive Log-rank test will compare 
the linagliptin group and the empagliflozin group versus the placebo 
group individually up to Week 26.
The change in HbA1c from baseline to the end of 26 week will be 
analysed based on a REML approach using MMRM to access the 
effectiveness and efficacy.
The change in HbA1c from baseline to the end of 26 week will also 
be analysed using an ANCOVA model including treatment as a 
fixed classification effect, baseline HbA1c as a linear covariate, and 
age as a categorical covariate. The secondary endpoints of change in
FPG, body weight, SBP and DBP from baseline to the end of 26 
week will be analysed in the same way as DINAMOTM with the 
DINAMOTM Mono data.
The proportion of patients who achieve HbA1c < 7.0% and < 6.5%
at the end of 26 week will be determined per treatment group and 
the risk difference of active treatments versus placebo will be 
determined and assessed by an exact 2-sided 90% confidence 
interval.


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FLOW CHART
Trial Periods
Screening
Placebo 
Run-in1
Randomised treatment period4
Follow-
up
Visit
1A
1B
22
3
4A
4B3
52
6
7
82
EOT5
913
Days calculated from the day of 
first (randomised) treatment
-21 to -14
-14
Day 1
29
85
99
183
211
295
365
386
Weeks from date of first 
randomised treatment 
(**)
4
12
14
26
30
42
52
55
Time window for visits
+7 days1 1
+7 days1 2
none
±7 days
±7 days
±7 days
±7 days
±7 days
±7 days
±7 days
+7 days
Informed consent and assent (*)
X
Demographics
X
Medical history
X
Physical examination
X
X
X
X
X
Tanner staging (modified)6
X
X
X
Vital signs (seated)14
X
X
X
X
X
X
X
X
X
12 lead-ECG
X
X
X
Safety Laboratory tests14
X7
X2
X
X
X2
X
X
X2
X
HbA1c14
X
X
X
X
X
X
X
X
PK blood sampling
X8
X8
Fasting plasma glucose (FPG)
X2
X2
X2


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FLOW CHART (cont.)
Trial Periods
Screening
Placebo 
Run-in1
Randomised treatment period4
Follow-
up
Visit
1A
1B
22
3
4A
4B3
52
6
7
82
EOT5
913
Days calculated from the day of 
first (randomised) treatment
-21 to -14
-14
Day 1
29
85
99
183
211
295
365
386
Weeks from date of first 
randomised treatment 
(**)
4
12
14
26
30
42
52
55
IGF-1, IGF-BP3 and markers of bone 
turnover14
X
X9
X
X9
X
X
DPP-4 activity
X10
Pregnancy test14
X
X
X
X
X
X
X
X
Auto-antibodies for diabetes (IA-2 
and GADA)
X
Serum C-peptide
X
X2
X2
X2
Height
X
X
X
Weight14
X
X
X
X
X
X
X
X
X
BMI
X
X
X
Review of in-/exclusion criteria
X
X
X
Dispense open-label trial drugs
X
Administer open-label trial drugs
X
Randomisation
X
X
X


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FLOW CHART (cont.)
Trial Periods
Screening
Placebo 
Run-in1
Randomised treatment period4
Follow-
up
Visit
1A
1B
22
3
4A
4B3
52
6
7
82
EOT5
913
Days calculated from the day of 
first (randomised) treatment
-21 to -14
-14
Day 1
29
85
99
183
211
295
365
386
Weeks from date of first 
randomised treatment 
(**)
4
12
14
26
30
42
52
55
Dispense double-blind trial drugs16
X
X
X
X
X
X
X
Administer double-blind trial drugs16
X
X
X
X
X
X
X
X
Instructions/reminder on blood ketone 
measurements15
X
X
X
X
X
X
X
Self-blood ketone monitoring11
X
X
X
X
X
X
X
X
X
Instructions/reminder on glucometer 
use15
X
X
X
X
X
X
X
X
Self-blood glucose monitoring 
(SBGM)
X
X
X
X
X
X
X
X
X
X
Adverse events15
X
X
X
X
X
X
X
X
X
X
X
Compliance check15
X
X
X
X
X
X
X
X
Concomitant therapy15
X
X
X
X
X
X
X
X
X
X
X
Completion of patient participation 
(***)
X
Vital status collection12
X
1
This visit can be performed on the same day as Visit 1A.
1.1
Visit 1A can occur -28 days before Visit 2 per allowed out of window.
1.2
Visit 1B can occur -21 days before Visit 2 per allowed out of window.


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2
Visits to be performed in a fasted state (overnight fast for at least 8 hours).
3
This visit could be either on-site visit or ambulatory visit (nurse/health care professional/validated courier to be assigned for delivering the trial medications at home and retrieving the 
previous ones dispensed at Visit 4A) as per the investigator’s decision. In case of ambulatory visit not performed by a site representative, a phone contact by the investigator or a site staff 
representative is required to check any new adverse event or concomitant therapy. 
4
Additional interactions (phone contact, text messaging or emails, as deemed appropriate) with the patient will be performed a day or two after randomised treatment started and then after 
2, 8, 18, 22, 34, 38, 46 and 50 weeks of treatment. Visits 3, 4A, 6, 7, 9 can be done remotely/by telephone/telemedicine under exceptional circumstances due to the Corona Virus Disease-
year 2019 (COVID-19) pandemic. Reasons a remote/telephone/telemedicine visit may be performed may include confirmed or suspected COVID-19 infection or unwillingness to return 
to the investigator site due to concerns of COVID-19 exposure.
5
If a patient discontinues treatment early, an immediate End of Treatment (EOT) visit would be conducted. 
6
For patients with Tanner stage V at Visit 2, further assessment is not required at the subsequent visits.
7
Laboratory tests at Visit 1A include TSH, liver enzymes, alkaline phosphatase, serum creatinine, cystatine C, haemoglobin and haematocrit only in addition to HbA1c and C-peptide and 
do not need to be collected in a fasted state.
8
Blood samples for pharmacokinetic analysis will be collected within 30 minutes prior to drug administration at site (and preferably approximately 24 hours after drug administration on 
the previous day) and 1.5h ± 15 min after drug administration.
9
IGF-1 and IGF-BP3 will not be measured at this Visit.
10
Blood sample for DPP-4 activity measurement will be collected within 30 minutes prior to trial drug administration.
11
Daily blood ketone measurements in the first 4 weeks of treatment and the 4 subsequent weeks after Visit 5; otherwise at least 3 times per week and in case of intercurrent illness/stress or 
if deemed necessary by the investigator. In addition, blood ketone levels will be checked by using the meter at clinic visits.
12
Patients who complete an early End of Treatment visit and do not accept to attend all remaining planned visits will be contacted for vital status collection at Week 55. This can be done by 
phone.
13
Patients who discontinue treatment early should attend Visit 9 at Week 55 in person or by telephone if agreed. At minimum, data on adverse events, concomitant therapies, and vital status 
should be collected at Visit 9 at Week 55. 
14
Vital signs, weight, and local laboratory testing is allowed for Visits 3, 4A, 6, 7, 9 under exceptional circumstances due to the COVID-19 pandemic.
15
Study procedure for Visits 3, 4A, 6, 7, 9  can be done remotely/by telephone/telemedicine/in-home visits under exceptional circumstances due to the COVID-19 pandemic.
16
Shipment/dispensing/administration of study medication to/at the patient’s home is allowed for Visits 3, 4A, 6, 7 under exceptional circumstances due to the COVID-19 pandemic and
requires discussion with the sponsor first using a sponsor-approved shipment provider. Prior to shipment of study medication to the patient’s home, the investigator should first conduct a 
remote/telephone/telemedicine/in-home visit to discuss adverse events, concomitant therapies, glucose/ketone monitoring, and study medication compliance. The review of local 
laboratory results can occur after shipment of study medication but within the protocol defined window of the visit. Reasons for shipment of study medication to a patient’s home may 
include unwillingness to return to the investigator site due to concerns of COVID-19 exposure or suspected COVID-19 infection.
(*)
All patients’ legal representative(s) must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial. Re-consenting may become necessary when 
new relevant information becomes available and should be conducted according to the sponsor’s instructions. Re-consent can be done remotely/by telephone/telemedicine/in-home 
visit under exceptional circumstances due to the COVID-19 pandemic. The initial informed consent and assent at Visit 1A must be done in the clinic.
(**)
Day of Randomisation / Day of first intake of randomised medication.
(***)
Completion of patient participation also needs to be completed if the patient withdraws prematurely following randomisation (see Section 3.3.4).


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART......................................................................................................................12
TABLE OF CONTENTS ......................................................................................................16
ABBREVIATIONS................................................................................................................20
1.
INTRODUCTION...............................................................................................23
1.1
MEDICAL BACKGROUND.............................................................................23
1.2
DRUG PROFILE................................................................................................24
1.2.1
Empagliflozin......................................................................................................24
1.2.2
Linagliptin...........................................................................................................26
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....30
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................30
2.2
TRIAL OBJECTIVES........................................................................................31
2.3
BENEFIT - RISK ASSESSMENT.....................................................................31
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................36
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................36
3.1.1
Administrative structure of the trial ................................................................38
3.1.1.1
Clinical Event Committee – cardiovascular events ..............................................39
3.1.1.2
Clinical Event Committee – DKA ........................................................................40
3.1.1.3
Clinical Event Committee – Hepatic external adjudication..................................40
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) .....................................................................................40
3.3
SELECTION OF TRIAL POPULATION .......................................................42
3.3.1
Main diagnosis for trial entry............................................................................43
3.3.2
Inclusion criteria.................................................................................................43
3.3.3
Exclusion criteria................................................................................................44
3.3.4
Removal of patients from therapy or assessments ..........................................46
3.3.4.1
Withdrawal from trial treatment ...........................................................................46
3.3.4.2
Withdrawal of consent for trial participation........................................................47
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................47
4.
TREATMENTS...................................................................................................48
4.1
INVESTIGATIONAL TREATMENTS ...........................................................48
4.1.1
Identity of the Investigational Medicinal Products.........................................48
4.1.2
Selection of doses in the trial .............................................................................50
4.1.3
Method of assigning patients to treatment groups..........................................50
4.1.4
Drug assignment and administration of doses for each patient.....................51
4.1.5
Blinding and procedures for unblinding..........................................................53
4.1.5.1
Blinding.................................................................................................................53
4.1.5.2
Unblinding and breaking the code ........................................................................54
4.1.6
Packaging, labelling, and re-supply..................................................................54


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4.1.7
Storage conditions ..............................................................................................54
4.1.8
Drug accountability............................................................................................54
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS................................................................................................55
4.2.1
Other treatments and emergency procedures .................................................55
4.2.2
Restrictions..........................................................................................................57
4.2.2.1
Restrictions regarding concomitant treatment ......................................................57
4.2.2.2
Restrictions on diet and life style..........................................................................58
4.2.2.3
Restrictions regarding women of childbearing potential ......................................58
4.3
TREATMENT COMPLIANCE........................................................................59
5.
VARIABLES AND THEIR ASSESSMENT ....................................................60
5.1
TRIAL ENDPOINTS..........................................................................................60
5.1.1
Primary Endpoint(s) ..........................................................................................60
5.1.2
Secondary Endpoint(s).......................................................................................60
5.1.3
Further Endpoint(s) ...........................................................................................60
5.1.3.2
Further endpoint to assess safety ..........................................................................61
5.2
ASSESSMENT OF EFFICACY........................................................................62
5.2.1
HbA1c and fasting plasma glucose (FPG)........................................................62
5.2.2
Body weight.........................................................................................................62
5.2.3
Systolic/diastolic blood pressure (SBP and DBP) and heart rate (vital signs)
..............................................................................................................................63
5.3
ASSESSMENT OF SAFETY.............................................................................63
5.3.1
Physical examination..........................................................................................63
5.3.2
Vital signs............................................................................................................63
5.3.3
Safety laboratory parameters............................................................................63
5.3.4
Electrocardiogram..............................................................................................67
5.3.5
Other safety parameters ....................................................................................67
5.3.5.1
Height and Body Mass Index (BMI).....................................................................67
5.3.5.2
Self-blood glucose monitoring..............................................................................67
5.3.5.3
Self-blood ketone monitoring ...............................................................................68
5.3.5.4
C-peptide...............................................................................................................69
5.3.5.5
Tanner staging (modified).....................................................................................69
5.3.5.6
Criteria for hypoglycaemic event..........................................................................70
5.3.6
Assessment of adverse events ............................................................................70
5.3.6.1
Definitions of AEs ................................................................................................70
5.3.6.2
Adverse event collection and reporting ................................................................74
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ..................................................................................76
5.4.1
Assessment of Pharmacokinetics ......................................................................76
5.4.2
Methods of sample collection.............................................................................77
5.4.2.1
Plasma sampling for pharmacokinetic analysis ....................................................77


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5.4.4
Pharmacokinetic – Pharmacodynamic Relationship......................................78
5.5
ASSESSMENT OF BIOMARKER(S) ..............................................................78
5.5.1
Biobanking ..........................................................................................................78
5.5.2
DPP-4 activity .....................................................................................................78
5.6
OTHER ASSESSMENTS...................................................................................79
5.6.1
Auto-antibodies for diabetes..............................................................................79
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................79
6.
INVESTIGATIONAL PLAN.............................................................................80
6.1
VISIT SCHEDULE.............................................................................................80
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................80
6.2.1
Screening and run-in period(s) .........................................................................80
6.2.2
Treatment period(s) ...........................................................................................81
6.2.3
Follow Up Period and Trial Completion..........................................................82
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................84
7.1
STATISTICAL DESIGN - MODEL.................................................................84
7.1.1
DINAMO.............................................................................................................84
7.1.2
DINAMO Mono ..................................................................................................84
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................84
7.2.1
DINAMO.............................................................................................................84
7.2.1.1
Primary family of hypotheses ...............................................................................84
7.2.1.2
Secondary family of hypotheses ...........................................................................85
7.2.2
DINAMO Mono ..................................................................................................85
7.3
PLANNED ANALYSES.....................................................................................85
7.3.1
Primary endpoint analyses ................................................................................87
7.3.1.1
DINAMO ..............................................................................................................87
7.3.1.1.1
Analysis of the primary family of hypotheses ......................................................87
7.3.1.1.2
Analysis of the secondary family of hypotheses...................................................89
7.3.1.2
DINAMO Mono....................................................................................................89
7.3.2
Secondary endpoint analyses.............................................................................90
7.3.2.1
DINAMO ..............................................................................................................90
7.3.2.2
DINAMO Mono....................................................................................................91


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7.3.6
Safety analyses....................................................................................................95
7.3.7
Pharmacokinetic and pharmacodynamics analyses........................................96
7.4
INTERIM ANALYSES ......................................................................................96
7.5
HANDLING OF MISSING DATA ...................................................................96
7.6
RANDOMISATION ...........................................................................................96
7.7
DETERMINATION OF SAMPLE SIZE .........................................................97
7.7.1
DINAMO.............................................................................................................97
7.7.2
DINAMO Mono..................................................................................................99
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY................................................................................101
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT.........................................................................................................101
8.2
DATA QUALITY ASSURANCE ....................................................................102
8.3
RECORDS.........................................................................................................102
8.3.1
Source documents.............................................................................................102
8.3.2
Direct access to source data and documents..................................................103
8.3.3
Storage period of records.................................................................................104
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................104
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......104
8.5.1
Collection, storage and future use of biological samples and corresponding 
data ....................................................................................................................104
8.6
TRIAL MILESTONES.....................................................................................105
9.
REFERENCES..................................................................................................106
9.1
PUBLISHED REFERENCES..........................................................................106
9.2
UNPUBLISHED REFERENCES....................................................................109
10.
APPENDICES...................................................................................................112
10.1
TANNER STAGING MODIFIED ..................................................................112
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................113
11.1
GLOBAL AMENDMENT 1 ............................................................................113
11.2
GLOBAL AMENDMENT 2 ............................................................................126
11.3
GLOBAL AMENDMENT 3 ............................................................................132
11.4
GLOBAL AMENDMENT 4 – SENT TO FDA ONLY .................................134
11.5
GLOBAL AMENDMENT 5 ............................................................................139
11.6
GLOBAL AMENDMENT 6 ............................................................................140


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine transaminase
AMP
Auxiliary Medicinal Product
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
AUC
Area under the Curve
BI
Boehringer Ingelheim
MI
Body Mass Index
BOCF
Baseline Observation Carried Forward
BP
Blood Pressure
CA
Competent Authority
CEC
CGM
Clinical Event Committee
Continuous Glucose Monitoring
CI
Confidence Interval
COVID-19
COronaVIrus Disease– year 2019
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Clinical Research Organisation
CTM
CTP
Clinical Trial Manager
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database lock
DBP
Diastolic Blood Pressure
DCCT
Diabetes Control and Complications Trial
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
DPP-4
Dipeptidyl Peptidase-4
ECG
Electrocardiogram
eDC
electronic Data Capturing
ePRO
Electronic Patient Reported Outcome
EDTA
Ethylene Diamine Tetracetic Acid
EMA
EoT
EudraCT
European Medicines Agency
End of Treatment
European Clinical Trials Database
FC
Flow Chart
FDA
Food and Drug Administration
FPG
Fasting Plasma Glucose
FUP
Follow-up
GADA
Glutamic Acid Decarboxylase Auto-antibodies
GCP
Good Clinical Practice
GFR or eGFR
Glomerular Filtration Rate or estimated Glomerular Filtration Rate
GLP-1
Glucagon-like Peptide-1


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GMP
Good Manufacturing Practice
HbA1c
Glycated Hemoglobin
IA-2
Islet cell Antigen auto-antibodies
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IFCC
International Federation of Clinical Chemistry
IGF-1
Insulin-like Growth Factor-1
IGF-BP3
Insulin-like Growth Factor-Binding Protein 3
IMP
Investigational Medicinal Product
IPD(s)
Important Protocol Deviation(s)
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LC-MS/MS
Liquid Chromatography Tandem Mass Spectrometry
LDL
Low Density Lipoprotein
MACE
Major Adverse Cardiac Events
MAR
Missing At Random
MCMC-MI
Markov Chain Monte Carlo - Multiple Imputation
MDI
Multiple Dose Injection
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Multiple Imputation
mITT
modified Intention-to-Treat
MMRM
Mixed Model for Repeated Measurements
MNAR
Missing Not At Random
NGSP
National Glycohemoglobin Standardisation Program
NIMP
Non Investigational Medicinal Product
OPU
Operative Unit
PD
Pharmacodynamics
PDC
Pediatric Diabetes Consortium
PDCO
PIP
PK
Paediatric Committee
Paediatric Investigational Plan
Pharmacokinetics
PMR
Post-Marketing Requirement
p.o.
per os (oral)
PPARγ
Peroxisome Proliferator-Activated Receptors gamma
PPS
Per Protocol Set
q.d.
quaque die (once a day)
REP
Residual effect period
REML
Restricted Maximum Likelihood
SAE
Serious Adverse Event
SARS
SBGM
Severe Acute Respiratory Syndrome
Self-Blood Glucose Monitoring
SBKM
Self-blood Ketone Monitoring
SBP
Systolic Blood Pressure
SDS
Standard Deviation Score
SGLT-2
SI
Sodium-Glucose Co-Transporter 2
International System of Units


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SLC-5
Sodium-Glucose Co-transport 5
SLR-MI
Sequential Linear Regression – Multiple Imputation
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 Diabetes Mellitus
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UACR
Urine Albumin Creatinine Ratio
UGE
Urinary Glucose Excretion
ULN
Upper Limit of Normal
UTI
Urinary Tract Infection
WBC
White Blood Cells
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Diabetes is an in prevalence increasing disease with an estimated 415 million affected people 
worldwide. In high-income countries, up to 91% of adults with the disease have type 2 
diabetes mellitus (T2DM) [R16-4703]. Complications associated with chronic
hyperglycaemia are currently one of the most frequent causes of adult-onset loss of vision, 
renal failure, and amputation in the industrialized world. Type 2 diabetes mellitus is 
associated with macrovascular complications with a 2- to 4-fold increase in cardiovascular 
disease risk. The high frequency of complications leads to a significant reduction of life 
expectancy.
T2DM in children and adolescents (youth-onset T2DM) has also become an increasingly 
important public health concern throughout the world with unique characteristics and 
demographics in many countries. Youth-onset T2DM occurs most often during the second 
decade of life and coincides with the peak of physiologic pubertal insulin resistance. T2DM
in children and adolescents occurs in all races but at a much greater prevalence in those of 
non-White European descent, e.g. those of Black African descent, native North American, 
Hispanic (especially Mexican)-American, Asian, South Asian, and Native Pacific islanders. 
In the USA and Europe, nearly all youth with T2DM have a body mass index (BMI) above 
the 85th percentile for age and sex. [P15-01571]. In the USA and Europe, youth-onset T2DM
is predominately found in populations characterised by low socioeconomic and educational 
status whereas in emerging countries like China and India, more affluent children are more 
likely to develop T2DM than poorer children [P15-01571].
Prevention and reversal of disease progression with diet and exercise is presently the 
preferred therapeutic approach but is rarely sufficient. Only 10% of children and adolescents 
with T2DM achieve glycaemic goals through diet and exercise alone. Although several 
antidiabetic compounds have been developed to improve glucose control in adults, metformin 
is the only oral agent recommended and approved as the initial pharmacologic treatment for 
T2DM in youth [P12-09397]. However, metformin is not suitable for all patients, as 
insufficient efficacy over time has been observed in several paediatric studies [R07-4400; 
R10-0796]. Insulin can also be used to lower plasma glucose levels but is often unacceptable 
to patients in the paediatric population due to the injectable route of delivery and the higher 
rates of hypoglycaemia and weight gain. Therefore there is a medical need for new 
antidiabetic drugs for children and adolescents for whom lifestyle change is not sufficient.
Empagliflozin is a reversible, highly potent (IC50 1.3 nM) and selective competitive inhibitor 
of sodium-glucose co-transporter 2 (SGLT-2), a member of a larger group of sodium 
substrate co-transporters, the sodium-glucose co-transport 5 (SLC5) gene family [R05-0939].
Under normoglycaemia, glucose is completely reabsorbed by SGLTs in the kidney, whereas 
the reuptake capacity of the kidney is saturated at plasma glucose concentrations higher than 
approximately 10-11 mmol/L, resulting in glycosuria. This threshold concentration can be 
decreased by SGLT-2 inhibition [c01678844-17]; an approximately 5000-fold selectivity 
over human SGLT-1 (IC50 6278 nM), responsible for glucose absorption in the gut, was 
calculated for empagliflozin [U06-1742].


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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 [c018916941-04].
Both compounds are approved for use as adjunct to diet and exercise as monotherapy and 
combined with other antidiabetic drugs including insulin. Empagliflozin and linagliptin are 
expected to show efficacy in terms of glucose control when used alone, as adjunct to diet and 
exercise and in combination with metformin and/or insulin in children and adolescents with 
T2DM.
1.2
DRUG PROFILE
1.2.1
Empagliflozin
Empagliflozin is an orally available, potent, and selective inhibitor of the SGLT-2. Its 
selective inhibition reduces renal reabsorption of glucose and promotes increased urinary
glucose excretion (UGE) resulting in reduction of blood glucose levels.
Empagliflozin for the treatment of T2DM is approved in over 100 countries including the 
European Union and the USA where it is marketed under the brand name Jardiance®.
Non-clinical assessment of safety
Empagliflozin has been extensively tested as part of the adult T2DM program as described in 
the Investigator’s Brochure [c01678844-17].
Clinical pharmacokinetics (PK), pharmacodynamics and safety in children and adolescents
The primary objective of the paediatric empagliflozin trial 1245.87 [c09087100] was to 
assess the pharmacokinetics of a single dose of empagliflozin (5 mg, 10 mg, and 25 mg) in 
paediatric patients with T2DM. The secondary objective of this study was to investigate the 
pharmacodynamics of a single dose of empagliflozin in the same population. 
Twenty seven patients with T2DM who were in the age range of 10 to less than 18 years and 
who had insufficient glycaemic control despite treatment with diet and exercise and/or stable 
metformin and/or stable basal or multiple dose injection (MDI) insulin therapy were
randomised and treated in this paediatric PK single dose trial. Following single dose 
administration of 5 mg or 10 mg or 25 mg, empagliflozin was rapidly absorbed in paediatric 
patients with T2DM with median values ranging from 1.25 h to 1.78 h. Empagliflozin 
exposure (both with respect to AUC and Cmax) increased with increasing dose. Mean terminal 
half-life (t1/2) was 7 to 8 h for all dose groups. The pharmacokinetic parameters of 10 mg and 
25 mg empagliflozin in paediatric patients with T2DM were compared with the results from a 
previous trial in adults [U09-1970] and with the results from population pharmacokinetic 
modelling in adult patients with T2DM [c02090424]. The pharmacokinetic exposure was 
generally comparable between paediatric and adult patients with T2DM, with a slightly lower 
exposure (with respect to AUC and Cmax) in paediatric patients in the 10 mg dose group 
compared with the adult patients. For the 2 doses (10 mg and 25 mg), median tmax and mean 
t1/2 were similar in adult and paediatric populations. The slightly lower exposure of paediatric 


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patients in the 10 mg dose group compared with adult patients may be related to the higher 
body weight of the paediatric population [c09087100].
In the paediatric patients included in this trial, a dose-dependent increase of UGE in the 24 h 
following empagliflozin administration was observed, with mean (standard error (SE)) 
changes from baseline (adjusted for baseline UGE and baseline FPG) of 53.1 (10.2) g/24 h in 
the 5 mg dose group, 73.0 (10.1) g/24 h in the 10 mg dose group, and 87.4 (9.4) g/24 h in the 
25 mg dose group. The effect on UGE in paediatric patients was comparable with the 
increase seen in a previous trial with adult patients with T2DM [U09-1970].
An exposure-response model, linking AUC0-24 to UGE at baseline and to UGE during the first 
24 h following empagliflozin administration (UGE0-24,1), was developed based on data from 3 
clinical trials in adult patients with T2DM [U09-1271; U09-1970; U10-2326] and the data 
from the 1245.87 trial with paediatric patients. After accounting for all significant covariates, 
adult and paediatric patients with T2DM had similar exposure-response relationships, 
following a single oral dose of empagliflozin.
All 3 single doses of empagliflozin were well tolerated in the 1245.87 trial. No new safety 
signals were observed. The safety results of this trial were consistent with those observed in 
previous empagliflozin trials in adults [c01678844-17].
Clinical efficacy and safety in adults
Empagliflozin has been studied as part of a global development program with more than 
20000 patients with T2DM treated in clinical studies of which more than 13000 were treated 
with empagliflozin, either alone or in combination with metformin, a sulphonylurea, a 
PPARγ agonist, dipeptidyl peptidase-4 inhibitors, or insulin.
The Phase III studies in T2DM showed that treatment with empagliflozin 10 mg or 25 mg 
once daily for up to 24 weeks results in a reduction of HbA1c up to 0.85%, body weight up to 
2.2 kg and systolic blood pressure (SBP) up to 4.8 mmHg compared with placebo. This was 
consistently observed with empagliflozin as monotherapy, add on to metformin, to the 
combination of metformin and sulphonylurea, to pioglitazone with or without metformin, and
to basal insulin with metformin and/or sulphonylurea. One Phase III study up to 204 weeks in 
T2DM supports the sustained effect of empagliflozin.
In clinical studies, empagliflozin was well tolerated in both healthy volunteers and patients 
with T2DM up to maximal treatment duration of 208 weeks in completed studies. The 
frequency of overall adverse events (AEs), AEs leading to discontinuation and serious AE 
(SAEs) were comparable to that with placebo. There was no significant increase in frequency 
of hypoglycaemia with empagliflozin compared to placebo except when used in combination 
with a sulphonylurea or basal insulin. There was an increase in frequency of genital 
infections with the use of empagliflozin. Empagliflozin treatment also increased urination and 
thirst. There was a small increase in total cholesterol, low-density lipoprotein (LDL) 
cholesterol and high-density lipoprotein (HDL) cholesterol and no significant changes of 
LDL/HDL cholesterol ratio and in triglycerides. In addition, increases in haematocrit, 
haemoglobin and red blood cell were observed with empagliflozin.  No clinically relevant 
changes in electrolytes were observed with empagliflozin. 


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The safety profile of empagliflozin in patients with renal impairment and decreased eGFR 
down to 15 mL/min/1.73m2 was consistent with that reported in patients with normal renal 
function; there is no experience in patients with endstage renal disease and in patients on 
dialysis. In the EMPA-REG OUTCOME® study, the overall safety profile of empagliflozin 
was comparable to the known safety profile of this agent.
In a phase III randomised, double-blind cardiovascular outcome trial (the EMPA-REG 
OUTCOME® study [c01678844-17]), empagliflozin was shown to be superior in reducing 
the primary endpoint 3 point Major Adverse Cardiac Events (MACE), a composite of 
cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke compared to 
placebo on top of standard of care in patient with T2DM and established cardiovascular 
disease. Empagliflozin treatment showed a nominally significant reduction in cardiovascular 
death with no significant change in non-fatal MI or non-fatal stroke. An improved overall 
survival driven by a reduction in cardiovascular death was also observed. Empagliflozin 
reduced the risk of hospitalization for heart failure and the composite of cardiovascular death 
or hospitalization for heart failure compared with placebo. The risk of new or worsening 
nephropathy (including onset of macroalbuminuria, doubling of serum creatinine and 
initiation of renal replacement therapy (i.e. haemodialysis)) was reduced in empagliflozin 
group compared to placebo. Empagliflozin showed a higher occurrence of sustained normo-
or microalbuminuria in patients with baseline macroalbuminuria compared with placebo. 
After an initial drop in eGFR, treatment with empagliflozin slowed progression of renal 
disease and eGFR returned to baseline 4 weeks after drug discontinuation while the placebo 
group showed a gradual decline in eGFR during the course of the study with no further 
change during the 4-week follow-up.
For a more detailed description of the empagliflozin profile, please refer to the respective 
current Investigator’s Brochure (IB) [c01678844-17].
1.2.2
Linagliptin
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 [c018916941-04].
Linagliptin for the treatment of T2DM is approved in over 90 countries including the 
European Union (Trajenta®), the USA (Tradjenta®), and Japan (Trazenta®).
Non-clinical assessment of safety
Linagliptin has been extensively tested as part of the adult T2DM program as described in the 
Investigator’s Brochure [c018916941-04].
Clinical pharmacokinetics, pharmacodynamics, efficacy and safety in children and 
adolescents
The primary objective of trial 1218.56 [c09060697] was to identify the appropriate dose of 
linagliptin in paediatric patients with T2DM. Two doses of linagliptin (1 mg and 5 mg) were 
compared with placebo. A protocol-defined interim analysis was performed, which showed 
superiority of the linagliptin 5 mg dose over the linagliptin 1 mg dose regarding DPP-4 
inhibition at trough at steady state and a plasma DPP-4 inhibition by linagliptin 1 mg of less 


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than 80%. These results demonstrated inferior DPP-4 inhibition of linagliptin 1 mg and 
allowed early termination of the trial.
Thirty-eight treated patients between 10 and 17 years were randomised and included in the 
interim analysis. At final database lock (DBL), 39 patients had been randomised to and 
treated with placebo (15 patients), linagliptin 1 mg (10 patients) or linagliptin 5 mg (14 
patients). Patients had a documented diagnosis of T2DM obtained at least 3 months prior to 
randomisation and had insufficient glycaemic control despite treatment with diet and exercise 
and/or metformin with or without concomitant stable basal insulin therapy. 
The primary endpoint of the final analysis was the change from baseline in HbA1c (%) after 
12 weeks of treatment. Because of the early termination of the study, the trial had limited 
statistical power. After 12 weeks of treatment, the adjusted mean treatment difference 
between linagliptin 5 mg and placebo was −0.63 (95% CI: −1.50, 0.23; p = 0.1447). The 
adjusted mean treatment difference between linagliptin 1 mg and placebo was −0.48 (95% 
CI: −1.47, 0.51; p = 0.3295). As expected because of the limited power of the trial, a 
statistically significant difference to placebo could be demonstrated neither for the linagliptin 
1 mg dose nor for the linagliptin 5 mg dose. The reduction of −0.63 with linagliptin 5 mg is 
considered clinically meaningful. The results were in accordance with data from adult 
patients after 12 weeks of treatment with linagliptin 5 mg. The median change from baseline 
in HbA1c (%) was +0.50 in the placebo group, -0.05 in the linagliptin 1 mg group, and -0.30 
in the linagliptin 5 mg group. The difference to placebo was -0.80 in the linagliptin 5 mg 
group compared with -0.55 in the linagliptin 1 mg group. The results were consistent with 
data from adult patients after 12 weeks of treatment with linagliptin 5 mg. In the linagliptin 5 
mg group, a reduction in HbA1c compared with baseline was seen over the entire randomised 
treatment period. In contrast, HbA1c had returned almost to baseline in the linagliptin 1 mg 
group and had increased beyond baseline HbA1c in the placebo group at Week 12. The 
percentage of patients with a relative efficacy response (HbA1c lowering by at least 0.5%) 
was greater in the linagliptin 5 mg group (30.8%) than in the linagliptin 1 mg group (20.0%) 
or placebo group (14.3%). Furthermore, the proportion of patients who had a baseline HbA1c 
≥7% and reached target HbA1c <7% (absolute efficacy response) was greater with linagliptin 
5 mg (36.4%) than with placebo (18.2%), whereas it was 10.0% with linagliptin 1 mg. A 
target HbA1c <7% is more difficult to achieve for patients with a higher baseline HbA1c 
value than for patients with a lower baseline HbA1c value.
For this trial, DPP-4 inhibition was defined as key secondary endpoint. Baseline DPP-4 
activity was similar across treatment groups. DPP-4 inhibition at trough at steady-state was 
clearly more pronounced for the linagliptin 5 mg dose group than for the 1 mg dose group, 
with median values of 79% and 38%, respectively. Median DPP-4 inhibition by linagliptin 5 
mg in the paediatric patients of trial 1218.56 was similar to the median DPP-4 inhibition 
obtained with linagliptin 5 mg in adults after 12 weeks of treatment (study 1218.6 [U08-
1056]: 85.0%; study 1218.5 [U08-3761]: 82.5%).
Fasting plasma glucose (FPG) was analysed as secondary endpoint. The placebo-corrected
adjusted mean change from baseline in the linagliptin 5 mg group was −34.2 mg/dL (95% CI: 
−77.7, 9.3; p = 0.1189). The placebo-corrected adjusted mean change from baseline in the 
linagliptin 1 mg group was considerably lower with −5.6 mg/dL (95% CI: −55.5, 44.4; p = 


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0.8216). The reduction in FPG with linagliptin 5 mg was similar to that in adult patients 
treated with linagliptin 5 mg. The median change from baseline in FPG was +19.5 mg/dL 
with placebo, +29.5 mg/dL with linagliptin 1 mg, and -5.0 mg/dL with linagliptin 5 mg. The 
placebo-corrected median FPG change from baseline at Week 12 was -24.5 mg/dL in the 
linagliptin 5 mg group and +10.0 mg/dL in the linagliptin 1 mg group. The placebo-corrected 
median FPG change from baseline of -24.5 mg/dL with linagliptin 5 mg is considered 
clinically meaningful and was comparable with that in adults receiving linagliptin 5 mg over 
12 weeks [U08-1056].
Systemic exposure was assessed based on linagliptin plasma levels. Linagliptin trough levels
in the 5 mg dose group were higher than in the 1 mg dose group, with geometric mean 
(gMean) values of 7.42 and 3.80 nmol/L, respectively.
Linagliptin was well tolerated. No new safety signals were detected in paediatric patients who
received linagliptin. The safety profile of linagliptin in paediatric patients was consistent with
that in adults [c018916941-04].
Clinical efficacy and safety in adults
Treatment with linagliptin 5 mg q.d. 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.
The treatment difference to placebo in the HbA1c change from baseline after 24 weeks of 
treatment was -0.69% (95% CI: -0.85, -0.32) for linagliptin 5 mg monotherapy (trial 
1218.16), -0.64% (95% CI: -0.78, -0.50) for linagliptin 5 mg with metformin background
therapy (trial 1218.17) and -0.65% (95% CI: -0.74, -0.55) for linagliptin 5 mg with basal 
insulin background therapy (trial 1218.36) [c018916941-04].
In the phase III studies the overall incidence of AEs, drug related AEs, AEs of severe
intensity, AEs leading to discontinuation, and serious adverse events (SAEs) were very
similar across studies, with linagliptin being mostly comparable to placebo. 
For monotherapy with linagliptin, nasopharyngitis, cough, hypersensitivity, lipase increase
and pancreatitis have been identified as adverse drug reactions. In addition, based on post-
marketing data, angioedema, urticaria, rash, mouth ulceration and bullous pemphigoid, are 
other ADRs listed for linagliptin.
Studies in patients on metformin background showed that the percentages of patients with 
adverse events were comparable between treatments (54.3% placebo plus metformin, 49.0% 
linagliptin 5 mg plus metformin). The number of patients with SAEs was low in both 
treatment groups (2.5% placebo plus metformin, 3.0% linagliptin 5 mg plus metformin).
The combination of linagliptin and insulin has been tested in clinical trials in different 
populations. Studies in patients on insulin background (with or without other oral antidiabetic 
drugs) had the highest reported frequency of investigator reported hypoglycaemic adverse 
events in both treatment arms, with comparable rates between the placebo group and 


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linagliptin. 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, c018916941-04].
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, 
c018916941-04].
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.
For a more detailed description of the linagliptin profile please refer to the current 
Investigator’s Brochure (IB) [c018916941-04].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Empagliflozin (10 mg and 25 mg) and linagliptin (5 mg) are approved for the treatment of 
adult patients with T2DM.
The paediatric T2DM prevalence is growing and positively correlated with obesity. 
Prevention and reversal of disease progression with diet and exercise is presently the 
preferred initial therapy when hyperglycaemia is not considered as severe. However, lifestyle 
modifications are difficult to implement and require intensive follow-up to be effective. 
Overall, less than 10% of paediatric patients diagnosed with T2DM can achieve glycaemic 
targets (HbA1c < 7.0% and FPG < 126 mg/dl) by following lifestyle interventions alone 
[R07-4402]. As a result, pharmacotherapy is often required and although there are many 
agents available to improve the metabolic abnormalities, there are little data concerning their 
use in children and adolescents.
Based on the results from two dose-finding studies in paediatric patients with T2DM with 
each of the compounds [c09087100 ; c09060697], this phase III trial is planned to confirm 
the efficacy and safety of empagliflozin and linagliptin in children and adolescents with 
T2DM.
There is a medical need for new antidiabetic drugs for children and adolescents for whom 
lifestyle change is not sufficient and as add-on to metformin and/or insulin therapy. In 
addition, this trial is being conducted to satisfy both the empagliflozin and linagliptin 
Paediatric Investigation Plans (PIPs) approved by the European Medicines Agency as well as 
the Post-Marketing Requirements (PMRs) agreed with FDA.
Rationale for background therapies
The trial is planned to be conducted in children and adolescents treated with diet and exercise 
and metformin and/or insulin background, reflecting the current standard of care. Patients not 
tolerating metformin (as defined in Section 3.3.2) and treated with diet and exercise only will 
also be eligible. This subgroup of pediatric patients has a high unmet medical need for oral 
antidiabetic drugs beside metformin and is expected to highly benefit from inclusion into this 
trial. Recent data from the Pediatric Diabetes Consortium (PDC) showed that 35% of children 
and adolescents with T2DM were treated with metformin alone, 19% with insulin alone, 31% 
with both metformin and insulin, 13% with lifestyle modification alone, and only 3% were 
treated with other glucose-lowering medications with/without metformin or insulin. Overall, 
51% of included patients were on insulin therapy [R16-2240].
Metformin is approved and largely used in youth but insufficient efficacy in terms of durable 
glycaemic control has been confirmed in a recent paediatric study [R07-4397]. Moreover, 
metformin is not suitable for all patients, as insufficient efficacy over time has been observed 
in several paediatric studies [R07-4400; R10-0796]. The alternative option for paediatric 
patients is the administration of insulin by injection as the only other approved medication for 


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treating their T2DM. Insulin is often unacceptable in the paediatric population due to the 
subcutaneous route of delivery and the higher rates of hypoglycaemia and weight gain.
DINAMOTM Mono
The TODAY study has shown that the majority of youth with T2D can be effectively treated 
with metformin monotherapy during the first 12 months of the disease [R12-3961]. However, 
the TODAY study also demonstrated that metformin monotherapy fails to maintain HbA1c <
8.0% in most adolescents during the second year of treatment [R18-2686], even in the face of 
substantial residual endogenous insulin [R18-2687]. Therefore, studies are warranted to 
assess whether oral antidiabetic medications can either replace metformin as initial therapy or 
whether a patients can switch from metformin monotherapy in case of metformin failure to 
another oral antidiabetic medication instead of initiation of insulin therapy. 
Therefore, in order to assess the efficacy and safety of empagliflozin and linagliptin as 
monotherapy, the ancillary study DINAMOTM Mono will be conducted in children and 
adolescents who are drug-naïve patients or patients not on active treatment (including 
discontinuation of metformin due to intolerance [or previous discontinuation for other 
reasons] and/or discontinuation of insulin [insulin use must be 8 weeks or less] at 
investigator’s discretion) prior to or at Visit 1A.
2.2
TRIAL OBJECTIVES
DINAMOTM (main study)
The objective of this study is to assess the efficacy and safety of an empagliflozin dosing 
regimen and one dose of linagliptin versus placebo after 26 weeks of treatment in children 
and adolescents with type 2 diabetes mellitus treated with metformin and/or insulin or who 
are not tolerating metformin.
DINAMOTM Mono (ancillary study)
The objective of this study is to explore the effect of an empagliflozin dosing regimen and 
one dose of linagliptin as Monotherapy in children and adolescents with type 2 diabetes 
mellitus.
In addition, the trial will assess the long term safety of empagliflozin and linagliptin after 52 
weeks of treatment.
2.3
BENEFIT - RISK ASSESSMENT
The clinical development programs in adults showed a favourable benefit-risk ratio for the 
use of linagliptin and empagliflozin in patients with T2DM. Besides, the linagliptin paediatric 
dose-finding trial as well as the empagliflozin paediatric PK single dose trial allowed 
identifying the appropriate dose(s) of each compounds for the paediatric population. Since
the paediatric population is considered as a vulnerable population, this combined phase III 
trial was therefore designed to conduct one confirmatory trial to assess efficacy and the long 
term safety of empagliflozin and linagliptin in children and adolescents with T2DM.


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According to the drug assignment planned in this trial, 67% of the patients will be treated 
with either linagliptin or empagliflozin up to 52 weeks. These patients might benefit from 
positive glycaemic effects since they will receive an investigational medication that has 
already demonstrated favourable HbA1c and fasting plasma glucose changes in adults. 
Patients initially randomised to placebo treatment will continue treatment with diet and 
exercise alone or with metformin and/or insulin, reflecting the current standard of care. Due 
to the study procedures, such as regular visits, it is expected that patients will also benefit 
during the placebo treatment phase. In case of deterioration of glycaemic control, criteria for 
initiation of rescue therapy are in place (see Section 4.2.1). However, after 26 weeks of 
treatment, patients who were initially randomised to placebo will be re-randomised to either 
linagliptin 5 mg or empagliflozin 10 mg or 25 mg, to ensure a minimum of 26 weeks active 
treatment for all patients included into this trial. 
Patients in the placebo group may have a higher probability of treatment failure, i.e. of 
increased FPG and HbA1c values. However, the trial eligibility criteria (see Section 3.3.2 and 
Section 3.3.3) will ensure that unstable patients in terms of glycaemic control are excluded 
from being randomised. Following randomisation, appropriate criteria (based on HbA1c and 
blood ketone levels) have been defined for the initiation of rescue medication (please refer to 
Section 4.2.1 for further details). In addition, the patient safety will be monitored and a 
number of discontinuation criteria have been defined (see Section 3.3.4 for further details). 
The trial design with a two-week placebo run-in phase is a well-established design for T2DM
trials [P10-14001]. In this trial, daily monitoring of blood glucose will be performed by 
patients with a self-blood glucose monitoring (SBGM) device. Thus the risk of the two-week 
placebo treatment will be minimal.
Blood volumes drawn for safety analysis and efficacy endpoints analysis have been reduced 
since this trial is conducted in the paediatric population. Furthermore, to minimise pain and 
distress, local anaesthetic product will be offered to all patients as pain relief for 
venepuncture. Attempts to draw blood will be limited to three. Children with needle phobia 
will be excluded from the study.
Due to the mechanism of action of empagliflozin and linagliptin, the risk of hypoglycaemic 
episodes is considered to be very low. Add-on of empagliflozin and linagliptin to a stable 
dose of insulin/metformin therapy is deemed acceptable as there are no relevant drug-drug 
interactions and no potentiated effects are expected. In a study of adult patients receiving 
linagliptin as add-on therapy to a stable dose of insulin, no significant difference was 
observed in the incidence of hypoglycaemia between the linagliptin and placebo treated 
groups. Hypoglycaemia was seen more frequently compared to placebo in adult patients 
treated with linagliptin on background of metformin+sulfonylurea. Also, the risk of severe 
hypoglycaemic episodes is considered to be low for empagliflozin (<1%) and similar for 
empagliflozin and placebo as monotherapy and as add-on to metformin. Compared to placebo 
when empagliflozin is given as add-on to insulin the number of major hypoglycaemic events 
may be increased.
However, in order to closely monitor hypoglycaemic events, all patients will be required to 
perform regular blood glucose measurements (self-blood glucose monitoring – SBGM) 


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throughout the duration of the trial. Minimum requirements have been defined in the protocol 
(See Section 5.3.5.2 for further details).
For linagliptin, pancreatitis is an important but uncommon risk. Other important known risks 
of linagliptin include hypersensitivity and angioedema/urticaria. 
Cases of diabetic ketoacidosis (DKA), a serious life-threatening condition requiring urgent 
hospitalization, have been reported in patients treated with SGLT-2 inhibitors, including 
empagliflozin. It needs to be taken into account that, due to the insulin independent mode of 
action, empagliflozin may potentially modify the clinical presentation of DKA. In some of 
reported cases, the presentation of the condition was atypical with only moderately increased 
blood glucose values, below 14 mmol/L (250 mg/dL). The risk of DKA must be considered 
in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, 
excessive thirst, difficulty in breathing, confusion, unusual fatigue or sleepiness. Patients 
should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood 
glucose level. In patients treated with empagliflozin consider monitoring for ketoacidosis and 
temporarily discontinuing empagliflozin in clinical situations known to predispose to 
ketoacidosis (i.e. prolonged fasting due to acute illness or surgery). In these situations, 
consider monitoring of ketones, even if empagliflozin treatment has been interrupted.
Patients receiving empagliflozin may be at risk to underestimate their need for insulin if 
blood sugar levels are within individual target ranges or only slightly elevated. Insulin 
deficiency might lead to ketoacidosis which could be life-threatening if not recognized and 
appropriately treated. All patients receiving insulin will be made aware of this risk and be 
instructed not to reduce their insulin dose below investigator recommendations. 
In addition to blood glucose monitoring, patients will be equipped with an electronic device 
to determine their ketone concentration (i.e. a blood glucose monitoring device/meter that is 
also capable of measuring blood ketones) (for further details see Section 5.3.5.3). Patients 
will be reminded how to determine ketones in case of any symptoms of DKA, e.g. nausea, 
vomiting, abdominal pain etc. They will be instructed to do this irrespective of the glucose 
value in the event of DKA symptoms occurring. More frequent ketone testing (e.g. once 
daily) will be recommended during the first 4 weeks of the treatment period and during 4 
weeks after Visit 5; this will allow patients and investigators to understand baseline ketosis 
rates and compare them, as appropriate, to the incidence of ketosis following the initiation of 
study medication. As stated above, a meter will be provided to the patient for this purpose; as 
an additional safeguard, the meter will also be used to check ketone levels at most clinic 
visits (see Flow Chart). Patients will be reminded of the interpretation of ketone values 
measured by the meter, and on appropriate action to be taken in the event of increased ketone 
levels (see Section 5.3.5.3). In addition, patients with insulin background therapy will be 
reminded about insulin adjustment during “sick days” and about the importance of keeping 
themselves hydrated.
Investigators should also differentiate deteriorating ketosis/DKA from any mild to moderate
increase of ketones which may be seen due to the mechanism of action of empagliflozin,
especially in the fasted state (e.g. in the morning). 


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Cases of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare, but serious and 
life-threatening necrotizing infection, have been reported in patients with diabetes mellitus 
treated with SGLT-2 inhibitors, including empagliflozin. Patients who present with 
suggestive symptoms are instructed to seek medical attention immediately and should be 
evaluated for necrotizing fasciitis. 
Patients will be carefully selected for the trial in line with the eligibility criteria, to ensure, in
the investigator’s judgment, that they have a good understanding of their disease and how to
manage it. They should also be selected in terms of their ability to be compliant with the
demands of the trial.
In the embryo-foetal and fertility studies in rats and rabbits, no effects on early embryonic 
development, mating, male and female fertility, and bearing live young were observed up to a 
linagliptin dose of 240 mg/kg and up to a dose of 300 mg/kg with empagliflozin. Therefore, 
female patients who have reached menarche (i.e. those who have had any vaginal bleeding, 
however scant or irregular) and are of child-bearing potential will be included in this study 
provided that they are using adequate contraceptive methods. In addition, regular pregnancy 
tests will be performed throughout their trial participation.
As with all drugs, the potential for hypersensitivity and allergic reactions have to be taken 
into consideration when empagliflozin or linagliptin is administered. Other risks to the 
patients are the risks inherent to any investigational medicinal product used in a clinical trial 
setting, such as unexpected adverse clinical or laboratory events. 
Hence, for sites taking part in this trial, the investigator and designated site personnel must be 
trained in paediatric emergencies. Patient discomfort will be minimised as far as possible, and 
all sites selected to take part in this trial will be knowledgeable and skilled in dealing with the 
paediatric population and its age-appropriate needs. Furthermore, sites will be assessed for a 
child-friendly infrastructure (e.g. familiar environment, appropriate physical setting, 
parent(s)/legal guardian allowed to accompany patient during procedures).
Individual patient safety/risks will be minimised by close observation throughout the trial, 
and by monitoring the patients for adverse events both clinically and by laboratory testing.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.3.6.1.
To continue the assessment of the long-term safety of empagliflozin and linagliptin, an 
adjudication of cardiovascular, DKA and certain hepatic events will be performed. The 
progress of the trial will also be assessed at regular intervals by an independent Data 
Monitoring Committee (DMC). For further details please refer to Section 3.1.1.
Given the safety profile derived from toxicology studies, the good tolerability seen in 
previous studies in adult and paediatric patients and the monitoring activities including the 
blood glucose and ketone monitoring described above, the sponsor is of the opinion that the 


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risks for participating patients are minimised and justified when compared to the potential 
benefits of a successful development of empagliflozin and linagliptin for children and 
adolescents with T2DM.
COVID-19 Pandemic
Due to the COVID-19 pandemic, the enrollment of new patients and the initiation of new 
sites were temporarily put on hold on 17 March 2020 and resumed on a per country level in 
April 2020. Potential risks with regard to COVID-19 exposure and treatment for patients 
already enrolled in the trial have been evaluated and described in a specific Benefit-Risk 
assessment document [c32537051-02 ; c32537611-02].
Based on the pharmacological mechanism of empagliflozin and linagliptin and review of data 
derived from clinical and post-marketing databases, there is no indication that these 
investigational drugs could increase the risk of severe viral infections. Moreover, no relevant 
Drug-Drug Interactions between empagliflozin and linagliptin and the medications currently 
used for treatment of COVID-19 are expected based on the information in their product 
labels, nor have they been described in the literature. Please refer to the respective current 
Investigator Brochures (IB). 
As with any acute illness, a Severe Acute Respiratory Syndrome (SARS) CoV-2 infection 
may increase the risk of DKA. The risk of ketoacidosis in case of acute illness during 
empagliflozin intake is adequately addressed in the IB. Consistent with the guidance on 
illness-related treatment discontinuation, the study drug should be discontinued in case of 
severe COVID-19 disease and re-introduced once the patient has recovered, as described in 
Section 3.3.4.1.
Patients with diabetes are in general at higher risk of infections and might be at higher risk 
for severe illness from COVID-19. The majority of patients in the DINAMO trial are 
randomized to active treatment due to the trial design and would, therefore, be expected to be 
in a better blood glucose control. Nevertheless, in order to minimize the risk of exposure to 
COVID-19, physical visits should be avoided depending on the COVID-19 pandemic status 
of the site. The use of phone visits and local laboratory services for safety and efficacy 
parameters measurements should be considered when necessary. Furthermore, study drug 
shipment to patient’s homes should also be considered. Investigators should complete study 
procedures according to the protocol to the extent possible. If protocol-mandated visits, safety 
laboratory schedules, and/or study drug availability cannot be accomplished, patients should 
temporarily discontinue study medication.
Based on the above considerations, the Benefit-Risk assessment for trial participants remains 
positive.




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increasing the dose of empagliflozin is beneficial to paediatric patients with T2DM. Since 
patients and investigators will stay blinded, investigators will have to perform an IRT call for 
all patients at Week 14 in order to get new trial medication kits assigned (see Section 4.1.4
for further details). The re-randomisation will be stratified by age at baseline (< 15 years; ≥ 
15 and < 18 years) as described in Section 7.6.
Re-randomisation at Week 26
After the 26-week treatment period, all patients will enter a double-blind safety extension 
period up to 52 weeks. Patients who received placebo during the 26-week treatment period 
will be re-randomised to receive either linagliptin 5 mg or empagliflozin 10 mg or 
empagliflozin 25 mg. Since patients and investigators will stay blinded, investigators will 
have to perform an IRT call for all patients at Week 26 in order to get new trial medication 
kits assigned (see Section 4.1.4 for further details). The re-randomisation will be stratified by 
age at baseline (< 15 years; ≥ 15 and < 18 years) as described in Section 7.6.
After the 52-week extension period, all patients will enter a 3-week follow-up period during 
which they will not be treated with study medication. The patient’s participation is concluded 
when he has undergone the last planned visit (i.e. Trial Completion Visit); last-patient-last-
visit-primary-endpoint will occur when all patients have completed 26 weeks of treatment. 
The end of the trial is defined as “last patient out” (i.e. last Trial Completion Visit completed 
by the last patient in the trial). 
Except for patients who would discontinue the trial treatment for safety reasons, every effort 
should be made to re-introduce trial treatment after a temporary trial drug discontinuation. 
For the analysis of this trial it is very important that assessments for each planned visit are 
still performed in accordance with the Flow Chart even if patients discontinue trial treatment.
Patients who discontinue study drug prematurely should continue study visits until study end. 
Study assessments may be omitted if a patient is willing to return to the pre-defined study 
visits, with exception of blood drawing for safety lab tests, HbA1c and FPG, body weight, 
blood pressure and collection of adverse events and concomitant therapy. Refer to Section 
6.2.3 for premature discontinuation of treatment guidance.
Every attempt will be made by the investigator to ensure patients continue participating in the 
study during interruptions in trial drug intake and after permanent discontinuation of trial 
drug. The modified Intention-to-Treat (mITT) analysis requires that all trial patients be 
followed until study end even if the trial drug was temporarily interrupted or discontinued.
For a graphical presentation of the DINAMOTM trial and DINAMOTM Mono trial, see
Figure 3.1: 2 below.




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and retention rates in order to make recommendations about actions that could improve these 
rates. The SC is comprised of university- and sponsor-based scientists with clinical and 
methodological expertise. Details on the composition of the committee, its procedures and 
interactions are provided in a separate SC Charter.
A data monitoring committee (DMC), which is independent of the sponsor, will be 
established to assess the progress of the clinical trial, including an unblinded safety review at 
specified intervals, and to recommend to the sponsor whether to continue, modify, or stop the 
trial. The tasks and responsibilities of the DMC will be specified in a separate DMC charter. 
The DMC will maintain written records of all its meetings.
Boehringer Ingelheim has appointed a Clinical Trial Leader, responsible for coordinating all 
required activities, in order to:
∀
manage the trial in accordance with applicable regulations and internal SOPs,
∀
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
∀
ensure appropriate training and information of local clinical trial managers (CTMs), 
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 IRT vendor will be used in this trial. Details will be 
provided in IRT Manual and Central Laboratory Manual, available in ISF.
3.1.1.1
Clinical Event Committee – cardiovascular events
An independent external committee (Clinical Event Committee, [CEC]) will be established to 
adjudicate centrally and in a blinded fashion events suspect of stroke, myocardial ischemia
(including myocardial infarction), cardiovascular death and other relevant events (e.g. 
hospitalisation for heart failure) based on the FDA guideline [R09-2151]. Such adjudication 
is performed in all Phase 2 and 3 clinical trials with empagliflozin and linagliptin. The CEC 
will evaluate whether pre-specified criteria for adjudication endpoints are met.
For any events that qualify for adjudication, study sites will be asked to provide clinical 
documentation such as electrocardiograms (ECGs), laboratory values, angiography, 
echocardiography reports, CT and/or MRI scans, discharge summaries, and autopsy reports to 
support the external event adjudication.


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The tasks and responsibilities of the CEC will be specified in a charter. The CEC will 
maintain the adjudication results in writing.
3.1.1.2
Clinical Event Committee – DKA 
An independent external committee (CEC) will be established to adjudicate centrally and in a 
blinded fashion events suspect of DKA. The CEC will evaluate whether pre-specified criteria 
for adjudication endpoints are met.
For any events that qualify for adjudication, study sites will be asked to provide clinical 
documentation such as laboratory values, discharge summaries etc. to support the external 
event adjudication.
The tasks and responsibilities of the CEC will be specified in a charter. The CEC will 
maintain the adjudication results in writing.
3.1.1.3
Clinical Event Committee – Hepatic external adjudication
Certain hepatic events will be adjudicated by external independent experts for severity and 
causal relationship with the trial medication in a blinded fashion. The events which will be 
reviewed will be defined in a charter. Events may either be defined by abnormal laboratory 
values and/or relevant adverse events or both. For example, assessments will be made for 
events of hepatic injury events, including liver enzyme elevations.
For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including laboratory values, histological analysis, results of 
ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other 
physicians. All evaluations will be performed in a blinded fashion. 
The tasks and responsibilities of the CEC will be specified in a charter. The CEC will 
maintain the adjudication results in writing.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial will investigate the efficacy and safety of an empagliflozin dosing regimen and one 
dose of linagliptin on top of standard treatment in children and adolescents with T2DM.
HbA1c as the primary endpoint has been demonstrated to be a reflection of the glycaemic 
control over the preceding 12 weeks and maintenance data over a period of approximately 6 
months are requested by the different regulatory agencies. Therefore the primary endpoint for 
DINAMOTM is the change in HbA1c from baseline to the end of 26 weeks of randomised 
treatment. 
For DINAMOTM Mono, the endpoint “occurrence of treatment failure” is selected to evaluate 
whether an early initial monotherapy is beneficial in children and adolescents with T2DM. A 
major component of the endpoint is “use of rescue medication”. Virtually all patients in 
DINAMOTM Mono who will not achieve the glycemic goals defined in guidelines will 


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require rescue medication and will be classified as failure. Therefore, the study will inform 
whether the initial monotherapy can bring patients to glycemic target. Comparison with a 
placebo group is needed to better understand the failure rate of an “untreated population” in 
order to bring the results for empagliflozin and linagliptin into perspective. A similar 
endpoint was used in the TODAY study [R12-3961]. Since strict rescue criteria are defined 
for DINAMOTM Mono, the commonly used endpoint “HbA1c change from baseline” would 
not be informative. In the placebo group a high rate of rescue medication is expected, i.e. 
most patients randomised to placebo will benefit from metformin or insulin therapy. Since 
metformin and insulin are very effective especially in newly diagnosed patients, it  is 
expected to observe no difference in HbA1c after 26 weeks in patients randomised to 
empagliflozin or linagliptin and placebo (on rescue treatment).
The randomised period is planned for 52 weeks in order to collect one year safety and 
efficacy data for empagliflozin and linagliptin in patients with T2DM aged 10-17 years
(inclusive).
For the linagliptin treatment arm, one dose (i.e. linagliptin 5 mg) will be evaluated for safety 
over 52 weeks. For empagliflozin, two doses (i.e. empagliflozin 10 mg and 25 mg) will be 
evaluated as well as whether increasing the dose of empagliflozin 10 mg to 25 mg is 
beneficial to paediatric patients. So that, patients initially randomised to the empagliflozin 10 
mg group who will not achieve an HbA1c target < 7.0% at Week 12 will be re-randomised at 
Week 14 to receive either empagliflozin 10 mg or empagliflozin 25 mg. 
The rationale for the empagliflozin and linagliptin dose selection is described in section 4.1.2.
Patients who were randomised to placebo will be re-randomised after 26 weeks to either 
linagliptin 5 mg or empagliflozin 10 mg or empagliflozin 25 mg. This reduces the duration of 
the placebo period in this trial to the requested minimum (26 weeks) and will ensure that all 
patients will receive active treatment for at least 26 weeks. Moreover, this will generate 
additional safety and efficacy data over 26 weeks of treatment for both empagliflozin doses 
and one linagliptin dose.
The design of this trial includes a 2-week open-label placebo run-in period; the intention of 
this period is to familiarise the patient with the procedures for study medication intake prior 
to randomisation, giving an opportunity for assessing the patient ability to be compliant with 
the study medication intake. This is of particular importance within the paediatric population 
where adherence to medical regimens is often less than desired. The run-in period will 
therefore ensure that only patients who are likely to be compliant are exposed to the study 
drugs.
The 3-week follow-up period is considered to be sufficient, as previous studies with 
empagliflozin and linagliptin have shown that its’ PD effect only extends to about 3 and 7
days after the last dose. Furthermore, it will allow for the assessment of reversibility of 
unexpected long-term side effects.


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3.3
SELECTION OF TRIAL POPULATION
A sufficient number of patients with T2DM will be screened to ensure the randomisation of 
at least 150 and approximately 20 patients from approximately 110 trial sites in DINAMOTM
and DINAMOTM Mono respectively. The planned number of patients randomized at each site 
is at least one patient in DINAMOTM and at least one patient in those sites that participate in 
DINAMOTM Mono.
If enrolment is delayed, additional sites may be recruited. 
At least 30% and not more than 70% of patients should be below 15 year of age. In addition
for DINAMOTM only, between 30% and 70% of randomised patients must be girls.
Screening of patients for this trial is competitive across all countries within the trial, i.e. 
screening for the trial will stop at all sites when the desired number of patients to be 
randomised in this trial is reached. Investigators will be notified when sufficient patients have 
been randomised and when screening is complete and will not be allowed to recruit additional 
patients for the study. Patients who have completed Visit 1A 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 in this Clinical Trial Protocol.
Re-screening and/or re-testing (of assessments) are permitted.
Whilst the information provided below is not an exhaustive list, it provides some guidance as 
to when such re-screening and/or re-testing would be considered appropriate.
Re-testing:
Re-testing for eligibility criteria is only to be performed for a laboratory test that has been 
cancelled by the central laboratory (e.g. for specimen not received or received beyond 
stability) or for a laboratory result thought to be a spurious result based on previously 
available laboratory results. The re-test should be carried out as soon as possible so the 
laboratory test results will be received within the next planned visit windows in order to 
avoid protocol window deviations.
Re-screening:
For patients failing screening due to modifiable exclusion criteria, like HbA1c level too low 
or too high, unrecognized hypothyroidism (high TSH), re-screening may be considered up to 
5 times with at least 8 weeks between screening visits.
The patient should be declared as a screening failure in the eCRF and IRT with their original 
patient number.
Upon re-screening, a new patient number will be assigned by the IRT. The old patient 
number, with which the patient failed screening, will be recorded in the eCRF.
The patients’ legal representative(s) must be re-consented using the current approved version 
of the information sheet and consent form. The patient should give again his/her assent.


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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.
DINAMOTM Mono
Patients could be eligible for DINAMOTM Mono in case of HbA1c ≥ 6.5% and < 9.0% and 
metformin discontinuation due to intolerance [or previous discontinuation for other reasons] 
and/or discontinuation of insulin [insulin use must be 8 weeks or less] at investigator’s 
discretion prior to or at Visit 1A.
3.3.1
Main diagnosis for trial entry
Only patients aged 10 to 17 years (inclusive) who meet the following criteria at Visit 1A will 
be screened for suitability for the study. 
∀
In DINAMO™, patients with documented T2DM for at least 8 weeks
∀
In DINAMO™ Mono, patients with confirmation of T2DM
Inclusion will be based upon a complete medical history including physical examination, 
vital signs, 12-lead ECG and clinical laboratory tests.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Patients aged 10 to 17 years (inclusive) at the time of randomisation (Visit 2)
2. Male and female patients
3. Women of childbearing potential (WOCBP)1 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’s legal representative information sheet 
as well as in Section 4.2.2.3.
4. Signed and dated written informed consent provided by the patient’s parent(s) (or legal 
guardian) and patient’s assent in accordance with ICH-GCP and local legislation prior to 
admission to the trial (informed assent will be sought according to the patient’s age, level 
of maturity, competence and capacity)
5. Documented diagnosis of T2DM at Visit 1A:
a.
DINAMOTM: Documented diagnosis of T2DM for at least 8 weeks at Visit 1A
b. DINAMOTM Mono: Confirmation of T2DM at Visit 1A
                                                
1 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.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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6. Insufficient glycaemic control as measured by the central laboratory at Visit 1A:
a.
DINAMOTM: HbA1c ≥ 6.5% and ≤ 10.5%
b. DINAMOTM Mono: HbA1c ≥ 6.5% and ≤ 9.0%
7. a. DINAMOTM: Patients treated with 
-
diet and exercise plus metformin at least 1000 mg/day (or up to a 
maximal tolerated dose) at a stable dose for 8 weeks prior to Visit 2 or not 
tolerating metformin (defined as patients who were on metformin treatment 
for at least 1 week and had to discontinue metformin due to metformin-related 
side effects as assessed by the investigator) 
AND/OR 
-
diet and exercise plus stable basal or MDI insulin therapy, defined as a 
weekly average variation of the basal insulin dose ≤ 0.1 IU/kg over 8 weeks 
prior to Visit 2        
b. DINAMOTM Mono: Drug-naïve patients or patients not on active treatment (including 
discontinuation of metformin due to intolerance [or previous discontinuation for other 
reasons] and/or discontinuation of insulin [insulin use must be 8 weeks or less] at 
investigator’s discretion) prior to or at Visit 1A)
8. BMI ≥ 85th percentile for age and sex according to WHO references at Visit 1B
9. Non-fasting serum C-peptide levels ≥ 0.6 ng/ml or > 0.199 nmol/L as measured by the 
central laboratory at Visit 1A
10. Compliance with trial medication intake must be between 75% and 125% during the 
open-label placebo run-in period
11. Negative for both islet cell antigen auto-antibodies (IA-2) and glutamic acid 
decarboxylase (GAD) auto-antibodies as measured by the central laboratory at Visit 1A
3.3.3
Exclusion criteria
1. Any history of acute metabolic decompensation such as diabetic ketoacidosis within 8 
weeks prior to Visit 1A and up to randomisation (mild to moderate polyuria at the time of 
randomisation is acceptable)
2. Diagnosis of monogenic diabetes (e.g. MODY)
3. History of pancreatitis
4. Diagnosis of metabolic bone disease
5. Gastrointestinal disorders that might interfere with study drug absorption according to 
investigator assessment
6. Secondary obesity as part of a syndrome (e.g. Prader-Willi syndrome)


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7. Any antidiabetic medication (with the exception of metformin and/or insulin background 
therapy for DINAMOTM) within 8 weeks prior to Visit 1A and until Visit 2
8. Treatment with weight reduction medications (including anti-obesity drugs) within 3 
months prior to Visit 1A and until Visit 2
9. History of weight-loss surgery or current aggressive diet regimen (according to 
investigator assessment) at Visit 1A and until Visit 2
10. Treatment with systemic corticosteroids for > 1 week within 4 weeks prior to Visit 1A 
and up to Visit 2. Inhaled or topical use of corticosteroids (e.g. for asthma/chronic 
obstructive pulmonary disease) is acceptable.
11. Change in dose of thyroid hormones within 6 weeks prior to Visit 1A or planned change 
or initiation of such therapy before Visit 2
12. Known hypersensitivity or allergy to the investigational products or their excipients
13. Impaired renal function defined as estimated Glomerular Filtration Rate (eGFR) < 60 
ml/min/1.73m² (according to Zappitelli formula) as measured by the central laboratory at 
Visit 1A
14. Indication of liver disease defined by serum level of either alanine transaminase (ALT), 
aspartate transaminase (AST) or alkaline phosphatase above 3 fold upper limit of normal 
(ULN) at Visit 1A as measured by the central laboratory at Visit 1A
15. History of belonephobia (needle phobia)
16. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to Visit 1A, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix
17. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. 
malaria, babesiosis, haemolytic anaemia)
18. Any other acute or chronic medical or psychiatric condition or laboratory abnormality 
that, based on investigator’s judgement, would jeopardize patient safety during trial 
participation or would affect the study outcome
19. Medical contraindications to metformin according to the local label (for patient on 
metformin background therapy)
20. Patient not able or cannot be supported by his/her parent(s) or legal guardian to 
understand and comply with study requirements based on investigator’s judgement
21. Previous randomisation in this trial


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22. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s)
23. Chronic alcohol or drug abuse within 3 months prior to Visit 1A or any condition that, in 
the investigator’s opinion, makes them an unreliable trial patient or unlikely to complete 
the trial
24. Female patients who are pregnant, nursing, or who plan to become pregnant in the trial
3.3.4
Removal of patients from therapy or assessments
Patients may be withdrawn from trial treatment or from the trial as a whole (“withdrawal of 
consent”) with very different implications, please see sections 3.3.4.1 and 3.3.4.2 below.
Every effort should be made to keep the randomised patients in the trial, if possible on 
treatment or at least to collect important trial data.
Measures to control the withdrawal rate include but is not limited to careful patient selection, 
appropriate explanation of the trial requirements and procedures prior to randomisation, 
investigator’s training to clearly explain the consequences of consent withdrawal, regular 
oversight of retention rates by the SC and the sponsor-based clinical monitors, reimbursement 
of travel costs, offers for snack or breakfast during clinic visits, option for an ambulatory visit 
as detailed in the Flow Chart, telephone calls to the patient or the patient’s family. 
The decision to withdraw from trial treatment or to withdraw consent as well as the reason 
must be documented in the patient files and CRF.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:
∀
The patient or parent(s) (or legal guardian) wants to withdraw from trial treatment, 
without the need to justify the decision.
∀
The patient needs to start a restricted concomitant therapy that, in the investigator’s 
opinion, poses a safety risk if taken as add-on to the trial medication (see section 
4.2.2.1).
∀
The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or 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.
∀
Pancreatitis, bullous pemphigoid, ketoacidosis, arthralgia, or Fournier’s gangrene is 
suspected.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and all subsequent planned visits up to the follow up visit as outlined in 
section 6.2.3.


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For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the eCRF. These data will be included in the trial database and reported.
Except for patients who would discontinue the trial treatment for safety reasons, every effort 
should be made to re-introduce trial treatment after a temporary trial drug discontinuation. 
For the analysis of this trial it is very important that assessments for each planned visit are 
still performed in accordance with the Flow Chart even if patients discontinue trial treatment. 
Patients who discontinue treatment prematurely will be followed up until the end of the 
study, unless they withdraw their consent for this to happen. All assessments related to the 
primary and secondary endpoints (i.e., blood drawing for HbA1c and FPG, body weight, 
blood pressure and collection of adverse events and concomitant therapy) and safety lab tests 
still have to be performed as if the patient had remained on trial treatment.
Patients who withdraw from the trial treatment after randomisation will not be replaced.
However, one exception is patients who discontinue due to the COVID-19 pandemic (i.e. 
missed visits, SARS CoV-2 infection, withdrawal of consent) may be replaced based on 
blinded assessment of the number of premature treatment or trial discontinuation.
3.3.4.2
Withdrawal of consent for trial participation
Patients or parent(s) (or legal guardian) may withdraw their consent/assent for trial 
participation at any time without the need to justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow-up on safety cannot occur.
If a patient or parent(s) (or legal guardian) wants to withdraw consent/assent, the investigator 
should explain the difference between treatment withdrawal and withdrawal of consent for 
trial participation and explain the scientific relevance of their data even if he/she discontinue 
the trial treatment.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
∀
Failure to meet expected enrolment goals overall or at a particular trial site
∀
Emergence of any efficacy/safety information invalidating the earlier positive 
benefit-risk assessment that could significantly affect the continuation of the trial
∀
Violation of GCP, the trial protocol, or the contract impairing 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
4.1
INVESTIGATIONAL TREATMENTS
The study medication will be provided by BI.
Metformin and insulin as background therapies and rescue medications are not considered as 
part of the clinical trial supplies and therefore will not be provided.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are as shown below.
Table 4.1.1: 1
Test product 1
Substance:
Linagliptin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
5 mg
Posology
Once daily
Route of administration:
oral
Table 4.1.1: 2
Test product 2
Substance:
Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
10 mg
Posology
Once daily
Route of administration:
Oral


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Table 4.1.1: 3
Test product 3
Substance:
Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
25 mg
Posology
Once daily
Route of administration:
oral
Table 4.1.1: 4
Reference product 1
Substance:
Placebo matching Linagliptin 5 mg
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
-
Posology
Once daily
Route of administration:
oral
Table 4.1.1: 5
Reference product 2
Substance:
Placebo matching Empagliflozin 10 mg
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
-
Posology
Once daily
Route of administration:
oral


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Table 4.1.1: 6
Reference product 3
Substance:
Placebo matching Empagliflozin 25 mg
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
-
Posology
Once daily
Route of administration:
oral
4.1.2
Selection of doses in the trial
Empagliflozin will be administered as 10 mg and 25 mg tablets once daily, linagliptin as 5 
mg tablet once daily. These doses were selected based on the results from previous dose 
finding studies in paediatric patients with T2DM (see below) and are the same doses that are 
approved in adult patients with T2DM. 
Empagliflozin
The empagliflozin paediatric PK/PD trial 1245.87 [c09087100] showed that, following a 
single oral dose of empagliflozin, adult and paediatric patients with T2DM had similar 
exposure-response relationships after accounting for significant covariates. Therefore, the 
paediatric dose finding trial results support the use of empagliflozin 10 mg and 25 mg in this 
phase III trial (the same doses that are approved/used for adult patients with T2DM). See 
sections 1.2 and 3.2 for further details.
Linagliptin
The linagliptin paediatric dose finding trial 1218.56 [c09060697] interim analysis showed 
superiority of the linagliptin 5 mg dose over the linagliptin 1 mg dose regarding DPP-4 
inhibition at trough at steady state. Besides, the results were consistent with clinical efficacy 
and safety data for linagliptin in adults. As a consequence, the paediatric dose finding trial 
findings support the evaluation of the long-term safety and efficacy of linagliptin 5 mg in this 
phase III trial in children and adolescents (the same dose that is approved/used in adult 
patients with T2DM). See sections 1.2 and 3.2 for further details.
4.1.3
Method of assigning patients to treatment groups
During Visit 2, eligible patients will be randomised to receive either linagliptin 5 mg or 
empagliflozin 10 mg or placebo in a 1:1:1 ratio according to a randomisation plan. The 
assignment will occur in a blinded fashion via Interactive Response Technology (IRT).


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At Visit 4B, patients assigned to the empagliflozin group who do not achieve an HbA1c value 
< 7% at Week 12 will be re-randomised to receive either empagliflozin 10 mg or 
empagliflozin 25 mg in a 1:1 ratio. The assignment will occur in a blinded fashion via 
Interactive Response Technology (IRT).
At Visit 5, patients assigned to the placebo group will be re-randomised to receive either 
linagliptin 5 mg or empagliflozin 10 mg or empagliflozin 25 mg in a 1:1:1 ratio according to 
a randomisation plan. The assignment will occur in a blinded fashion via IRT.
To ensure double-blind conduct, investigators will have to perform an IRT call for all patients 
at Week 14 (Visit 4B) and Week 26 (Visit 5).
Access to the codes will be controlled and documented. Technical and statistical features of 
the process of treatment allocation are described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each patient
The treatment groups and the drug assignment for each patient are outlined in Table 4.1.4:1
below. 
Table 4.1.4: 1
Drug assignment and dispensation per treatment group and visits
Placebo Run-in
Randomised treatment
(Double-blind, double dummy)
Dispensation 
visits
V1B
V2, V3, V4A
V4B
V5, V6, V7
Treatment 
duration
2 weeks
14 weeks
12 weeks
26 weeks
Linagliptin 5 
mg group
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Empagliflozin 
10 mg group
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg 
Placebo matching 
empagliflozin 25 
mg
Placebo matching 
linagliptin 5 mg
Empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Placebo matching 
linagliptin 5 mg
Empagliflozin 10 mg
Placebo matching 
empagliflozin 25 
mg
Placebo matching 
linagliptin 5 mg
Empagliflozin 10 mg
Placebo matching 
empagliflozin 25 
mg


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Table 4.1.4: 1
Drug assignment and dispensation per treatment group and visits 
(cont.)
Placebo Run-in
Randomised treatment
(Double-blind, double dummy)
Empagliflozin 
10 mg group 
– Patients not 
achieving 
glycaemic 
target at week 
12 
Placebo matching 
linagliptin 5 mg 
Placebo matching 
empagliflozin 10 mg 
Placebo matching 
empagliflozin 25 mg
Placebo matching 
linagliptin 5 mg
Empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg 
Empagliflozin 25 mg
OR
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg 
Empagliflozin 25 mg
OR
Placebo matching 
linagliptin 5 mg
Empagliflozin 10 mg 
Placebo matching 
empagliflozin 25 mg
Placebo matching 
linagliptin 5 mg
Empagliflozin 10 mg 
Placebo matching 
empagliflozin 25 mg
Placebo group
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
Linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
OR
Placebo matching 
Linagliptin 5 mg
Empagliflozin 10 mg
Placebo matching 
empagliflozin 25 mg
OR
Placebo matching 
linagliptin 5 mg
Placebo matching 
empagliflozin 10 mg
Empagliflozin 25 mg
All eligible patients will be assigned an open-label placebo run-in kit by the IRT at Visit 1B. 
As mentioned in Table 4.1.4:1 during the placebo run-in period, patients will take 3 placebo 
tablets once daily in the morning. 
Patients who qualify for randomisation will be randomly assigned by the IRT to one of the 
treatment groups listed above. Patients will take 3 tablets once daily in the morning up to 52 
weeks as detailed in Table 4.1.4: 1 Dispensation of kits by the IRT will begin at Visit 2 for 
the randomised period (double-blind, double-dummy). Dispensations will occur on 7 
occasions over 52 weeks.


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Patients initially randomised to empagliflozin 10 mg and who do not achieve an HbA1c value 
< 7.0% at Week 12 will be re-randomised by the IRT to receive either empagliflozin 10 mg 
or 25 mg at Visit 4B.
For patients randomised in the placebo group, they will be re-randomised by the IRT to 
receive either linagliptin 5 mg or one of the empagliflozin doses at Visit 5.
Since patients and investigators will stay blinded, investigators will have to perform an IRT 
call for all patients at Week 14 and Week 26 in order to get new trial medication kits 
assigned.
From the start of the placebo run-in period (Visit 1B), patients should be instructed to take 
their trial medication once daily with approximately 150 ml of water. To ensure a dose 
interval of 24 hours, the study medication should be taken at the same time every day in the 
morning. If a dose is missed by more than 12 hours, that dose should be skipped and the next 
dose should be taken as scheduled. No double doses should be taken and dose reductions are 
not permitted. Study medication can be taken with or without food.
Patients should be instructed not to take their trial medication as well as metformin 
background therapy in the morning of visit days as they will be dosed whilst in the clinic. For 
visits with PK assessments (as detailed in the Flow Chart), patients who fail to do so should 
have the visit rescheduled as soon as possible, ideally on the following day. Insulin 
administration (basal and/or bolus) in the morning of clinic visits will be left to the discretion 
of the patient and/or investigator and may be dependent on planned meal intake etc. For visits 
to be performed in a fasted state, visits should be scheduled in the morning, at approximately 
the same time of day (e.g. 7am to 11am). 
Specific requirement before the visits with PK assessments (Visit 5 and 8): 
Patients will be asked to record the actual administration date and time of the last 3 doses of 
trial medication before Visit 5 and 8 on the patient diary. If a dose was missed, the date/time 
field should be left empty. These data will be transferred to the eCRF. Patients (or their 
parent(s) or legal guardian, if more appropriate) should be contacted by phone several days 
before the visit, to remind them to complete the patient diary as requested and to attend for 
the visit as arranged.
Each medication kit dispensed will include some reserve medications to allow flexibility for 
the trial visit schedule.
Site personnel will enter the medication numbers dispensed to each patient in the eCRF.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
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.


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The randomisation code for DINAMOTM and DINAMOTM Mono will be kept secret by 
Clinical Trial Support up to the corresponding database lock. The bioanalytical lab will 
remain blinded during the course of the corresponding study. However, in an exceptional 
case, the bioanalytical lab may receive access to the randomisation code. In that case, 
bioanalytics will not disclose the randomisation code or the results of their measurements 
until the corresponding study is officially unblinded.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator 
in order to provide appropriate medical treatment or otherwise assure safety of trial 
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate eCRF 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). 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.
If the storage conditions are found to be outside the specified range and are considered as 
unacceptable, the sponsor must be contacted immediately. Please refer to the ISF for further 
details.
4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:
∀
Approval of the trial protocol by the 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,


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∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol
∀
Availability of the proof of a medical license for the Principal Investigator
∀
Availability of FDA Form 1572 (if applicable)
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients and legal representative(s) 
should be instructed to return unused investigational drug.
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 and/or 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.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Background therapy
Throughout the duration of the trial, patients should continue to take their background 
therapy (metformin and/or insulin). The dose of background therapy at the time of screening 
will be recorded in the source documentation and on the appropriate pages of the eCRF. If 
medically appropriate, the dose and dosing frequency should then remain unchanged. For 
patients on insulin, the weekly average variation of the basal insulin dose should remain ≤ 0.1
IU/kg.
Background therapies will not be provided by BI as part of the clinical trial supplies, unless 
required by local laws and regulations.
For patients on insulin, investigators are advised to adjust the patient’s total insulin dose 
based on need as assessed by frequent SBGM and close patient follow-up upon initiation of 
randomised trial medication. In all cases, the actual reduction will be dependent upon 
individual glucose values. Thereafter and until the end of the trial, further adjustments to 
insulin therapy (both basal and, MDI insulin) may be implemented as necessary to avoid 
hypoglycaemia and also hyperglycaemia to ensure that, in the investigator’s opinion, the 
patient is achieving the best standard of care in accordance with local guidelines. In addition, 


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transfers to another type or brand of insulin as well as changes of the type of insulin pen 
should be avoided.
For patients on metformin, in case a vascular administration of iodine containing contrast 
agent is required, metformin should be temporarily discontinued as specified in the SmPC.
Rescue medication
The use of rescue medication will be permitted in this trial and will be metformin and/or 
insulin. The use of rescue medication will be permitted from the first day of treatment (after 
randomisation) until the end of the trial. 
DINAMOTM
Rescue medication (insulin or increased doses of insulin) should be initiated:
1. from the first day of treatment (after randomisation) until Week 52 in case of acute 
metabolic decompensation accompanied by significant symptoms (e.g., vomiting, 
dehydration, lethargy) and/or repeatedly elevated blood ketone (beta hydroxybutyrate) 
values > 1.5 mmol/L measured with the provided electronic device (meter), irrespective 
of the glucose value (due to its mechanism of action, empagliflozin may potentially 
modify the clinical presentation of acute metabolic decompensation, e.g. with lower blood 
glucose values than expected).
However, in case of sustained hyperglycaemia during SBGM (80% of blood glucose tests 
are > 300mg/dL (16.6 mmol/L) (non-fasting) or > 200 mg/dL (11.1 mmol/L) (fasting) for 
1 week) initiation of rescue therapy should also be considered.
2. from Week 12 (Visit 4A) until Week 52 (Visit 8) if on two successive occasions
(separated by at least 4 weeks) HbA1c is ≥9.0% and an absolute increase of HbA1c ≥ 1% 
compared with the baseline value is observed (even in the absence of symptoms related to 
hyperglycaemia and ketoacidosis). 
The type of insulin and its dosage will be left at the investigator’s discretion. 
If new insulin treatment or insulin treatment at increased doses (i.e. dose increase of basal 
insulin of more than 0.1 IU/kg above the baseline prescribed dose) continues for more than 
21 consecutive days (including the weaning phase) then the patient will be classified as 
requiring rescue therapy.
DINAMOTM Mono
Rescue medication (metformin and/or insulin) should be initiated:
-
at anytime in case of acute metabolic decompensation;
-
if HbA1c > 7.0% AND
o
there is no HbA1c decrease at Week 12
o
the HbA1c decrease is less than 0.5% at Week 26 and later
In addition, rescue medication could be initiated at any time as per the investigator’s 
judgement. The type of insulin and its dosage as well as the dosage of metformin will be left 
at the investigator’s discretion.


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On top of the HbA1c measurements performed at the time points defined in the Flowchart, 
additional HbA1c measurements can be performed at any time if deemed necessary by the 
investigator. Besides, additional interactions (e.g. phone calls, text messaging or emails, as 
deemed appropriate by the investigator and the patient) must be planned every 4 weeks 
between 2 visits where the interval exceeds 4 weeks.
Furthermore, some patients may require use of insulin due to temporary medical conditions 
such as hospitalisation or intercurrent illness. Any type or dose of insulin can be used at the 
discretion of the investigator. In such cases, an attempt is made to withdraw insulin once the 
acute event has resolved. In the case of a temporary medical condition such as hospitalisation 
or intercurrent illness, weaning occurs within 2 weeks if the event lasted 2 weeks or less; if 
the event lasted more than 2 weeks, weaning occurs within 1 month. Withdrawal of insulin 
occurs regardless of blood glucose values; if metabolic decompensation occurs, appropriate 
safety procedures are followed as detailed in Section 5.3.5.3.
In the case of hypoglycaemia that may put patient on risk (e.g. repeated symptomatic 
hypoglycaemia or severe hypoglycaemia), appropriate adjustment of oral antidiabetic therapy
and/or insulin 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.
Any rescue medication or dose change in background therapy will be recorded in the source 
documents and on the appropriate pages of the eCRF.
Any additional treatment that does not qualify as a rescue medication and is considered as 
deemed necessary for the patient’s welfare may be given at the investigator’s discretion. 
Exceptions to this are the restrictions described in section 4.2.2.1.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
With the exception of metformin and insulin used as background therapy, in any other 
situation than rescue condition, the use of any other antidiabetic agents will be prohibited 
during the course of the trial. As described in section 4.2.1, insulin is also allowed as rescue 
medication.
Additionally, weight reduction medications and long-term use of systemic corticosteroids
(more than 1 week) are prohibited due to their influence on glucose metabolism. However, 
therapy with non-systemic corticosteroids such as inhaled or local use will be permitted.
Furthermore, for patients taking thyroids hormones, any dose change should be avoided. If 
such dose change does occur, it should be recorded in the source documents and onto the 
appropriate eCRF page.


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4.2.2.2
Restrictions on diet and life style
All patients and their families must be encouraged to make dietary changes consistent with 
healthy eating recommendation, including counselling for weight reduction, reduced 
carbohydrate and total and saturated fat intake, increased fiber intake and increased physical 
activity along with decreased sedentary behaviors.
Smoking is not permitted prior to or during any of the visits (from the start of the overnight 
fast that precedes visits). Any alcohol intake should be avoided within 2 days prior to each 
visit.
4.2.2.3
Restrictions regarding women of childbearing potential
Women of childbearing potential must use the contraception methods described in the 
patient’s legal representative information sheet. 
In the unexpected and rare cases where women are not of childbearing potential because they 
are permanently sterilised, they do not need to use contraception to be eligible for the trial. 
All other female patients are considered to have childbearing potential and must use adequate 
contraception throughout the trial (from screening until 3 weeks after the last dose of trial 
medication). 
Adequate contraception is defined per ICH M3 (R2) as highly effective or acceptable 
methods. Highly effective methods of birth control which should be used by women of 
childbearing potential are those, which alone or in combination, result in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly, and must be in accordance 
with local regulations where applicable. 
Based on the recommendations of the European Union Heads of Medicines Agency related to 
contraception and pregnancy testing in clinical trials (CTFG, 2014), the following 
contraception methods can achieve a failure rate of less than 1% per year when used 
consistently and correctly: 
1. Use of hormonal methods of contraception associated with inhibition of ovulation 
a. Combined (estrogen and progestogen containing) hormonal contraception: 
• Oral 
• Intravaginal 
• Transdermal 
b. Progestogen-only hormonal contraception: 
• Oral 
• Injectable 
• Implantable 
2. Placement of intrauterine device or intrauterine system. 
3. Bilateral tubal occlusion 
4. Male sterilization (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate) 
5. Complete sexual abstinence 


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The list of acceptable contraception methods is also provided in the patient’s legal 
representative information sheet. 
Women who become pregnant while participating in the trial must discontinue trial 
medication immediately.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on counts, treatment compliance will be calculated as shown in the formula below.
Compliance will be verified by CRA authorised by the sponsor.
Treatment compliance (%) =
Number of actually taken # 100
     Number of which should have been taken
Compliance during the open-label placebo run-in period must be between 75% and 125%. If 
compliance is outside this range, the patient should not be randomised as described in section 
3.3.2.
Compliance during the randomised period should also be between 75% and 125%. 
Patients who are not compliant with their medication should be carefully interviewed and 
informed about the purpose and the conduct of the trial. This discussion should be 
documented.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint(s)
DINAMOTM
The primary efficacy endpoint will be the change in HbA1c (%) from baseline to the end of 
26 weeks.
DINAMOTM Mono
The primary efficacy endpoint will be the occurrence of treatment failure up to or at Week 26 
as a binary endpoint, defined as meeting at least one of the following criteria:
∀
Use of rescue medication at any time up to Week 26
∀
Increase from baseline in HbA1c by 0.5% at Week 26
∀
Increase from baseline in HbA1c to above 7.0% at Week 26 in patients with baseline 
HbA1c < 7.0%.
5.1.2
Secondary Endpoint(s)
The secondary endpoints to assess efficacy are listed below:
DINAMOTM
∀
Change in FPG (mg/dL) from baseline to the end of 26 weeks
∀
Change in body weight (kg) from baseline to the end of 26 weeks
∀
Change in SBP (mmHg) from baseline to the end of 26 weeks
∀
Change in DBP (mmHg) from baseline to the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 6.5% at the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 7.0% at the end of 26 weeks
DINAMOTM Mono
∀
Time to treatment failure
∀
Change in HbA1c (%) from baseline to the end of 26 weeks
∀
Change in FPG (mg/dL) from baseline to the end of 26 weeks
∀
Change in body weight (kg) from baseline to the end of 26 weeks
∀
Change in SBP (mmHg) from baseline to the end of 26 weeks
∀
Change in DBP (mmHg) from baseline to the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 6.5% at the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 7.0% at the end of 26 weeks
5.1.3
Further Endpoint(s)


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5.1.3.2
Further endpoint to assess safety
Further endpoints to assess safety are listed below for both DINAMOTM and DINAMOTM
Mono:
∀
Adverse events after 26 and 52 weeks, including adverse events of special interest 
(see section 5.3.6.1), genital infections, bone fracture, urinary tract infections, 
arthralgia, bullous pemphigoid, adverse events related to reduced intravascular 
volume, and ketone measurements reported as AE
∀
Percentage of patients with reported hypoglycaemia after 26 and 52 weeks
∀
Vital signs and heart rate after 26 and 52 weeks
∀
Change from baseline in Tanner staging after 26 and 52 weeks
∀
Change from baseline in serum electrolytes, hematology, biochemistry, lipids, IGF-1 
and IGF-BP3 and markers of mineral and bone metabolism after 26 and 52 weeks
∀
Change from baseline in height (cm) and BMI (kg/m²) after 26 and 52 weeks
∀
Growth velocity (cm/year) after 26 and 52 weeks


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5.2
ASSESSMENT OF EFFICACY
5.2.1
HbA1c and fasting plasma glucose (FPG)
HbA1c and FPG will be analysed by the central laboratory at the time points indicated in the 
Flow Chart. However, due to the COVID-19 pandemic, HbA1c and FPG may be analysed by
the local laboratory.
The samples will be analysed at a central laboratory or its affiliates having a National 
Glycohemoglobin Standardisation Program (NGSP) Level I certificate. HbA1c results will be 
reported in both NGSP (%) and International Federation of Clinical Chemistry, IFCC 
(mmol/mol) units. The relationship between HbA1c results from the NGSP network (% 
HbA1c) and the IFCC network (mmol/mol) has been evaluated and a master equation has 
been developed (NGSP = [0.09148*IFCC] + 2.152). This relationship is continuously 
monitored and any changes are investigated. The NGSP certification process and test results 
for NGSP-certified methods do not change as a result of the IFCC standardisation of HbA1c, 
and will continue to be directly traceable to the Diabetes Control and Complications Trial 
(DCCT) reference and now also the IFCC reference. If a centrally analyzed, NGSP-certified 
hemoglobin A1c assay is unavailable (e.g. due to the COVID-19 pandemic), an HbA1c assay 
performed at a local laboratory is acceptable.
Further details about HbA1c sample handling, shipment, and assay procedures can be found 
in the laboratory manual in the ISF.
Blood samples for the determination of FPG at the central laboratory will be taken after an
overnight fast (no food or drinks except for water for at least 8 hours). The samples should be 
taken before trial medication administration. The samples will be measured at a central
laboratory using validated assays. Plasma glucose results will be reported in mmol/l and 
mg/dl.
Further details about FPG sample handling and shipment can be found in the laboratory 
manual in the ISF.
5.2.2
Body weight
Body weight measurements should always be done on the same calibrated scales for an 
individual patient at the time points indicated in the Flow Chart.  However, due to the 
COVID-19 pandemic, body weight measurements may be done at the local laboratory.
In order to get comparable body weight values, it should ideally be performed in the 
following way:
∀
fasting (at visits to which a patient has to come fasted, see Flow Chart)
∀
after bladder voiding
∀
shoes and coat/jackets should be taken off
∀
pockets should be emptied of heavy objects (i.e. keys, coins etc.)


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5.2.3
Systolic/diastolic blood pressure (SBP and DBP) and heart rate (vital signs)
SBP and DBP as well as heart rate (electronically or by palpation, count for 1 minute) will be 
measured at the time points indicated in the Flow Chart with a calibrated electronic 
sphygmomanometer. The BP measurement should be performed three times at each time 
point and the mean value of the measurements will be analysed.  However, due to the 
COVID-19 pandemic, vital signs may be done at the local laboratory.  
Initially, BP should be taken 3 times in both arms. The arm with the higher average pressure 
(systolic or – if equal – diastolic) should be used for subsequent measurements; if 
measurements for both arms are equal, the non-dominant arm should be chosen.
BP measurements should always be performed on the same arm and, if possible, by the same
person and using the same device. The same method must be used throughout the trial for a
given patient i.e. if a patient receives the first BP measurement for example with an electronic
device, the same method and device should be used throughout the study for this patient.
After patients have rested quietly, in the seated position for at least 5 minutes, 3 BP
measurements will be taken approximately 2 minutes apart. The seated pulse rate should be
from the second BP reading.
BP measurements should be recorded to the nearest 1 mmHg. BP should always be measured 
before any blood samples are taken.
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
The results must be included in the source documents available at the site. 
Throughout the physical examination, the privacy of the patient will be respected and local 
culture/requirements will be taken into consideration (e.g. same sex chaperone or same sex 
doctor performing the examinations).
For patients on insulin, injection sites should be checked regularly.
5.3.2
Vital signs
Please refer to Section 5.2.3.
5.3.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.3.3: 1 and Table 5.3.3: 2. For 
the sampling time points please see the Flow Chart.


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All analyses will be performed by a central laboratory, or at a local laboratory at designated 
visits per the Flow Chart under exceptional circumstances due to the COVID-19 pandemic, 
the respective reference ranges will be provided in the ISF. 
For Visit 2, Visit 5 and Visit 8, all safety laboratory samples will be collected from the 
patient after an overnight fast (i.e. nothing to eat or drink except water for at least 8 hours). 
When applicable, laboratory samples should be collected before trial medication is taken.
To minimise pain and distress, local anaesthetic product will be offered to all patients before 
any venepuncture is carried out. 
For female patients, pregnancy testing will be performed locally using the urine pregnancy 
test kits supplied by the central laboratory or local laboratory under exceptional 
circumstances due to the COVID-19 pandemic. Immediately after the result of a pregnancy 
test is known, the pregnancy test kit will be discarded at the site. In case of positive result, a 
serum pregnancy test will be performed by the central laboratory, or at a local laboratory 
under exceptional circumstances due to the COVID-19 pandemic. The results of the test must 
therefore be documented in the source documents available at the site for future verification 
by the CRA.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
Laboratory reports will be provided through the central laboratory web-based system. It is the 
responsibility of the investigator to retrieve and evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the investigator will be reported as adverse events 
(please refer to Section 5.3.6.2).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.3.6.2 and the DILI Checklist provided in the eDC system). 
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling. The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.3.3: 1
Safety laboratory parameters – blood, serum or plasma
Haematology
Haematocrit1
Haemoglobin1
o
reticulocyte count (reflex test if 
haemoglobin is outside normal 
range)
Red blood cells (RBC)/erythrocytes
White blood cells (WBC)/leukocytes
Platelet count/thrombocytes
Differential automatic (relative and 
absolute count):
o
neutrophils, eosinophils, baso-
phils, monocytes, lymphocytes
Clinical chemistry
Albumin
Alkaline phosphatase1
o
gamma-glutamyl transferase (γ-GT, 
reflex test triggered by elevated 
alkaline phosphatase on two 
sequential measures)
ALT (alanine aminotransferase, SGPT)1
AST (aspartate aminotransferase, SGOT)1
Bilirubin total, fractionated if elevated
Beta-hydroxy-butyrate
Bicarbonate
Calcium
Chloride
C-peptide2
Creatinine1
Cystatin C
Creatine kinase (CK)
o
troponin I (reflex test if CK is 
elevated)
Lactate dehydrogenase
Lipase
Magnesium
Phosphate
Potassium
Protein total
Sodium
TSH (at screening only)
Blood urea nitrogen (BUN)
Uric acid
Lipids
Cholesterol (total)
HDL cholesterol
LDL cholesterol (calculated)
Triglycerides
1 At the screening visit (Visit 1A) the following parameters are part of the profile: liver transaminases, alkaline phosphatase, 
serum creatinine, Cystatine C, TSH, haemoglobin, haematocrit and C-peptide only in addition to HbA1c. Blood 
samples do not need to be collected in a fasted state.
2 C-peptide will only be assessed at specific visits as described in Section 5.3.5.4.


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Table 5.3.3: 2 
Safety laboratory parameters – urine
Semi quantitative (dipstick)
Quantitative urinalysis
Nitrite1
Protein
Ketones
Urine pH
Leukocyte esterase (for WBC)1
Albumin
Creatinine
Human chorionic gonadotrophin (hCG)2
Microscopic urinalysis
Microscopic analysis will be performed as a reflex test if any of the above semi-
quantitative (dipstick) tests except for ketones are abnormal:
Urine RBC/erythrocyte
Urine WBC/leukocytes1
Urine sediment microscopic examination
Urine culture
Urine culture will be triggered by positive leukocyte esterase (for WBC) and/or nitrite in 
the semi-quantitative test/dipstick. The culture will include an antibiogram
1 Nitrite and leukocyte esterase (for WBC) will be determined both locally on site (not recorded in eCRF) and via the central 
laboratory. A positive result at site triggers the sampling of mid-stream urine for urine culture
2 Urine pregnancy testing will be performed locally in female patients of child-bearing potential only according to the 
timepoints indicated in the Flow Chart. A positive result at site will be confirmed by a serum pregnancy test performed 
by the central laboratory.
Albumin/creatinine ratio in spot urine will be calculated at the central laboratory.
The estimated glomerular filtration rate (eGFR) will be calculated according to Zappitelli et 
al formula (validated for patients from 10 to 20 years of age inclusive) [R16-2476 ; R16-
2470]:
eGFR (mL/min/1.73m²) = 
(507.76 x e0.003xheight) / (Cystatine C0.635xSerum Creatinine0.547 [μmol/L])
If renal transplant, x 1.165
Follow-up on suspicion for urinary tract infection (UTI) and genital infection
Patients having a history of chronic/recurrent UTI or genital infection or an acute episode of 
UTI or genital infection at screening will be identified and this condition must be documented 
as medical history or as a baseline condition in the eCRF, respectively.
Throughout the trial, patients should be closely observed for symptoms of UTI or genital 
infection. In case these symptoms occur, symptomatic relief and anti-infectives should be 
provided as appropriate [c01678844-17].
For documentation of acute UTI during trial conduct, the following measures have to be 
taken. In any case of suspected UTI (symptomatic or asymptomatic), a dipstick test 
(leukocyte esterase [for WBC] and nitrite) will be performed at the site at the time points 
indicated in the Flow Chart. In case of a positive result at site, a urine culture sample must be 


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obtained and sent to the central laboratory for confirmation of the diagnosis and to obtain an 
antibiogram.
IGF-1, IGF-BP3 and markers of bone turnover
IGF-1, IGF-BP3 and bone metabolism biomarkers will be measured by the central lab at the 
time points indicated in the Flow Chart. 
The following markers of bone turnover will be measured:
∀
Calcium
∀
Phosphate
∀
Alkaline phosphatase
∀
25-OH-vitamin D
∀
Intact parathyroid hormone
∀
Serum Procollagen type I N-terminal propeptide (PINP) (for bone formation)
∀
Serum N-terminal cross-linked telopeptide (NTx) (for bone resorption)
IGF-1 and IGF-BP3 will be measured in samples collected from the patient after an overnight 
fast (i.e. nothing to eat or drink except water for at least 8 hours).
5.3.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the Flow Chart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.3.5
Other safety parameters
5.3.5.1
Height and Body Mass Index (BMI)
Height and weight will be measured at the time points indicated in the Flow Chart.
Height should be measured using the same stadiometer for one patient.
SDS (Standard Deviation Score), e.g. z-score, values for height and BMI will be calculated 
by the sponsor for the statistical analysis using the WHO age-specific references.
5.3.5.2
Self-blood glucose monitoring
All patients will be provided with SBGM equipment (i.e. an electronic blood glucose 
monitoring device/meter that is also capable of measuring blood ketones) and supplies for use 


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at home during the study for self-measurement of blood glucose. Instructions on the proper 
use of the SBGM equipment will be provided by the site staff. The patient or his/her 
parent(s)/legal guardian will be asked to enter data from the device to a patient diary. The 
investigator or delegated site personnel should also print out the record list and include it in 
the patient medical records. To avoid additional finger pricks for blood glucose measurement, 
patients with a continuous glucose monitoring (CGM) device can use relevant readings from 
the device following the minimum testing requirements below. It is the PI discretion to report 
clinically relevant readings as adverse events. It is also the PI discretion regarding patient 
diary management entry as long as the minimum testing requirements below are met.
Only in case of linked adverse events, the single value from the glucometer will be recorded 
in the eCRF.
SBGM should be performed regularly and ideally its frequency should be individualised as 
per local clinical guidelines. Especially for patients on insulin, more frequent SBGM may be 
performed. Nevertheless, minimum requirements are defined by this clinical trial protocol 
and are as follows:
∀
Placebo run-in period
Daily SBGM in a fasted state is recommended.
∀
Randomised treatment period
SBGM at least 3 times per week in a fasted state is recommended.
∀
Follow-up period
At least one SBGM per week in a fasted state is recommended. 
Throughout the trial, additional blood glucose measurements may be performed any time the 
patient is symptomatic, i.e. experiences signs/symptoms of hyper- or hypoglycaemia.
5.3.5.3
Self-blood ketone monitoring
Patients will be equipped with an electronic device to determine their ketone concentration 
(i.e. the electronic blood glucose monitoring device/meter that is also capable of measuring 
blood ketones). The patient or his/her parent(s)/legal guardian will be asked to enter data 
from the device to a patient diary. The investigator or delegated site personnel should also 
print out the record list and include it in the patient medical records. 
Patients should be instructed to test their ketones in case of any symptoms of DKA, e.g. 
nausea, vomiting, abdominal pain etc., irrespective of the glucose value. Patients must be 
reminded about the signs and symptoms of DKA, on the interpretation of ketone values 
measured via the meter, and on appropriate action to take in the event of increased ketone 
levels (see below). 
Daily measurements before breakfast are recommended during the first 4 weeks of the 
treatment period and during the 4 subsequent weeks after Visit 5. Otherwise, measurements 
should be performed at least 3 times per week. In addition, blood ketone levels will be 
checked by using the meter at most clinic visits (see Flow Chart).


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Daily blood ketone monitoring should also be performed in case of concomitant illness/stress 
or if deemed necessary by the investigator. In the event of increased ketones (> 0.6 mmol/l), 
patients should contact their trial site. In case of deteriorating ketosis, blood glucose and 
ketone levels should be checked every 1-2 hours until they are back in a range considered to 
be normal for the patient. Patients should be instructed to immediately refer themselves to 
hospital and/or the investigator, or to contact an emergency physician, in case of a blood 
ketone concentration > 1.5 mmol/L (as indicated in the meter manual). Blood ketone 
concentration > 1.5 mmol/L should be reported as AE by the investigator and the blood 
ketone values should be recorded in the eCRF. 
In case of a suspected DKA, the investigator should ensure that appropriate tests are 
performed at the earliest opportunity according to local guidelines, such as a blood gas test 
(pH, bicarbonate). The results will be collected on the relevant page of the eCRF.
Investigators should also differentiate deteriorating ketosis/DKA from any mild to moderate 
increase of ketones which may be seen due to the mechanism of action of empagliflozin, 
especially in the fasted state (e.g. in the morning). In accordance with Section 3.3.2, 
investigators should carefully select patients for the study in terms of their ability to comply 
with ketone measurement requirements. Patients not adhering to the instructions given by the 
investigator should be retrained at the earliest possible opportunity.
5.3.5.4
C-peptide
Laboratory samples for C-peptide will be collected at the time points indicated in the Flow 
Chart.
Except for the screening visit, samples will be collected from the patient after an overnight 
fast (i.e. nothing to eat or drink except water for at least 8 hours). When applicable, samples 
should be collected before trial medication is taken.
The analysis will be performed by a central laboratory. Non-fasting serum C-peptide at Visit 
1A will be used to check the patient eligibility as described in Section 3.3.1. The respective 
reference ranges and details about sample handling and shipment will be provided in the 
laboratory manual in the ISF.
5.3.5.5
Tanner staging (modified)
Tanner staging is a scale of pubertal development in children, adolescents and adults which is 
routinely used for defining physical measures of development based on external primary and 
secondary sex characteristics, such as the size of the breasts, genitalia and development of 
pubic hair. Due to natural variation, individuals pass through the Tanner stages at different 
rates depending on the timing of puberty.
To assess the stage of puberty of each patient throughout the trial, a modified version of this 
scale will be used at the time points indicated in the Flow Chart. For patients with Tanner 
stage V at Visit 2, further assessment is not required at the subsequent visits. For details 
regarding the modified Tanner staging, please refer to Appendix 10.1.


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5.3.5.6
Criteria for hypoglycaemic event
Every episode of plasma glucose equal to or below 70 mg/dl (3.9 mmol/l) should be 
documented in the eCRF with the respective time and date of occurrence. Any 
hypoglycaemia with glucose values < 54 mg/dl (< 3.0 mmol/l) as well as all symptomatic and 
severe hypoglycaemic event (requiring active assistance by another person to administer 
carbohydrate) should be documented with the respective time and date of occurrence as an 
AE "hypoglycaemic event".
For the analysis, all hypoglycaemias will be classified according to the following criteria:
∀
Documented symptomatic hypoglycaemia AE with glucose concentration < 70 mg/dL 
(< 3.9 mmol/L), as well as asymptomatic hypoglycaemia event < 70 mg/dL  (< 3.9 
mmol/L)
∀
Documented any hypoglycaemia AE with glucose concentration < 54 mg/dL (< 3.0 
mmol/L)
∀
Severe hypoglycaemia AE: event requiring the assistance of another person to 
actively administer carbohydrates, glucagon or take other corrective actions. Plasma 
glucose concentrations may not be available during an event, but neurological 
recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration 
[R17-0216].
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs 
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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
∀
results in death,
∀
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
∀
requires inpatient hospitalisation or 
∀
requires prolongation of existing hospitalisation,
∀
results in persistent or significant disability or incapacity, or
∀
is a congenital anomaly / birth defect, or


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∀
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse. 
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.3.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
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 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC 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. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs.
Protocol-specified AESIs (as identified by the investigator based on the below list 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 (i.e. non serious 
AESI should be reported as a non-serious event on the SAE form for reporting).
The following events are considered as protocol-specified adverse events of special interest 
(AESI):
∀
Hypersensitivity reactions such as angioedema, angioedema-like events, and 
anaphylaxis (an identified risk with DPP-4 inhibitors)
∀
Skin lesions such as exfoliative rash, skin necrosis, or bullous dermatitis (a potential 
risk with DPP-4 inhibitors)
∀
Pancreatitis (an identified risk with DPP-4 inhibitors)
∀
Pancreatic cancer (a potential risk with DPP-4 inhibitors)
∀
Hepatic injury (of potential interest for all investigational drugs)
∀
Decreased renal function (of potential interest for all investigational drugs)
∀
Diabetic Ketoacidosis (DKA) (an identified risk with SGLT-2 inhibitors)


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∀
Events involving lower limb amputation (a potential risk with SGLT-2 inhibitors)
Details on hepatic injury, decreased renal function, DKA and events involving lower limb 
amputation are provided below.
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters after 
randomisation: 
∀
an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin > 2 fold ULN measured in the same blood draw sample, and/or
∀
isolated elevation of ALT and/or AST ≥ 5 fold ULN
These laboratory findings constitute a hepatic injury alert and the patients showing these 
laboratory abnormalities need to be followed up according to the “DILI checklist” provided 
in the eDC system. 
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.
Decreased renal function
Decreased renal function diagnosed as acute kidney injury or defined by a creatinine value 
showing a ≥ 2 fold increase from baseline and is above the ULN.
For the AESI “decreased renal function” the investigator shall collect an unscheduled 
laboratory sample for creatinine as soon as possible and initiate follow-up laboratory tests of 
creatinine according to medical judgement.
Diabetic ketoacidosis (DKA)
DKA is defined by the diagnostic criteria in Table 5.3.6.1: 1 below, and as defined by the 
American Diabetes Association (ADA) [R14-5435].
Investigators should note that not all criteria in the table below need to apply for the diagnosis 
of DKA, and clinical judgement should also be taken into consideration. Due to its 
mechanism of action, empagliflozin may potentially modify the clinical presentation of DKA 
which may occur at lower plasma glucose levels than stated in Table 5.3.6.1: 1 below 
(see Sections 1.2.1 and 2.3 for further details).


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Table 5.3.6.1: 1 
Diagnosis criteria for DKA according to the American Diabetic 
Association
DKA
Mild
Moderate
Severe
Plasma glucose (mg/dL)
>250§
>250§
>250§
Arterial pH
7.25-7.30
7.00-7.24
<7.00
Serum bicarbonate (mEq/L)
15-18
10 to <15
<10
Urine ketones*
Positive
Positive
Positive
Serum ketones*
Positive
Positive
Positive
Effective serum osmolality (mOsm/kg)**
Variable
Variable
Variable
Anion gap***
>10
>12
>12
Alteration in sensoria or mental obtundation
Alert
Alert/drowsy
Stupor/coma
§ In patients treated with SGLT2-inhibitors, including empagliflozin, a plasma glucose < 250 mg/dl does not exclude the diagnosis 
of DKA. In these patients DKA may occur at lower plasma glucose levels
* Nitroprusside reaction method
** Calculation: 2[measured Na (mEq/L) + glucose (mg/dL)/18
*** Calculation: (Na+) – (Cl- + HcO3-) (mEq/L)
Events involving lower limb amputation
This definition includes amputation (i.e. resection of a limb through a bone), disarticulation 
(i.e. resection of a limb through a joint) and auto-amputations (i.e. spontaneous separation of 
non-viable portion of the lower limb).
Not included in this definition are debridement (removal of callus or dead tissue), procedures 
on a stump (like stump revision, drainage of an abscess, wound revision etc.) and other 
procedures (e.g. nail resection or removal) without a concomitant resection of a limb 
(amputation or disarticulation).
Each lower limb amputation, disarticulation, or auto-amputation should be reported 
separately. The SAE report should include the date of the procedure, the level of amputation 
or disarticulation, the medical condition(s) leading to the procedure and if the patient had 
some of the known risk factor(s) for lower limb amputation.
In addition to the safety topics defined as AESI above, the following safety topics will be 
monitored during the trial and assessed:  Arthralgia, bullous pemphigoid, genital infections 
(including mycotic infections, such as vulvovaginal or balanitis), bone fracture, urinary tract 
infections (including urosepsis or pyelonephritis), AEs related to reduced intravascular 
volume and osmotic diuresis (including symptomatic hypotension).
Intensity of AEs
The intensity of the AE should be judged based on the following:


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Mild:
Awareness of sign(s) or symptom(s) that is/are 
easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual 
activities
Causal relationship of AEs
Medical judgement 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 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.3.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in their patient files.


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The following must be collected and documented on the appropriate eCRF page(s) by the 
investigator:
∀
From signing the informed consent onwards until individual patient’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
∀
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report related SAEs and related AESIs of which the investigator may become aware of 
by any means of communication, e.g. phone call. Those AEs should however, not be 
reported in the eCRF.
Figure 5.3.6.2: 1
Trial periods for collection of AEs
Patients who discontinue trial medication prematurely and agree to be contacted further, but 
do not agree to physical visits should be followed up as described in section 3.3.4.1. From the 
individual patient’s end of the trial the investigator must report all deaths/fatal AEs regardless 
of relationship, related SAEs and related AESIs the investigator becomes aware of.
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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. On specific occasions the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication and any possible interactions between the trial medication 
and a Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP).


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The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):
∀
Worsening of the underlying disease or of other pre-existing conditions 
∀
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable”, or no further information can be obtained.
Pregnancy
In rare cases pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point. 
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 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Blood samples for pharmacokinetic analysis will be collected at the following time points 
(see also the Flow Chart):
Visit 5
∀
pre-dose: within 30 minutes prior to drug administration at site (and preferably 
approximately 24 hours after drug administration on the previous day) 
∀
1.5 h ± 15 min after drug administration
Visit 8 (EoT)
∀
pre-dose: within 30 minutes prior to drug administration at site (and preferably 
approximately 24 hours after drug administration on the previous day) 
∀
1.5 h ± 15 min after drug administration
The date and exact clock time of drug administration and of sampling times have to be 
recorded and documented in the eCRF by the investigator or designated site-personnel. These 


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actual dates and times will be used to evaluate pharmacokinetics. Dates and clock times of 
drug administrations on the 3 days prior to Visit 5 and 8 have to be recorded as well (see 
Section 4.1.4).
5.4.2
Methods of sample collection
The planned PK analyses will require blood sampling at the time points indicated in the 
Flowchart. Correct, complete and legible documentation of drug administrations and blood 
sampling times as well as adequate handling and identification of PK samples are mandatory 
to obtain data of adequate quality for the PK analysis.
In order to allow the sample identification, the sample tube labels should list at a minimum 
the following information: BI trial number, patient number, visit number and planned 
sampling time. Two x 2 plasma aliquots will be obtained from blood samples (two aliquots 
for empagliflozin analysis, and two aliquots for linagliptin analysis). Each aliquot should 
contain at least 0.5 mL plasma. All aliquots will be stored at about -20°C or below and be 
shipped on dry ice. 
Further details on sample collection, preparation of plasma aliquots, sample handling, and 
shipping are provided in the ISF and/or lab manual.
5.4.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of analyte plasma concentrations, blood will be taken from an antecubital 
or forearm vein into a blood drawing tube that contains potassium EDTA–anticoagulant at 
the time points indicated in the Flowchart. Blood will be withdrawn by means of either an 
indwelling venous catheter or by venipuncture with a metal needle. If a forearm vein cannot 
be used for any reason, then the most easily found vein can be used instead. It is 
recommended to use local anesthetics for the skin to avoid pain upon blood withdrawal. 
Attempts to draw blood are limited to three.
During the whole trial, a maximum of approximately 16 mL of blood will be drawn for PK 
purposes. Plasma samples will be obtained by centrifugation. Sample aliquots will be stored 
at the trial site and at the logistics central laboratory until shipment and at the analytical 
laboratory until analysis. First and second sample aliquots are to be shipped separately. For 
further details please refer to the ISF and/or lab manual. 
The trial samples will be discarded after completion upon the final study report has been 
signed.


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5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
This section is not applicable for this trial.
5.5
ASSESSMENT OF BIOMARKER(S) 
5.5.1
Biobanking
This section is not applicable for this trial.
5.5.2
DPP-4 activity
Measurement of DPP-4 activity will require blood sampling at the time points indicated in the 
Flowchart. 
In order to allow the sample identification, the sample tube labels should list at a minimum 
the following information: BI trial number, patient number, visit number and planned 
sampling time. Two plasma aliquots will be obtained and stored in polypropylene tubes at -20 
C° or colder.
Blood will be taken from an antecubital or forearm vein into a blood drawing tube that 
contains potassium EDTA–anticoagulant. Blood will be withdrawn by means of either an 
indwelling venous catheter or by venipuncture with a metal needle. If a forearm vein cannot 
be used for any reason, then the most easily found vein can be used instead. It is
recommended to use local anesthetics for the skin to avoid pain upon blood withdrawal. 
Attempts to draw blood are limited to three.
At Visit 2, at least 4 mL of blood will be drawn. Plasma samples will be obtained by 
centrifugation. Sample aliquots will be stored at the trial site and at the logistics until 
shipment and at the analytical laboratory until analysis. First and second sample aliquots are 
to be shipped separately. 
Further details on sample collection, preparation of plasma aliquots, sample handling, and 
shipping are provided in the ISF and/or lab manual.
The trial samples will be discarded after completion upon the final study report has been 
signed.


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Plasma DPP-4 activity will be measured using a validated fluorescence assay at 
 
.
5.6
OTHER ASSESSMENTS
5.6.1
Auto-antibodies for diabetes
Auto-antibodies can be detected early in the development of type 1 diabetes and are 
considered as markers of autoimmune beta cell destruction. In conjunction with the 
measurement of C-peptide levels, the presence of T2DM will be confirmed at Visit 1A in all 
trial patients by measuring auto-antibodies to IA-2 and glutamic acid decarboxylase auto-
antibodies (GADA).
The analysis will be performed by a central laboratory. The details about sample handling 
and shipment will be provided in the laboratory manual in the ISF.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are considered standard measurements in the 
clinical development of non-insulin products such as empagliflozin and linagliptin, and/or 
standard as part of routine care for T2DM [P12-09397]. All defined measurements will be 
performed in order to monitor safety and tolerability aspects and to determine efficacy in an 
appropriate way.
A surrogate endpoint (i.e. the laboratory parameter HbA1c) is used as the primary efficacy 
endpoint, since for the purposes of drug approval and labelling, which will support an 
indication of glycaemic control, regulatory authorities state that this endpoint, albeit 
surrogate, is the primary endpoint of choice [R08-2669].


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6.
INVESTIGATIONAL PLAN
Visits should take place at a location within the clinical site that has a child-friendly 
infrastructure (e.g. an environment that is familiar to the patients, the setting is physically 
appropriate, if desired by the patient, parent(s)/legal guardian are allowed to stay with them 
during the trial procedures). Furthermore, site-personnel should be knowledgeable and skilled 
in dealing with the paediatric population and its age-appropriate needs. However, Visits 3, 
4A, 6, 7, 9 can be done remotely/by telephone/telemedicine under exceptional circumstances 
due to the COVID-19 pandemic. Reasons a remote/telephone/telemedicine visit may be 
performed may include a confirmed or suspected COVID-19 infection or unwillingness to 
return to the investigator site due to concerns of COVID-19 exposure.
6.1
VISIT SCHEDULE
Trial visits should start between 7.00 AM and 11.00 AM and ideally should be scheduled as 
early as possible when overnight fast is required (at least 8 hours with no food or drink and 
water only).
Smoking is not permitted prior to or during any of the visits (this includes from the start of 
the overnight fast that precedes all visits). Excessive food and alcohol intake should be 
avoided in the 2 days prior to each visit.
All patients are to adhere to the visit schedule as specified in the Flow Chart. Some flexibility 
is allowed in scheduling the visits according to the visit time windows as specified. The trial 
medication kits will contain sufficient medication to allow for these protocol-permitted visit 
windows. All deviations from the planned visit schedule will be documented. If any visit has 
to be re-scheduled, subsequent visits should follow the original visit schedule (calculated 
from Visit 2).
If a patient mistakenly takes trial medication in the morning of a visit where blood samples 
are drawn for PK assessment or comes in non-fasted where a fasting condition is required, the 
visit should be re-scheduled to the next day reminding the patient about the expected 
conditions. 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart. Study procedures 
should be performed in the same order as in the Flow Chart. Blood pressure and pulse rate as 
well as 12-lead ECG should always be measured before any blood samples are drawn. 
Weight should be measured after urine sampling.
Additional details regarding visit procedures are provided below. 
6.2.1
Screening and run-in period(s)
No trial procedure is allowed unless the appropriate consent and assent are in place. Consent 
and assent must be obtained prior to the screening visit procedures.


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Screening Period (Visit 1A to 1B)
Visit 1A is the beginning of the screening period. The patient should be recorded on the
enrolment log and be registered in the IRT as a screened patient when Visit 1A is performed.
Once Visit 1A procedures are complete and laboratory results are received, 
inclusion/exclusion criteria must be reviewed. If the patient meets inclusion/exclusion
criteria, he/she should be contacted to schedule the next visit.
If the patient does not meet inclusion/exclusion criteria, the patient must be recorded in eCRF 
as a screen failure. Patient must be registered as a screen failure in IRT.
Run-in Period (Visits 1B to 2)
Visit 1B is the beginning of the run-in period. This visit can be performed on the same day as 
Visit 1A.
Following completion of Visit 1B procedures, eligible patients will be dispensed a placebo 
run-in kit for the 2 week run-in period which will be assigned via the IRT system. 
The SBGM/SBKM device is delivered to the patient at Visit 1B. Only blood glucose 
measurements are expected during the run-in period. The measures have to be captured by 
the patient or his/her legal representative in a paper diary every day during run in period.
Medical History
Any pre-existing medical conditions considered as relevant by the investigator, excluding the 
indication of the trial, are recorded into the eCRF in the appropriate page. This concern all 
active pathology, chronic disease or recurrent event.
6.2.2
Treatment period(s)
For patients eligible to be randomised, assessments should be performed as mentioned in the 
Flow Chart and the respective protocol sections.
Visits 2, 5 and 8 have to be performed in a fasted state (overnight fast for at least 8 hours, no
food intake, only water allowed).
Initial randomisation at Visit 2
Eligible patients will be randomised by using the IRT system; all visit assessments should 
have been completed prior to this, and before the first intake of study medication. First dose 
of trial drugs will be administered in the clinic (Day 1).
Starting from Visit 2, the SBGM/CGM/SBKM device will also be used by the patient to 
measure his/her blood glucose concentration and blood ketone concentration before 
breakfast. He/she or his/her parents/legal guardian should enter the values in the patient diary.
Those values will then be reviewed by the investigator or delegated site personnel at each 
clinic visit. In order to make sure those measurements are well performed, the investigator or 
a delegated site staff representative should contact the patient or the parent/legal guardian by 
phone/text message/email a day or two after randomised treatment is started and then after 2, 
8, 18, 22, 34, 38, 46 and 50 weeks of treatment.


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These measurements should be performed as described in the Flow Chart and in Section 
5.3.5.2 and 5.3.5.3.
Next clinic visits will be scheduled after 4, 12, 14, 26, 30, 42 and 52 weeks of treatment 
(Visit 3 to 8). For detailed description of the trial procedures at each visit and dispensing 
schedule, please refer to the Flow Chart.
Re-randomisation at Visit 4B (Week 14)
Patients not achieving an HbA1c value < 7.0% at Visit 4A (as measured by the central 
laboratory) and initially randomised to empagliflozin 10 mg will be re-randomised to receive 
either empagliflozin 10 mg or empagliflozin 25 mg. In order to maintain the blinding, an IRT 
call will be performed for all patients. Medication numbers will be assigned through the IRT 
system based on the HbA1c value at Visit 4A and the age at baseline.
Visit 4B could be a site visit or medication kits could be delivered at the patient’s home by a 
dedicated study nurse/study site staff/delegated courier at the investigator’s discretion and as 
per the local regulations. In case the medication kits would be delivered at the patient’s home, 
a phone contact should be performed by a site staff representative. Following completion of 
the visit procedures, eligible patients will be re-randomised and the first dose of re-
randomised trial drugs should be administered on the same day.
Re-randomisation at Visit 5 (Week 26)
After the 26-week treatment period, all patients will enter a double-blind safety extension 
period up to 52 weeks. 
Patients who received placebo during the 26-week treatment period will be re-randomised to 
receive either linagliptin 5 mg or empagliflozin 10 mg or empagliflozin 25 mg. The re-
randomisation will be stratified by age at baseline. At Visit 5, in order to preserve the trial 
blinding, the investigator will assign medication kits for all patients through the IRT system.
Following completion of the visit procedures, eligible patients will be re-randomised and the 
first dose of re-randomised trial drugs should be administered on the same day
6.2.3
Follow Up Period and Trial Completion
For patients who complete treatment as planned, a follow-up (FUP) visit should be planned 3 
weeks after last trial drug administration. For detailed description of the trial procedures at 
the FUP visit, please refer to the Flow Chart.
Trial completion
The trial completion eCRF end-of-study page has to be filled-in when the patient has 
terminated the trial.


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The end of the trial is:
•
At the end of the follow-up visit for patients who have completed the trial on
treatment as planned;
•
After the early unscheduled end of treatment (EOT) visit, if a patient did not agree to 
come to the remaining planned study visits and also disagrees to be contacted at all;
•
After the Visit 9/FUP visit (in person or by telephone) at Week 55, for patients who 
discontinued drug early but agreed to come to the remaining planned study visits, or 
agree to be contacted/allow access to medical records.
Patients who prematurely discontinued trial medication
Patients who prematurely discontinue study drug (refer to section 3.3.4) before the planned 
end of treatment at Visit 8, should come to the clinic as soon as possible after last drug intake 
for an immediate unscheduled early EOT visit. The reason for premature trial drug 
discontinuation must be documented in the eCRF. For detailed description of the trial 
procedures at this visit, please refer to the Flow Chart.
In addition patients will be encouraged to attend all subsequent planned visits despite not 
being under treatment anymore and perform all study procedures except pharmacokinetic 
sampling.
Study assessments may be omitted if a patient is willing to return to the pre-defined study 
visits, with exception of blood drawing for safety lab tests, HbA1c and FPG, body weight, 
blood pressure and collection of adverse events, and concomitant therapy.
The need for coming to future visits in case of premature discontinuation of trial medication
will be explained to patients prior to their participation in the trial.
Vital status information
In case of early discontinuation of trial medication, if the patient does not agree to come to
future visits as planned,every attempt will be made to get information on vital status at Week
55 after his/her randomisation.
Patients and parents/legal guardian will be asked to agree to be contacted by the site 
personnel, which could be by telephone calls, to allow collection of this information.
If death occurs, the investigator will review the circumstances, including the relevant medical
records to ascertain the most likely primary and secondary causes of death.
Collection of vital status will be performed in accordance with national ethical and regulatory
guidelines. The need for vital status information will be explained to patients prior to their
participation in the trial.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a multinational, randomised, placebo-controlled, double-blind trial to assess the 
efficacy and safety of pooled empagliflozin (empagliflozin 10 mg and empagliflozin 25 mg)
and linagliptin 5 mg versus placebo after 26 weeks of treatment in children and adolescents
with T2DM.
7.1.1
DINAMO
The primary endpoint is the change in HbA1c (%) from baseline to the end of 26 weeks. This 
endpoint will be analysed in a confirmatory way. For the primary analyses, treatment 
comparisons will be made between the randomised pooled empagliflozin (empagliflozin 10
mg and empagliflozin 25 mg, i.e. independent of patients achieving the glycaemic target at 
Week 12 and re-randomisation at Week 14) versus placebo and between the randomised 
linagliptin 5 mg versus placebo according to the initial randomisation.  The change in HbA1c 
(%) from baseline to the end of 26 weeks will be analysed using a “wash-out” approach.
7.1.2
DINAMO Mono
The primary endpoint is the occurrence of treatment failure up to or at Week 26 as a binary 
endpoint. This endpoint will be analysed in an exploratory way. The primary analysis will be 
a comparison of the treatment failure rate of linagliptin 5 mg, pooled empagliflozin and 
placebo. The risk difference of active treatments versus placebo will be determined and 
assessed by an exact 2 sided 90% confidence interval based on the method of Chan and 
Zhang [R15-1346]. Patients will be assigned to the treatment they were randomised to at the 
initial randomisation. Non-completers who prematurely discontinue intake of study drug will 
be considered treatment failures.
7.2
NULL AND ALTERNATIVE HYPOTHESES
7.2.1
DINAMO
7.2.1.1
Primary family of hypotheses
The following two hypotheses are the set of primary hypotheses in this trial.
For empagliflozin, the following null hypothesis will be tested:
H0,1: 
Mean change in HbA1c (%) from baseline to the end of 26 weeks in the pooled 
empagliflozin group
= Mean change in HbA1c (%) from baseline to the end of 26 weeks in the placebo 
group
For linagliptin, the following null hypothesis will be tested:
H0,2: 
Mean change in HbA1c (%) from baseline to the end of 26 weeks in the linagliptin 5
mg group


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= Mean change in HbA1c (%) from baseline to the end of 26 weeks in the placebo 
group
The hypotheses will be tested simultaneously at the study-wise level of α = 0.05 (two-sided). 
The Hochberg-procedure will account for multiple testing within the primary family of 
hypotheses.
7.2.1.2
Secondary family of hypotheses
After having obtained statistically significant results for both hypotheses H0,1 and H0,2 of the 
primary family of hypotheses, the following two hypotheses will be tested in a hierarchical 
order at the significance level α = 0.05 (two-sided) for the comparison of empagliflozin 
versus placebo:
H’0,1: Mean change in HbA1c (%) from baseline to the end of 26 weeks in regimen starting 
on empagliflozin 10 mg and either having a dose increase to empagliflozin 25 mg in 
patients who were non-responders (i.e. patients that did not achieve HbA1c < 7.0%) at 
Week 12, or who were responders (i.e. patients that did achieve HbA1c < 7.0%) at 
Week 12 and continue with empagliflozin 10 mg
= Mean change in HbA1c (%) from baseline to the end of 26 weeks in the placebo 
group.
followed by:
H’0,2: Mean change in HbA1c (%) from baseline to the end of 26 weeks in regimen starting 
on empagliflozin 10 mg and either were responders or were non-responders at Week 
12, and continue with empagliflozin 10 mg
= Mean change in HbA1c (%) from baseline to the end of 26 weeks in the placebo 
group.
7.2.2
DINAMO Mono
It is not planned to test specific hypotheses because of the exploratory nature of DINAMOTM 
Mono.  
7.3
PLANNED ANALYSES
The statistical analysis will be based on the following populations.
Treated set
The treated set (TS) will include all patients who are treated with at least one dose of 
randomised study medication. The TS is the basis for safety analyses.


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Modified intention-to-treat set
The modified intention-to-treat set (mITT) will include all randomised patients who are 
treated with at least one dose of study medication and have a baseline HbA1c measurement. 
The mITT is the basis for the primary analyses.
Per protocol set
The per protocol set (PPS) will include all patients in the mITT set who do not have any 
important protocol deviations (IPD) which can be expected to have a distorting influence on 
the assessment of the primary endpoint. Details regarding the definitions of IPDs will be 
provided in the Trial Statistical Analysis Plan (TSAP) and the decision to exclude patients 
from the PPS will be made prior to database lock.
The term “baseline” refers to the following definitions according to the individual analysis 
period.
∀
Study baseline: Last observed measurement prior to administration of any initially 
randomised study medication at Day 1.
∀
Titration baseline: Last observed measurement prior to administration of the re-
randomised study medication for the initial empagliflozin patients at Week 14.
∀
Safety baseline: Last observed measurement prior to administration of the re-
randomised study medication for the initial placebo patients at Week 26.
For analyses up to Week 26, data collected after the first intake of study medication in the 
extension period will be censored.
Analyses up to Week 12 and Week 52 will be considered exploratory in nature. The study is 
not powered to compare empagliflozin with linagliptin at Week 12, Week 26 and Week 52, 
or to compare empagliflozin 10 mg with empagliflozin 25 mg at Week 52. No hypothesis 
testing is planned, and only descriptive statistics will be provided.
The anticipation for the patients who would have taken the wrong study medication is low. 
Therefore all analyses will be based on the randomised treatments. All patients with wrong 
study medication will be listed.
For HbA1c analyses, both NGSP certified and non-NGSP certified HbA1c values will be 
used in HbA1c endpoints analyses, given that they are in the same unit. The order of 
preference for the laboratory values are: (1) NGSP certified central laboratory values, (2) 
NGSP certified local laboratory values, and (3) non-NGSP certified local laboratory values. If 
a visit window includes a NGSP certified local laboratory value as well as a non-NGSP 
certified local laboratory value (either both being on- or post-treatment), then the NGSP 
certified value will be selected rather than the non-NGSP certified value.  For study baseline, 
if none of these preference HbA1c values are available at Visit 2, then Screening data will be 
used.


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7.3.1
Primary endpoint analyses
7.3.1.1
DINAMO
The primary endpoint of DINAMOTM is defined in Section 5.1.1.
7.3.1.1.1
Analysis of the primary family of hypotheses
These confirmatory primary analyses will be performed using an effectiveness “wash-out” 
approach based on the mITT set with multiplicity adjustment for simultaneous testing of 
linagliptin and empagliflozin using the Hochberg-procedure. Patients will be assigned to the 
treatment they were randomised to at the initial randomisation, i.e. linagliptin 5 mg, pooled 
empagliflozin or placebo. HbA1c values measured after premature discontinuation of study 
drug or after rescue therapy was initiated will be included in the analyses. All available on-
and off-treatment data up to the Week 26 time point will be included.
There will be different types of missing data to be considered for the imputation.
Table 7.3.1.1.1: 1
“Wash-out” approach – the missing data imputation method
Randomised treatment group: Placebo
Missing HbA1c data will be imputed for all scheduled visits up to Week 26, that includes 
Week 4, Week 12 and Week 26. Baseline will not be imputed.
Type of 
missing data
Data used for imputation
Method to use for
Non-monotone 
missing data
Monotone 
missing data
On-and off-
treatment4 data 
Observed on- and off-treatment 
HbA1c data in the placebo group, 
including Baseline, Week 4, 
Week 12 and Week 26.
MCMC-MI1
(MAR3)
SLR-MI2
(MAR3)
Randomised treatment groups: linagliptin 5 mg and empagliflozin pooled.
Missing HbA1c data will be imputed for Week 26 only.
Type of missing data
Data used for imputation
Method
On-treatment data
Observed on-treatment HbA1c data in the 
respective treatment group, including 
Baseline and Week 26.
SLR-MI2
(MAR3)
Off-treatment4 data 
Observed on- and off-treatment HbA1c 
data in the placebo group, including 
Baseline and Week 26.
SLR-MI2
(MNAR5)
1 Markov Chain Monte Carlo – Multiple imputation (MCMC-MI)
2 Sequential linear regression – Multiple imputation (SLR-MI)
3 Missing at random (MAR)
4 Missing post-treatment data after permanent treatment discontinuation
5 Missing not at random (MNAR)


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For the placebo group, missing HbA1c data, regardless on- or off-treatment, will be imputed 
for all scheduled visits up to Week 26.
The non-monotone missing data will be imputed using Markov Chain Monte Carlo (MCMC) 
simulation and standard techniques; multiple imputation (MI) will be performed on a data set 
including on- and off-treatment HbA1c data in the placebo group at baseline, Week 4, Week 
12 and Week 26 with baseline HbA1c as a continuous covariate and age as a set of binary 
covariates corresponding to its class categorisation levels (age <15 years or age ≥15 to <18 
years). 500 imputations will be performed to ensure adequate efficiency and stability of the 
estimation for missing data. This step will be referred to as “MCMC-MI”.
For the monotone missing data, a sequential linear regression MI approach will be used and 
referred to as ‘SLR-MI’. The MI will be performed on a data set including on- and off-
treatment data and once per imputation from the previous step. This procedure will impute 
values for all missing time points both on- and off-treatment. The regression models will be 
fitted with baseline HbA1c as a continuous covariate and age as a binary covariate (age < 15 
years and age ≥15 to <18 years). 500 imputations for the placebo group will be completed.
For the active treatment groups (linagliptin 5 mg and empagliflozin pooled, regardless of the 
dose level), missing HbA1c data will be imputed for Week 26 only separately for missing on-
treatment data and missing off-treatment data. 
To impute the missing on-treatment data, the MI will be performed on a data set including 
on-treatment HbA1c data in the respective treatment group at baseline and Week 26 only.  
The regression models will be fitted separately by active treatment group with baseline 
HbA1c as a continuous covariate and age as a binary covariate (age <15 years or age ≥15 to 
<18 years). 500 imputations for each active treatment group on-treatment data will be 
completed.
To impute the missing off-treatment data, the MI will be performed on a data set including
patients with missing off-treatment HbA1c data at Week 26 in the active treatment groups 
and available on- and off-treatment HbA1c data in the placebo group at baseline and Week 
26.  The regression models will be fitted separately by active treatment group with baseline 
HbA1c as a continuous covariate and age as a binary covariate (age <15 years or age ≥15 to 
<18 years). 500 imputations for each active treatment group off-treatment data will be 
completed.
The effectiveness analyses will be performed on these imputed data sets plus the retrieved 
HbA1c data at Week 26 from the off-treatment patients, using an ANCOVA model with 
baseline HbA1c as a continuous model term, and with categorical terms for treatment and 
age. Rubin’s rules will be used to combine treatment estimates across the 500 completed
imputations.
The implicit assumption underlying the imputations and analyses is that unobserved off-
treatment patient measurements will lose any treatment effect immediately post-treatment 
discontinuation.


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7.3.1.1.2
Analysis of the secondary family of hypotheses 
If the “wash-out” approach analysis for both hypotheses in the primary family of hypotheses 
shows a statistically significant result, the secondary family of hypotheses will be tested as 
ordered hypotheses at the significance level α = 0.05 (two-sided), i.e., the hypotheses H’0,1
will be tested first and if this hypothesis can be rejected at the level α = 0.05, the hypotheses 
H’0,2 will be tested at the same level.
In using two sets of hypotheses families in a hierarchical order and using all hypotheses in the 
primary family as a gatekeeper for the secondary family, the experimentwise Type I error rate 
across both families is controlled by the significance level α = 0.05.
These secondary family of hypotheses for the primary endpoint will be tested using the
“wash-out” approach described in Section 7.3.1.1 but the ANCOVA used for analysis of the 
completely imputed set will apply an “inverse probability weighting” approach based on the 
mITT set.  
The ANCOVA model will utilise a weight variable having a value of 0 for the patients who 
are not in the hypothesis test of interest; a value of 2 for re-randomised patients who are in 
the hypothesis test of interest and a value of 1 otherwise. The model terms will include 
baseline HbA1c as a continuous variable, and treatment and age as categorical variables. 
Rubin’s rules will be used to combine treatment estimates across the 500 imputations.
Patients will be assigned to the treatment they were randomised to at the initial randomisation 
together with the treatment allocation at Week 14 randomisation. HbA1c values measured 
after premature discontinuation of study drug or after rescue therapy was initiated will be 
included in the analyses. All data up to the Week 26 time point will be included.
The treatment comparisons for H’0,1 and H’0,2 according to Section 7.2.2 are as follows:
For H’0,1, this is a contrast between patients who started empagliflozin 10 mg and either 
having a dose increase in patients who were non-responder at Week 12, or who were 
responders at Week 12 and continue with empagliflozin 10 mg, and placebo.
For H’0,2, this is a contrast between patients who started empagliflozin 10 mg and either were 
responders or were non-responders at Week 12 and continue with empagliflozin 10 mg, and 
placebo.
7.3.1.2
DINAMO Mono
The primary endpoint of DINAMOTM Mono is defined in Section 5.1.1.
The primary analysis will be a comparison of the treatment failure rates of linagliptin 5 mg, 
pooled empagliflozin and placebo. The risk difference of active treatments versus placebo 
will be determined and assessed by an exact 2-sided 90% confidence interval based on the 
method of Chan and Zhang [R15-1346]. Patients will be assigned to the treatment they were 


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randomised to at the initial randomisation. Non-completers who prematurely discontinue 
intake of study drug will be considered treatment failures. 
7.3.2
Secondary endpoint analyses
7.3.2.1
DINAMO
Secondary endpoints of DINAMOTM are defined in Section 5.1.2.
For the secondary endpoints, the patients initially randomised to empagliflozin 
(empagliflozin 10 mg and empagliflozin 25 mg pooled) and linagliptin 5 mg will be
compared versus placebo. Analyses will be performed on the mITT set and will apply two 
approaches. 
  
The first approach will use all observed data including data after premature discontinuation 
of study drug or post rescue medication data up to Week 26.
The change in FPG from baseline to the end of 26 weeks will be analysed using an 
ANCOVA model. The statistical model will be:
FPG change from baseline to the end of 26 weeks =
overall mean + treatment + baseline FPG + age + random error
Treatment is a fixed classification effect. Baseline FPG is a linear covariate and age a 
categorical covariate. The random error is assumed to be normally distributed with mean 0 
and unknown variance σ².
The other continuous secondary endpoints will be analysed based on a restricted maximum 
likelihood (REML) approach using a mixed model for repeated measurements (MMRM). The 
analyses will include the fixed categorical effects of treatment, visit, and treatment by visit
interaction, as well as the categorical covariate age and the continuous, fixed covariates of 
baseline of the response variable and baseline of the response variable by visit interaction. 
The covariate visit will be treated as the repeated measure with an unstructured covariance 
structure used to model the within-patient measurements.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. The residuals are assumed to have a multivariate normal 
distribution with zero means and covariance matrix as specified above.
The second approach will include only on-treatment values measured prior to the start of any 
rescue medication up to Week 26.
The change in FPG from baseline to the end of 26 weeks will be analysed using the 
ANCOVA model, which is described in the first approach, but using the second approach 
data. 


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For the other continuous secondary endpoints analyses, values measured after rescue therapy 
was initiated or after premature discontinuation of study drug will be set to missing. The 
missing data will not be imputed. The MMRM model will handle missing data based on a 
likelihood method under the "missing at random” assumption.
The proportion of patients who achieve HbA1c < 7.0% and < 6.5% at the end of 26 weeks
will be determined per treatment group and the risk difference of active treatments versus 
placebo will be determined and assessed by an exact 2-sided 95% confidence interval.
7.3.2.2
DINAMO Mono
Secondary endpoints of DINAMOTM Mono are defined in Section 5.1.2.
The secondary endpoint of time to treatment failure will be analysed and graphically 
described by Kaplan-Meier estimates up to the planned end of the study. A descriptive Log-
rank test will compare linagliptin 5 mg and pooled empagliflozin versus placebo individually
up to Week 26. Patients in the placebo group will be censored after 26 weeks unless a prior 
treatment failure is observed. Data obtained after re-randomisation in the placebo group will 
not be utilised for the determination of time to treatment failure. 
The change in HbA1c from baseline to the end of 26 weeks will be analysed based on a 
REML approach using MMRM to access the effectiveness and efficacy, using the same 
sensitivity methods as described in Section 7.3.4.1.1 and Section 7.3.4.1.3 respectively.
It is expected that a large group of drug naïve patients will require early intervention of 
rescue medication as early as first on-treatment visit, therefore the change in HbA1c from 
baseline to the end of 26 weeks will also be analysed using an ANCOVA model including 
treatment as a fixed classification effect, baseline HbA1c as a linear covariate, and age as a 
categorical covariate. The missing data will be imputed by the last on-treatment observation 
without rescue medication carried forwards. In case, there is no on-treatment observation 
without rescue medication, baseline value will be carried forward.
The following secondary endpoints will be analysed using the same methods described in 
section 7.3.2.1.
∀
Change in FPG (mg/dl) from baseline to the end of 26 weeks
∀
Change in body weight (kg) from baseline to the end of 26 weeks
∀
Change in SBP (mmHg) from baseline to the end of 26 weeks
∀
Change in DBP (mmHg) from baseline to the end of 26 weeks
The change in FPG (mg/dl) from baseline to the end of 26 weeks will also be analysed using 
an ANCOVA model including treatment as a fixed classification effect, baseline FPG as a 
linear covariate, and age as a categorical covariate. The third approach will have any post-
baseline missing values, off-treatment values and values after rescue medication imputed by 
BOCF since FPG is measured only at baseline and Week 26.


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The proportion of patients who achieve HbA1c < 7.0% and < 6.5% at the end of 26 weeks
will be determined per treatment group and the risk difference of active treatments versus 
placebo will be determined and assessed by an exact 2-sided 90% confidence interval.


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7.3.6
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. In 
general, safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Statistical analyses and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect
period is defined as 7 days after the date of the last dose of trial medication. Adverse events 
that start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’. All AEs occurring before first study medication intake will be assigned 
to ‘pre-treatment’ and all AEs occurring after last study medication intake plus 7 days will be 
assigned to ‘post-treatment’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of 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.
The safety analyses will be performed using the following population set and randomised 
study treatment combinations according to the defined period, separately for DINAMOTM and 
DINAMOTM Mono.
∀
Comparison vs. placebo: All patients in the TS will be included in the safety 
analyses up to Week 26 presented by placebo, linagliptin 5 mg and empagliflozin 
pooled.
∀
Safety during active treatment periods: All patients on active treatment at anytime 
in the TS will be included in the safety analyses up to Week 52 presented by 
linagliptin pooled and empagliflozin pooled. For patients on active treatment and 
initially randomised to placebo at the start of the study, analyses will be restricted to 
data collected after Week 26.  
∀
Assessment of up-titration to empagliflozin 25 mg (For DINAMOTM only):
Patients initially randomised to empagliflozin in the TS, excluding the responders at 
Week 12 and the patients who did not proceed to re-randomisation at Week 14, will 


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be included in the safety analyses from Week 15 to Week 52 presented by 
empagliflozin 10 mg and 25 mg non-responder at Week 12 after initial randomisation.
∀
Long term safety: All patients in the TS, excluding patients initially randomised to 
placebo, will be included in the safety analyses up to Week 52 presented by 
linagliptin 5 mg and empagliflozin pooled.
7.3.7
Pharmacokinetic and pharmacodynamics analyses
In order to complement the pharmacokinetic characterisations of linagliptin and 
empagliflozin in paediatric patients with T2DM, in a first step, a descriptive analysis of the 
plasma concentrations will be performed to allow for a comparison to adults. In a second 
step, a population PK analysis may be conducted if the descriptive analysis suggests 
meaningful differences in the PK of adolescents compared to adults. 
No pharmacodynamics analyses are planned.
PK analyses will be performed in the treated patients. Further information regarding the 
statistical analysis will be documented in the TSAP.
7.4
INTERIM ANALYSES
No interim analysis is planned, but the conduct of the trial will be monitored by a DMC.
7.5
HANDLING OF MISSING DATA
The handling of missing data in the primary and secondary analyses is described in Section 
7.3.1 and Section 7.3.2 respectively. 
Details regarding the imputation rule for further endpoints will be specified in the TSAP.
Missing or incomplete AE data will be imputed according to BI standards. Other missing 
safety data will not be imputed.
7.6
RANDOMISATION
At visit 2, patients will be randomised in blocks to double-blind treatment. Approximately 
equal numbers of patients will be randomised to each treatment group. The randomisation 
will be stratified by age (<15 years; ≥15 to <18 years). It will be monitored and capped so 
that at least 30% but no more than 70% of the randomised patients are < 15 years. For 
DINAMOTM only, the randomisation system will also include caps for gender so that at least 
30% but no more than 70% of the randomised patients are girls.
At visit 4B, patients from the empagliflozin 10 mg arm who do not achieve an HbA1c < 7.0% 
at Week 12 will be re-randomised in blocks to double-blind treatment with either 
empagliflozin 10 mg or empagliflozin 25 mg. This re-randomisation will be stratified by age 
at baseline (< 15 years; ≥ 15 to <18 years). Practically, an IRT call will be performed for all 
patients to maintain double-blind conditions but only patients on empagliflozin 10 mg with 
HbA1c ≥ 7.0% at Week 12 may get new trial treatment re-assigned. 


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At visit 5, patients from the placebo arm will be re-randomised in blocks to double-blind 
treatment. Approximately equal numbers of patients will be re-randomised to empagliflozin 
10 mg, empagliflozin 25 mg, or linagliptin 5 mg. The re-randomisation will be stratified by 
age at baseline (<15 years; ≥15 to <18 years). Practically, an IRT call will be performed for 
all patients to maintain double-blind conditions but only patients on placebo may get new 
trial treatment re-assigned.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report (CTR). Access to 
the codes will be controlled and documented. The method of assigning patients to treatment 
groups is described in Section 4.1.3.
7.7
DETERMINATION OF SAMPLE SIZE
7.7.1
DINAMO
To support the sample size determination various sample size scenarios were considered. The 
underlying assumptions and the power estimates for the final sample size are described in 
details in this section for the “wash out” effectiveness analysis. These estimates are based on 
available study data in adults with T2DM treated with placebo, linagliptin or empagliflozin. 
Sample size calculation for the “wash out” effectiveness analyses
Based on the “wash out” analysis, the superiority of pooled empagliflozin doses 
(empagliflozin 10 mg, empagliflozin 25 mg) and the superiority of linagliptin 5 mg compared 
to placebo will be tested simultaneously using the Hochberg procedure at the study-wise 
alpha level of 0.05 (see section 7.2.1).
For the corresponding power considerations post-rescue data will be included, and it will be 
assumed that there is no treatment difference for off-treatment patients. Average treatment 
effects including HbA1c values after the start of rescue therapy can be obtained from the 
studies quoted below and are summarised in Table 7.7.1: 1. The corrected treatment 
difference in this table was calculated assuming patients discontinuing active treatment show 
the same HbA1c change from baseline as the average placebo patient. 
In Table 7.7.1: 1 HbA1c results are summarised as a basis for the efficacy analysis. Where 
available data for Week 24 are quoted, otherwise for Week 18:
-
Study 1218.17, patients treated with linagliptin 5 mg or placebo in combination with 
metformin background therapy [U09-2533-03]
-
Study 1218.36, patients treated with linagliptin 5 mg or placebo in combination with 
basal insulin therapy [c02697848 ; U11-2286-01]
-
Study 1245.23, patients treated with empagliflozin 10 mg, empagliflozin 25 mg, or 
placebo in combination with metformin background therapy only [U12-1518-01]


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-
Study 1245.33, patients treated with empagliflozin 10 mg, empagliflozin 25 mg, or 
placebo in combination with basal insulin therapy [U12-3817]
-
Study 1245.49, patients treated with empagliflozin 10 mg, empagliflozin 25 mg, or 
placebo in combination with insulin or metformin background therapy [U13-2122]
Studies 1218.17, 1218.36 and 1245.23 assessed the change from baseline to Week 24 as 
primary endpoint, in studies 1245.33 and 1245.49 the primary endpoint was change from 
baseline to Week 18. For all calculations raw means and standard deviations for the primary 
endpoint were considered as initial basis for further calculations. 
Table 7.7.1: 1
HbA1c (%) change from baseline to Week 18 or 24 for studies with 
T2DM patients treated with linagliptin or empagliflozin
Placebo
Active treatment
Corrected 
treatment 
difference4
Study number
N
Mean1
SD2
N
Mean1
SD2
N 
disc.3
Mean Active -
Placebo
1218.17 - Week 24
linagliptin 5 mg
156
-0.07
1.03
471
-0.66
0.85
39
-0.54
1218.36 - Week 24
linagliptin 5 mg
560
0.01
0.93
568
-0.66
0.89
36
-0.63
1245.23 – Week 24
empagliflozin 10 mg
183
-0.26
0.79
206
-0.76
0.76
8
-0.48
1245.33 – Week 18
empagliflozin 10 mg
145
0.06
0.89
152
-0.69
0.88
16
-0.68
1245.49 – Week 18 
empagliflozin 10 mg
173
-0.59
0.85
170
-1.04
0.79
17a
-0.41
1 Mean change from baseline in HbA1c at Week 18 or 24 based on the observed means in the raw data (including post rescue 
medication data)
2 Observed standard deviation in the raw data up to Week 18 or 24 (including post rescue medication data)
3 Number of patients prematurely discontinuing active treatment prior to endpoint visit according to report disposition table
4 Assuming placebo response for patients prematurely discontinuing active treatment
a Number of patients excluded from full analysis completers set, estimate of treatment discontinuations up to Week 18
Based on these results a mean treatment difference in HbA1c change from baseline of -0.55% 
with a SD of 0.9% between active drugs and placebo can be assumed. For the effectiveness 
analysis a covariate adjusted standard deviation of 0.9% can be regarded as the expected 
scenario, while 0.8% will probably be optimistic. A conservative scenario of 1.0% is added 
because of the potential of increased variability through the multiple imputations performed 
for the “wash out”. Power estimates in Table 7.7.1: 2 are based on a two-sided t-test at alpha-
level of 0.05. Additionally the power is given for the alpha-level of 0.025 to provide a lower 
bound of the expected power due to the Hochberg correction for multiplicity. 


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Table 7.7.1: 2
Power estimates for various scenarios for the “wash out” 
effectiveness analysis
Alpha
(2-sided)
Treatment 
effect (%)
Covariate-
adjusted 
standard 
deviation 
(%)
Sample 
size per 
group
Power
0.05
-0.55
1.00
50
77%
0.05
-0.55
0.90
50
85%
0.05
-0.55
0.80
50
92%
0.025
-0.55
1.00
50
68%
0.025
-0.55
0.90
50
78%
0.025
-0.55
0.80
50
87%
Summary
The final sample size of 50 randomised patients per group was chosen as a balance of 
clinical, regulatory, ethical, feasibility and statistical considerations. The objective is to 
minimise exposure of children, given that the available paediatric population is also limited in 
number, while maintaining acceptable statistical properties.
Calculations were performed using nQuery Advisor® 7.0 statistical package by
7.7.2
DINAMO Mono
Data from the empagliflozin Phase III study 1245.20 in adult patients with Type 2 Diabetes 
were analysed to derive estimates for the treatment failure rate based on the definition in 
DINAMOTM Mono. Restricted to a study population with a baseline HbA1c from 6.5% to 
9.0% the treatment failure rates as in Table 7.7.2:1 were determined. 
Table 7.7.2: 1
Treatment failure rate in 1245.20 based on endpoint definition for 
DINAMO Mono
Frequency of treatment failure
Placebo 
N (%)
Empagliflozin 10 mg 
N  (%)
Empagliflozin 25 mg 
N (%)
Sitagliptin 
N (%)
Analysed patients
207 (100)
195 (100)
201 (100)
203 (100)
Treatment failure
138 (  67)
  56 (  29)
43 (  21)
40 (  20)


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A treatment failure rate between 65% and 85% is expected in the placebo group in 
DINAMOTM Mono. The initial minimum sample size of 12 patients per group was chosen so 
that the upper limit of the 90% confidence interval for the risk difference would not include 0 
for an approximate risk difference of 40% (see Table 7.7.2: 2).  
Table 7.7.2: 2
Exact 90% confidence interval for risk difference scenarios in 
DINAMO Mono
Frequency of treatment failure
N per group
Placebo 
N (%)
Active treatment
N (%)
Risk difference
%
Exact 
90% CI 
6
5 (83.3)
1 (16.7)
-66.7
(-93.9, -12.4)
5 (83.3)
2 (33.3)
-50.0
(-85.6, 5.5)
8
6 (75.0)
2 (25.0)
-50.0
(-82.0, -3.1)
6 (75.0)
3 (37.5)
-37.5
(-73.6, 9.7)
10
8 (80.0)
3 (30.0)
-50.0
(-79.2, -8.7)
8 (80.0)
4 (40.0)
-40.0
(-70.8, -0.5)
7 (70.0)
3 (30.0)
-40.0
(-72.1, 1.6)
12
10 (83.3)
5 (41.7)
-41.7
(-69.4, -6.9)
9 (75.0)
4 (33.3)
-41.7
(-70.9, -4.2)
9 (75.0)
5 (41.7)
-33.3
(-63.2, 2.3)
8 (66.7)
3 (25.0)
-41.7
(-70.9, -4.2)
New patient recruitment for DINAMO™Mono was prematurely discontinued due only to 
patient recruitment difficulties. The initially planned recruitment period up to April 2022 was 
preserved, resulting in a sample size of approximately 20 patients in DINAMO™Mono.   


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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), the EU 
regulation 536/2014 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 (Investigator Site File).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective 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 one 
or both parents of the patient (or the patient’s legally accepted representative) according to 
ICH GCP and to the local 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/parent(s)-information form retained by the investigator as part of the trial 
records. A signed copy of the informed consent and any additional parent(s) information must 
be given to each parent or the patient’s legally accepted representative. 
In addition to this document, the patient will be provided with an information sheet adapted 
to his/her age group (two groups: from 10 to 14 years; from 15 to 17 years included). The 
version prepared for the younger patient should be used for the older patient if judged more 
appropriate by the investigator) where his/her assent will be collected according to the 
regulatory and legal requirements of the participating country. Except if the patient is unable 
to do it, he/she will have to sign or write his/her name on this document and to date it in the 
day she/he assents to participate.


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It is important that the investigator ensure at each visit that the patient still assents to 
participate in the study. In addition, the refusal of the patient to participate must be accepted 
independently of the consent of his/her parent(s)/legal guardian.
The patient and his/her parent(s)/legal guardian must be informed that his/her personal trial-
related data will be used by Boehringer Ingelheim in accordance with the local data 
protection law. The level of disclosure must also be explained to the patient and his/her 
parent(s)/legal guardian.
The patient and his/her parent(s)/legal guardian must be informed that the patient’s medical 
records may be examined by authorized monitors (CTM/CRA) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by 
inspectors from regulatory authorities.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. Re-consent can be done 
remotely/by telephone/telemedicine/in-home visit under exceptional circumstances due to the 
COVID-19 pandemic. The initial informed consent and assent at Visit 1A must be done in the 
clinic.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
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 patient. 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 eCRF must be consistent with the source data or the discrepancies must 
be explained. The current medical history of the patient may not be sufficient to confirm 
eligibility for the trial and the investigator may need to request previous medical histories and 
evidence of any diagnostic tests. In this case the investigator must make 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.


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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 eCRF, 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 
and parent(s)/legal guardian was informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if 
available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)
∀
Completion of “Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The 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 eCRF 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 eCRFs 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.
Remote source data verification in exceptional cases at the time of restricted on-site 
monitoring visits due to a COVID-19 pandemic, when such decision has been taken centrally 


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for a trial, must first be discussed with the sponsor before implementation to ensure 
alignment with local regulations.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
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.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
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 
facilityare 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.


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8.6
TRIAL MILESTONES
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.
The IEC / competent authority in each participating country will be notified about the trial 
milestones according to the respective laws.
Two separate clinical trial reports will be written for DINAMOTM and DINAMOTM Mono.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P10-14001
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Woerle HJ. Safety and efficacy of linagliptin as add-on therapy to 
metformin in patients with type 2 diabetes: a randomized, double-blind, 
placebo-controlled study. Diabetes Obes Metab 13 (1), 65 - 74 (2011)
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 
beta-cell function in patients with inadequately controlled type 2 diabetes: a 
randomized controlled trial. Diabetes Obes Metab 13 (3), 258 - 267 (2011)
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 randomized, double-blind, 
placebo-controlled study. Diabetes Obes Metab 13 (7), 653 - 661 (2011)
P11-09378
Schlosser A, Owens D, Taskinen MR, Prato S del, Gomis R, Patel S, 
Pivovarova A, Woerle HJ. 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 54 (1), S108, 
Abstr 242 (2011)
P11-12477
Gallwitz B, Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, 
Dugi K, Woerle HJ. Efficacy and safety of linagliptin in with metformin 
monotherapy inadequately controlled type 2 diabetes. Wirksamkeit und 
Sicherheit von Linagliptin bei mit Metformin-Monotherapie unzureichend 
kontrolliertem Typ-2-Diabetes. 46th Ann Mtg of the German Society of 
Diabetes, Leipzig, 1 - 4 Jun 2011. Diabetologie 6 (Suppl 1), S19, Abstr 
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P12-09397
Global IDF/ISPAD guideline for diabetes in childhood and adolescence. 
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%20Adolesc ence%20Guidelines_0.pdf (access date: 8 August 2012); 
Brussels: International Diabetes Federation (IDF) (2011)
P13-07824
Inzucchi SE, Nauck M, Eynatten M von, Hehnke U, Woerle HJ, Henry R. 
Lower risk of hypoglycemia 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 
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P13-09565
Barnett AH, Huisman H, Jones R, Eynatten M von, Patel S, Woerle HJ. 
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inadequately controlled with common antidiabetes treatments: a 
randomised, double-blind, placebo-controlled trial. Lancet 382 (9902), 1413 
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Websky K von, Reichetzeder C, Hocher B. Linagliptin as add-on therapy to 
insulin for patients with type 2 diabetes. Vasc Health Risk Manage 9, 681 -
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Zeitler P, Fu J, Tandon N, Nadeau K, Urakami T, Barrett T, Maahs D. Type 
2 diabetes in the child and adolescent. Pediatr Diabetes 15 (Suppl 20), 26 -
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Wright EM, Turk E. The sodium/glucose cotransport family SLC5. 
Pfluegers Arch 447 (5), 510 - 518 (2004)
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and youth: a study of the comparative efficacy of metformin alone or in 
combination with rosiglitazone or lifestyle intervention in adolescents with 
type 2 diabetes. Pediatr Diabetes 8, 74 - 87 (2007)
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Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of 
metformin in pediatric patients with type 2 diabetes: a randomized 
controlled trial. Diabetes Care 25 (1), 89 - 94 (2002)
R07-4402
Kaufman FR. Type 2 diabetes in children and youth. Rev Endocr Metab 
Disord 4, 33 - 42 (2003)
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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
Guidance for industry: diabetes mellitus - evaluating cardiovascular risk in 
new antidiabetic therapies to treat type 2 diabetes (December 2008). Silver 
Spring: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) (2008)
R10-0696
Rosenbloom AL, Silverstein JH, Amemiya S, Zeitler P, Klingensmith G. 
Type 2 diabetes in children and adolescents. Pediatr Diabetes 10 (Suppl 12), 
17 - 32 (2009)
R10-0796
Grinstein G, Muzumdar R, Aponte L, Vuguin P, Saenger P, DiMartino-
Nardi J. Presentation and 5-year follow-up of type 2 diabetes mellitus in 
African-American and Caribbean-Hispanic adolescents. Horm Res 60, 121 
- 126 (2003)


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R12-3961
TODAY Study Group. A clinical trial to maintain glycemic control in youth 
with type 2 diabetes. N Engl J Med 366 (24), 2247 - 2256 (2012)
R12-4055
Silverstein JH, Rosenbloom AL. Treatment of type 2 diabetes mellitus in 
children and adolescents. J Pediatr Endocrinol Metab 13 (Suppl 6), 1403 -
1409 (2000)
R14-4331
Liu XS. Sample size for confidence interval of covariate-adjusted mean 
difference. J Educ Behav Stat 35 (6), 714 - 725 (2010)
R14-5435
American Diabetes Association. Hyperglycemic crises in diabetes. Diabetes
Care 27 (Suppl 1), S94 - S102 (2004)
R15-1346
Chan ISF, Zhang Z. Test-Based Exact Confidence Intervals for the 
Difference of Two Binomial Proportions, Biometrics, 55, 1202–1209, 1999.
R16-2240
Nambam B, Silverstein J, Cheng P, Ruedy KJ, Beck RW, Wadwa RP, et al, 
Pediatric Diabetes Consortium. A cross-sectional view of the current state 
of treatment of youth with type 2 diabetes in the USA: enrollment data from 
the Pediatric Diabetes Consortium Type 2 Diabetes Registry. Pediatr 
Diabetes, (2016)
R16-2470
Zappitelli M, Parvex P, Joseph L, Paradis G, Grey V, Lau S, et al. 
Derivation and validation of cystatin C-based prediction equations for GFR 
in children. Am J Kidney Dis 48 (2), 221 - 230 (2006)
R16-2476
Bacchetta J, Cochat P, Rognant N, Ranchin B, Hadj-Aissa A, Dubourg L. 
Which creatinine and cystatin C equations can be reliably used in children. 
Clin J Am Soc Nephrol 6, 552 - 560 (2011)
R16-4703
International Diabetes Federation (IDF) IDFdiabetesatlas
http://www.diabetesatlas.org/ (access date: 29 September 2016) ; 7th ed. 
Brussels: International Diabetes Federation (IDF) (2015)
R17-0216
International Hypoglycaemia Study Group Glucose concentrations of less 
than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint 
position statement of the American Diabetes Association and the European 
Association for the Study of Diabetes. Diabetes Care, (2016)
R18-2686
Zeitler P, Hirst K, Copeland KC, Ghormli L el, Katz LL, Levitsky LL, et al, 
TODAY Study Group. HbA1c after a short period of monotherapy with 
metformin identifies durable glycemic control among adolescents with type 
2 diabetes. Diabetes Care 38 (12), 2285 - 2292 (2015)




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U06-1742 
 BI 10773: In vitro inhibition of SGLT-2 and selectivity vs. 
SGLT1 and GLUT1 transporters. MD2006/007/Lab12. 28 September 2006.
U08-1056
A randomised, double-blind, placebo-controlled, five parallel groups study 
investigating the efficacy and safety of BI 1356 (1 mg, 5 mg and 10 mg 
administered orally once daily) over 12 weeks as add-on therapy in patients 
with type 2 diabetes and insufficient glycaemic control despite metformin 
therapy, including an open-label glimepiride treatment arm.1218.6. 22 Oct
2009.
U08-3761
A randomized, double-blind, placebo-controlled, five parallel group study 
investigating the efficacy and safety of BI 1356 (0.5 mg, 2.5 mg and 5 mg 
administered orally once daily) over 12 weeks in drug naïve and treated 
patients with Type 2 diabetes with insufficient glycemic control (study 
includes an open-label metformin treatment arm). 1218.5. 20 May 2010.
U09-1970
Safety, tolerability, pharmacokinetics and pharmacodynamics of 4 weeks 
treatment with three oral doses of BI 10773 as tablets in female and male 
patients with type 2 diabetes. 1245.4. 23 Sep 2009.
U09-1271
Safety, tolerability, pharmacokinetics and pharmacodynamics of 4 multiple 
rising oral doses (2.5 mg to 100 mg) of BI 10773 tablets in male and female 
type 2 diabetic patients. 1245.2. 24 Mar 2009.
U09-2533-03
A randomised, double-blind, placebo-controlled parallel group efficacy and 
safety study of linagliptin (5 mg administered orally once daily) over 24 
weeks in type 2 diabetic patients with insufficient glycaemic control despite 
metformin therapy. 1218.17. 11 Mar 2011.
U10-2326
A Phase II, randomised, double-blind, placebo-controlled, multiple dose 
study to evaluate pharmacodynamics, pharmacokinetics, safety, and 
tolerability of once daily oral administration of BI 10773 (1 mg, 5 mg, 10 
mg, and 25 mg) for 28 days in Japanese patients with type 2 diabetes 
mellitus. 1245.15. 23 Aug 2010.
U11-2286-01
 A Phase III randomised, double-blind, 
placebo-controlled, parallel group efficacy and safety study of Linagliptin 
(5 mg), administered orally once daily for at least 52 weeks in type 2 
diabetic patients in combination with basal insulin therapy. BI trial 1218.36 
final report date: 21 September 2011.
U10-1103
A randomised, double-blind, placebo-controlled parallel group efficacy and 
safety study of linagliptin (5 mg administered orally once daily) over 24 
weeks, in drug naïve or previously treated (6 weeks washout) type 2 
diabetic patients with insufficient glycaemic control. 1218.16. 15 Mar 2011.


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U12-1518-01
A phase III randomised, double-blind, placebo-controlled, parallel group, 
efficacy and safety study of BI 10773 (10 mg, 25 mg) administered orally, 
once daily over 24 weeks in patients with type 2 diabetes mellitus with 
insufficient glycaemic control despite treatment with metformin alone or 
metformin in combination with a sulphonylurea
U12-3817
A phase IIb, randomised, double-blind, placebo-controlled, parallel group, 
safety and efficacy study of BI 10773 (10 mg and 25 mg) administered 
orally, once daily over 78 weeks in type 2 diabetic patients receiving 
treatment with basal insulin (glargine, detemir, or NPH insulin only) with or 
without concomitant metformin and/or sulfonylurea therapy and insufficient 
glycaemic control. 1245.33. 11 January 2013
U13-2122
A phase III, randomized, double-blind, placebo-controlled, parallel group 
safety and efficacy study of BI 10773 (10 mg and 25 mg administered 
orally once daily) during 52 weeks in patients with type 2 diabetes mellitus 
and insufficient glycemic control on MDI insulin regimen alone or with 
metformin. 1245.49. 20 September 2013


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10.
APPENDICES
10.1
TANNER STAGING MODIFIED
The evaluation of the Tanner stage will be performed during the physical examination at the 
time points defined in the Flow Chart to assess the patient’s pubertal stage.
To determine the Tanner stage, the investigator should perform a brief check of external 
primary and secondary sex characteristics during the physical examination. The investigator 
will then score against the scale after the child has left the examination room. The most 
advanced pubertal stage will be documented.
Age appropriate explanations will be given, with emphasis that their privacy will be respected 
at all times. They will be reassured that their research records will be anonymised and only 
authorized trusted persons will monitor their notes to ensure the research is being conducted 
properly.
Here is a representation of the Tanner staging scale for both female and male children.
Figure 10.1: 1 
Tanner Stages


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Number of global amendment
1
Date of CTP revision
03 Oct 2019
EudraCT number
2016-000669-21
BI Trial number
1218-0091
BI Investigational Product(s)
Linagliptin (BI 1356) 
Empagliflozin (BI 10773)
Title of protocol
A double-blind, randomised, placebo-controlled, 
parallel group trial to evaluate the efficacy and 
safety of empagliflozin and linagliptin over 26 
weeks, with a double-blind active treatment 
safety extension period up to 52 weeks, in 
children and adolescents with type 2 diabetes 
mellitus
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
X
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
Title Page
Description of change
New TCM assignment, updated version and date
Section to be changed
Synopsis
Description of change
No. of patients:
Number of patients increased in DINAMO. 
Addition of the number of patients to be included 
in DINAMOTM Mono.
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA.
Section to be changed
Synopsis
Description of change
Trial rationale added


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Rationale for change
Consistency with current sponsor CTP template
Section to be changed
Synopsis
Description of change
“Treated with metformin and/or insulin” text 
bolded
DINAMOTM Mono objective added
Rationale for change
To clarify the difference between the two studies
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA.
Section to be changed
Synopsis
Description of change
Main inclusion criteria:
1.
Different patient 
population (HbA1c ranges and treatment) 
defined for the inclusion of patients in 
DINAMOTM and DINAMOTM Mono 
2.
Additional of DINAMOTM
Mono patients
3.
Clarification of the 
criterion related to acute metabolic 
decompensation 
4.
Clarification of the 
criterion related to auto-antibodies
Rationale for change
1.
To reflect the linagliptin 
and empagliflozin Proposed Pediatric Study 
Request (PPSR) agreed with FDA
2.
To reflect the linagliptin 
and empagliflozin Proposed Pediatric Study 
Request (PPSR) agreed with FDA
3.
To reflect the linagliptin 
and empagliflozin Proposed Pediatric Study 
Request (PPSR) agreed with FDA
4.
Patients should be 
negative for both IA-2 and GADA auto-
antibodies to be eligible for this trial.
Section to be changed
Synopsis
Description of change
Endpoints:
Different primary and secondary endpoints 
defined for DINAMOTM Mono
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
Synopsis
Description of change
Statistical methods: 
1.
The primary endpoint will 
be analysed using a Pattern Mixture Model 
(PMM) only; the efficacy Mixed Model for 


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Repeated Measurements (MMRM) will no 
longer be used.
2.
Description of the 
statistical methods that will be used for 
DINAMOTM Mono
Rationale for change
1. To reflect the last PIP modification request 
agreed with EMA/PDCO.
2. To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) 
agreed with FDA
Section to be changed
Flowchart
Description of change
Visit window added for V1A and Foot note 1 for 
out of window allowances at Visits 1A and 1B
Rationale for change
To enable the availability of auto-antibodies 
results before the Visit 2 in case Visit 1B is 
performed on the same day as Visit 1A. The 
turn-around-time is 13 working days for the IA-2 
auto-antibodies assay
Section to be changed
Flowchart
Description of change
Height to be performed at V1A instead of V1B
Rationale for change
Height is required for eGFR calculation at V1A
Section to be changed
Flowchart
Description of change
Administer double-blind trial drugs added at 
Visit 8
Rationale for change
To ensure consistency in the protocol. Last study 
drug intake will occur at Visit 8 while the patient 
is at the clinic.
Section to be changed
Flowchart
Description of change
Self-blood glucose and ketone monitoring added 
at V4B
Rationale for change
To reflect the regular measurements to be 
performed during the entire treatment period
Section to be changed
Flowchart
Description of change
Foot note 4 revised to include additional 
interactions between the site and the patient 
(every 4 weeks between each clinic visits) 
Rationale for change
To reflect the last PIP modification request 
agreed with EMA/PDCO
Section to be changed
Flowchart
Description of change
Foot note 5: concomitant medication to be 
collected at subsequent visits in case of 
premature treatment discontinuation.
Rationale for change
To be consistent with Section 6.2.3.
Section to be changed
Flowchart
Description of change
Foot note 7: Clarification on the reduced panel 
for the screening visit only.


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Rationale for change
Upon request of Medicine and Healthcare 
products Regulatory Agency (MHRA) in UK
Section to be changed
Flowchart
Description of change
Footnote 11: Revision of the frequency for blood 
ketone bodies measurement
Rationale for change
To reflect the last PIP modification request 
agreed with EMA/PDCO
Section to be changed
Flowchart
Description of change
Footnote 13 added
Rationale for change
To clarify the visits to be performed in case of 
early EOT for patients not accepting to attend 
subsequent planned visits.
Section to be changed
Abbreviations
Description of change
Some abbreviations removed/added
Rationale for change
To reflect the changes in the protocol 
amendment
Section to be changed
1.2.1 Drug profile -Empagliflozin
Description of change
Update on safety information
Rationale for change
To be aligned with the Investigator Brochure 
version 18
Section to be changed
2.1 Rationale for performing the trial
Description of change
Addition of the rationale for conducting 
DINAMOTM Mono
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
2.2 Trial objectives
Description of change
Addition of DINAMOTM Mono objectives.
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
2.3 Benefit-risk assessment
Description of change
Details on background therapies and HbA1c 
ranges removed, references to the appropriate 
sections are included, and updated important 
safety information
Rationale for change
To cover the specificities of DINAMOTM Mono
and alignment with the Investigator Brochure 
version 18
Section to be changed
3.1 Overall trial design and plan
Description of change
Addition of DINAMOTM Mono
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
Figure 3.1:2


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Description of change
To outline the trial duration, primary endpoint, 
and treatment groups defined for both 
DINAMOTM and DINAMOTM Mono using two 
pictorials instead of one
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
3.1 Overall trial design and plan
Description of change
Increased number of patients randomized in 
DINAMOTM and number of patients to be 
randomized in DINAMOTM Mono, clarity on 
randomization for DINAMOTM
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
3.1.1 Administrative structure of the trial
Description of change
Sponsor template language updated to reference 
Clinergize portal repository for study documents
Rationale for change
Consistent text with sponsor CTP template
Section to be changed
3.1.1.1 CEC – cardiovascular events
Description of change
Removal of hospitalisation for unstable angina 
from the adjudication process.
Rationale for change
Unstable angina is not a specific safety concern 
for any of the IMPs and no efficacy endpoint (or 
part of an endpoint); alignment with other BI 
trials. 
Section to be changed
3.1.1.3 CEC- Pancreatic events
Description of change
Section removed.
Rationale for change
Based on linagliptin data in adult T2DM 
(including large outcome trials) very low rates of 
pancreatitis anticipated; formal adjudication of 
isolated cases in the paediatric population to be 
replaced by case-by-case expert consultation for 
potential pancreatitis events.  
Section to be changed
3.2 Discussion of trial design, including the 
choice of control group(s)
Description of change
Addition of the rationale for the DINAMOTM
Mono primary endpoint.
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
3.3 Selection of trial population
Description of change
Revision of the number of trial site, increased 
number of patients randomized in DINAMO, and 
addition of the number of patients to be included 


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in DINAMOTM Mono, and estimated patients 
randomized per site.
Protocol violations replaced by protocol 
deviations.
Patients with HbA1c < 6.5% can discontinue 
metformin and undergo HbA1c retesting after 12 
weeks for possible eligibility into DINAMOTM
Mono.
Rationale for change
To reflect the actual trial status and the 
linagliptin and empagliflozin Proposed Pediatric 
Study Request (PPSR) agreed with FDA
To align with BI SOPs and CTP template text.
Eligibility for DINAMOTM Mono patients 
regarding metformin use.
Section to be changed
3.3.2 Inclusion criteria
Description of change
1. Revision of inclusion criteria #6 and #7
2. Addition of inclusion criterion #10
Rationale for change
1. To reflect the actual trial status and the 
linagliptin and empagliflozin Proposed 
Pediatric Study Request (PPSR) agreed with 
FDA
2. Patients should be negative for both IA-2 and 
GADA auto-antibodies to be eligible for this 
trial.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Removal of exclusion criterion #1
Rationale for change
Patients should be negative for both IA-2 and 
GADA auto-antibodies to be eligible for this 
trial. Added in the inclusion criteria section.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Revision of exclusion criterion #2
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Addition of criteria (pancreatitis, bullous 
pemphigoid, arthralgia, Fournier’s gangrene, or 
ketoacidosis) for stopping trial treatment intake
Rationale for change
To reflect the Investigator Brochure guidance
Section to be changed
4.1.1 Identity of the Investigational Medicinal 
Products
Description of change
The words Linagliptin and Empagliflozin 
capitolized
Rationale for change
Administrative update
Section to be changed
4.1.3 Method of assigning patients to 
treatment groups


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Description of change
Correction of visit number at week 26
Rationale for change
To be consistent with the Flowchart
Section to be changed
4.2.1 Other treatments and emergency 
procedures
Description of change
Clarify MDI insulin
Revision of the criteria for initiating rescue 
medication for DINAMOTM (addition of regular 
interactions between the patient and the site 
between clinic visits) and addition of specific 
criteria for initiating rescue medication for 
DINAMOTM Mono.
Rationale for change
Administrative update
To reflect the last PIP modification request 
agreed with EMA/PDCO and the linagliptin and 
empagliflozin Proposed Pediatric Study Request 
(PPSR) agreed with FDA
Section to be changed
4.2.2.2 Restrictions on diet and life style
Description of change
New guidance on diet and exercise 
recommendations to be provided by the site to 
the patient.
Rationale for change
To reflect the last PIP modification request 
agreed with EMA/PDCO
Section to be changed
5.1.1 Primary endpoints
Description of change
Different primary endpoint for DINAMOTM
Mono
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
5.1.2 Secondary endpoints
Description of change
Additional secondary endpoints for DINAMOTM
Mono
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change


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Section to be changed
Description of change
Rationale for change
Section to be changed
5.2.3 Systolic/diastolic blood pressure and 
heart rate
Description of change
Clarify heart rate will be measured and not just 
pulse rate
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
Clarification of the Table 5.3.3:1 Footnote 1, 
reduced panel for screening visit only.
Rationale for change
Upon request of Medecine and Healthcare 
products Regulatory Agency (MHRA) in UK
Section to be changed
5.3.5.2 Self-blood glucose monitoring
Description of change
Revision of the minimum requirements 
(frequency of measurement).
Rationale for change
To reflect the last PIP modification request 
agreed with EMA/PDCO
Section to be changed
5.3.5.3 Self-blood ketone monitoring
Description of change
Revision of the measurement frequency.
Rationale for change
To reflect the last PIP modification request 
agreed with EMA/PDCO
Section to be changed
5.3.5.6 Criteria for hypoglycaemic event
Description of change
Plasma glucose equal to or below 70 mg/dL shall 
be documented in the eCRF, this guidance is 
consistent with ADA guidelines
Rationale for change
A value of 70 mg/dL was excluded from 
reporting erroneously.
Section to be changed
5.3.6.1 Definitions of AEs
Description of change
AESI
Removal of the section related to the “list of 
additional search categories for safety topics of 
interest” available in the ISF/eDC
Rationale for change
To reflect the actual process, list not available in 
the ISF/eDC
Section to be changed
5.3.6.1 Definitions of AEs
Description of change
Addition of bullous pemphigoid, arthralgia and 
monitoring of safety assessments during the trial.
Rationale for change
To reflect the linagliptin and empagliflozin 
Proposed Pediatric Study Request (PPSR) agreed 
with FDA


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Section to be changed
5.3.6.2 Adverse event collection and reporting
Description of change
AE collection
Clarification of AE collection for patients who 
discontinue trial medication prematurely. 
Rationale for change
To correct protocol inconsistency.
Section to be changed
5.3.6.2 Adverse event collection and reporting
Description of change
Pregnancy
Removal of the following sentence: Similarly, 
potential drug exposure during pregnancy must 
be reported if a partner of a male trial participant 
becomes pregnant. This requires a written 
consent of the pregnant partner
Rationale for change
No risk identified in the Investigator Brochures 
in case of pregnancy in a partner of a male trial 
participant, to reflect BI CTP template and 
Guidance on contraception in clinical trials.
Section to be changed
5.4.2.1 Plasma sampling for pharmacokinetic 
analysis
Description of change
Revision of the volume of blood to be drawn.
Rationale for change
To be consistent with the lab manual
Section to be changed
6.2.2 Treatment period(s)
Description of change
Addition of regular interactions with the patient 
between clinic visits.
Rationale for change
To reflect the last PIP modification request 
agreed with EMA/PDCO
Section to be changed
7.1 Statistical design - Model
Description of change
Removed the efficacy MMRM confirmatory 
primary analysis for the primary family of 
hypotheses. 
Renamed the primary PMM analysis to PMM 
“jump-to-placebo” analysis.
Added new Section 7.1.1 for the existing primary 
endpoint for DINAMOTM
Added new Section 7.1.2 for different primary 
endpoint for DINAMOTM Mono
Rationale for change
The EMA has requested the same confirmatory 
primary analysis as the FDA, Therefore the 
MMRM is no longer required.
To clarify the approach used for PMM.
To reflect the linagliptin and empagliflozin 
PPSR agreed with FDA
Section to be changed
7.2.1 Primary family of hypotheses 
Description of change
Renamed section 7.2.1 
Added section 7.2.1.1 for primary family of 
hypotheses (include the content of the legacy 
section 7.2.1) and section 7.2.1.2 for secondary 


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family of hypotheses (include the content of the 
legacy section 7.2.2)
Rationale for change
To reflect the linagliptin and empagliflozin 
PPSR agreed with FDA
Section to be changed
(New) 7.2.1.1 Primary family of hypotheses
Description of change
Added “The Hochberg-procedure will account 
for multiple testing within the primary family of 
hypotheses.”
Rationale for change
To clarify how to address the multiplicity.
Section to be changed
(New) 7.2.1.2 Secondary family of hypotheses
Description of change
Renamed the primary PMM analysis to PMM 
“jump-to-placebo” analysis.
Rephrased the treatment groups’ description for 
the hypotheses. 
Rationale for change
To clarify the approach used for PMM.
To remove the ambiguity of the treatment group 
description.
Section to be changed
7.2.2 Secondary family of hypotheses
Description of change
Renamed section 7.2.2 to DINAMOTM Mono 
and described the DINAMOTM Mono primary 
hypothesis.
Rationale for change
To clarify the required hypothesis.
Section to be changed
7.3 Planned analyses
Description of change
Section re-organised to consolidated information 
into the corresponding sections
Provided analysis sets definition and new 
baseline definition.
Rationale for change
Simplified the section to allow clear information 
for the main and ancillary study.
Section to be changed
7.3.1.1 Analysis of the primary family of 
hypothesis for the primary endpoint
Description of change
Renamed section 7.3.1.1 to DINAMOTM
Added section 7.3.1.1.1 Analysis of the primary 
family of hypothesis (include the content of the 
legacy section 7.3.1.1) and section 7.3.1.1.2 
Analysis of the secondary family of hypothesis 
(include the content of the legacy section 7.3.1.2)
Rationale for change
To reflect the linagliptin and empagliflozin 
PPSR agreed with FDA
Section to be changed
(New) 7.3.1.1.1 Analysis of the primary family 
of hypotheses
Description of change
Removed the efficacy MMRM confirmatory 
primary analysis for the primary family of 
hypotheses.  


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Clarified the PMM “jump-to-placebo” approach 
by adding Table 7.3.1.1.1: 1 and other wording 
update.
Rationale for change
To reflect the FDA suggestion
To be consistent with Section 7.1
Section to be changed
(New) 7.3.1.1.2 Analysis of the secondary 
family of hypotheses
Description of change
Re-organised section for the ease of 
understanding.
Added new description for the new PMM 
“inverse probability weighting” approach.
Removed the previous MMRM model 
description to sensitivity analyses.
Rationale for change
To reflect the FDA suggestion
Section to be changed
7.3.1.2 Analysis of the secondary family of 
hypotheses for the primary endpoint
Description of change
Renamed section 7.3.1.2 to DINAMOTM Mono 
and described the DINAMOTM Mono primary 
analysis 
Rationale for change
To reflect the linagliptin and empagliflozin 
PPSR agreed with FDA. To be consistent with 
Section 7.3
Section to be changed
7.3.1.3 Secondary analyses of the primary 
endpoint
Description of change
Section removed. Content added into new 
section 7.3.4 Sensitivity analysis
Rationale for change
To tidy the section for the ease of understanding.
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
(New) 7.3.2.1 DINAMOTM
Description of change
Swapped the order of the 2 different analysis 
approaches. 
Updated 24 weeks to 26 weeks in the FPG 
model.
Moved the paragraph of how to the handle 
missing data from Section 7.5.
Added new secondary endpoints: proportion of 
patients who achieve HbA1c < 7.0% and < 6.5% 
at the end of 26 week.


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Clarify baseline of the response variable
Rationale for change
To be consistent with the primary analysis to 
analyse the data with off-treatment first.
To correct the typo.
To line up with the primary analysis which 
described how to handle the missing data within 
the section.
New endpoints added according to FDA written 
requests.
Clarify what baseline variable is used in the 
model.
Section to be changed
(New) 7.3.2.2 DINAMOTM Mono
Description of change
Described the DINAMOTM Mono secondary 
analyses
Added new secondary endpoints: proportion of 
patients who achieve HbA1c < 7.0% and < 6.5% 
at the end of 26 week.
Clarify the reference method is a sensitivity 
method
Rationale for change
To reflect the linagliptin and empagliflozin 
PPSR agreed with FDA
New endpoints added according to FDA written 
requests.
Clarify what method is used
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed


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Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
7.3.6 Safety analysis
Description of change
Section number changed to 7.3.6 from 7.3.4.
Added 4 different approaches to present the 
safely data.
Rationale for change
To clarify how to perform the safety analyses.
Section to be changed
7.5 Handling of missing data
Description of change
Moved the FPG missing data handling 
description to Section 7.3.2.
Added reference to Section 7.3.1 and Section 
7.3.2 for the primary and secondary endpoints 
missing data handling. 
Rationale for change
To make the content of the protocol easier to 
follow.
Section to be changed
7.6 Randomisation
Description of change
Clarified the gender cap at visit 2 is for 
DINAMOTM only
Rationale for change
To indicate where the rule should applied
Section to be changed
7.7 Determination of sample size
Description of change
Added section 7.7.1 for DINAMOTM (include the 
original section 7.7 content) and section 7.7.2 for 
DINAMOTM Mono
Rationale for change
To reflect the linagliptin and empagliflozin 
PPSR agreed with FDA


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Section to be changed
(New) 7.7.1 for DINAMOTM
Description of change
Removed sample size calculation for the primary 
MMRM efficacy analyses.
Re-numbered Table 7.7: 3 to Table 7.7.1: 1, and 
Table 7.7: 4 to Table 7.7.1: 2.
Updated Table 7.7.1:2 with 50 patients and new 
power.
Rationale for change
Primary MMRM efficacy analysis is no longer 
required by the EMA.
Re-organised the table numbers within the 
section. 
To agreed FDA written requests to increase the 
number of patients to 50.
Section to be changed
(New) 7.7.2 for DINAMOTM Mono
Description of change
Described the determination of sample size for 
DINAMOTM Mono
Rationale for change
To reflect the linagliptin and empagliflozin 
PPSR agreed with FDA
Section to be changed
8.6 Trial Milestones
Description of change
Separate Clinical Trial Reports for DINAMOTM
and DINAMOTM Mono.
Rationale for change
To write the DINAMOTM Clinical Trial Report 
as soon as the last patient last visit milestones is 
reached for DINAMOTM.
Section to be changed
9.1 Published references
Description of change
Additional references
Rationale for change
Related to DINAMOTM Mono.
11.2
GLOBAL AMENDMENT 2
Number of global amendment
2
Date of CTP revision
28 Sep 2020
EudraCT number
2016-000669-21
BI Trial number
1218-0091
BI Investigational Product(s)
Linagliptin (BI 1356) 
Empagliflozin (BI 10773)
Title of protocol
A double-blind, randomised, placebo-controlled, 
parallel group trial to evaluate the efficacy and 
safety of empagliflozin and linagliptin over 26 
weeks, with a double-blind active treatment 
safety extension period up to 52 weeks, in 
children and adolescents with type 2 diabetes 
mellitus


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To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Title Page
Description of change
Updated document number, version, and date
Section to be changed
Synopsis
Description of change
1. Updated status and revision date 
2. Main inclusion criterion was updated to reduce 
T2DM diagnosis to 8 weeks; added minimum 
daily metformin dosage; and for DINAMO 
Mono: replaced washout of metformin with 
discontinuation of metformin
3. Updated the primary endpoint analysis from 
“Pattern Mixed Model (PMM) “Jump-to-
placebo” approach” to ““wash-out” approach”
Rationale for change
1. Updated status and revision date
2. Allow patients to screen for the trial at an 
earlier timeframe; reflect the last PIP 
modification request agreed with EMA/PDCO;
and for better understanding of stopping 
metformin
3. Based on FDA request
Section to be changed
Flowchart
Description of change
1. Footnote 4 updated to allow for remote visits 
due to exceptional circumstances 
2. Footnote 5 updated to clarify actions if a 
patient terminates treatment prematurely
3. Footnote 13 updated to clarify actions if a 
patient terminates treatment prematurely
4. Footnote 14 added to allow for vital signs, 
weight, and local laboratory testing due to 
exceptional circumstances 


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5. Footnote15 added to allow for study 
procedures to be conducted remotely due to 
exceptional circumstances 
6. Footnote16 added to allow for shipment of 
study medication to a patient’s home due to 
exceptional circumstances 
Rationale for change
1. COVID-19 pandemic alternative process
2. Clarify procedures if a patient discontinues 
study medication prematurely 
3. Clarify procedures if a patient discontinues 
study medication prematurely
4. COVID-19 pandemic alternative process
5. COVID-19 pandemic alternative process
6. COVID-19 pandemic alternative process
Section to be changed
Table of Contents
Description to be changed
7.3.4 – 7.3.7 updated/corrected and 11.1 and 11.2 
added
Rationale for change
Correction to section names and addition of new 
sections
Section to be changed
Abbreviations
Description of change
COVID-19, EoT, and SARS added and PMM 
removed. The abbreviation for “MI” added to 
MCMC and SLR defintions.
Rationale for change
To reflect the changes in the protocol amendment
or prior content not defined
Section to be changed
1.1 Medical Background
Description of change
Clarify compounds are now approved as 
monotherapy for adjunct to diet and exercise
Rationale for change
Updated drug profile
Section to be changed
1.2.1 Empagliflozin
Description of change
Updated number of approved countries
Rationale for change
Number of countries that have approved 
compound use has increased
Section to be changed
2.1 Rationale for Performing the Trial
Section to be changed
Clarify results from two dose-finding studies 
involved both compounds
Rationale for change
Administrative clarification
Section to be changed
2.3 Benefit-Risk Assessment
Description of change
1. Administrative corrections/updates and added 
guidance to consider discontinuation of 
empagliflozin in cases that predispose 
ketoacidosis
2. Added section titled COVID-19 Pandemic
Rationale for change
1. Additional ketoacidosis monitoring
2. Due to the pandemic, an assessment was 
performed and risk management measures added


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Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Added reference to early treatment 
discontinuation guidance
Rationale for change
Provide location for source of additional guidance
Section to be changed
3.1.1.1 Clinical Event Committee –
cardiovascular events
Description of change
Removal of reference to meta-analysis
Rationale for change
Administrative update
Section to be changed
3.3 Selection of Trial Population
Description of change
Replaced washout of metformin with 
discontinuation of metformin
Rationale for change
Allow for better understanding of stopping 
metformin
Section to be changed
3.3.2 Inclusion criteria
Description of change
1. Inclusion criteria 5 was updated to reduce 
T2DM diagnosis to 8 weeks
2. Inclusion criteria 7A added minimum daily 
metformin dosage and moved metformin 
intolerance text to appropriate location 
3. Inclusion criteria 7B replaced washout of 
metformin with discontinuation of metformin
4. Inclusion criteria 11 was changed to inclusion 
criteria 10 
Rationale for change
1. Allow patients to screen for the trial at an 
earlier timeframe
2. To reflect the last PIP modification request 
agreed with EMA/PDCO and an administrative 
update
3. Allow for better understanding of stopping 
metformin4. To align with the numbering in the 
eCRFs from CTP2 to avoid a mismatch
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Added ability to replace patients in exceptional
cases due to COVID-19 pandemic
Rationale for change
Trial has a small sample size and this change 
gives more flexibility to collect sufficient data, if 
needed
Section to be changed
4.2.1 Other treatments and emergency 
procedures
Description of change
Administrative clarifications
Rationale for change
Administrative clarifications
Section to be changed
5.2.1 HbA1c and fasting plasma glucose (FPG)
Description of change
Testing may also be done at a local laboratory
Rationale for change
COVID-19 pandemic alternative process
Section to be changed
5.2.2 Body weight
Description of change
Testing  may also be done at a local laboratory


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Rationale for change
COVID-19 pandemic alternative process
Section to be changed
5.2.3 Systolic/diastolic blood pressure and 
heart rate (vital signs)
Description of change
Testing may also be done at a local laboratory
Rational for change
COVID-19 pandemic alternative process
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
Testing may also be done at a local laboratory
Rationale for change
COVID-19 pandemic alternative process
Section to be changed
5.3.6.2 Adverse event collection and reporting
Description of change
Removed reference to fax and added in country 
specific reporting process clarification
Rationale for change
Alternative methods of SAE report transmission
are allowed for some countries
Section to be changed
6. Investigational Plan
Decription of change
Updated to allow for remote visits due to 
exceptional circumstances
Rationale for change
COVID-19 pandemic alternative process
Section to be changed
6.2.3 Follow Up Period and Trial Completion
Description of change
1. Clarification of which patient group completes 
FUP visit and what eCRF to complete
2. Clarification of what constitutes the end of trial 
and timing of EOT visit
Rationale for change
1. Administrative clarifications
2. Administrative clarifications
Section to be changed
7.1.1 DINAMOTM
Description of change
Updated the primary endpoint analysis from 
“Pattern Mixed Model (PMM) “Jump-to-
placebo” approach” to ““washout” approach”
Rationale for change
Based on FDA request
Section to be changed
7.2.1.1 Primary family of hypotheses
Description of change
Added significance level
Rationale for change
To provide more information about the 
hypotheses
Section to be changed
7.2.1.2 Secondary family of hypotheses
Description of change
Added significance level
Rationale for change
To provide more information about the 
hypotheses
Section to be changed
7.3 PLANNED ANALYSES
Description of change
Addressed all analyses are using randomised 
treatments. Wrong medication will be listed.
Rationale for change
To clarify how to handle wrong medication.
Section to be changed
7.3.1.1.1 Analysis of the primary family of 
hypotheses
Description of change
Updated the primary endpoint analysis from 
“PMM “Jump-to-placebo” approach” to ““wash-


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out” approach” and description of the new 
method
Rationale for change
Based on FDA request
Section to be changed
7.3.1.1.2 Analysis of the secondary family of 
hypotheses
Description of change
Updated the primary endpoint analysis from 
“PMM “Jump-to-placebo” approach” to ““wash-
out” approach”
Rationale for change
Based on FDA request
Section to be changed
7.3.2.1 DINAMOTM
Description of change
Removed the analysis of the proportion of 
patients who achieve HbA1c < 7.0% and < 6.5% 
at the end of 26 weeks from the secondary 
endpoint analysis first approach 
Rationale for change
To be consistent with the TSAP
Section to be changed
7.3.4.5 Primary family of hypotheses –
COVID-19 related intercurrent events (New)
Description of change
New additional sensitivity analysis for the 
primary endpoint, hypothetical for COVID-19
Rationale for change
COVID-19 pandemic response to analysis
Section to be changed
Description of change
Rationale for change
Section to be changed
7.3.6 Safety analyses
Description of change
Clarified randomised treatments are used in the 
safety analysis.
Rationale for change
To clarify randomised treatments are in used for 
the safety analyses.
Section to be changed
7.3.7 Pharmacokinetic and pharmacodynamics 
analyses
Description of change
Added population TS for the PK analysis and 
further information will be in the TSAP.
Rationale for change
To clarify which population to be used for PK 
anslysis and the location for further information.
Section to be changed
7.7.1 DINAMO™
Description of change
Updated the primary endpoint analysis from 
“PMM “Jump-to-placebo” approach” to ““wash-
out” approach”
Rationale for change
Based on FDA request


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Section to be changed
8.3.2 Direct access to source data and 
documents
Description of change
Added new paragraph:
Remote source data verification in exceptional 
cases at the time of restricted on-site monitoring 
visits due to a COVID-19 pandemic, when such 
decision has been taken centrally for a trial, must 
first be discussed with the sponsor before 
implementing to ensure alignment with local 
regulations.
Rationale for change
COVID-19 pandemic mitigation
Section to be changed
8.6 Trial Milestones
Description of change
Removal of reference of final report submission 
to the EU database
Rationale for change
Administrative update
Section to be changed
9.2 Unpublished References
Description of change
New sources cited regarding risk-benefit and 
document numbers U09-2533 and U11-2286 
corrected to U09-2533-03 and U11-2286-01
Rationale for change
New sources cited and administrative update
Section to be changed
11.1 Global amendment 1 (new)
Description of change
Sub section title added for amendment 1 and 
number of global amendment corrected
Rationale for change
Administrative update
Section to be changed
11.2 Global amendment 2 (new)
Description of change
Sub section title added for amendment 2
Rationale for change
Administrative update
11.3
GLOBAL AMENDMENT 3
Number of global amendment
3
Date of CTP revision
14 Dec 2020
EudraCT number
2016-000669-21
BI Trial number
1218-0091
BI Investigational Product(s)
Linagliptin (BI 1356) 
Empagliflozin (BI 10773)
Title of protocol
A double-blind, randomised, placebo-controlled, 
parallel group trial to evaluate the efficacy and 
safety of empagliflozin and linagliptin over 26 
weeks, with a double-blind active treatment 
safety extension period up to 52 weeks, in 
children and adolescents with type 2 diabetes 
mellitus


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To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Title Page
Description of change
Updated version and date
Section to be changed
Flow Chart
Description of change
Footnote * updated to allow for re-consent to be 
conducted remotely due to exceptional 
circumstances. Clarification that the initial 
informed consent and assent at visit 1A are done 
in the clinic as visit 1A cannot be done remotely 
due to exceptional circumstances.
Rationale for change
COVID-19 pandemic alternative process
Section to be changed
Table of Contents
Description of change
Add new section 11.3 
Rationale for change
Addition of new section
Section to be changed
Abbreviations
Description of change
EMA, PDCO, PIP added
Rationale for change
Administrative update
Section to be changed
1.1 Medical Background
Description of change
Document number in reference to Empagliflozin 
and Linagliptin Investigator’s Brochure updated 
Rationale for change
Administrative update
Section to be changed
1.2.1 Empagliflozin
Description of change
Document number in reference to Empagliflozin 
Investigator’s Brochure updated 
Rationale for change
Administrative update
Section to be changed
1.2.2 Linagliptin
Description of change
Document number in reference to Linagliptin 
Investigator’s Brochure updated 
Rationale for change
Administrative update
Section to be changed
3.3.1 Main diagnosis for trial entry


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Description of change
Amend time to diagnosis of T2DM from 12 
weeks to 8 weeks to align with inclusion criteria 
5 that was updated in CTP4
Rationale for change
Align the time to diagnosis of T2DM in all 
relevant sections of protocol. The reduction in 
time to diagnosis will allow patients to be 
considered for study participation sooner.
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
1. In case of a positive urine pregnancy test, a 
serum pregnancy test can be done at a local 
laboratory due to exceptional circumstances
2. Update the document number for 
Empagliflozin Investigator’s Brochure
Rationale for change
1. COVID-19 pandemic alternative process
2. Administrative update
Section to be changed
6.2.2 Treatment period(s)
Description of change
Additional text added to re-randomization visits 
4B and 5 to confirm patients take trial drugs on 
the same day
Rational for change
Consistency with guidance provided at initial 
randomization
Section to be changed
8.1 Trial Approval, Patient Information, 
Informed Consent
Description of change
Additional text added to allow for re-consent to 
be conducted remotely due to exceptional 
circumstances. Clarification that the initial 
informed consent and assent at visit 1A are done 
in the clinic as visit 1A cannot be done remotely 
due to exceptional circumstances.
Rationale for change
COVID-19 pandemic alternative process
Section to be changed
9.2 Unpublished References
Description of change
Update the document number for Empagliflozin 
and Linagliptin Investigator’s Brochure
Rationale for change
Administrative update
Section to be changed
11.3 Global amendment 3 (new)
Description of change
Sub section title added for amendment 3 
summary of changes
Rationale for change
Administrative update
11.4
GLOBAL AMENDMENT 4 – SENT TO FDA ONLY
Number of global amendment
4
Date of CTP revision
14 Jul 2021
EudraCT number
2016-000669-21
BI Trial number
1218-0091


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BI Investigational Product(s)
Linagliptin (BI 1356) 
Empagliflozin (BI 10773)
Title of protocol
A double-blind, randomised, placebo-controlled, 
parallel group trial to evaluate the efficacy and 
safety of empagliflozin and linagliptin over 26 
weeks, with a double-blind active treatment 
safety extension period up to 52 weeks, in 
children and adolescents with type 2 diabetes 
mellitus
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Title Page
Description of change
Updated version and date
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Revision date and main criteria for inclusion 
updated
Rationale for change
Patient recruitment support in DINAMO™
Mono; show both conventional and SI units for 
entry criteria
Section to be changed
Table of Contents
Description of change
Add new sections 7.3.4.6 and 11.4
Rationale for change
Addition of new sections
Section to be changed
Abbreviations
Description of change
CGM, CTM, and SI added
Rationale for change
Administrative update
Section to be changed
1.1 Medical Background
Description of change
Update the document number for Empagliflozin 
Investigator’s Brochure
Rationale for change
Administrative change
Section to be changed
1.2.1 Empagliflozin
Description of change
Update the document number for Empagliflozin 
Investigator’s Brochure


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Rationale for change
Administrative change
Section to be changed
2.1 Rationale for Performing Trial
Description of change
Removal of metformin discontinuation for at 
least 12 weeks, adding insulin discontinuation in 
DINAMO™ Mono
Rationale for change
Representative of clinician actions if metformin 
is discontinued vs. waiting 12 weeks to start 
another antidiabetic therapy, clarification for 
actions if patients are on insulin
Section to be changed
3.1.1 Administrative structure of the trial
Description of change
Replaced Trial Clinical Monitor with Clinical 
Trial Leader, replaced Local Clinical Monitor 
with Clinical Trial Manager
Rationale for change
Administrative update
Section to be changed
3.3 Selection of Trial Population
Description of change
1. Changed time between rescreening visits from 
12 to 8 weeks
2. Removal of investigator discretion to 
withdraw metformin and retest in 12 weeks
3. Removal of metformin discontinuation for at 
least 12 weeks, adding insulin discontinuation in 
DINAMO™ Mono
Rationale for change
1. Allows patients to rescreen sooner
2. Representative of clinician actions to mimic 
real world if metformin is discontinued vs. 
waiting 12 weeks to retest and start another 
antidiabetic therapy
3. Representative of clinician actions to mimic 
real world if metformin is discontinued vs. 
waiting 12 weeks to start another antidiabetic 
therapy and clarification for actions if patients 
are on insulin
Section to be changed
3.3.1 Main diagnosis for trial entry
Description of change
Removal of time to diagnosis of T2DM of 8 
weeks in DINAMO™ Mono patients
Rationale for change
Allows newly diagnosed patients to enroll 
sooner and is consistent with pediatric 
guidelines to start antidiabetic therapy vs. 
waiting 8 weeks to achieve stable glycemic 
control with diet/exercise
Section to be changed
3.3.2 Inclusion criteria
Description of change
5. Removal of time to diagnosis of T2DM of 8 
weeks in DINAMO™ Mono patients
7b. Removal of metformin discontinuation for at 
least 12 weeks, adding metformin intolerance 


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and insulin discontinuation at investigator’s 
discretion in DINAMO™ Mono
9. Addition of SI units of c-peptide laboratory 
value
Rationale for change
1.  Allows newly diagnosed patients to enroll 
sooner and is consistent with pediatric 
guidelines to start antidiabetic therapy vs. 
waiting 8 weeks to achieve stable glycemic 
control with diet/exercise
2. Representative of clinician actions if 
metformin is discontinued vs. waiting 12 weeks 
to start another antidiabetic therapy, clarification 
for actions if patients are on insulin 
3. Provide both conventional and SI central 
laboratory units for investigators to assess entry 
criteria
Section to be changed
4.1.5.1 Blinding
Description of change
Clarify bioanalyst blinding access for both trials
Rational for change
Clarify bioanalyst blinding access for both trials
Section to be changed
5.2.1 HbA1c and fasting plasma glucose
Description of change
Add if a centrally analyzed, NGSP-certified 
hemoglobin A1c assay is unavailable (e.g. due 
to the COVID-19 pandemic), an HbA1c assay 
performed at a local laboratory is acceptable.
Rationale for change
Clarification requested by the FDA in CTP4
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
Update the document number for Empagliflozin 
Investigator’s Brochure
Rationale for change
Administrative change
Section to be changed
5.3.5.1 Height and Body Mass Index (BMI)
Description of change
Added “e.g. z score” to SDS
Rationale for change
Administrative update to align with TSAP
Section to be changed
5.3.5.2 Self-blood glucose monitoring
Description of change
Add continuous glucose monitoring device as an 
alternative to glucometer measurements
Rationale for change
Patients with a CGM device do not also have to 
use the SBGM device 
Section to be changed
6.2.2 Treatment period(s)
Description of change
Add CGM
Rationale for change
An alternative means to measure blood glucose 
concentration
Section to be changed
7.3 Planned Analyses
Description of change
New paragraph added to describe the type of 
HbA1c values will be used in the analyses.
Rationale for change
Clarification requested by the FDA in CTP4


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Section to be changed
7.3.1.1.1 Analysis of the primary family of 
hypotheses
Description of change
Table 7.3.1.1.1: 1 footnote 4 update from “Any 
instance of a patient permanently discontinuing 
or changing treatment (excluding change of 
empagliflozin dose and excluding start of rescue 
medication) will lead to all future measurements 
being considered as off-treatment.” to “Missing 
post-treatment data after permanent treatment 
discontinuation”.
Rationale for change
To clarify what off-treatment data is included in 
the analysis
Section to be changed
7.3.1.1.2 Analysis of the secondary family of 
hypotheses
Description of change
Change from “The ANCOVA model will utilise 
a weight variable having a value of 0 for the 
patients who are not in the hypothesis test of 
interest; a value of 2 for re-randomised patients 
who are in the hypothesis test of interest and a 
value of 1 otherwise.” to “The ANCOVA 
models performed for each hypothesis will 
utilise a weight variable having a value of 2 for 
re-randomised patients and a value of 1 for all 
other patients for the respective hypothesis test.”
Rationale for change
To clarify the secondary family of hypotheses 
ANCOVA model.
Section to be changed
Description of change
Rationale for change
Section to be changed
8.1 Trial Approval, Patient Information, 
Informed Consent
Description of change
Changed abbreviation of CML to CTM
Rationale for change
Administrative change
Section to be changed
9.2 Unpublished References
Desription of change
Update the document number for Empagliflozin 
Investigator’s Brochure
Rationale for change
Administrative change
Section to be changed
11.4 Global amendment 4 (new)
Description of change
Sub section title added for amendment 4 
summary of changes
Rationale for change
Administrative update


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11.5
GLOBAL AMENDMENT 5
Number of global amendment
5
Date of CTP revision
28 Sep 2021
EudraCT number
2016-000669-21
BI Trial number
1218-0091
BI Investigational Product(s)
Linagliptin (BI 1356) 
Empagliflozin (BI 10773)
Title of protocol
A double-blind, randomised, placebo-controlled, 
parallel group trial to evaluate the efficacy and 
safety of empagliflozin and linagliptin over 26 
weeks, with a double-blind active treatment 
safety extension period up to 52 weeks, in 
children and adolescents with type 2 diabetes 
mellitus
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Title Page
Description of change
Updated status, version, and date
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Updated date 
Rationale for change
Administrative change
Section to be changed
Table of Contents
Description of change
Add new section 11.5
Rationale for change
Addition of new section
Section to be changed
5.3.5.2 Self-blood glucose monitoring
Description of change
Added “To avoid additional finger pricks for 
blood glucose measurement.”
Rationale for change
Clarify that subjects with a CGM device may 
forego additional SBGM in order to avoid 
additional finger pricks for blood glucose 


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measurement, in response to feedback from the 
FDA.
Section to be changed
7.3.1.1.2 Analysis of the secondary family of 
hypotheses
Description of change
Replaced text with “The ANCOVA model will 
utilise a weight variable having a value of 0 for 
the patients who are not in the hypothesis test of 
interest; a value of 2 for re-randomised patients 
who are in the hypothesis test of interest and a 
value of 1 otherwise.”
Rationale for change
Revert to original text and reject proposed 
changes in global amendment 4 based on 
feedback from the FDA.
Section to be changed
11.4 Global amendment 4
Description of change
Added “Sent to FDA Only”
Rationale for change
Clarify that this amendment was sent to the 
FDA only for initial feedback before 
implementation in all countries as DINAMO 
Mono was a written request from the FDA.
Section to be changed
11.5 Global amendment 5 (new)
Description of change
Sub section title added for amendment 5 
summary of changes
Rationale for change
Provide a summary of the changes implemented.
11.6
GLOBAL AMENDMENT 6
Number of global amendment
6
Date of CTP revision
23 May 2022
EudraCT number
2016-000669-21
BI Trial number
1218-0091
BI Investigational Product(s)
Linagliptin (BI 1356) 
Empagliflozin (BI 10773)
Title of protocol
A double-blind, randomised, placebo-controlled, 
parallel group trial to evaluate the efficacy and 
safety of empagliflozin and linagliptin over 26 
weeks, with a double-blind active treatment 
safety extension period up to 52 weeks, in 
children and adolescents with type 2 diabetes 
mellitus
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 


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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
Title Page
Description of change
Updated document number, status, version, and 
date
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Updated date, reduced DINAMO™ Mono 
sample size; addition of bone fracture as an 
additional safety criteria
Rationale for change
Administrative change; analysis of bone fracture 
is part of the safety analysis
Section to be changed
Flowchart
Description of change
“r” from rPK blood sampling removed
Rationale for change
Administrative change
Section to be changed
Table of Contents
Description of change
Update section 7.3.4 and add new section 11.6
Rationale for change
Administrative format updates and addition of 
new section
Section to be changed
1.1 Medical Background
Description of change
Updated Empagliflozin Investigator Brochure 
number
Rationale for change
Administrative change
Section to be changed
1.2.1 Empagliflozin
Description of change
Updated Empagliflozin Investigator Brochure 
number
Rationale for change
Administrative change
Section to be changed
2.3 Benefit – Risk Assessment
Description of change
Clarification of no drug-drug interactions for 
Covid treatments based on product labels
Rationale for change
Administrative change
Section to be changed
3.1 Overall Trial Design Plan
Description of change
(1) Reduced DINAMO™ Mono sample size; (2) 
Figure 3.1:1 and 3.1:2 reduced DINAMO™ 
Mono sample size
Rationale for change
Sponsor decision to stop new patient enrollment 
in April 2022, the FDA’s view of the value of 
monotherapy pediatric trials has changed with 
the evolving standards of care
Section to be changed
3.3 Selection of Trial Population
Description of change
Reduced DINAMO™ Mono sample size


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Rationale for change
Sponsor decision to stop new patient enrollment 
in April 2022, the FDA’s view of the value of 
monotherapy pediatric trials has changed with 
the evolving standards of care
Section to be changed
Description of change
Rationale for change
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
Updated Empagliflozin Investigator Brochure 
number
Rationale for change
Administrative change
Section to be changed
5.3.6.1 Definitions of AEs
Description of change
Addition of bone fracture as an additional safety 
topic
Rationale for change
Analysis of bone fracture is part of the safety 
analysis
Section to be changed
7.3.2.2 DINAMO™ Mono
Description of change
Renumbering of link to section headers
Rationale for change
Administrative change
Section to be changed
7.3.4 Sensitivity analysis of the primary 
endpoint (for DINAMO only)
Description of change
Removal of DINAMO only in section header
Rationale for change
A sensitivity analysis will be performed in 
DINAMO™ Mono
Section to be changed
7.3.4.1 DINAMO™ (new)
Description of change
New section header added specific to 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.1.1 Primary family of hypotheses –
MMRM effectiveness analysis
Description of change
Renumbering of section headers for 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.1.2 Secondary family of hypotheses –
MMRM effectiveness analysis
Description of change
Renumbering of section headers for 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.1.3 MMRM efficacy analysis
Description of change
Renumbering of section headers for 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.1.4 Analyses on further patient set


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Description of change
Renumbering of section headers for 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.1.5 Primary family of hypotheses –
COVID-19 related intercurrent events
Description of change
Renumbering of section headers for 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.1.6 Primary family of hypotheses – Non-
NGSP certified laboratories HbA1c values
Description of change
Renumbering of section headers for 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.2 DINAMO™ Mono (new)
Description of change
New section header added specific to 
DINAMO™
Rationale for change
Administrative change
Section to be changed
7.3.4.2.1 Primary analysis with DINAMO 
eligible patients (new)
Description of change
Description of DINAMO™ Mono sensitivity 
analysis
Rationale for change
Inclusion of DINAMO™ patients with no 
background therapy in the DINAMO™ Mono 
sensitivity analysis
Section to be changed
7.7.2 DINAMO™ Mono
Description of change
(1) Old text: “The minimum sample size of 12 
patients per group was chosen … “ to new text
“The initial minimum sample size of 12 patients 
per group was chosen …”; (2) Added  “N per 
group = 6” into intext Table 7.7.2:2; (3) Added 
explanation for early termination of patient 
recruitment in DINAMO™ Mono
Rationale for change
Sponsor decision to stop new patient enrollment 
in April 2022, the FDA’s view of the value of 
monotherapy pediatric trials has changed with 
the evolving standards of care
Section to be changed
8.6 Trial Milestones
Description of change
Removed reference to the potential for 
DINAMO™ and DINAMO™ Mono patients 
finishing at the same time
Rationale for change
Administrative change
Section to be changed
9.2 Unpublished References
Description of change
Updated Empagliflozin Investigator Brochure 
and BI 10773 and Linagliptin Benefit-Risk 
document numbers


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Rationale for change
Administrative change due to updated document 
versions
Section to be changed
11.6 Global amendment 6 (new)
Description of change
Subsection title added for amendment 6 
summary of changes
Rationale for change
Provide a summary of the changes implemented


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
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Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F


SAP_001.pdf: 
 
Trial Statistical Analysis Plan
c20394975-05
BI Trial No.:
1218-0091
Title:
A double-blind, randomised, placebo-controlled, parallel group trial 
to evaluate the efficacy and safety of empagliflozin and linagliptin 
over 26 weeks, with a double-blind active treatment safety extension 
period up to 52 weeks, in children and adolescents with type 2 
diabetes mellitus.
The DINAMOTM (main study) and DINAMOTM Mono (ancillary 
study) studies.
Including Revised Protocol (Global Amendment 6) [c03490746-08]
Investigational 
Product(s):
Linagliptin (BI 1356)
Empagliflozin (BI 10773)
Responsible trial 
statistician(s):
Phone: +
Date of statistical 
analysis plan:
28 JUL 2022 REVISED
Version:
Revised
Page 1 of 125
Proprietary confidential information
! 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1
TABLE OF CONTENTS ......................................................................2
2
LIST OF ABBREVIATIONS ...............................................................6
3
INTRODUCTION..................................................................................9
4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.......10
5
ENDPOINTS ........................................................................................11
5.1
PRIMARY ENDPOINTS.......................................................................................11
5.2
SECONDARY ENDPOINTS.................................................................................11
5.2.1
Key secondary endpoints........................................................................................11
5.2.2
Secondary endpoints...............................................................................................11
5.4
OTHER VARIABLES............................................................................................14
5.4.4
Safety data ...............................................................................................................15
6
GENERAL ANALYSIS DEFINITION.............................................16
6.1
TREATMENTS ......................................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS .......................................................19
6.3
PATIENT SETS ANALYSED...............................................................................19
6.5
POOLING OF CENTRES.....................................................................................33
6.6
HANDLING OF MISSING DATA AND OUTLIERS........................................33
6.6.1
Methods of data selection.......................................................................................33
6.6.2
Imputation methods................................................................................................34
6.6.3
Missing dates and times..........................................................................................34
6.6.4
Missing and incomplete laboratory reference ranges .........................................35
6.7
BASELINE, TIME WINDOW, AND CALCULATED VISITS ........................35
7
PLANNED ANALYSES......................................................................40
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS...........41
7.1.1
Baseline evaluation .................................................................................................41
7.2
CONCOMITANT DISEASES AND MEDICATION .........................................42
7.3
TREATMENT COMPLIANCE............................................................................43
7.4
PRIMARY ENDPOINTS.......................................................................................44
7.4.1
DINAMO .................................................................................................................44
7.4.1.1
Primary family of analyses .......................................................................................44
7.4.1.2
Secondary family of analyses ...................................................................................46
7.4.1.4
Effect of centre..........................................................................................................53


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7.4.2
DINAMO Mono ......................................................................................................54
7.4.3
HbA1c data summary.............................................................................................55
7.5
SECONDARY ENDPOINTS.................................................................................55
7.5.1
Key secondary endpoints........................................................................................55
7.5.2
(Other) Secondary endpoint(s) ..............................................................................55
7.5.2.1
DINAMO..................................................................................................................55
7.5.2.2
DINAMO Mono........................................................................................................56
7.7
EXTENT OF EXPOSURE.....................................................................................59
7.8
SAFETY ANALYSIS .............................................................................................60
7.8.1
Adverse events.........................................................................................................61
7.8.1.1
Assignment of AEs to treatment...............................................................................61
7.8.1.2
Analysis of other significant AEs.............................................................................61
7.8.1.3
AE summaries...........................................................................................................62
7.8.1.4
Protocol-specified AEs of special interest (AESI) ...................................................63
7.8.1.5
Other specific adverse events ...................................................................................63
7.8.1.6
Events qualifying for external adjudication by the Clinical Event Committee........66
7.8.1.7
AEs while patients taking wrong study medication..................................................67
7.8.1.8
AE incidence rates ....................................................................................................67
7.8.1.9
COVID-19 ................................................................................................................67
7.8.2
Laboratory data......................................................................................................68
7.8.2.1
General laboratory evaluation...................................................................................68
7.8.2.2
Elevated liver enzymes .............................................................................................69
7.8.2.3
Lipid parameters .......................................................................................................70
7.8.2.4
Renal laboratory parameters .....................................................................................70
7.8.2.5
Biomarkers................................................................................................................71
7.8.3
Vital signs.................................................................................................................71
7.8.4
ECG ……………………………………………………………………………….72
8
REFERENCES.....................................................................................73


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10
HISTORY TABLE...............................................................................99




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2
LIST OF ABBREVIATIONS
Term
Definition / description
ADaM
Analysis Data Model
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
AP
Alkaline phosphatase
ASA
Acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
BI
Boehringer Ingelheim
BIcMQ
BI-customised MedDRA query
BMI
Body mass index
BMI z-score
BMI Standard Deviation Score
BOCF
Baseline observation carried forward
CEC
Clinical event committee
COVID-19
Corona virus disease – year 2019
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database lock
DBP
Diastolic blood pressure
DKA
Diabetic Ketoacidosis
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EOS
End of study
EOT
End of treatment
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FPG
Fasting plasma glucose
Height z-score
Height Standard Deviation Score


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Term
Definition / description
ADaM
Analysis Data Model
HbA1c
Glycated haemoglobin
HLT
High level term
ICH
International Conference on Harmonisation
IRT
Interactive Response Technology
L
Skewness
M
Median
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MCMC
Markov Chain Monte Carlo
MI
Multiple imputation
mITT
Modified intention to treat
MMRM
Mixed model for repeated measures
MNAR
Missing not at random
NCF
Non-completers considered failure
NGSP
National Glycohemoglobin Standardization Program
NTx
N-terminal cross-linked telopeptide
OC
Observed cases
OC-AD
Observed cases – all data
OC-AD-BOCF
Observed cases - all data and baseline observation carry forward
OC-LOCF
Observed cases – Last observation carry forward
OC-ROC
Observed cases – rescue observed cases
OR
Original results
PCSA
Potentially clinically significant abnormalities
PD
Protocol deviation
PG
Plasma glucose
PK
Pharmacokinetics
PKS
PK parameter analysis set
PMM
Pattern mixed model
PPS
Per protocol set
PT
Preferred term


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Term
Definition / description
ADaM
Analysis Data Model
PD
Protocol deviation
Q1
Lower quartile
Q3
Upper quartile
REML
Restricted maximum likelihood
RS
Randomised set
S
Coefficient of variation
SBP
Systolic blood pressure
SCR
Screened set
SD
Standard deviation
SE
Standard error
SLR
Sequential linear regression
SMQ
Standardised MedDRA query
SOC
System Organ Class
SSC
Special search category
TBILI
Total bilirubin
TDMAP
Trial Data Management and Analysis Plan
TSactive
Treated set active
TSAP
Trial statistical analysis plan
UACR
Urine Albumin Creatinine Ratio
ULN
Upper limit of normal
UTI
Urinary tract infection
WHO
World health organisation
WHO DD
Word Health Organisation Drug Dictionary


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3
INTRODUCTION
As per the ICH E9 guideline (1), the purpose of this document is to provide a more technical 
and detailed elaboration of the principal features of the analysis described in Clinical Trial 
Protocol (CTP), and to include detailed procedures for executing the statistical analysis of the 
primary and secondary variables and other data.
The Trial Statistical Analysis Plan (TSAP) assumes familiarity with the 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, randomisation.
SAS Version 9.4 or later version will be used for all analyses.


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4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY
Analyses updated according to CTP global amendment 6 dated 23 May 2022.


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5
ENDPOINTS
5.1
PRIMARY ENDPOINTS
DINAMO
The primary efficacy endpoint is the change in HbA1c [%] from baseline to the end of 26 
weeks.
For the definition of baseline HbA1c refer to Section 6.7.
DINAMO Mono
The primary efficacy endpoint is the occurrence of treatment failure up to or at Week 26 as a 
binary endpoint. Treatment failure is defined as meeting at least one of the following criteria:
∀
Use of rescue medication, see Section 7.6.1, at any time up to Week 26 (including 
Week 26)
∀
Increase from baseline in HbA1c by 0.5% (at least 0.5% in absolute value) at Week 
26
∀
Increase from baseline in HbA1c to above 7.0% at Week 26 in patients with baseline 
HbA1c < 7.0%
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Since there are no key secondary endpoints specified in the CTP, this section is not 
applicable. 
5.2.2
Secondary endpoints
DINAMOTM
∀
Change in fasting plasma glucose (FPG) [mg/dl] from baseline to the end of 26 weeks
∀
Change in body weight [kg] from baseline to the end of 26 weeks
∀
Change in systolic blood pressure (SBP) [mmHg] from baseline to the end of 26 
weeks
∀
Change in diastolic blood pressure (DBP) [mmHg] from baseline to the end of 26 
weeks
∀
Proportion of patients who achieve HbA1c < 6.5% at the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 7.0% at the end of 26 weeks


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DINAMO Mono
∀
Time to treatment failure
o
Time to treatment failure is the first of the following criteria:

Time to first use of rescue medication

Time to first increase from baseline in HbA1c by at least 0.5% in 
absolute value, or

Time to first increase from baseline in HbA1c to above 7.0% in 
patients with baseline HbA1c < 7.0%, or

Time to premature discontinuation of treatment 
∀
Change in HbA1c [%] from baseline to the end of 26 weeks
∀
Change in FPG [mg/dl] from baseline to the end of 26 weeks
∀
Change in body weight [kg] from baseline to the end of 26 weeks
∀
Change in SBP [mmHg] from baseline to the end of 26 weeks
∀
Change in DBP [mmHg] from baseline to the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 6.5% at the end of 26 weeks
∀
Proportion of patients who achieve HbA1c < 7.0% at the end of 26 weeks
For baseline definitions for each endpoint, refer to Section 6.7.  


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5.4
OTHER VARIABLES


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5.4.4
Safety data
The SBP and DBP will be derived for use in the statistical analysis as the mean of all 
available SBP and DBP readings, respectively, at the same visit.
Standard adverse event attributes (seriousness, intensity, relationship of AEs, AEs leading to 
study medication discontinuation), laboratory endpoints, vital signs and BMI z-score will be 
analysed.
For the full definition of safety endpoints, refer to CTP Section 5.3.


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6
GENERAL ANALYSIS DEFINITION
6.1
TREATMENTS
There will be five analysis phases: screening, placebo run-in, double-blind study treatment 
phase, post-treatment and post-study, as follows:
∀
Screening period: Starts from the date of informed consent and ends on the day before 
the start date of the placebo run-in period (inclusive).
∀
Placebo run-in period: From the date of first administration of placebo run-in 
medication up to the first administration of the initial randomised study medication.
∀
On-treatment period: From the date (and time, if measured) of first administration of 
the initial randomised study medication up to last administration of study medication 
plus X days (inclusive). See definition of X in Table 6.7: 1.
∀
Post-treatment period: From the date of last administration of study medication plus
X+1 days up to the last contact date (inclusive). The last contact date is defined as the 
latest of the following dates (last contact date from end-of-study eCRF page, the last 
administration of study medication date from end-of-treatment eCRF page, the last 
visit date). If the last contact date is prior to the date of last administration of study 
medication plus X+1 days the post-treatment period will not be defined.
∀
Post-study period: From the last contact date plus 1 day and ends at study database 
lock date for the corresponding study (i.e. DINAMO or DINAMO Mono). 
Both safety and efficacy analyses will follow the intention-to-treat principle in assigning 
patients to treatment groups, i.e. patients will be analysed in the treatment group to which 
they were randomised. In addition, AEs with an onset during the time of any incorrect study 
treatment intake will be listed separately.
The following treatment groupings will be used for the efficacy and safety analyses:
Treatment grouping 1 (TG1) for Placebo controlled period from Day 1 to Week 26:
∀
Placebo (Pbo)
∀
Linagliptin 5 mg (L5)           
∀
Empagliflozin pooled (E Pooled), consisting of
o
Empagliflozin 10 mg responders at Week 12 to 10 mg (E10R-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 10 mg (E10NR-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 25 mg (E10NR-25)
o
Empagliflozin 10 mg  and not proceed to re-randomisation at Week 14 (E10)


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Treatment grouping 2 (TG2) for Empagliflozin 25 mg titration period from Day 1 to 
Week 26:
∀
Placebo (Pbo)
∀
Empagliflozin titration start with 10 mg and increased dose at re-randomisation if 
needed (E Titr25), consisting of
o
Empagliflozin 10 mg responders at Week 12 to 10 mg (E10R-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 25 mg (E10NR-25)
o
Empagliflozin 10 mg and not proceed to re-randomisation at Week 14 (E10)
Treatment grouping 3 (TG3) for Empagliflozin 10 mg titration period from Day 1 to 
Week 26:
∀
Placebo (Pbo)
∀
Empagliflozin titration start with 10 mg and dose remained at re-randomisation if 
needed (E Titr10), consisting of
o
Empagliflozin 10 mg responders at Week 12 to 10 mg (E10R-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 10 mg (E10NR-10)
o
Empagliflozin 10 mg and not proceed to re-randomisation at Week 14 (E10)
Treatment grouping 4 (TG4) for the period following the administration of the re-
randomised medication planned at Week 14 up to Week 26/Week 52:
∀
Empagliflozin 10 mg after initial Empagliflozin 10 mg non-response (E10NR/10*)
∀
Empagliflozin 25 mg after initial Empagliflozin 10 mg non-response (E10NR/25*)
Treatment grouping 5 (TG5) for long term analysis period from Day 1 to Week 52:
∀
Linagliptin 5 mg (L5)
∀
Empagliflozin pooled (E Pooled), consisting of
o
Empagliflozin 10 mg responders at Week 12 to 10 mg (E10R-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 10 mg (E10NR-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 25 mg (E10NR-25)
o
Empagliflozin 10 mg and not proceed to re-randomisation at Week 14 (E10)


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Treatment grouping 6 (TG6) for active treatment period:
∀
Linagliptin 5 mg active pooled (L5 active), consisting of 
o
Linagliptin 5 mg from the initial randomisation (L5)
o
Linagliptin 5 mg after initial placebo (P/L5*)
∀
Empagliflozin active pooled (E active), consisting of
o
Empagliflozin 10 mg responders at Week 12 to 10 mg (E10R-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 10 mg (E10NR-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 25 mg (E10NR-25)
o
Empagliflozin 10 mg and not proceed to re-randomisation at Week 14 (E10)
o
Empagliflozin 10 mg after initial placebo (P/E10*)
o
Empagliflozin 25 mg after initial placebo (P/E25*)
Treatment grouping 7 (TG7) for the period following  the administration of the re-
randomised medication planned at Week 26 up to Week 52:
∀
Linagliptin 5 mg after initial placebo (P/L5*)
∀
Empagliflozin 10 mg after initial placebo (P/E10*)
∀
Empagliflozin 25 mg after initial placebo (P/E25*)
Treatment grouping 8 (TG8) for result disclosure from Day 1 to Week 52:
∀
Placebo and not proceed to re-randomisation at Week 26 (Pbo)
∀
Placebo to empagliflozin 10 mg at Week 26 (P-E10)
∀
Placebo to empagliflozin 25 mg at Week 26 (P-E25)
∀
Placebo to linagliptin 5 mg at Week 26 (P-L5)
∀
Linagliptin 5 mg (L5)
∀
Empagliflozin 10 mg (E10) consisting of
o
Empagliflozin 10 mg responders at Week 12 to 10 mg (E10R-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 10 mg (E10NR-10)
o
Empagliflozin 10 mg and not proceed to re-randomisation at Week 14 (E10)
∀
Empagliflozin 10 mg non-responders at Week 12 to 25 mg (E10NR-25)
Treatment grouping 9 (TG9) for AE result disclosure from Day 1 to Week 52:
∀
Placebo before re-randomisation at Week 26 (Pbo)
∀
Linagliptin 5 mg active pooled (L5 active), consisting of 
o
Linagliptin 5 mg from the initial randomisation (L5)
o
Linagliptin 5 mg after initial placebo (P/L5*)
∀
Empagliflozin 10 mg active pooled (E10 active), consisting of
o
Empagliflozin 10 mg and not proceed to re-randomisation at Week 14 (E10)
o
Empagliflozin 10 mg responders at Week 12 to 10 mg (E10R-10)
o
Empagliflozin 10 mg non-responders at Week 12 to 10 mg (E10NR-10)
o
Empagliflozin 10 mg non-responders at Week 12 before re-randomisation to 
25 mg (E10NR*/25)
o
Empagliflozin 10 mg after initial placebo (P/E10*)


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∀
Empagliflozin 25 mg active pooled (E25 active), consisting of
o
Empagliflozin 25 mg after initial Empagliflozin 10 mg non-response
(E10NR/25*)
o
Empagliflozin 25 mg after initial placebo (P/E25*)
The treatment grouping TGx will be used according to the type of analysis, that has been 
assigned for each analysis throughout the TSAP. The treatment (or a combination of 
treatments) with the solid bullet point will be used in the analyses and the outputs 
presentation will use the short name as shown in bold in brackets. Each combination of 
treatments is defined by a list of treatments identifying the type and timing of the treatment. 
As a first example, the treatment identifier “E10R-10” means the patient was initially 
assigned to empagliflozin 10 mg and then carried on to empagliflozin 10 mg as a responder at 
Week 12, the entire treatment period is included. As a second example, the treatment 
identifier “E10NR/25*” means the patient was initially assigned to empagliflozin 10 mg and 
then carried on to empagliflozin 25 mg as a non-responder at Week 12, but only the re-
randomised treatment period from Week 14 is included. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important if it affects the rights or safety of the study patients, or 
if it can potentially influence the primary outcome measurement for the respective patients in 
a way that is neither negligible nor in accordance with the study objectives.  The specification 
and handling of PDs that are determined to be important will be documented in 4-12-01-
sdtm-dv-domain-specification located in BIRDS.  Not all important PDs will generate 
exclusion from an analysis population set. The specifications will indicate which important 
PDs will lead to an exclusion. 
The specification document will also list the PDs that have been manually evaluated and 
determined to be important, and confirmed at the final report planning meeting. 
The impact of COVID-19 on important PDs and other COVID-19 related PDs will be also 
captured.
6.3
PATIENT SETS ANALYSED
Screened set (SCR):
This patient set includes all patients screened for the trial, with informed consent given.
Randomised set (RS):
This patient set includes all patients from the screened set who were randomised to study 
drug, regardless of whether any study drug was taken.
Treated set (TS):
This patient set includes all patients who are treated with at least one dose of randomised 
study medication. The TS is the basis for safety analyses.


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Treated set active (TSactive):
The TSactive is defined as all patients treated with at least one dose of active randomised 
study medication (linagliptin or empagliflozin) at any time in the study.
Modified Intention-to-Treat Set (mITT):
This patient set includes all randomised patients who are treated with at least one dose of 
study medication and have a baseline HbA1c measurement. The mITT is the basis for the 
primary analyses.
Per protocol set (PPS):
This patient set includes all patients in the mITT set who do not have any important PD
which can be expected to have a distorting influence on the assessment of the primary 
endpoint. As the DINAMO primary endpoint is analysed after 26 weeks of study treatment, 
important PDs related to efficacy that occur after the assessment of the DINAMO primary 
endpoint measurement will not lead to exclusion from analysis sets. See Section 6.2 for 
details.
PK parameter analysis set (PKS):
The pharmacokinetic set consists of all treated patients who have at least one evaluable PK 
plasma concentration measurement.
Table 6.3: 1
Patient sets analysed and treatment groupings
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
Disposition
OR 
(TG1)
OR 
(TG4, TG7)
OR
(TG6)
OR1
(TG8)
Definition of analysis sets
(TG6)
(TG1)
Important protocol deviations
(TG1)
Demographics
OR 
(TG1)
OR1
(TG8)
Baseline efficacy variables
OR
(TG1)
Background antidiabetic 
therapy at baseline
OR 
(TG1)
Antidiabetic medication newly 
introduced on treatment
OR 
(TG1, TG5)
Relevant medical history
OR 
(TG1)
Exposure to study medication
OR 
(TG1)
OR 
(TG6)
Compliance data by visit
OR 
(TG1)
OR 
(TG6)


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Table 6.3: 1
Patient sets analysed and treatment groupings (continued)
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
DINAMO - Primary efficacy endpoint 
Primary family of hypothesis -
HbA1c [%] CFB - ANCOVA 
analysis - washout approach 
OC-AD 
(TG1)
Secondary family of hypothesis 
- HbA1c [%] CFB - ANCOVA 
analysis - washout and inverse 
probability weighting approach 
OC-AD
(TG2, TG3)
DINAMO Mono - Primary efficacy endpoint 
Occurrence of treatment failure
up to or at Week 26 (DINAMO
Mono patients only)
NCF
(TG1)


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Table 6.3: 1
Patient sets analysed and treatment groupings (continued)
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
Secondary efficacy endpoints
Change in FPG [mg/dl] from 
baseline - ANCOVA 
OC-AD-
BOCF; OC
(TG1)
Change in body weight [kg] / 
SBP [mmHg] / DBP [mmHg] 
from baseline – MMRM 
OC-AD; OC
(TG1)
Proportion of patients who 
achieve HbA1c goals < 6.5% 
and < 7.0%. Exact CI
NCF; OC
(TG1)


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Table 6.3: 1
Patient sets analysed and treatment groupings (continued)
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
Further safety endpoints 
Shift tables for the Tanner 
staging score from baseline 
OC-AD
(TG1, TG5)
Descriptive statistics over time 
for growth velocity
OC-AD 
(TG1, TG5)
Safety evaluation 
Overall summary of AEs 
TG1, TG5,
TG4
TG6
Freq. of patients with the 
following AEs by treatment, 
SOC and PT 
∀
AEs
∀
AEs by worst intensity 
∀
Drug-related AEs 
∀
AEs leading to treatment 
discontinuation 
∀
SAEs
∀
Other significant adverse 
events 
∀
AESIs(except DKA and 
lower limb amputation)
TG1, TG5,
TG4
TG6
Incidence rate of patients with 
AEs by treatment, SOC and PT
TG1, TG5
List of patients with 
AESIs/other significant AE
∀
DKA
∀
Events involving lower 
limb amputation 
∀
Bone fracture
TS
Freq. of patients with other 
specific AE by treatment, SOC 
and PT:
∀
Hypoglycaemic AE
∀
UTI  (also investigator 
assessment, serious and 
leading to treatment 
discontinuation) 
∀
Genital infection (also 
investigator assessment, 
serious and leading to 
treatment discontinuation)
∀
Acute pyelonephritis or 
urosepsis
∀
Volume depletion 
∀
Ketone measurements 
TG1, TG4
TG6


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Table 6.3: 1
Patient sets analysed and treatment groupings (continued)
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
Freq. of patients with other 
specific AE by treatment, SOC 
and PT: 
∀
Arthralgia
∀
Pemphigoid in bullous 
conditions) 
TG1
TG6
Freq. of patients by 
characteristics of 
hypoglycaemia
∀
reported AE 
∀
any hypoglycaemia 
Freq. of patients with  
symptomatic hypoglycaemia
AE with plasma glucose < 54 
mg/dL (< 3.0 mmol/L) and/or 
severe hypoglycaemia AE by 
age at randomisation in 
categories.
Number of any hypoglycaemia
– time at risk
TG1, TG4
TG6
Freq. of patients with the 
following events (investigator 
assessment) by characteristics 
of events
∀
UTI 
∀
Genital infection 
∀
Acute pyelonephritis or 
urosepsis 
Freq. of patients with genital 
infection (investigator 
assessment) by type of the 
genital infection
TG1, TG4
TG6
Freq. of patients with CEC 
adjudicated events 
TG1
TG6
Freq. of patients with the 
following AEs by SOC and PT
∀
AEs
∀
AEs by outcome
∀
SAEs 
∀
Drug-related SAEs
TG1
TG6
Freq. of patients with AEs by 
treatment, SOC and PT
∀
Non-serious AE with an 
incidence in preferred term 
greater than 5% 
∀
SAE
TG91


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Table 6.3: 1
Patient sets analysed and treatment groupings (continued)
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
AEs per treatment arm 
(including number of patients 
exposed, affected by SAEs, 
affected by non-serious AEs 
with incidence > 5% in any 
treatment arm for each PT, 
number of death of all causes, 
number of deaths resulting 
from AEs).
TG91
Non-serious AEs with 
incidence > 5% in any 
treatment arm for each 
preferred term (including 
number of patients affected, 
exposed, total occurrences.)
TG91
SAEs on PT (including number 
of patients affected, exposed, 
number of occurrences, 
occurrences causality related, 
fatalities, fatalities causally 
related to treatment.)
TG91
Clinical laboratory evaluation 
Descriptive statistics of 
laboratory values at baseline, 
last value on-treatment, and 
change from baseline to last 
value on-treatment (normalised 
value) and over time
Freq. of patients within and 
outside the reference range at 
baseline and last value on 
treatment.
Freq. of patients of categorical 
laboratory parameters at 
baseline and last value on-
treatment
TG1, TG5
Freq. of patients with possibly 
clinical significant abnormality 
(PCSA)
TG1, TG5, 
TG4
TG6
Freq. of patients with elevated 
liver enzymes 
TG1, TG5
TG6


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Table 6.3: 1
Patient sets analysed and treatment groupings (continued)
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
Descriptive statistics over time
∀
Lipid parameters
∀
Renal parameters
∀
Vital signs 
Freq. of patients with increase 
of serum creatinine shows a >= 
2 fold increase from baseline 
and serum creatinine > upper 
limit normal
(OC-ROC)
TG1, TG5 
Change from baseline over time 
- MMRM 
∀
Lipid parameters
(OC-ROC)
TG1
Shift in renal function category 
from baseline to last and 
minimum value on treatment 
TG1
Descriptive statistics 
∀
Biomarkers
(OC-ROC)
TG1, TG5 
(except 
DPP-4)
SCR=screened set, RS=randomised set, mITT=modified intention-to treat set, PPS=per protocol set, TS=treated set, TSactive=treated set 
active; patient sets are defined in Section 6.3
OR=original results, OC=observed cases, OC-AD=observed cases-all data, OC-AD-BOCF=observed cases-all data and baseline observation 
carry forward, OC-ROC=observed cases-rescue observed cases, NCF=Non-completers considered failures. Handling of missing data is 
described in Section 6.6. CFB: change from baseline, ANCOVA= Analysis of covariance, SMQ= Standardised MedDRA query, MMRM= 
Mixed model for repeated measures, HLGT, HLT= High level term, CEC= Clinical event committee
1 Present once at the end of the trial combining both DINAMO and DINAMO Mono data.


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Table 6.3: 2
Patient sets analysed and treatment groupings for COVID-19 related 
outputs
Patient sets
Class of endpoint
SCR
TS
TSactive
RS
mITT
PPS
Premature discontinuation of 
trial medication or study 
OR 
(TG1)
Patient screened and study 
conduct 
OR 
(TOTAL)
Protocol deviations
(TG1)
Demographic data 
OR 
(TG1)
Baseline efficacy variables
OR 
(TG1)
Exposure to study medication
OR 
(TG1)
OR 
(TG6)
Compliance data by visit
OR 
(TG1)
OR 
(TG6)
Compliance with study 
medication by visit
OR 
(TOTAL)
Freq. of patients and rate of 
treatment interruptions 
(TG1)
Summary of patients who 
completed, altered or missed 
HbA1c sampling at Week 26 
visit
OR
(TG1)
Primary family of hypothesis -
HbA1c (%) CFB - ANCOVA 
analysis-multiple imputation 
with washout approach using a 
specific COVID-19 imputation
OC-AD
(TG1)
Freq. of patients with COVID-
19 intercurrent events
OC-AD
(TG1)
Freq. of patients and rate of 
AEs before and from the start 
of COVID-19 disruption
TG1
TG6
Sub-population: SARS-CoV-2 
infected patients
∀
Overall summary of AEs
∀
Freq. of patients with AEs
∀
Freq. of patients with AEs 
leading to treatment
discontinuation 
∀
Freq. of patients with 
SAEs.
TG1
TG6


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6.5
POOLING OF CENTRES
There is no analysis planned by centre due to the small number of patients to be recruited per 
centre.
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.
6.6.1
Methods of data selection 
Original results (OR) analysis
Original result analysis implies the analysis of data exactly as observed. OR analysis will be 
performed on endpoints where it is not meaningful to apply any imputation rule on them for 
replacing missing values.
Observed cases (OC) analysis
OC analyses only use the available data that were observed while patients were on-treatment.
Any values collected after treatment discontinuation and any values collected after the start of 
rescue medication will be set to missing. 
Observed cases – Rescue observed cases (OC-ROC) analysis
Only the available data that were observed while patients were on-treatment will be 
considered. Any values taken after rescue medication intake will be kept. Any values 
collected after treatment discontinuation will be set to missing. 
Observed cases – Last observation carry forward (OC-LOCF) analysis
Based on the OC data, the post-baseline missing values, post-treatment values and values 
after rescue medication will be imputed by the last on-treatment observation without rescue 
medication carried forward. In case, there is no on-treatment observation without rescue 
medication, baseline value will be carried forward. 
Observed cases - all data (OC-AD) analysis
All available data that were observed are considered. Any values taken after the start of 
rescue medication and any on- and post-treatment values will be kept. 
Observed cases - all data and baseline observation carry forward (OC-AD-BOCF) analysis
Based on the OC-AD data, baseline observation will be carried forward to impute the missing 
data.
Non-completers considered failure (NCF)
For binary endpoints, like the occurrence of a response, a conservative method to replace 
missing values is to consider them as "failures". Post-treatment values will be set to missing. 
Missing data due to early discontinuation of treatment and values after the start of rescue 


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medication will be replaced as "failure" (e.g. non-responder) up to the planned time point for 
the analysis. 
For binary endpoints that are derived from quantitative endpoints (e.g. HbA1c) missing on-
treatment data at the planned time point for the analysis will be replaced by NCF.
6.6.2
Imputation methods
A multiple imputations (MI) approach will be considered to impute missing data. Multiple 
imputation approaches taken are specified in Section 7 within the planned analyses.  
Missing safety data will not be replaced.
6.6.3
Missing dates and times
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (3).
Missing data and outliers of PK data are handled according to (2).
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration the missing day will be imputed as the first day of 
the month.
A missing time of first drug administration will be imputed as 08:00 o'clock in the morning, 
missing administration times at on-treatment visits will be imputed by 08:00 o'clock in the 
morning.
The earliest of the listed dates will be picked to impute the missing or incomplete drug stop 
date:
∀
Date of End of Treatment (EOT) visit (either premature treatment discontinue visit 
date or Visit 8 / EOT)
∀
Last contact date recorded in the EOS page
∀
Date of death
∀
Imputation of partial last date of study medication (imputed as last day of the month if 
only day is missing / last day of year if only year is provided)
For partial start and stop dates for concomitant therapies the following derivations will be 
used to impute 'worst case' values:
∀
If the day of the end date is missing then the end date is set to last day of the month.
∀
If the day and month of the end date are missing then end date is set to 31st December 
of the year.
∀
If the day of the start date is missing the start date is set to first day of the month.


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∀
If the day and month of the start date are missing then the start date is set to 1st 
January of the year.
For other incomplete date information (except to assess the overall compliance, see below) 
always the midpoint of the possible interval will be used. If only the year is present the day 
and month will be imputed as 01 July, if year and month is present the day will be imputed as 
15. If the year is missing, the date will be considered missing.
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.
6.6.4
Missing and incomplete laboratory reference ranges
Incomplete (one-sided) laboratory reference ranges are imputed according to BI standards 
(see “Handling of incomplete reference ranges”) (14).
In case of serum N-terminal cross-linked telopeptide (NTx), central lab reference range was 
not included in the data transfer as it was based on the Tanner stage score.  The Tanner stage 
score was unknown to the central lab. This missing central lab reference range will be 
incorporated in the Analysis Data Model (ADaM) dataset based on the Tanner stage score 
according to the central lab reference ranges (15). 
6.7
BASELINE, TIME WINDOW, AND CALCULATED VISITS
The term “baseline” refers to the following definitions according to the individual analysis 
period.
∀
Study baseline: Last observed measurement prior to administration of any initially 
randomised study medication at Day 1. 
∀
Titration baseline: Last observed measurement prior to administration of the re-
randomised study medication for the initial empagliflozin patients at Week 14. If last 
observed measurement is after rescue medication then there is no titration baseline for 
OC analysis. 
∀
Safety extension baseline: Last observed measurement prior to administration of the 
re-randomised study medication for the initial placebo patients at Week 26.
Note: On or prior to date of randomisation will be used, instead of prior to date of drug 
administration, for randomised patients who have not taken any blinded study drug.
Both date and time of administration of the randomised study medication are expected to be 
recorded at Day 1, Week 14 and Week 26.  In the determination of baseline for a parameter, 
if the parameter of interest:
∀
is collected with date and time: both date and time are used in the calculation of ‘last 
observed measurement prior to administration’.  If the dates and times are equal, the 
parameter will be determined to be prior to administration.  


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∀
is collected with only date:  the dates are equal, the parameter will be determined to 
be prior to administration.
The exception to this rule, is HbA1c, whereby even though time of sample is collected, it will 
be handled as if it was collected only with date.
Measurements taken after the first intake of randomised study drug will be considered on-
treatment values if they have been obtained up to the end of the endpoint specific follow-up 
period as defined in Table 6.7: 1.
Table 6.7: 1
Endpoint specific follow-up period for the assignment to treatment phase
Endpoint
Last day of assignment to treatment phase
(days after study drug stop date)
Efficacy
HbA1c
7
FPG
1
Body weight
1
BMI z-score
1
Blood pressure (systolic, diastolic)
1
UACR
7
Safety
Adverse events
7
AESI Hepatic injury [1]
30
AESI Lower limb amputation
End of study
Safety laboratory measurements
7
AST/ALT/TBILI [2]
30
Pulse rate
1
C-peptide
1
Tanner staging
1
[1] Refers to a specific safety analysis including all hepatic injuries with an onset date up to 30 days after the 
study treatment stop. 
[2] Refers to a specific safety analysis on elevated liver enzymes, for which events with an onset date up to 30 
days after the study treatment stop will be included in the analysis. See Section 7.8.2.2.
Measurements taken after the last intake of study drug and
end of the endpoint specific follow-up period will be considered post-treatment values. In 
efficacy analyses, the words off-treatment and post-treatment are used synonymously. 


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Efficacy and safety 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 (see Table 6.7: 2).


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Table 6.7: 2
Time windows for efficacy and safety measurements at scheduled visits 
after randomisation 
Visit 
number
Visit 
label
Planned 
days on 
treatment
Planned days
after 
randomisation
Time window
(actual days on treatment)
Start
EndA
2
Baseline
1
0C
NA
1B
3
Week 4
29
28
2
56
4A
Week 12
85
84
57
91
4B
Week 14
99
98
92
140B
5
Week 26
183
182
141
Max(Day 141, 
Visit 5 drug 
intake date, 
Min(Day 210, 
Visit 6 date – 1 
day))
6
Week 30
211
210
Max(Day 141, 
Visit 5 drug 
intake date, 
Min(Day 210, 
Visit 6 date – 1 
day)) + 1 day 
225
7
Week 42
295
294
226
329
8
Week 52 
/ EoT
365
364
330
Study drug stop 
date + X days
A  In case of premature discontinuation of the study drug an early EoT visit has to be performed. 
Measurements from the early EoT visit will be assigned to the appropriate visit according to the table. 
Patients will then be asked to continue in the study according to the visit schedule. Post-treatment 
measurements will be assigned to visits in the same manner.   
B     Only values taken prior to the start of treatment at Day 1, Week 14 and Week 26, with randomised 
study drug can be considered study baseline, titration baseline and safety extension baseline 
accordingly. Time windows will be used for assignment of measurements to scheduled visits. 
C
Reference day (day 0) is day of randomisation
The mid-point between two 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). As endpoints are planned to 
be measured according to different visit schedules, this midpoint algorithm will be applied 
and the time windows modified accordingly. 
Only one observation per time window will be selected for analysis. If there are multiple 
values within a time-window, the value closest to the CTP planned visit day will be selected. 
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 


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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. For the Week 26 primary analysis, this 
is applicable if study drug is stopped during the time window of the Week 26 visit.
In addition to the HbA1c values, both National Glycohemoglobin Standardization Program 
(NGSP) certified and non-NGSP certified HbA1c values, will be used in HbA1c endpoints
analyses, given that they are in the same unit. The order of preference for the laboratory 
values are: (1) NGSP certified central laboratory values, (2) NGSP certified local laboratory 
values and (3) non-NGSP certified local laboratory values. If a visit window includes a 
NGSP certified local laboratory value as well as a non-NGSP certified local laboratory value
(either both being on- or post-treatment), then the NGSP certified value will be selected 
rather than the non-NGSP certified value.  For study baseline, if none of these preference 
HbA1c values are available at Visit 2, then Screening data will be used.
For standard descriptive tables of laboratory parameters by visit, in case of multiple 
measurements within a post-baseline time window for a visit, the worst value of these 
multiple measurements will be used for calculations.


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7
PLANNED ANALYSES
Disposition of the patient population participating in the trial, the overall disposition 
information and the disposition status will be analysed by treatment grouping 1 and 6 
separately. Disposition of the patients after re-randomisation of the initial placebo group will 
be analysed by TG7 and after re-randomisation of the initial empagliflozin group will be 
analysed by TG4. They will be presented in the clinical trial report as a frequency-
distribution. 
The number of patients participating (screened, randomised, treated, and prematurely 
discontinued treatment) in the study by region and country will also be analysed and 
presented as a frequency distribution. The primary reason for patients failing screening will 
also be summarised. See Table 9.1: 1 for assignment of countries within region.
In addition, the following analyses will be done for public data disclosure on European Union 
Drug Regulating Authorities Clinical Trials (EudraCT) and display in Appendix 16.1.13 for 
both DINAMO and DINAMO Mono together.
∀
Disposition of patients, including number of patients who discontinued trial 
medication due to fatal and non-fatal adverse events, by TG8 based on RS
∀
Number of screened patients by country based on SCR
∀
Number of screened patients by age (at time of informed consent) groups (Children 
(2-11 years), Adolescents (12-17 years)) based on SCR
A summary of the number of patients in each randomisation stratum per treatment for each of 
the 3 randomisations (i.e. Day 1, Week 14 and Week 26) will also be shown. These
summaries will be based upon the data received from the IRT provider.
An IPD table will be presented including all CTP deviations leading to exclusion from 
analysis set (PPS, mITT, TS and/or TSactive) and an additional IPD table will be created to 
summarise all the IPDs not leading to exclusion from an analysis set using treatment 
grouping 1 based on RS.
For in-text tables presenting descriptive analysis of the endpoints and other variables, the set 
of summary statistics is: N (number of patients with non-missing values), mean, standard 
deviation (SD).
For End-Of-Text tables, the set of summary statistics is: N (number of patients with non-
missing values) / Mean / SD / standard error (SE) / Min / Q1 (lower quartile)/ Median / Q3 
(upper quartile)/ Max. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Reporting of Clinical Trials and Project Summaries” (4). Figures will be 
added if deemed necessary. 


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HbA1c and FPG in conventional unit will be analysed in Appendix 15.2 and SI unit will be 
analysed in Appendix 16.1.13.1. All analyses of laboratory parameters with SI unit will be 
analysed in Appendix 15 and the analyses of laboratory parameters with conventional unit 
will be analysed in Appendix 16.1.13.1.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
The following analyses will be performed to assess the impact of COVID-19.
∀
Premature discontinuation of trial medication or study due to COVID-19 disruption, 
by TG1 on SCR
∀
Patients screened and study conduct (assessed HbA1c at Week 26 (regardless on or 
post-treatment), last intake of study medication, completed study participation)
relative to start of COVID-19 disruption by before and from start of COVID-19 
disruption on SCR
∀
Number of patients with protocol deviations associated with COVID-19 disruption, 
by TG1 on RS
∀
Listing of patients with COVID-19 related study disruption on SCR
All described outputs, except result disclosure outputs, will be presented separately for 
DINAMO and DINAMO mono. 
All result disclosure outputs will be presented in the final reporting only at the same time as 
DINAMO Mono reporting.
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
7.1.1
Baseline evaluation
Descriptive analysis of the following demographic variables measured at study baseline will 
be presented:
Sex, race, ethnicity, region, age [years] at informed consent (continuous), age [years] at 
randomisation (categories), BMI [kg/m2] (continuous and categories), BMI z-score
(continuous and categories), height [cm], height z-score, smoking history, time since 
diagnosis of diabetes [years] (categories), eGFR [mL/min/1.73m²] (Zappitelli) (continuous 
and categories) and Tanner stages.
See Section 7.8.2.4 for details on the derivation of eGFR endpoints.
Descriptive analysis of the following variables measured at study baseline will be presented:


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HbA1c [%] (continuous and categories), FPG [mg/dL] (continuous and categories), FPG 
[mmol/L] (continuous and categories), weight [kg] (continuous and categories), blood 
pressure [mmHg] (categories), fasting C-peptide [nmol/L], UACR [mg/g crea] (continuous 
and categories).
Categories for baseline characteristics are defined in Table 6.4: 1.
Demographic and baseline characteristics tables will be presented using the TS by treatment 
grouping 1.
The demographic analysis will be repeated on the randomised set by TG8 in Appendix 
16.1.13 for disclosure on EudraCT for both DINAMO and DINAMO Mono together.
The following analyses will be performed to assess the impact of COVID-19 for DINAMO
only.
∀
Demographic data by patients randomised before and from the start of COVID-19 
disruption, by TG1 based on TS
∀
Baseline efficacy variables by patients randomised before and from the start of 
COVID-19 disruption, by TG1 based on TS
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the TS and TSactive
accordingly.
Concomitant therapy use will be summarised by Anatomical-Therapeutic-Chemical 
classification level 3 (ATC3) and preferred name. Only therapies under their available ATC3 
code(s) will be presented. Summaries will be presented for concomitant therapies taken 
during randomised treatment which are newly initiated (i.e. new preferred name) during the 
dedicated randomised treatment period and those taken at baseline (i.e. on day 1) of the 
dedicated randomised treatment period. 
The summary on concomitant therapies during randomised treatment will be presented up to 
Week 26 by treatment grouping 1 and Week 52 by treatment grouping 6.
Separate summary of use of antihypertensives, ASA, or lipid lowering drugs at baseline will 
be presented by TG1 and during randomised treatment will be presented up to Week 26 by 
treatment grouping 1 and Week 52 by treatment grouping 6. The displayed categories and 
defining ATC levels and ATC codes are shown in Section 9.2.
Concomitant diagnoses and non-drug therapies at any time of the study will be summarised 
by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and 
preferred term (PT). Relevant diabetic medical history will also be presented by treatment 
grouping 1.


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Background antidiabetic treatment at baseline (i.e. on day 1) will be summarised for the 
DINAMO patients only by treatment grouping 1 presenting number of background 
antidiabetic treatments (0, 1, 2), background antidiabetic treatment (metformin only, insulin 
only, metformin and insulin, none (diet and exercise only, metformin not tolerated)), 
metformin total daily dose [mg] (continuous and categories), and basal insulin total daily 
dose [IU/day].
Antidiabetic medication newly introduced on treatment will be presented up to Week 26 by 
treatment grouping 1 and Week 52 by treatment grouping 5. The increase dose of insulin 
during the on-treatment period is not included in this presentation for the DINAMO patients
but it will be presented in the “initiate glycaemic rescue therapy” further efficacy endpoint. 
The antidiabetic medication newly introduced on treatment will be regarded as rescue 
medication for the DINAMO Mono patients. 
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
Descriptive summary of compliance [%] and frequency distribution of patients with 
compliance [%] in categories (< 75, 75 to 125, > 125, incalculable (i.e. Not collectable 
compliance with reason for missing compliance)) will be reported by visit and treatment 
grouping 1 and 6 using TS and TSactive. Post-treatment period will not be included in the 
compliance analysis.  In case of premature discontinuation of treatment up to Week 26 for the 
TG1 summary table, premature discontinuation visit or Visit 8/End of treatment compliance 
will be presented together as ‘PTD prior to Week 26’. For up to Week 52 TG6 summary 
table, all end of treatment visits including premature discontinuation of treatment will be 
presented together as ‘Visit 8/EOT’. 
The following analyses will be provided to assess the impact of COVID-19 for DINAMO
only.
∀
Compliance data over time up to Week 26 by visit and permanent discontinuation of
study medication or/and completion of Week 26 visit before/from the start of COVID-
19 disruption, by TG1 on TS.
∀
Compliance data over time up to Week 52 by visit and permanent discontinuation of 
study medication before and from the start of COVID-19 disruption, by TG6 on 
TSactive.
∀
Compliance with study medication before and from the start of COVID-19 disruption 
by visit on TS
∀
Frequency of patients and rate of treatment interruptions up to Week 26 before and 
from the start of COVID-19 disruption by TG1 on TS. The time at risk is the entire 
treatment duration. The time at risk for the period before start of COVID-19 
disruption is defined as first dose of treatment until either the day before COVID-19 
start date or treatment end date (whichever comes earlier). The time at risk for the 


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period from start of COVID-19 disruption is defined as COVID-19 start date or 
treatment start date (whichever comes later) until treatment end date. Treatment 
interruptions which started during the defined period will be counted toward that 
specific defined period. 
7.4
PRIMARY ENDPOINTS
7.4.1
DINAMO
The primary endpoint in this trial is the change in HbA1c [%] from baseline to the end of 26 
weeks. 
7.4.1.1
Primary family of analyses
The primary family of null hypotheses will be tested using alpha level of 5% (two-sided):
For empagliflozin, the following null hypothesis will be tested:
H0,1:  Mean change in HbA1c [%] from baseline to the end of 26 weeks in the 
pooled empagliflozin groups 
         = Mean change in HbA1c [%] from baseline to the end of 26 weeks in the 
placebo group
For linagliptin, the following null hypothesis will be tested:
H0,2:  Mean change in HbA1c [%] from baseline to the end of 26 weeks in the 
linagliptin 5 mg group 
= Mean change in HbA1c [%] from baseline to the end of 26 weeks in the 
placebo group 
These confirmatory primary analyses will be performed using an effectiveness “wash-out” 
approach based on the mITT (OC-AD) set with multiplicity adjustment for simultaneous 
testing of linagliptin and empagliflozin using the Hochberg procedure by treatment grouping
1. Patients will be assigned to the treatment they were randomised to at the initial 
randomisation. All randomised treatment groups will be included in the same analysis. The 
seed used in the DINAMO confirmatory analyses will be 1218009101.
HbA1c values measured after premature discontinuation of study drug or after rescue therapy 
was initiated will be included in the analyses. All available on- and off-treatment data up to 
the Week 26 time point will be included.
There will be different types of missing data to be considered for the imputation.


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Table 7.4.1.1: 1 “Wash-out” approach – the missing data imputation method  
Randomised treatment group: Placebo
Missing HbA1c data will be imputed for all scheduled visits up to Week 26, that includes 
Week 4, Week 12 and Week 26. 
Type of 
missing data
Data used for imputation
Method to use for
Non-monotone 
missing data
Monotone 
missing data
On- and off-
treatment data 
Observed on- and off-treatment 
HbA1c data in the placebo group, 
including Baseline, Week 4, 
Week 12 and Week 26.
MCMC-MI1
(MAR3)
SLR-MI2
(MAR3)
Randomised treatment groups: Linagliptin 5 mg and empagliflozin pooled
Missing HbA1c data will be imputed for Week 26 only.
Type of missing data
Data used for imputation
Method
On-treatment data
Observed on-treatment HbA1c data in the 
respective treatment group, including only
Baseline and Week 26.
SLR-MI2
(MAR3)
Off-treatment5 data 
Observed on- and off-treatment5 HbA1c 
data in the placebo group, including only
Baseline and Week 26.
SLR-MI2
(MNAR4)
1 Markov Chain Monte Carlo – Multiple imputation (MCMC-MI)
2 Sequential linear regression – Multiple imputation (SLR-MI)
3 Missing at random (MAR)
4 Missing not at random (MNAR)
5 Missing post-treatment data after permanent treatment discontinuation
Method of imputation
For the placebo group, missing HbA1c data, regardless on- or off-treatment, will be imputed 
for all scheduled visits up to Week 26. 
*
The non-monotone missing data will be imputed using Markov Chain Monte Carlo 
(MCMC) simulation and standard techniques; MI will be performed on a data set including 
on- and off-treatment HbA1c data in the placebo group at baseline, Week 4, Week 12 and 
Week 26 with baseline HbA1c as a continuous covariate and age at randomisation as  binary 
covariate corresponding to its class categorisation levels (age <15 years or age ≥15 to <18 
years). 500 imputations will be performed to ensure adequate efficiency and stability of the 
estimation for missing data.  This step will be referred to as ‘MCMC-MI’.
*
For the monotone missing data in the placebo group, a sequential linear regression MI 
approach will be used and referred to as ‘SLR-MI’. The MI will be performed on a data set 


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including on- and off-treatment data and once per imputation from the previous step. This 
procedure will impute values for all missing time points both on- and off-treatment. The 
regression models will be fitted with baseline HbA1c as a continuous covariate and age at 
randomisation as a binary covariate (age <15 years or age ≥15 to <18 years).  500 
imputations for the placebo group will be completed.
For the active treatment groups (linagliptin 5 mg and empagliflozin pooled, regardless of the 
dose level), missing HbA1c data will be imputed for Week 26 only separately for missing on-
treatment data and missing off-treatment data. 
*
To impute the missing on-treatment data at Week 26, the MI will be performed on a 
data set including only patients who were on active treatment at Week 26, using the baseline 
and Week 26 (both missing and non-missing values).  The regression models will be fitted 
separately by active treatment group with baseline HbA1c as a continuous covariate and age 
at randomisation as a binary covariate (age <15 years or age ≥15 to <18 years). 500 
imputations for missing on-treatment data in each active treatment group will be completed.
*
To impute the missing off-treatment data at Week 26, the MI will be performed on a 
data set including the baseline of the active treated patients with missing off-treatment 
HbA1c data at Week 26, and the placebo patients with baseline and the original (i.e. not 
imputed) on- and off-treatment HbA1c data from Week 26.  The regression models will be 
fitted separately by active treatment group with baseline HbA1c as a continuous covariate 
and age at randomisation as a binary covariate (age <15 years or age ≥15 to <18 years). 500 
imputations for missing off-treatment data in each active treatment group will be completed.
The effectiveness analyses will be performed on these imputed data sets plus the observed
HbA1c data at Week 26  using an ANCOVA model with baseline HbA1c as a continuous 
model term, and with categorical terms for treatment and age at randomisation. Rubin’s rules 
will be used to combine treatment estimates across the 500 complete imputations.
The implicit assumption underlying the imputations and analyses is that unobserved off-
treatment patient measurements will lose any treatment effect immediately off-treatment 
discontinuation in the active treatment groups.
The least square mean differences of the active treatments to placebo, confidence intervals
and p-values of change in HbA1c from baseline to the end of 26 weeks will be displayed via 
forest plots for the primary (primary family of hypotheses) and corresponding sensitivity 
analyses, refer to Section 7.4.1.3, separately for linagliptin and empagliflozin pooled.
A more technical description of the method can be found in Section 9.4.
7.4.1.2
Secondary family of analyses
After having obtained statistically significant results for both hypotheses H0,1 and H0,2 of the 
primary family of hypotheses in the effectiveness “wash-out” approach analysis , the 
following two hypotheses will be tested in a hierarchical order at significance level α=0.05 
(two-sided) for the comparison of empagliflozin versus placebo:


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H’0,1: Mean change in HbA1c [%] from baseline to the end of 26 weeks in regimen starting 
on empagliflozin 10 mg and either having a dose increase to empagliflozin 25 mg in 
patients who were non-responders (i.e. patients that did not achieve HbA1c < 7.0%) at 
Week 12, or who were responders (i.e. patients that did achieve HbA1c < 7.0%) at 
Week 12 and continue with empagliflozin 10 mg
= Mean change in HbA1c [%] from baseline to the end of 26 weeks in the placebo 
group.
followed by:
H’0,2: Mean change in HbA1c [%] from baseline to the end of 26 weeks in regimen starting 
on empagliflozin 10 mg and either were responders or were non-responders at Week 
12, and continue with empagliflozin 10 mg
= Mean change in HbA1c [%] from baseline to the end of 26 weeks in the placebo 
group.
The hypotheses H’0,1 (by treatment grouping 2) will be tested first and if this hypothesis can 
be rejected at the significance level α = 0.05, the hypotheses H’0,2 (by treatment grouping 3) 
will be tested at the same level. The empagliflozin 10 mg patients who did not proceed to re-
randomisation at Week 14 will also be included in the analysis.
In using two sets of hypotheses families in a hierarchical order and using all hypotheses in the 
primary family as a gatekeeper for the secondary family, the experiment wise Type I error 
rate across both families is controlled by the significance level α = 0.05.
These secondary family of hypotheses for the primary endpoint will be tested using the 
“wash-out” approach described in Section 7.4.1.1 but the ANCOVA used for analysis of the 
completely imputed set will apply an “inverse probability weighting” approach based on the 
mITT (OC-AD) set.
The ANCOVA models will utilise a weight having a value of 0 for the patients who are not in 
the hypothesis test of interest; a value of 2 for re-randomised patients who are in the 
hypothesis test of interest and a value of 1 otherwise. The model terms will include baseline 
HbA1c as a continuous variable, and treatment and age at randomisation as categorical 
variables. Rubin’s rules will be used to combine treatment estimates across the 500 
imputations.
Patients will be assigned to the treatment they were randomised to at the initial randomisation 
together with the treatment allocation at Week 14 randomisation. HbA1c values measured 
after premature discontinuation of study drug or after rescue therapy was initiated will be 
included in the analyses.  Patients discontinued from the randomised study medication prior 
to Week 15 will also be included in the analysis.
The least square mean differences for each of the empagliflozin doses versus placebo, 
confidence intervals and p-values of change in HbA1c from baseline to the end of 26 weeks 


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will be displayed via forest plots for the analyses of the secondary family of hypotheses and 
corresponding sensitivity analyses, refer to Section 7.4.1.3, separately for TG2 and TG3.


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7.4.1.4
Effect of centre
There is no analysis planned by centre due to the small number of patients to be recruited per 
centre. 


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7.4.2
DINAMO Mono
The primary analysis will be a comparison of the treatment failure rates of linagliptin 5 mg, 
empagliflozin pooled and placebo (i.e. treatment grouping 1) using mITT set (NCF). The risk 
difference of active treatments versus placebo will be determined and assessed by an exact 2-
sided 90% confidence interval based on the method of Chan and Zhang (12). Patients will be 
assigned to the treatment they were randomised to at the initial randomisation. Non-
completers who prematurely discontinue intake of study drug will be considered treatment 
failures.


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7.4.3
HbA1c data summary 
An overall summary for the availability of HbA1c [%] data at Week 26 will be presented by 
TG1 on mITT (OC-AD) set showing captured and missing Week 26 data and further 
classified as on- and off-treatment and within these categories further sub-classified as 
‘without prior rescue’ and ‘with prior rescue'.
Frequency of patients who completed, altered or missed the HbA1c [%] measurement at 
Week 26 will be tabulated by TG1 on mITT set to assess the impact of COVID-19.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the CTP.
7.5.2
(Other) Secondary endpoint(s)
7.5.2.1
DINAMO
For the DINAMO secondary endpoints, the patients initially randomised to empagliflozin
(empagliflozin 10 mg and empagliflozin 25 mg pooled) and linagliptin 5 mg will be 
compared versus placebo (i.e. treatment grouping 1). Analyses will be performed on the 
mITT set and will apply two approaches.
The first approach will use all observed data including data after premature discontinuation 
of study drug or post rescue medication data up to Week 26 (OC-AD).
Since FPG [mg/dL] is measured only at baseline and Week 26 within the analysis period, 
OC-AD-BOCF will be considered instead of OC-AD. The change in FPG [mg/dL] from 
baseline to the end of 26 weeks will be analysed using an ANCOVA model. This analysis 
will be repeated for FPG [mmol/L] in Appendix 16.1.13.
The statistical model will be:
Change in FPG [mg/dL] from baseline to the end of 26 weeks
= overall mean + treatment + baseline FPG + categorical age at 
randomisation + random error
Treatment is a fixed classification effect. Baseline FPG is a linear covariate and age at 
randomisation a categorical covariate. The random error is assumed to be normally 
distributed with mean 0 and unknown variance σ².


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The other continuous secondary endpoints will be analysed based on a REML approach using 
MMRM. The analyses will include the fixed categorical effects of treatment, visit, and 
treatment-by-visit interaction, as well as the categorical covariate age at randomisation and 
the continuous, fixed covariates of baseline of the response variable and baseline of the 
response variable-by-visit interaction. The covariate visit will be treated as the repeated 
measure with an unstructured covariance structure used to model the within-patient 
measurements.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. The residuals are assumed to have a multivariate normal 
distribution with zero means and covariance matrix as specified above.
Descriptive statistics up to the end of 26 weeks of FPG [mg/dL], weight [kg], SBP [mmHg]
and DBP [mmHg] will be summarised by treatment grouping 1 and subgroup. See Table 
6.4:1 for the subgroups. 
The proportion of patients who achieve HbA1c < 7.0% and < 6.5% at the end of 26 weeks 
will be determined per treatment grouping 1 using mITT (NCF) set and the risk difference of 
active treatments versus placebo will be determined and assessed by an exact 2-sided 95% 
confidence interval.
The second approach will include only on-treatment values measured prior to the start of any 
rescue medication up to Week 26 (OC).
The change in FPG [mg/dL] from baseline to the end of 26 weeks will be analysed using the 
ANCOVA model, which is described in the first approach, but using the second approach 
data.  
For the other continuous secondary endpoints analyses, values measured after rescue therapy 
was initiated or after premature discontinuation of study drug will be set to missing. The 
missing data will not be imputed. The MMRM model will handle missing data based on a 
likelihood method under the "missing at random” assumption.
The proportion of patients who achieve HbA1c < 7.0% and < 6.5% at the end of 26 weeks 
will be determined per treatment grouping 1 using mITT (OC) set and the risk difference of 
active treatments versus placebo will be determined and assessed by an exact 2-sided 95% 
confidence interval.
7.5.2.2
DINAMO Mono
The secondary endpoint of time to treatment failure will be analysed and graphically 
described by Kaplan-Meier estimates up to the planned end of the study (Week 52) by 
placebo in TG1, L5 and E Pooled in TG5. Patients in the placebo group will be censored 
after 26 weeks unless a prior treatment failure is observed. Data obtained after re-
randomisation in the placebo group will not be utilised for the determination of time to 
treatment failure. 


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A descriptive Log-rank test will compare linagliptin 5 mg and pooled empagliflozin versus 
placebo individually up to Week 26 using mITT (NCF) set by treatment grouping 1. Patients 
will be censored after 26 weeks unless a prior treatment failure is observed. 
The change in HbA1c [%] from baseline to the end of 26 weeks will be analysed based on a 
REML approach using MMRM to assess the effectiveness and efficacy, using the same 
sensitivity methods as described in Section 7.4.1.3(A) and Section 7.4.1.3(C) respectively.
Analysis described in Section 7.4.1.3(C) will be repeated for HbA1c [mmol/mol] in 
Appendix 16.1.13.
It is expected that a large group of drug naïve patients will require early intervention of 
rescue medication as early as first on-treatment visit, therefore the change in HbA1c from 
baseline to the end of 26 weeks will also be analysed using an ANCOVA model including 
treatment as a fixed classification effect, baseline HbA1c as a linear covariate, and age at 
randomisation as a categorical covariate using mITT (OC-LOCF) set. 
The following continuous secondary endpoints will be analysed using the same methods 
described in Section 7.5.2.1, excluding the subgroup analyses.
∀
Change in FPG [mg/dl, mmol/L] from baseline to the end of 26 weeks
∀
Change in body weight [kg] from baseline to the end of 26 weeks
∀
Change in SBP [mmHg] from baseline to the end of 26 weeks
∀
Change in DBP [mmHg] from baseline to the end of 26 weeks
In addition, the change in FPG [mg/dl] from baseline to the end of 26 weeks will also be 
analysed using an ANCOVA model including treatment as a fixed classification effect, 
baseline FPG as a linear covariate, and age at randomisation as a categorical covariate using 
mITT (OC-LOCF) set. 
The proportion of patients who achieve HbA1c < 7.0% and < 6.5% at the end of 26 weeks 
will be determined by treatment grouping 1 using mITT (NCF, OC) set and the risk 
difference of active treatments versus placebo will be determined and assessed by an exact 2-
sided 90% confidence interval.


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7.7
EXTENT OF EXPOSURE
An overall descriptive statistics table with mean, SD, median and range of the number of 
days a patient was on-treatment and patient-years together with the frequency count of on-
treatment patients for the exposure in categories and exposure cumulative categories will be 
provided by TG1 and TG6. See Table 7.7: 1 for the presentation details. 
Table 7.7: 1
Details for displays of treatment exposure, including exposure in categories 
and exposure cumulative categories 
Placebo comparisons 
period
Active treatment period
Treatment grouping
TG1
TG6
Period
Up to Week 26
Up to Week 52
Exposure in categories
>0 to 4 weeks, 
>4 to 8 weeks, 
>8 to 16 weeks, 
>16 to 24 weeks, 
>24 to 28 weeks, 
>28 weeks.
>0 to 4 weeks, 
>4 to 8 weeks, 
>8 to 16 weeks, 
>16 to 24 weeks, 
>24 to 32 weeks, 
>32 to 40 weeks, 
>40 to 46 weeks, 
>46 to 54 weeks, 
>54 weeks.
Exposure cumulative 
categories
≥1 week, 
≥4 weeks, 
≥8 weeks, 
≥16 weeks, 
≥26 weeks, 
≥28 weeks.
≥1 week, 
≥4 weeks, 
≥8 weeks, 
≥16 weeks, 
≥26 weeks, 
≥32 weeks, 
≥40 weeks, 


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≥46 weeks, 
≥54 weeks.
First administration of 
study drug
Date of first study drug 
intake
Date of first active study drug 
intake
Last administration of 
study drug
Date of study drug 
intake at Week 26 
minus 1 day
Date of last active study drug 
intake
In addition, the adjusted treatment exposure (treatment exposure minus total number of days 
of reported treatment interruption in relevant treatment period) will be summarised in 
descriptive statistics and patient-years by TG1 and TG6. 
In order to assess the impact of COVID-19 to the treatment exposure in DINAMO only, the 
planned analyses for the treatment exposure will be repeated and summarised by permanent 
discontinuation of study medication or/and completed Week 26 visit before/from the start of 
COVID-19 disruption for up to Week 26 table and by permanent discontinuation of study 
medication before and from the start of COVID-19 disruption for up to Week 52 table.
A separate listing will be created of any patients that switched treatment at any time 
indicating exposure to the actual treatment against the randomised treatment.
All the above mentioned analyses will be presented for DINAMO and DINAMO Mono 
separately.
7.8
SAFETY ANALYSIS
Primary safety analysis (Comparison vs. placebo) (up to Week 26)
The primary safety analysis will be based on the TS. All safety variables will be analysed
from start of initial randomised treatment until Week 26 (except for AEs, which will be 
analysed up to the day before Week 26). The treatment grouping 1 will be used for the 
comparisons and presented for DINAMO and DINAMO Mono separately.
Safety analysis during active treatment period (up to Week 52)
The safety analysis during active treatments will be based on the TSactive (excluding all data 
observed while patients were on placebo). All AEs, SAEs, AEs leading to discontinuation, 
drug related AEs, AESIs and lab PCSAs will be analysed from start of active treatment up to 
Week 52. The treatment grouping 6 will be presented for DINAMO and DINAMO Mono 
separately.
Long term safety analysis (up to Week 52)
The long term safety analysis will be based on the TS (excluding patients initially randomised 
to placebo). All safety variables will be analysed from start of initial randomised treatment up 
to Week 52. The treatment grouping 5 will be presented for DINAMO and DINAMO Mono 
separately.
Impact of assessment of up-titration to empagliflozin 25 mg (the period following the 
administration of the re-randomised medication planned at Week 14 up to Week 26/Week 52)


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The up-titration safety analysis will be based on patients initially randomised to 
empagliflozin in the TS (only patients re-randomised at Week 14) for the assessment of up-
titration to empagliflozin 25 mg. All AEs, SAEs, AEs leading to discontinuation, drug related 
AEs, AESIs, selected other specific AEs (hypoglycaemia, UTI, genital infections, acute 
pyelonephritis or urosepsis, bone fractures, AE related to reduced intravascular volume, and 
ketone measurements reported as AE) and lab PCSAs will be analysed. The treatment 
grouping 4 will be presented for DINAMO and DINAMO Mono separately.
7.8.1
Adverse events
AEs will be coded using the latest version of the MedDRA coding dictionary at database 
lock.
Any clinically significant new finding in the physical examination, vital signs and in the 12-
lead ECG starting after Visit 2 (randomisation visit) will be considered as an AE and will be 
reported as such.
Unless otherwise specified the analyses of adverse events will be descriptive in nature and 
analyses of AEs will be based on the number of patients with AEs (not the number of AEs).  
All AEs will be reported according to the BI standard (5).
AE outputs for TG4 and TG5 will be presented for DINAMO only in Appendix 16.1.13 
unless otherwise stated.
7.8.1.1
Assignment of AEs to treatment
In general, the analysis of adverse events will be based on the concept of treatment emergent 
adverse events. This means that all adverse events occurring between first randomised or re-
randomised drug intake until 7 days after last drug intake or cut-off (depending on analysis 
period, see Section 7.8) will be assigned to the randomised treatment. 
In general, in-text AE tables will only present AEs assigned to the randomised treatment 
taken. For listings, AE will be assigned to one of the treatment phases of pre-treatment, 
treatment groups (depending on treatment grouping), post-treatment, post-study.
The cut off for the AEs outputs presentation period will be defined as the following.
∀
Prior to Week 26 treatment: Cut off at Visit 5 treatment date. If Visit 5 treatment date 
is not available, then the minimum of Day 183 or end of study date.
∀
Up to Week 52 present the whole treatment period plus the residual effect period. 
7.8.1.2
Analysis of other significant AEs
Other significant AEs will be reported and summarised according to ICH E3 criteria. Thus, 
AEs classified as 'other significant' will include those non-serious adverse events with:
∀
‘action taken = discontinuation’ or ‘action taken = reduced’, or


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∀
Marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality 
Review meeting or Blinded Report Planning Meeting.
Other significant AEs will be performed for the primary safety analysis and the safety during 
active treatment. See Section 7.8 for details.
7.8.1.3
AE summaries
An overall summary of adverse events will be presented by TG1, TG6, TG5 and TG4.
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. AEs will also be reported by intensity. Separate tables 
will be provided for patients with other significant adverse events according to ICH E3 (6),
for patients with serious adverse events, for patients with AEs leading to discontinuation, for 
patients with drug-related AEs and for patients with selected AESIs and other specific AEs.
Incidence rate as defined in Section 7.8.1.8 will apply to frequency tables: overall summary 
of AEs, patients with AEs, patients with drug-related AEs, patients with other significant AEs 
according to ICH E3, patients with AEs leading to discontinuation and patients with SAEs.
All above mentioned tables will be repeated by TG1, TG6, TG5 and TG4.
The system organ classes will be sorted in descending order of the total frequency count of all 
treatments then followed by preferred terms in descending order of the total frequency count.
Alphabetical ordering will be used for the same total frequency counts on PT level.   
Appendix 16.1.13 will include the following analyses by TG1 and TG6:
∀
Frequency of patients with AEs by SOC and preferred term
∀
Frequency of patients with SAEs by SOC and preferred term
∀
Frequency of patients with drug related serious AEs by SOC and preferred term
∀
Frequency of patients with adverse events by outcome, SOC and preferred term
Additionally, the following analyses will also be reported in Appendix 16.1.13 for disclosure 
on clinicaltrials.gov and EudraCT:
∀
Frequency of patients with non-serious adverse events occurring with an incidence in 
preferred term greater than 5% by treatment, SOC and PT for disclosure on 
clinicaltrials.gov.
∀
Frequency of patients with serious adverse events by treatment, SOC and PT for 
disclosure on clinicaltrials.gov
∀
AEs per treatment arm for disclosure on EudraCT (Number of patients exposed, 
affected by SAEs, affected by non-serious AEs with incidence > 5% in any treatment 
arm for each PT, number of death of all causes, number of deaths resulting from AEs 
will be presented.)


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∀
Non-serious AEs with incidence > 5% in any treatment arm for each preferred term 
(grouped by standard SOC terms) for disclosure on EudraCT (Number of patients 
affected, exposed, total occurrences will be presented.)
∀
Serious AEs on preferred term (grouped by standard SOC terms) for disclosure on 
EudraCT (Number of patients affected, exposed, number of occurrences, occurrences 
causality related, fatalities, fatalities causally related to treatment will be presented.)
These result disclosure AE analyses in Appendix 16.1.13 will be performed using treatment 
grouping 9 for both DINAMO and DINAMO Mono together. See (13) for details.
7.8.1.4
Protocol-specified AEs of special interest (AESI)
The protocol defines the following adverse events that for analysis purposes will be 
considered as AESIs:
∀
Hypersensitivity reactions (narrow SMQ) such as angioedema, angioedema-like 
events, and anaphylaxis
∀
Skin lesions (narrow SMQ) such as exfoliative rash, skin necrosis, bullous dermatitis
∀
Pancreatitis (narrow SMQ, PT)
∀
Pancreatic cancer (narrow BIcMQ)
∀
Hepatic injury (narrow sub SMQ)
∀
Decreased renal function (narrow SMQ)
∀
Diabetic Ketoacidosis (DKA) (narrow BIcMQ, investigator assessment)
∀
Events involving lower limb amputation (investigator-determined)
For those selected by SMQs/BIcMQ, the list of AESIs and other specific AEs, which is 
maintained as a separate file (8-01-tsap-adverse-event-topics) in Section 8 TSAP and 
Programming in the TDMAP folder “Data Management and Statistics”. The current version 
at the time of DBL will be used to be in line with the current MedDRA version.
The frequency of patients with AESIs will be summarised by treatment, primary system 
organ class and preferred term.
These AESI analyses will be performed for the primary safety analysis (TG1), safety during 
active treatment (TG6), long term safety (TG5) and assessment of up-titration (TG4). See 
Section 7.8 for details.
Events leading to lower limb amputation and DKA events will be listed only using the TS. 
7.8.1.5
Other specific adverse events
The analyses for the other specific adverse events will be performed for the primary safety 
analysis, safety during active treatment and selected other specific AE will be performed for 
the assessment of up-titration (Treatment grouping 1, 6 and 4 respectively).


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Hypoglycaemia
The investigator will record for each AE whether it represents a hypoglycaemic AE and, if 
so, record additional information to assess the intensity of the hypoglycaemic AE. On the 
basis of this information the investigator-defined hypoglycaemic AE will be classified as:
∀
Documented symptomatic hypoglycaemia AE with plasma glucose concentration 
≤70 mg/dL (< 3.9 mmol/L), as well as asymptomatic hypoglycaemia AE with
plasma glucose concentration ≤70 mg/dL (< 3.9 mmol/L)
∀
Documented (any) symptomatic and asymptomatic hypoglycaemia AE with 
plasma glucose concentration < 54 mg/dL (< 3.0 mmol/L)
∀
Severe hypoglycaemia AE: event requiring the assistance of another person to 
actively administer carbohydrates, glucagon or take other corrective actions. 
(Plasma glucose concentrations may not be available during an event, but 
neurological recovery following the return of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.)
Reported hypoglycaemia (investigator-defined hypoglycaemia) adverse event is defined as 
hypoglycaemia adverse event reported in the eCRF AE page.
Any hypoglycaemia (protocol-defined hypoglycaemia) is defined as reported hypoglycaemia 
adverse event or asymptomatic hypoglycaemia non-AE that had plasma glucose between >= 
54 mg/dL (>= 3.0 mmol/L) and <= 70 mg/dL (< 3.9 mmol/L).
Any hypoglycaemia that occurs on the same day, but, with a different start time, will be 
handled as a separate hypoglycaemic event.
The number and percentage of patients with reported hypoglycaemia AE will be tabulated by 
treatment, SOC and preferred term.
The characteristics of the episodes will be presented separately for the reported
hypoglycaemia AEs and any hypoglycaemia.
Similarly as for the analysis on patient level, a summary on the number of any 
hypoglycaemia, descriptive event rate, number of episodes by severity will be produced per 
patient-years. Only apply to TG1 and TG6.
A frequency table will be provided for number and percentage of patients with symptomatic
hypoglycaemia adverse event with confirmed plasma glucose < 54 mg/dL (< 3.0 mmol/L) 
and/or severe hypoglycaemia AE by baseline age at randomisation in categories. See Table 
6.4:1 for the subgroup details.
The treatment phase assignment of any hypoglycaemia (AE and non-AE) is exclusively based 
on the collected start date. These tables will be summarised up to the day before Week 26 by 
TG1 using TS, up to Week 52 by TG6 using TSactive and from the start of Week 14 to Week 
52 by TG4 using TS (only patients re-randomised at Week 14) unless stated specifically.


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Urinary tract and genital infections
The following other specific adverse events will be assessed and be tabulated by treatment, 
SOC, PT:
∀
Genital infections (narrow sub BIcMQ, investigator assessment)
∀
Urinary tract infections (UTI) (narrow sub BIcMQ, investigator assessment)
In addition using the narrow sub BIcMQ, serious genital infection events and genital 
infection events leading to treatment discontinuation will be summarised by treatment, SOC 
and PT. Similarly, the serious UTI events and the UTIs leading to treatment discontinuation 
will be summarised by treatment, SOC and PT.
Genital infections based on investigator assessment will be summarised by type (fungal 
balanitis or fungal vulvovaginitis, genital infection other than fungal balanitis or fungal 
vulvovaginitis), intensity (mild, moderate or severe),  time to onset of first episode (within 
the first 3 months of treatment or after), duration (<7 days, 7-14 days and >14 days), how the 
event was treated (no treatment, therapy assigned, hospitalisation), treatment (0, 1, 2, >2 
antimicrobials needed to treat), duration of treatment (≤7 days, >7 days),  whether leading to 
discontinuation of treatment, and the number of events per patient.
Furthermore, the above mentioned displays on genital infections based on investigator 
assessment will be repeated by the type of infection (fungal balanitis or fungal vulvovaginitis, 
genital infection other than fungal balanitis or fungal vulvovaginitis).
UTIs based on investigator assessment will be summarised by intensity (mild, moderate or 
severe),  time to onset of first episode (within the first 3 months of treatment or after), 
duration (<7 days, 7-14 days and >14 days), anatomical location (upper UTI (kidney), lower 
UTI (bladder and below)), how the event was treated (no treatment, therapy assigned, 
hospitalisation), treatment (0, 1, 2, >2 antimicrobials needed to treat), duration of treatment 
(≤7 days, >7 days),  whether leading to discontinuation of treatment, and the number of 
episodes per patient.
These tables will be summarised up to the day before Week 26 by TG1 using TS, up to Week 
52 by TG6 using TSactive and from the start of Week 14 to Week 52 by TG4 using TS (only 
patients re-randomised at Week 14).
Acute pyelonephritis or urosepsis
Frequency of acute pyelonephritis (narrow sub BIcMQ) or urosepsis (PT) will be tabulated 
by treatment, SOC and PT. 
Acute pyelonephritis or urosepsis based on investigator assessment will be summarised
overall and by intensity, and by additional treatment required (0, 1, 2, >2 antimicrobials 
needed to treat).


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These tables will be summarised up to the day before Week 26 by TG1 using TS, up to Week 
52 by TG6 using TSactive and from the start of Week 14 to Week 52 by TG4 using TS (only 
patients re-randomised at Week 14).
Bone fractures 
Bone fractures (narrow BIcMQ) will be listed using TS.
Arthralgia 
Arthralgia (HLGT (primary path)) will be summarised by treatment, SOC and PT using TS
(TG1) for up to the day before Week 26 and TSactive (TG6) for up to Week 52.
Pemphigoid in bullous conditions
Pemphigoid in bullous conditions (HLT(primary path)) will be summarised by treatment, 
SOC and PT using TS (TG1) for up to the day before Week 26 and TSactive (TG6) for up to 
Week 52.
AE related to reduced intravascular volume (Volume depletion)
Volume depletion (narrow BIcMQ) will be listed and summarised by treatment, SOC and PT 
using TS (TG1) for up to the day before Week 26, TSactive (TG6) for up to Week 52 and TS 
with only patients re-randomised at Week 14 (TG4) from the start of Week 14 to Week 52.
Ketone measurements reported as AE
Ketone measurements (narrow BIcMQ) reported as AE will be summarised by treatment, 
SOC and PT using TS (TG1) for up to the day before Week 26, TSactive (TG6) for up to 
Week 52 and TS with only patients re-randomised at Week 14 (TG4) from the start of Week 
14 to Week 52.
7.8.1.6
Events qualifying for external adjudication by the Clinical Event Committee
Independent external Clinical Event Committee (CEC) regularly review cardiovascular, 
neurology, hepatic and ketoacidosis events and evaluate whether pre-specified criteria for 
these adjudication endpoints are met. Details on composition of the CECs, responsibilities 
and clinical event definitions are provided in separate CEC charters. Events qualifying for 
adjudication will be selected based on the latest CEC charter versions.
The CECs will be provided with additional, specified background material on the patients 
with these events and perform an assessment of the events. Result of adjudication 
assessments will be incorporated to the database.
Frequency table will be provided for adjudicated cardiovascular and neurological events,
adjudicated hepatic events and adjudicated ketoacidosis events. All adjudication events and 
results will be listed. 
This analysis will be performed for the primary safety analysis (TG1) and the safety during 
active treatment (TG6). For definition of safety analyses see Section 7.8.


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7.8.1.7
AEs while patients taking wrong study medication
A listing using the TS will be provided for AEs that occurred while a patient was taking the 
wrong medication (planned and actual treatment taken) for DINAMO and DINAMO Mono 
separately.
7.8.1.8
AE incidence rates
In addition to the frequency tabulations, time-adjusted adverse event analyses will be 
performed for on-treatment AEs and on-treatment AEs by SOC, respectively HLT and PT.
The time at risk in patient years for an AE is derived as follows:
Patients with AE:
time at risk (AE) in days = date of start of AE with specified PT/SOC/HLT – initial 
randomised treatment start date + 1
Patients without AE:
time at risk (AE) in days = end date of time at risk – initial randomised treatment start date + 
1, 
where end date of time at risk is the minimum of date of last study drug intake + x days and 
date of death, if applicable.
The standard approach will be x=7 days, but for certain AEs in addition other approaches will 
be used.
Total AE-specific time at risk per treatment group is then derived as:
Time at risk (AE) [years] = Sum of time at risk [days] over all patients in a treatment 
group/365.25
For ‘each row of a table’ (e.g. displaying an SOC), time at risk is calculated using start of 
first AE summarised in this row; e.g. for patient with AE in a specified SOC, time at risk = 
date of start of AE with specified PT in this SOC – start of initial randomised treatment + 1.
The AE incidence rate per 100 patient years at risk will then be calculated as follows:
Incidence rate per 100 patient years (pt-yrs) = 100*number of patients with AE / time at risk
(AE) [years].
7.8.1.9
COVID-19
In order to assess the impact of COVID-19 on the reporting of any adverse events, frequency 
of patients and rate of AEs before and from the start of COVID-19 disruption up to the day 
before Week 26 by TG1 and up to Week 52 by TG6 will be presented for DINAMO only. In 
general, the time at risk is the entire treatment duration plus residual effect period. The time 
at risk for the period before start of COVID-19 disruption is defined as first dose of treatment 
until either the day before COVID-19 start date or Treatment end date plus residual effect 


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period (whichever comes earlier). The time at risk for the period from start of COVID-19 
disruption is defined as COVID-19 start date or treatment start date (whichever comes later) 
until treatment end date plus residual effect period. The residual effect period is within 7 days 
of treatment end date for treatment groups without a re-randomised treatment to follow on. 
Treatment emergent AEs occurred in the residual effect period after end of treatment will be 
counted toward the specific defined period based on the COVID-19 start date. For TG1, the 
residual effect period will not be added for patients who are still on treatment at Week 26 and 
the cut off for the AEs prior to Week 26 treatment will also apply. 
Patients with a SARS-CoV-2 infection will be identified based on the narrow BIcMQ 
‘SARS-CoV-2 infections’ plus the PT ‘Suspected COVID-19'. A listing of these AEs will be 
provided. The patients with such on-treatment AEs will define the subgroup of SARS-CoV-2 
infected patients and for this subgroup the following AE analyses will be provided for TG1 
and TG6:
∀
Overall summary of AEs
∀
Number of patients with AEs by SOC and PT
∀
Number of patients with AEs leading to discontinuation by SOC and PT
∀
Number of patients with SAEs by SOC and PT
To provide all available AE information on COVID-19 testing or infection status an 
additional listing will present all AEs related to SARS-CoV-2 infection based on the broad 
MedDRA SMQ ‘COVID-19’.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature for DINAMO and DINAMO
Mono separately. The results will be performed for the primary safety analysis (TG1) and
long term safety (TG5), presented based on SI units. The naming of the lab parameters will 
follow CTP. Some selected analyses will be repeated in conventional units and presented in 
Appendix 16.1.13.1.
The process of normalisation as well as standard analyses for safety laboratory data are 
described in the BI guidance for the Display and Analysis of Laboratory Data (7). All 
analyses considering multiple of times upper limit of normal (ULN) will be based on original 
and not normalised data.
Only patients with at least one available on-treatment value regardless of intake of rescue 
medication (OC-ROC) will be included in the analysis of an individual laboratory parameter.
All individual data will be presented in listings.
7.8.2.1
General laboratory evaluation
The following general laboratory evaluations will be performed for all laboratory data 
captured in the study including bone metabolism biomarkers (Calcium, phosphate, alkaline 
phosphatase, 25-OH-vitamin D, intact parathyroid hormone, serum N-terminal cross-linked 
telopeptide (NTx)). But excluding HBA1C, FPG, C-peptide and UACR that are separately 


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described in the planned efficacy analysis, and other biomarkers that are separately described 
in Section 7.8.2.3, 7.8.2.4 and 7.8.2.5):
∀
For quantitative lab results, descriptive statistics per treatment group at baseline, last 
value on-treatment, and change from baseline to last value on-treatment (in both SI and 
conventional units)
o
If both the BI adult standard and the central lab standard ranges are available, the 
descriptive statistics will be performed on the normalised value.
∀
Exception to NTx: the central lab standard range of female with tanner 
stage 5 will be used as the BI standard reference range.
o
Otherwise, the descriptive statistics will be performed on the standardised value
∀
For qualitative lab results, frequency tables per treatment group will be presented at 
baseline and at last value on treatment (only in SI unit).
o
Erythrocytes and leukocytes in urine analysis will be analysed as categorical 
data with 2 categories (“Normal” and “High”).
∀
Frequency table per treatment group will summarise the number of patients within and 
outside the reference range at baseline and the last measurement on treatment (only in 
SI unit). 
o
The age dependent reference range used for post-baseline values by the lab will be 
replaced by the reference range as provided for the respective patients' baseline 
measurement, and re-categorised.  
o
Exclude parameters only measured occasionally. 
∀
Frequency tables (include a patient listing) per treatment group will summarise the 
number of patients with any potentially clinically significant abnormality (PCSA) using 
company standard clinically significant criteria. PCSA will be determined based on SI 
units and only be counted in tables if the patient had no PCSA value at baseline. 
All the above analyses will be performed on the appropriate treated set for TG1 and
TG5.   The PCSA tables will additionally be produced for TG6 and TG4 (from Week 14 
up to Week 52).
∀
For quantitative lab results (as described above), descriptive statistics tables will be 
displayed per treatment group and per analysis visit over time for TG1 and TG5 in 
Appendix 16.1.13.
7.8.2.2
Elevated liver enzymes
Special attention will be paid to parameters characterising liver function. These include liver 
enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (AP)) and total bilirubin (TBILI).
The frequency of the number of patients with AST/ALT elevations >= 3xULN, >= 5xULN, 
>= 10xULN, and >= 20xULN will be displayed.


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To support analyses of liver related adverse drug effects, patients with AST and/or ALT >=
3xULN with concomitant or subsequent TBILI >= 2xULN in a 30 day period after AST/ALT 
elevation are of special interest. 
Patients with elevations as defined above by ALT and/or AST, total bilirubin and AP 
combinations, will be summarised and further classified by AP < 2xULN and >= 2xULN, 
where AP is the maximum value in the 30 day period. 
This analysis will be performed for the primary safety analysis (TG1), long term safety (TG5)
and the safety during active treatment (TG6). For the definition of safety analyses see Section 
7.8.
Details on patients with elevated liver enzymes will be listed using the TS.
7.8.2.3
Lipid parameters
Descriptive statistics over time up to 26 weeks by treatment grouping 1 and up to 52 weeks 
by treatment grouping 5 for the treated set (OC-ROC). 
For each lipid parameter, see CTP in-text Table 5.3.3:1, separate MMRM models for change 
from baseline up to Week 26 will be fitted on the treated set (OC-ROC) by TG1. The models 
will include treatment, visit and visit-by-treatment interaction as fixed categorical effects, as 
well as the categorical covariate age at randomisation and the continuous covariates baseline 
lipid parameter, baseline HbA1c, baseline lipid parameter by visit, baseline HbA1c by visit. 
An unstructured (co)variance structure will be used to model the within patient 
measurements, and the same other options as used for the primary family of MMRM analysis
model, as described in Section 7.4.1.3(A), will apply. 
All analyses in this section will be repeated for parameters in conventional unit and presented 
in Appendix 16.1.13.
7.8.2.4
Renal laboratory parameters
Creatinine and eGFR
All calculations for the grading of renal function will be based on the originally measured 
laboratory values, not on normalised values with BI standard reference ranges.  
The glomerular filtration rate will be estimated according to Zappitelli (8):
eGFR [mL/min/1.73m²] =
(507.76 x @.@@A(BCDEBF))
(Cystatin C@.LAM x Serum Creatinine@.MQR)
If renal transplant, x 1.165
(With height in cm, Cystatin C in mg/L and Serum Creatinine in μmol/L)


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For the analysis of eGFR and for the covariates in the efficacy statistical modelling the values 
calculated from the above formula using the serum creatinine values from the central 
laboratory will be used, and not the eGFR values provided by the central laboratory.
The endpoint will be derived at the visits where both serum creatinine and serum cystatin C 
are measured at the central laboratory. 
A shift table from baseline to last value on treatment, (and from baseline to minimum value 
on treatment) will be provided for the time period up to 26 weeks.
Descriptive statistics will also be created for creatinine and eGFR values over time up to 26 
weeks by treatment grouping 1 and up to 52 weeks by treatment grouping 5.
Additionally, summary tables will be created representing the number of patients per 
treatment group (i.e. TG1 (up to 26 weeks) and TG5 (up to 52 weeks)) who experienced a 
doubling in creatinine on treatment as compared to baseline and who were out of the normal 
range.
The UACR will be derived with the following formula.
UACR [mg/g crea] =
Urine Albumin [g/L] x 100
Urine Creatinine [mmol/L] x 0.011312217195
A shift table from baseline value to last and maximum values on-treatment will be provided
based on the following UACR categories (which used the derived UACR and not the 
albumin/creatinine ratio values provided by the lab): normal (< 30 mg/g crea), 
microalbuminuria (30 to <= 300 mg/g crea), macroalbuminuria (> 300 mg/g crea) by TG1 
and TG5.
7.8.2.5
Biomarkers
Descriptive statistics will be summarised over time up to Week 26 by TG1 and up to Week 
52 by TG5 on the standard units for PINP, IGF-1, and IGF-BP3.
Descriptive statistics by sex and tanner stage category version 2, see Table 6.4:1 for the 
category, will be summarised over time up to Week 26 by TG1 and up to Week 52 by TG5 
on the standard units for PINP, NTx, IGF-1, IGF-BP3.
Descriptive statistics of DPP-4 activity pre-dose measurement at Day 1 will be summarised 
by TG1 on the standard unit.
7.8.3
Vital signs
In addition to the analysis of body weight, SBP and DBP as secondary endpoints, descriptive 
statistics will be presented for the other vital signs as further safety endpoints, such as height 
(cm), heart rate (bpm) and BMI (kg/m2), together with their change from baseline over time 


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up to Week 26 by treatment grouping 1, up to Week 52 by treatment grouping 5 based on the 
treated set (OC-ROC).
7.8.4
ECG
12-lead ECG measurements will be taken during placebo run-in, at Week 26 and at EoT 
(Week 52). Any clinically significant new findings in the ECG measurement after the first 
ECG will be considered as AEs and analysed as planned in Section 7.8.1.


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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
BI-KMED-TMCP-MAN-0012: "Standards and processes for analyses performed 
within Clinical
Pharmacokinetics/Pharmacodynamics", current version; KMED
3
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", current 
version; KMED.
4
BI-KMED-BDS-HTG-0045: "Reporting of clinical trials and project summaries", 
current version; KMED.
5
BI-KMED-BDS-HTG-0041: "Analysis and presentation of adverse event data from
clinical trials", current version; KMED.
6
CPMP/ICH/137/95:  "Structure and content of clinical study reports", ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
7
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; KMED.
8
Zappitelli M, Parvex P, Joseph L, Paradis G, Grey V, Lau S, et al. Derivation and 
validation of cystatin C-based prediction equations for GFR in children. Am J Kidney 
Dis 2006;48(2):221-230[R16-2470]
9
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via 
multiple imputation. J Biopharm Stat 2013;23(6):1352-1371 [R15-1829]
10
Cole TJ, Green PJ. Smoothing reference centile curves: The LMS method and 
penalized likelihood. Stat Med 1992;11:1305-1319 [R21-0301]
11
BI Statistical Position Paper – Standards for Inferential Analyses, 1.1 Analyses of 
Continuous Endpoints – Parallel Group Studies
12
Chan ISF, Zhang Z. Test-based exact confidence intervals for the difference of two 
binomial proportions, Biometrics 1999;55(4):1202-1209 [R15-1346]
13
BI-KMED-BDS-QRG-0010: "Preparation of tables for results disclosure", current 
version; KMED.
14
BI-KMED-BDS-MAN-0025: “Handling of incomplete reference ranges”, current 
version; KMED.
15
Central laboratory reference ranges, current version; TMF. 


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10 HISTORY TABLE
Table 10: 1
History table for TSAP version 1.0 dated 15th Mar 2018
Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
1.0
15-Mar-2018
None
This is the initial TSAP without any modification.




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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
13-Nov-2019
General 
analysis 
definition (6)
Updated Section number from no number to 6.
5.5 (6.1)
Updated Section number from 5.5 to 6.1.
Added on-treatment period for up to Week 26 and 
for Week 26 up to Week 52.
Updated treatment groups and added new one for 
analyses and the presentation of the outputs.
5.6 (6.2)
Updated Section number from 5.6 to 6.2.
Paragraph started with “As the primary endpoint is 
analysed after 26 weeks, …” has moved to Section 
6.3 together with PPS.
Consolidate the IPD codes for empagliflozin and 
linagliptin into a study specific IPD code.
Made reference code to the ones for empagliflozin 
and linagliptin.
Updated the inclusion and exclusion numbering 
according to the change of exclusion 1 to become 
inclusion 10.
Combined columns “Category” and “Code” to “IPD 
Code”.
5.7 (6.3)
Updated Section number from 5.7 to 6.3.
Updated the text for the TSactive, mITT and PPS to 
help the clarity of the definition.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
13-Nov-2019
Table 6.3:1
Removed all primary endpoint analyses described 
as efficacy / effectiveness from the table.
Removed primary endpoint sensitivity test (MI).
Added DINAMO Primary endpoint analyses: 
primary & secondary family PMM analyses (mITT, 
PP); sensitivity primary & secondary family 
MMRM analyses (mITT); and sensitivity MMRM 
analysis (mITT).
Added DINAMO Mono Primary endpoint NCF 
analysis.
Demographics, baseline variables, concomitant 
medications, exposure/compliance will be analysed 
using TS instead of mITT.
5.9 (6.5)
Updated Section number from 5.9 to 6.5.
5.10 (6.6)
Updated Section number from 5.10 to 6.6.
5.10.1 (6.6.1)
Updated Section number from 5.10.1 to 6.6.1.
5.10.1.2 
(6.6.1.2)
Updated Section number from 5.10.1.2 to 6.6.1.2.
Added to exclude any values collected after the start 
of rescue medication to the OC definition.
5.10.1.3 
(6.6.1.3)
Updated Section number from 5.10.1.3 to 6.6.1.3.
Added to include any values collected after the start 
of rescue medication to the OC-AD definition.
5.10.1.4 
(6.6.1.4)
Updated Section number from 5.10.1.4 to 6.6.1.4.
Added to consider any values collected after the 
start of rescue medication as failure to the NCF 
definition.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
13-Nov-2019
5.10.2 (6.6.2)
Updated Section number from 5.10.2 to 6.6.2.
Updated the text to where to locate the missing data 
imputation approaches.
5.10.3 (6.6.3)
Updated Section number from 5.10.3 to 6.6.3.
5.10.4 (6.6.4)
Updated Section number from 5.10.4 to 6.6.4.
5.11 (6.7)
Updated Section number from 5.11 to 6.7.
Added three baseline definitions: Study baseline, 
titration baseline and safety extension baseline.
Clarified data from scheduled visit(s) will always 
be selected if they are collected correctly.
Table 6.7:2
Updated title from “Time window for HbA1c 
measurements at…” to “Time window for efficacy 
and safety measurements at…”
Rename Week 12 from Visit “4” to “4A”.
Rename Week 14 from Visit “5” to “4B”.
Rename Week 26 from Visit “6” to “5”.
Rename Week 30 from Visit “7” to “6”.
Rename Week 42 from Visit “8” to “7”.
Rename Week 52/EOT from Visit “9” to “8”.
Updated footnote B according to the newly defined 
baseline definitions.
Removed reference to BI XLAB2 macro.
6 (7)
Updated Section number from 6 to 7.
Updated the name of the treatment groups.
Added that DINAMO and DINAMO mono will be 
reported separately.
6.1 (7.1)
Updated Section number from 6.1 to 7.1.
6.1.1 (7.1.1)
Updated Section number from 6.1.1 to 7.1.1.
Added BMI continuous variable and Tanner stage 
for the demographic summary. 
Removed blood pressure continuous variable from 
the baseline characteristic summary.
Updated unit of UACR from “mg/gcrea” to “mg/g”.
Updated that the outputs will be presented by 
treatment group 1.
6.2 (7.2)
Updated Section number from 6.2 to 7.2.
Updated that the outputs will be presented by 
treatment group 1 and 6
6.3 (7.3)
Updated Section number from 6.3 to 7.3.
Updated reference Section 6.6.3 to Section 6.6.4.
Updated that the outputs will be presented by 
treatment group 1 and 6.
6.4 (7.4)
Updated Section number from 6.4 to 7.4.
6.4.1 (7.4.1)
Updated Section from 6.4.1 to 7.4.1 DINAMO.
6.4.1.1
Removed Section 6.4.1.1 Primary MMRM efficacy 
analysis.
6.4.1.1.1
Removed Section 6.4.1.1.1 Model diagnostics.




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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
13-Nov-2019
(7.4.2)
Added new Section 7.4.2 DINAMO Mono with 
DINAMO Mono primary endpoint analysis detail.
6.5 (7.5)
Updated Section number from 6.5 to 7.5.
6.5.1 (7.5.1)
Updated Section number from 6.5.1 to 7.5.1.
6.5.2 (7.5.2)
Updated Section number from 6.5.2 to 7.5.2.
(7.5.2.1)
Added new Section 7.5.2.1 DINAMO.
Added the content of the old Section 6.5.2.
Swapped the order of the first and second approach.
Moved paragraph “Baseline Observation Carried 
Forward (BOCF)… at baseline and week 26 within 
the analysis period.” from second approach (OC) to 
first approach (OC-AD) as first approach is closer 
to pure ITT.
Added which treatment groups will be used for 
presentation.
Added the analysis of “proportion of patients who 
achieve HbA1c goals < 6.5% and < 7.0% at the end 
of 26 weeks”.
(7.5.2.2)
Added new Section 7.5.2.2 DINAMO Mono with 
all the analyses details.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
13-Nov-2019
6.7 (7.7)
Updated Section number from 6.7 to 7.7.
Added an overall exposure table. 
Added which treatment groups will be used for 
presentation. And how to count the exposure of the 
re-randomised treatments for both placebo and 
empagliflozin patients.
The exposure categories and exposure cumulative 
categories of the assessment of up-titration to empa 
25 mg updated to use the primary safety analysis 
categories. 
Added the analysis period to each of the analysis 
type.
Updated section to apply for the 2 newly defined 
extent to exposure. One including off-treatment 
period and the other excluding off-treatment period.
6.8 (7.8)
Updated Section number from 6.8 to 7.8.
Added long term safety analysis.
Added which treatment groups will be used for 
presentation.
Added the reporting for DINAMO and DINAMO
Mono are separate.
Added details of what would be presented.
6.8.1 (7.8.1)
Updated Section number from 6.8.1 to 7.8.1.
Removed AE collapsing rule, replaced by following 
BI guideline.
6.8.1.1 
(7.8.1.1)
Updated Section number from 6.8.1.1 to 7.8.1.1.
Updated reference from “…see section 6.8), 
except…” to “…see Section 7.8), except…”.
Updated reference from “…see section 5.5.” to 
“…see Section 6.1”.
6.8.1.2 
(7.8.1.2)
Updated Section number from 6.8.1.2 to 7.8.1.2.
Added which treatment groups will be used for 
presentation.
6.8.1.3 
(7.8.1.3)
Updated Section number from 6.8.1.3 to 7.8.1.3.
Added which treatment groups will be used for 
presentation.
Added the reporting for DINAMO and DINAMO
Mono are separate.
6.8.1.4 
(7.8.1.4)
Updated Section number from 6.8.1.4 to 7.8.1.4.
Added bullous pemphigoid and arthralgia as AESI.
Added which treatment groups will be used for 
presentation.
Updated the location of the project level AESI list. 


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
13-Nov-2019
6.8.1.5 
(7.8.1.5)
Updated Section number from 6.8.1.5 to 7.8.1.5.
Added which treatment groups will be used for 
presentation.
Added a subgroup descriptive summary table for 
Hypoglycaemia.
Added Arthralgia.
Added Bullous pemphigoid.
Added AE related to reduced intravascular volume.
Added Ketone measurements reported as AE.
6.8.1.7 
(7.8.1.7)
Updated Section number from 6.8.1.7 to 7.8.1.7.
6.8.2 (7.8.2)
Updated Section number from 6.8.2 to 7.8.2.
Added for both DINAMO and DINAMO Mono.
Added it will presented for the primary safety 
analysis with both SI and US units.
6.8.2.1 
(7.8.2.1)
Updated Section number from 6.8.2.1 to 7.8.2.1.
Added further safety endpoint analyses.
Removed XLAB related text.
Removed table for change from baseline in 
haematocrit over time including during the follow 
up period. 
Added which safety analyses will be carry out.
6.8.2.2 
(7.8.2.2)
Updated Section number from 6.8.2.2 to 7.8.2.2.
Added which safety analyses will be carry out.
6.8.2.3 
(7.8.2.3)
Updated Section number from 6.8.2.3 to 7.8.2.3.
Added which safety analyses will be carry out.
6.8.2.4 
(7.8.2.4)
Updated Section number from 6.8.2.4 to 7.8.2.4.
Added which safety analyses will be carry out.
6.8.3 (7.8.3)
Updated Section number from 6.8.3 to 7.8.3.
Added further safety endpoint analyses.
Added for both DINAMO and DINAMO Mono.
Added it will presented for the primary safety 
analysis.
6.8.4 (7.8.4)
Updated Section number from 6.8.4 to 7.8.4.
Added for both DINAMO and DINAMO Mono.
7 (8)
Updated Section number from 7 to 8.
Updated references 3, 4, 5, and 7 from old SOPs to 
new KMED equivalent.
Added reference 12.


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Version
Date
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Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
13-Nov-2019
9 (10)
Updated Section number from 9 to 10.
Whole 
document
Updated “BMI SDS” to “BMI z-score”.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
23-Jul-2021
Whole 
document
Updated “off-treatment” to “post-treatment”.
5.1 
(DINAMO 
Mono 
primary 
endpoint)
Added “(including Week 26)” to the use of rescue 
medication criteria to clarify what exactly is 
included in the period.
Added “(at least 0.5% in absolute value)” to 
“Increase from baseline in HbA1c by 0.5% at Week 
26” to clarify the meaning of 0.5%.
5.2.2
Added criteria for “Time to treatment failure”.
6.1
Re-wrote the treatment periods as found them to be 
confusing.
Also updated the treatment groupings “treatment 
abbreviation labelling”.
Added TG7, TG8 and TG9 for the result disclosure.
6.2
Moved all IPDs criteria into DV specification, 
located in BIRDs.
  6.3
Added “PK parameter analysis set (PKS)”
Updated Table 6.3:1 (all outputs) and added Table 
6.3:2 COVID-19 related outputs.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
23-Jul-2021
6.6.1
Updated OC, OC-ROC.
Renamed OC-OCF to OC-LOCF.
Added OC-AD-BOCF.
6.6.3
Section 6.6.3 “Safety and other variables” deleted
6.6.4 (6.6.3)
Section 6.6.4 “Missing dates and times” became 
Section 6.6.3. 
Updated the rule for imputing the 
missing/incomplete drug stop date.
(6.6.4)
Added new section 6.6.4 “Missing and incomplete 
laboratory reference ranges”.


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Version
Date
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Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
23-Jul-2021
6.7
Added “If last observed measurement is after rescue 
medication then there is no titration baseline for OC 
analysis.” to Titration baseline. 
Added “In efficacy analyses, the words off-
treatment and post-treatment are used 
synonymously.” To clarify the meaning of off- and 
post-treatment.
Added more details of how to handle HbA1c data.
6.7:1
Added AESI Hepatic injury and lower limb 
amputation.
6.7:2
Updated time window cut-off.
Added how to select the HbA1c data for analysis 
(NGSP or not)
7
Deleted “For efficacy analyses, patients will be 
analysed according to the patient information given 
in the eCRF in the case of potentially erroneous 
data entered into the IRT system” as age used in 
analysis came from the IRT system. 
7
Added “All result disclosure outputs will be 
presented in the final reporting only at the same 
time as DINAMO Mono reporting.” to clarify when 
the result disclosure outputs will be provided. 
7.1.1
Added height z-score
Removed Background antidiabetic treatment at 
study baseline from the baseline descriptive table. 
Added “for DINAMO only” to the demographic 
and baseline efficacy variables tables by before and 
from start of COVID-19.
7.2
Added “Only therapies under their available ATC3 
code(s) will be presented.” to the concomitant 
therapy paragraph.
Added “during randomised treatment” for use of 
antihypertensive for TG1 and TG6.
7.3
Added details of how to handle the visit of  
premature discontinuation of treatment in the 
compliance summary.
Added “for DINAMO only” to the compliance 
tables by before and from start of COVID-19.


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Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
23-Jul-2021
7.4.1.2
Text updated from “The ANCOVA model will 
utilise a weight variable having a value of 0 for the 
patients who are not in the hypothesis test of 
interest, a value of 2 for re-randomised patients who 
are in the hypothesis test of interest and a value of 1 
otherwise.” to “The ANCOVA models performed 
for each hypothesis will utilise a weight variable 
having a value of 2 for re-randomised patients and a 
value of 1 for all other patients in the treatment 
grouping for the respective hypothesis test.”. 
7.4.1.3 E
Added details of how to define the COVID-19 ICE 
and the imputation method. 
7.4.1.3 F
Added new section for the sensitivity test “Primary 
family of hypotheses – Non-NGSP certified 
laboratories HbA1c values”. 
(7.4.3)
Added new section “HbA1c data summary”.
7.5.2.1
For the first approach FPG analysis, added data 
type OC-AD-BOCF.
Moved the proportion of patients who achieve 
HbA1c < 7.0% and < 6.5% at the end of 26 weeks 
will be determined per treatment grouping 1 using 
mITT (NCF) set to the first approach. Replaced OC 
for the second approach.
7.5.2.2
Added a descriptive Log-rank test comparing 
linagliptin 5 mg and pooled empagliflozin versus 
placebo individually up to Week 26 using mITT 
(NCF) set by TG1.
7.7
Re-organised the whole section. 
Added “for DINAMO only” to the exposure tables 
by before and from start of COVID-19.
7.8
Updated text to present TG4 for DINAMO Mono 
analyses.
7.8.1
Added the location for TG4 and TG5 AEs outputs, 
where they are relocated into Section 16.
7.8.1.1
Text added for the cut off of AEs occurred up to 
Week 26 and Week 52.
7.8.1.3
Added treatment grouping details into text. To 
clarify which TGX will be used in the table.
7.8.1.5
Added Hypoglycaemia derivation.
Added text to clarify what outputs to present.
(7.8.1.8)
New section “AE incidence rates” added.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised 
23-Jul-2021
(7.8.1.9) 
New section “COVID-19” added.
7.8.2.1
Section re-organised.
Added the bone metabolism biomarkers to the 
general lab summary table with the normalised 
values. 
7.8.2.2
Removed extra details of the liver enzyme elevation 
as it caused confusion. 
7.8.2.3
Updated the presentation of the descriptive table to 
over time instead of baseline and last value only. 
7.8.2.4
Added a shift table for UACR.
(7.8.2.5)
New section “Biomarkers” added.
7.8.3
Removed OC analysis from the vital signs 
parameters analysis.
8
Updated reference 8, 9, 10 and 12.
Added reference 14 and 15.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
Title page
Updated the document number “c20394975-03” to 
“c20394975-04”.
Updated CTP version “Including Protocol 
Amendment 1-8” to “Including Revised Protocol 
(Global Amendment 6)”.
4
Updated CTP amendment version from “…CTP 
amendment version 6.0 dated 14 Jul 2021” to 
“…CTP global amendment 6 dated 23 May 2022”.
5.2.2, 
5.3.1
Updated “Proportion of patients who achieve 
HbA1c goals …” to “Proportion of patients who 
achieve HbA1c …”. To follow CTP.
5.3.1
For proportion of patients who initiate glycaemic 
rescue therapy up to 26 weeks and 52 weeks, the 
word “(insulin)” has removed from DINAMO 
criteria and “(metformin and/or insulin)” has 
removed from DINAMO MONO criteria as to 
include all antidiabetic therapies as rescue 
medications and not limited to the allowed ones. 
5.3.2
Updated “Adverse events (AE) up to 26 and 52 
weeks, including adverse events of special interest 
(AESI) (see CTP Section 5.3.6.1)” to “Adverse 
events (AE) up to 26 and 52 weeks, including 
adverse events of special interest (AESI) (see CTP 
Section 5.3.6.1), genital infections, urinary tract 
infections, acute pyelonephritis or urosepsis, bone 
fracture, arthralgia, bullous pemphigoid, adverse 
events related to reduced intravascular volume and 
ketone measurements reported as AE”.
5.4.1
Updated the following texts to align with project 
level reporting. 
Old text” For analysis purposes, BMI will also be 
derived at visits where only weight was collected, 
using the last available height that was reported 
prior to the date of weight measurement.” to
New text “For analysis purposes, BMI will also be 
derived at visits where only weight was collected, 
using the last available height that was reported 
prior to the date of weight measurement. In case of 
missing height at screening, height can be 
carried backward for the derivation.”
Old text “The age in month at Screening will be 
used to determine the values of L, M and S.” to 
New text “The age in month at informed consent
will be used to determine the values of L, M and 
S.”.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
6.1
For TG9, added “active pooled” into the active 
treatments groups to clarify only active treatments 
period are included.
Old text “The treatment grouping X will be …” to 
New text “The treatment grouping TGx will be …”.
Old text “As a first example, the treatment identifier 
“E10-10R” means …” to 
New text “As a first example, the treatment 
identifier “E10R-10” means…”
Old text “As a second example, the treatment 
identifier “E10/E25NR*” means…” to 
New text “As a second example, the treatment 
identifier “E10NR/25*” means…”.
Table 6.3:1
Updated “Occurrence of treatment failure up to or 
at Week 26” to “Occurrence of treatment failure up 
to or at Week 26 (DINAMO Mono patients only)”.
Added “DINAMO Mono – Sensitivity analysis”
Occurrence of treatment failure up to or at Week 26
(DINAMO Mono and suitable DINAMO patients) 
Updated the following text to make clear the timing 
of the age.
Old text “Freq. of patients with  symptomatic 
hypoglycaemia AE with plasma glucose < 54 
mg/dL (< 3.0 mmol/L) and/or severe 
hypoglycaemia AE by baseline age in categories” 
to 
New test “Freq. of patients with  symptomatic 
hypoglycaemia AE with plasma glucose < 54 
mg/dL (< 3.0 mmol/L) and/or severe 
hypoglycaemia AE by age at randomisation in 
categories”


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Changes in 
old Section
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Section)
Brief description of change
Revised
7-JUL-2022


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
6.7
Added the following text to clarify how the baseline 
is defined for the not treated but randomised 
patients. 
“Note: On or prior to date of randomisation will be 
used, instead of prior to date of drug administration, 
for randomised patients who have not taken any 
blinded study drug.”
Removed the repeated words. 
Old text “Measurements taken after the last intake 
of study drug and after the end of the endpoint 
specific follow-up period will be considered post-
treatment values….” to 
New text “Measurements taken after the last intake 
of study drug and end of the endpoint specific 
follow-up period will be considered post-treatment 
values….”.
7
Updated the disclosure table title to clarify what 
AGE should be used. 
Old text “Number of screened patients by age 
groups …”
New text “Number of screened patients by age (at 
time of informed consent) groups …”.
Also added the following text to include both 
laboratory units: SI and Conventional units as 
requested by FDA. 
And added “Figures will be added if deemed
necessary”.
“HbA1c and FPG in conventional unit will be 
analysed in Appendix 15.2 and SI unit will be 
analysed in Appendix 16.1.13.1. All analyses of 
laboratory parameters with SI unit will be analysed 
in Appendix 15 and the analyses of laboratory 
parameters with conventional unit will be analysed 
in Appendix 16.1.13.1.”
7.1.1
Separated age [years] in demographic summary 
table into 2 variables: age [years] ay informed 
consent (continuous) and age [years] at 
randomisation (categories).


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
7.3
Updated the subgroup from old text: “
∀Compliance data over time up to Week 26 and up 
to Week 52 by visit and permanent 
discontinuation of study medication before and 
from the start of COVID-19 disruption, by TG1 
on TS, TG6 on TSactive.”.
To new text: “
∀Compliance data over time up to Week 26 by 
visit and permanent discontinuation of study 
medication or/and completed Week 26 visit 
before/from the start of COVID-19 disruption, by 
TG1 on TS. 
∀Compliance data over time up to Week 52 by visit 
and permanent discontinuation of study 
medication before and from the start of COVID-
19 disruption, by TG6 on TSactive.”.
7.4.1.1
Throughout the section, updated “age” to “age at 
randomisation”.
Also added “The seed used in the DINAMO 
primary family of analyses will be 1218009101”.
Also added “The least square mean differences of 
the active treatments to placebo, confidence 
intervals and p-values of change in HbA1c from 
baseline to the end of 26 weeks will be displayed 
via forest plots for the primary (primary family of 
hypotheses) and corresponding sensitivity analyses, 
refer to Section 7.4.1.3, separately for linagliptin 
and empagliflozin pooled.”.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
7.4.1.2
Updated “The ANCOVA models performed for 
each hypothesis will utilise a weight variable 
having a value of 2 for re-randomised patients and a 
value of 1 for all other patients in the treatment 
grouping for the respective hypothesis test. The 
model terms will include baseline HbA1c as a 
continuous variable, and treatment and age as 
categorical variables. Rubin’s rules will be used to 
combine treatment estimates across the 500 
imputations” to “The ANCOVA models will utilise 
a weight having a value of 0 for the patients who 
are not in the hypothesis test of interest; a value of 2 
for re-randomised patients who are in the 
hypothesis test of interest and a value of 1 
otherwise.  The model terms will include baseline 
HbA1c as a continuous variable, and treatment and 
age at randomisation as categorical variables. 
Rubin’s rules will be used to combine treatment 
estimates across the 500 imputations” to follow the 
update in CTP v7.0 and clarify what AGE category 
will be used in the model.
Also added “The seed used in the DINAMO 
secondary family of analyses will be 1218009102 
for hypothesis H’0,1 and 1218009103 for 
hypothesis H’0,2.”.
Also added “The least square mean differences for 
each of the empagliflozin doses versus placebo, 
confidence intervals and p-values of change in 
HbA1c from baseline to the end of 26 weeks will be 
displayed via forest plots for the analyses of the 
secondary family of hypotheses and corresponding 
sensitivity analyses, refer to Section 7.4.1.3, 
separately for TG2 and TG3.”.
7.4.1.3
Throughout the section, updated “age” to “age at 
randomisation”.
In C, added “In addition, the analysis will be carried 
out in SI unit in Appendix 16.1.13.1.” according to 
the FDA request.
7.4.1.5
Throughout the section, updated “age” to “age at 
randomisation”.
7.4.2
Added the following text after FDA confirmation. 
“Patients will be assigned to the treatment they 
were randomised to at the initial. Non-completers 
who prematurely discontinue intake of study drug 
will be considered treatment failures.”


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
(7.4.2.1)
New section added (Sensitivity analysis for 
DINAMO Mono) as a result of FDA discussion.
“The analysis of the DINAMO Mono primary 
endpoint will be repeated on DINAMO Mono 
patients plus the drug-naïve DINAMO patients who
satisfied the DINAMO Mono HbA1c inclusion 
criteria limit using the same statistical model.”
7.5.2.1
Throughout the section, updated “age” to “age at 
randomisation”.
Added unit to the variables. 
Added additional FPG [mmol/L] analysis to this
section: “This analysis will be repeated for FPG 
[mmol/L] in Appendix 16.1.13.”.
7.5.2.2
Throughout the section, updated “age” to “age at 
randomisation”.
Added additional HbA1c [mmol/mol] analysis to 
this section: “Analysis described in Section 
7.4.1.3(C) will be repeated for HbA1c [mmol/mol] 
in Appendix 16.1.13.”.
7.7
Updated subgroup categories from old text: “In 
order to assess the impact of COVID-19 to the 
treatment exposure in DINAMO only, the planned 
analyses for the treatment exposure will be repeated 
and summarised by permanent discontinuation of
study medication before and from the start of 
COVID-19 disruption.”.
To new text: “In order to assess the impact of 
COVID-19 to the treatment exposure in DINAMO 
only, the planned analyses for the treatment 
exposure will be repeated and summarised by 
permanent discontinuation of study medication 
or/and completed Week 26 visit before/from the 
start of COVID-19 disruption for up to Week 26 
table and by permanent discontinuation of study 
medication before and from the start of COVID-19 
disruption for up to Week 52 table.”.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
7.8.1
In response to the DINAMO Mono sample size 
reduction, TG4 and TG5 AE outputs are no longer 
required.
Updated “AE outputs for TG4 and TG5 will be 
presented in Section 16.1.13 unless otherwise 
stated.
” to “AE outputs for TG4 and TG5 will be 
presented for DINAMO only in Section 16.1.13 
unless otherwise stated.” 
7.8.1.1
Removed the following text as no longer required. 
“Appendix 16.1.13 will display in addition AEs 
observed 'pre-treatment' (including AEs observed 
during screening and placebo run-in regardless of 
treatment group). Selected summaries will be 
created to include an analysis where AEs and SAEs 
are assigned to the following phases: pre-treatment, 
each treatment group (according to the type of 
analysis), and post-treatment.”
7.8.1.3
Updated paragraph to include more exposure 
adjusted AE tables according to FDA request: 
“Incidence rate as defined in Section 7.8.1.8 will 
apply to frequency tables: overall summary of AEs, 
patients with AEs, patients with drug-related AEs, 
patients with other significant AEs according to 
ICH E3, patients with AEs leading to 
discontinuation and patients with SAEs. All above 
mentioned tables will be repeated by TG1, TG6, 
TG5 and TG4.”.
Updated the sorting order for the AE table:
Old text “The system organ classes will be sorted in 
descending order of frequency then followed by 
preferred terms in descending order of frequency. 
Alphabetical ordering will be used for same 
frequency counts on PT level.” to
New text “The system organ classes will be sorted 
in descending order of the total frequency count of 
all treatments then followed by preferred terms in 
descending order of the total frequency count. 
Alphabetical ordering will be used for the same
total frequency counts on PT level.”.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
7.8.1.4
Updated the following text:
Old text “Diabetic Ketoacidosis (DKA) (narrow 
BIcMQ)” to 
New text “Diabetic Ketoacidosis (DKA) (narrow 
BIcMQ, investigator assessment)”.
Old text “Lower limb amputation and DKA events 
will be listed only using the TS.”. to
New text “Events leading to lower limb amputation 
and DKA events will be listed only using the TS.”.
7.8.1.5
Throughout the section, updated “age” to “age at 
randomisation”.
Added this text to clarify how to classify the 
Hypoglycaemia “Any hypoglycaemia that occurs 
on the same day, but, with a different start time, 
will be handled as a separate hypoglycaemic event.”
Added this text to clarify how to derived the start 
date of Hypoglycaemia.
“The treatment phase assignment of any 
hypoglycaemia (AE and non-AE) is exclusively 
based on the collected start date.”
Updated Arthralgia (HLGT) to Arthralgia (HLGT 
(primary path)).
Updated Pemphigoid in bullous conditions (HLT) 
to Pemphigoid in bullous conditions (HLT (primary 
path)).
7.8.2
Added the following text according to FDA request: 
“Some selected analyses will be repeated in 
conventional units and presented in Appendix 
16.1.13.1”.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
7.8.2.1
Remove “serum-procollagen type I N-terminal 
propeptide (PINP)” from this laboratory evaluation 
section.
Updated to include both SI and conventional units 
for the quantitative lab results.
Added “Exception to NTx: the central lab standard 
range of female with tanner stage 5 will be used as 
the BI standard reference range.” for the normalised 
values tables. 
Updated to include only in SI unit for the 
qualitative lab results and by reference tables. 
Added the special categories for URBC and UWBC 
“Erythrocytes and leukocytes in urine analysis will 
be analysed as categorical data with 2 categories 
(“Normal” and “High”).”
Updated to exclude parameters only measured 
occasionally for the by reference tables.
7.8.2.1
Added the bold text into the PCSA bullet point.
• Frequency tables (include a patient listing) per 
treatment group will summarise the number of 
patients with any potentially clinically significant 
abnormality (PCSA) using company standard 
clinically significant criteria. PCSA will be 
determined based on SI units and only be 
counted in tables if the patient had no PCSA 
value at baseline.    
In order to clarify how the count should be done. 
All sections
Updated “AGE” to “age at randomisation” for all 
AGE in category, as this is the correct time point. 
And “AGE” to “age at inform consent” for all 
continuous AGE. 
7.8.2.3
Added the conventional unit tables according to 
FDA request: “All analyses in this section will be 
repeated for parameters in conventional unit and 
presented in Appendix 16.1.13.”.


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Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
7-JUL-2022
7.8.2.4
Updated the following text with the bold text to 
clarify what UACR values are used. “A shift table 
from baseline value to last and maximum values on-
treatment will be provided based on the following 
UACR categories (which used the derived UACR 
and not the albumin/creatinine ratio values provided 
by the lab): normal …”
Also added the derived UACR formula.
7.8.2.5
Added PINP to the biomarkers descriptive tables.
Added additional tables “Descriptive statistics by 
sex and tanner stage category version 2, see Table 
6.4:1 for the category, will be summarised over 
time up to Week 26 by TG1 and up to Week 52 by 
TG5 on the standard units for PINP, NTx, IGF-1, 
IGF-BP3.”.
8
Old text “001-MCS-36-472: "Standards and 
processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics", current 
version; IDEA for CON” to
New text “BI-KMED-TMCP-MAN-0012: 
"Standards and processes for analyses performed 
within Clinical 
Pharmacokinetics/Pharmacodynamics", current 
version; KMED”.


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History table for TSAP revised version dated 28th Jul 2022
Version
Date
Author
Changes in 
old Section
(new 
Section)
Brief description of change
Revised
28-JUL-2022
7.4.1.1
Updated to use one seed for the missing data 
imputation for all confirmatory analyses.
OLD Text … The seed used in the DINAMO 
primary family of analyses will be 1218009101.
NEW Text … The seed used in the DINAMO 
confirmatory analyses will be 1218009101.
7.4.1.2
Removed the seeds from this section in order to use 
the seed mentioned in section 7.4.1.1.
Deleted OLD Text … The seeds used in the 
DINAMO secondary family of analyses will be 
1218009102 for hypothesis H’0,1 and 1218009103 
for hypothesis H’0,2.


 
 
 
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