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Clinical Trial Results:
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.

Summary
EudraCT number	2016-000669-21
Trial protocol	PT Outside EU/EEA DE NL GB
Global end of trial date	31 May 2023

Results information
Results version number	v1(current)
This version publication date	14 Dec 2023
First version publication date	14 Dec 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1218-0091

ISRCTN number

US NCT number

NCT03429543

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127 x 001, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127 x 001, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000498-PIP01-08

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

20 Jun 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 May 2023

Global end of trial reached?

Yes

Global end of trial date

31 May 2023

Was the trial ended prematurely?

Main objective of the trial

The objective of DINAMOᵀᴹ was to assess the efficacy and safety of 1 dose of linagliptin and an empagliflozin dosing regimen versus placebo after 26 weeks of treatment in children and adolescents with type 2 diabetes mellitus (T2DM) who were treated with metformin and/or insulin or who were not tolerating metformin. In addition, this trial assessed the long-term safety of empagliflozin and linagliptin after 52 weeks of treatment. The objective of DINAMOᵀᴹ Mono was 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.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Apr 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 2

Country: Number of subjects enrolled

Brazil: 6

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

China: 3

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Israel: 10

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Mexico: 48

Country: Number of subjects enrolled

Russian Federation: 21

Country: Number of subjects enrolled

Thailand: 4

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

United States: 187

Worldwide total number of subjects

301

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

282

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

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 non-responder patients and an active treatment safety period up to 52 weeks.

Screening details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Blinding implementation details

Patients, investigators, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial remained blinded with regard to the randomised treatment assignments until after database lock.

Are arms mutually exclusive

Yes

Placebo - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.

Placebo - Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Arm description

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 5 milligram (mg) Linagliptin, taken once daily, until end of treatment.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.

Investigational medicinal product name

Linagliptin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of 5 milligram (mg) Linagliptin once daily.

Placebo - Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Arm description

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 type

Experimental

Investigational medicinal product name

Empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.

Placebo - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Arm description

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 type

Experimental

Investigational medicinal product name

Empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of 25 milligram (mg) Empagliflozin once daily.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.

Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Arm description

Arm type

Experimental

Investigational medicinal product name

Linagliptin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of 5 milligram (mg) Linagliptin once daily.

Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Arm description

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 type

Experimental

Investigational medicinal product name

Empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily.

Empagliflozin 10 mg - 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of 25 milligram (mg) Empagliflozin once daily.

Investigational medicinal product name

Empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily.

Number of subjects in period 1 ^[1]	Placebo - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Placebo - Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Placebo - Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Placebo - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 10 mg - 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Started	7	19	16	16	59	45	13
Treated	7	19	16	16	58	45	13
Completed	0	17	15	14	47	36	12
Not completed	7	2	1	2	12	9	1
Consent withdrawn by subject	5	-	1	2	6	3	1
Adverse event, non-fatal	1	1	-	-	-	2	-
Other reason than listed	-	1	-	-	4	4	-
Lost to follow-up	1	-	-	-	1	-	-
Not treated	-	-	-	-	1	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of the 301 enrolled subjects, 175 were randomised.

Baseline characteristics

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Reporting group title

Placebo - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Reporting group title

Placebo - Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Reporting group title

Placebo - Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Reporting group title

Placebo - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Reporting group title

Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Reporting group title

Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Reporting group title

Empagliflozin 10 mg - 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Reporting group values	Placebo - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Placebo - Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Placebo - Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Placebo - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 10 mg - 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Total
Number of subjects	7	19	16	16	59	45	13	175
Age categorical
The randomised set (RS) included all randomised patients, regardless whether they took trial medication.
Units: Subjects
<15 years	3	10	8	8	29	21	7	86
>=15 years to <18 years	4	9	8	8	30	24	6	89
Age Continuous
The randomised set (RS) included all randomised patients, regardless whether they took trial medication.
Units: years
arithmetic mean (standard deviation)	15.3 ( 1.4 )	14.3 ( 1.7 )	14.1 ( 2.2 )	14.8 ( 1.8 )	14.4 ( 2.1 )	14.6 ( 1.8 )	13.9 ( 2.2 )	-
Sex: Female, Male
The randomised set (RS) included all randomised patients, regardless whether they took trial medication.
Units: Participants
Female	6	12	11	8	36	31	8	112
Male	1	7	5	8	23	14	5	63
Race/Ethnicity, Customized
The randomised set (RS) included all randomised patients, regardless whether they took trial medication.
Units: Subjects
American Indian/Alaska Native	0	1	0	0	3	4	0	8
Asian	0	1	1	1	5	2	0	10
Black/African American	5	4	3	6	17	20	4	59
Native Hawaiian or other Pacific Islander	0	0	1	0	2	0	0	3
White	1	13	10	9	28	17	7	85
Other including mixed or missing race	1	0	1	0	4	2	2	10
Ethnicity (NIH/OMB)
The randomised set (RS) included all randomised patients, regardless whether they took trial medication.
Units: Subjects
Hispanic or Latino	1	10	5	7	24	12	6	65
Not Hispanic or Latino	6	9	11	9	35	33	7	110
Unknown or Not Reported	0	0	0	0	0	0	0	0
Glycated haemoglobin (HbA1c) (%)
Glycated haemoglobin (HbA1c) (%)
Units: Percentage
arithmetic mean (standard deviation)	7.40 ( 0.77 )	8.01 ( 1.42 )	8.00 ( 1.28 )	8.14 ( 1.17 )	7.98 ( 1.09 )	7.78 ( 1.33 )	8.24 ( 1.08 )	-

End points

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Reporting group title

Placebo - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Reporting group title

Placebo - Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Reporting group title

Placebo - Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Reporting group title

Placebo - Empagliflozin 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Reporting group title

Linagliptin 5 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Reporting group title

Empagliflozin 10 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Reporting group title

Empagliflozin 10 mg - 25 mg - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

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.

Subject analysis set title

Placebo - DINAMOᵀᴹ

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients treated with metformin and/or insulin or patients who do not tolerate metformin took 1 film-coated tablet of either Linagliptin or Empagliflozin matched placebo once daily.

Subject analysis set title

Linagliptin 5 mg - DINAMOᵀᴹ

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients treated with metformin and/or insulin or patients who do not tolerate metformin took 1 film-coated tablet of 5 milligram (mg) Linagliptin once daily.

Subject analysis set title

Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients treated with metformin and/or insulin or patients who do not tolerate metformin took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily. Patients who did not achieve an HbA1c value <7% at Week 12, were re-randomised to receive either 10 mg or 25 mg empagliflozin in a 1:1 ratio, taken once daily, until end of treatment.

Subject analysis set title

Empagliflozin 10 mg - DINAMOᵀᴹ

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients treated with metformin and/or insulin or patients who do not tolerate metformin took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily. Responder (achieve an HbA1c value <7% at Week 12) 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.

Subject analysis set title

Empagliflozin 25 mg - DINAMOᵀᴹ

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients treated with metformin and/or insulin or patients who do not tolerate metformin took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily. Patients who did not achieve an HbA1c value <7% at Week 12, were re-randomised to receive 25 mg empagliflozin, taken once daily, until end of treatment.

Subject analysis set title

Placebo - DINAMOᵀᴹ Mono

Subject analysis set type

Intention-to-treat

Subject analysis set description

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.

Subject analysis set title

Linagliptin 5 mg - DINAMOᵀᴹ Mono

Subject analysis set type

Intention-to-treat

Subject analysis set description

Treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 5 milligram (mg) Linagliptin once daily.

Subject analysis set title

Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Subject analysis set type

Intention-to-treat

Subject analysis set description

Treatment-naïve patients or patients who are not on active treatment took 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily. Patients who did not achieve an HbA₁c value <7% at Week 12, were re-randomised to receive either 10 mg or 25 mg empagliflozin in a 1:1 ratio, taken once daily, until end of treatment.

Primary: Change in glycated haemoglobin (HbA1c) (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ

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End point title

Change in glycated haemoglobin (HbA1c) (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ

End point description

Adjusted means taken from three models: Treatment group 1 (TG1): Placebo, Linagliptin 5 mg and Empagliflozin pooled Treatment group 2 (TG2): Placebo, Empagliflozin 25mg Treatment group 3 (TG3): Placebo, Empagliflozin 10mg Description of model used to obtain adjusted values can be found in the statistical analyses. mITT: patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. All available data as observed were included. Any values after start of rescue medication and any on- and post-treatment values were kept. As pre-specified in the Protocol, endpoint only includes the main study DINAMOᵀᴹ data. 9999= Adjusted mean (95%CI) per treatment group.

End point type

Primary

End point timeframe

Baseline (Day 1) and week 26 of treatment.

End point values	Placebo - DINAMOᵀᴹ	Linagliptin 5 mg - DINAMOᵀᴹ	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ	Empagliflozin 10 mg - DINAMOᵀᴹ	Empagliflozin 25 mg - DINAMOᵀᴹ
Number of subjects analysed	53 ^[1]	52	52	39	41
Units: Percent change
least squares mean (confidence interval 95%)	9999 (9999 to 9999)	0.33 (-0.13 to 0.79)	-0.17 (-0.64 to 0.31)	-0.49 (-1.03 to 0.04)	0.14 (-0.42 to 0.71)

Notes
[1] - 9999= Adj mean (95%CI): TG1: 0.68 (0.23, 1.13) TG2: 0.66 (0.12, 1.21) TG3: 0.68 (0.19, 1.17)

Statistical analysis 1

Statistical analysis description

Treatment group 1 (TG1) consisting of Placebo, Linagliptin 5 mg and Empagliflozin pooled Patients: Analysis of covariance (ANCOVA) model with a continuous covariate (baseline HbA1c) and categorical covariates (treatment and age). The effect of linagliptin and of empagliflozin (including responders and non-responders) was compared with placebo at an overall α of 0.05 (2-sided) using the Hochberg method to account for multiple testing.

Comparison groups

Placebo - DINAMOᵀᴹ v Linagliptin 5 mg - DINAMOᵀᴹ

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

^[2]

P-value

= 0.2935

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[2] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 2

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

^[3]

P-value

= 0.0116

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.84

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

-0.19

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[3] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 3

Statistical analysis description

Treatment group 2 (TG2) consisting of Placebo, Empagliflozin 25mg Patients: Analysis of covariance (ANCOVA) model with a continuous covariate (baseline HbA1c) and categorical covariates (treatment and age). The effect of linagliptin and of empagliflozin (including responders and non-responders) was compared with placebo at an overall α of 0.05 (2-sided) using the Hochberg method to account for multiple testing. Mean difference calculated as [Treatment] - Placebo.

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin 25 mg - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[4]

P-value

= 0.1943

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-1.31

upper limit

0.27

Variability estimate

Standard error of the mean

Dispersion value

0.4

Notes
[4] - Secondary hypotheses compared the empagliflozin doses vs placebo based on TG2 and TG3. ANCOVA utilised a weight of zero for patients who were not in the hypothesis test of interest, a value of 2 for re-randomised patients who were in the hypothesis test of interest and a value of 1 otherwise. Since the primary hypotheses (TG1) could not be both rejected, the hierarchical testing for TG2 and TG3 was not continued. Analyses were considered exploratory and the p-values regarded as nominal.

Statistical analysis 4

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin 10 mg - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[5]

P-value

= 0.0015

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.18

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

-0.45

Variability estimate

Standard error of the mean

Dispersion value

0.37

Notes
[5] - Secondary hypotheses compared the empagliflozin doses vs placebo based on TG2 and TG3. ANCOVA utilised a weight of zero for patients who were not in the hypothesis test of interest, a value of 2 for re-randomised patients who were in the hypothesis test of interest and a value of 1 otherwise. Since the primary hypotheses (TG1) could not be both rejected, the hierarchical testing for TG2 and TG3 was not continued. Analyses were considered exploratory and the p-values regarded as nominal.

Primary: Percentage of patients with treatment failure up to or at Week 26

Top of page

End point title

Percentage of patients with treatment failure up to or at Week 26

End point description

Percentage of patients with 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%. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. Missing values were regarded as ‘failures’. As pre-specified in the Protocol, endpoint only includes the ancillary study (DINAMOᵀᴹ Mono) data.

End point type

Primary

End point timeframe

Up to 26 weeks.

End point values	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	3	3	3
Units: Percentage of subjects
number (confidence interval 90%)	60.0 (18.9 to 92.4)	50.0 (15.3 to 84.7)	50.0 (15.3 to 84.7)

Statistical analysis 6

Statistical analysis description

Risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 90% confidence interval based on the method of Chan and Zhang. Patients were assigned to the treatment they were randomised to at the initial randomisation.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[6]

P-value

= 1

Method

Fisher exact

Parameter type

Risk difference (RD)

Point estimate

-10

Confidence interval

level

90%

sides

2-sided

lower limit

-58.7

upper limit

43.7

Notes
[6] - Risk difference calculated as [treatment]-[placebo].

Statistical analysis 5

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Linagliptin 5 mg - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[7]

P-value

= 1

Method

Fisher exact

Parameter type

Risk difference (RD)

Point estimate

-10

Confidence interval

level

90%

sides

2-sided

lower limit

-58.7

upper limit

43.7

Notes
[7] - Risk difference calculated as [treatment]-[placebo].

Secondary: Change in HbA1c (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ Mono

Top of page

End point title

Change in HbA1c (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ Mono

End point description

Change in Glycated haemoglobin (HbA1c) (%) from baseline to the end of 26 weeks. Adjusted values came from a restricted maximum likelihood (REML) approach with mixed model for repeated measures (MMRM). Analyses included 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 was treated as the repeated measure with an unstructured covariance structure used to model the within-patient measurements. mITT: included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. All available data as observed were included. Any values after start of rescue medication and any on- and post-treatment values were kept. As pre-specified in the Protocol, endpoint only includes the ancillary study (DINAMOᵀᴹ Mono) data.

End point type

Secondary

End point timeframe

Baseline (Day 1) and week 26 of treatment.

End point values	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	4	5	4
Units: Percent change
least squares mean (confidence interval 95%)	0.15 (-1.45 to 1.75)	-0.53 (-2.01 to 0.95)	-0.23 (-1.83 to 1.37)

Statistical analysis 8

Statistical analysis description

Restricted maximum likelihood (REML) approach with mixed model for repeated measures (MMRM). Fixed categorical effects of treatment, visit, and treatment-by-visit interaction and categorical covariate age (baseline) and continuous, fixed covariates of baseline of response variable and baseline of response variable-by-visit interaction. Covariate visit was treated as repeated measure with an unstructured covariance structure used to model within-patient measurements.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[8]

P-value

= 0.7047

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-2.64

upper limit

1.88

Notes
[8] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 7

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Linagliptin 5 mg - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[9]

P-value

= 0.4828

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-2.86

upper limit

1.49

Notes
[9] - Mean difference calculated as [Treatment] - Placebo.

Secondary: Time to treatment failure

Top of page

End point title

Time to treatment failure

End point description

Time to treatment failure was analysed by Kaplan-Meier estimates up to the end of the study (Week 52). Patients in the placebo group were censored after 26 weeks unless a prior treatment failure was observed. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. Missing values were regarded as ‘failures’. As pre-specified in the Protocol, endpoint only includes the ancillary study (DINAMOᵀᴹ Mono) data.

End point type

Secondary

End point timeframe

Up to 395 days.

End point values	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	3	4	3
Units: Days
arithmetic mean (standard error)	65.600 ( 19.941 )	72.167 ( 20.280 )	167.333 ( 26.711 )

Statistical analysis 10

Statistical analysis description

Time to treatment failure was analysed by Kaplan-Meier estimates up to the end of the study. A log-rank test compared linagliptin and empagliflozin pooled versus placebo up to Week 26.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2827

Method

Logrank

Confidence interval

Statistical analysis 9

Statistical analysis description

Time to treatment failure was analysed by Kaplan-Meier estimates up to the end of the study. A log-rank test compared linagliptin and empagliflozin pooled versus placebo up to Week 26.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Linagliptin 5 mg - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8626

Method

Logrank

Confidence interval

Secondary: Change in fasting plasma glucose (FPG, mg/dL) from baseline to the end of 26 weeks

Top of page

End point title

Change in fasting plasma glucose (FPG, mg/dL) from baseline to the end of 26 weeks

End point description

Change in fasting plasma glucose (FPG, Milligrams Per Deciliter (mg/dL)) from baseline to the end of 26 weeks. Adjusted values taken from analysis of covariance (ANCOVA) model with treatment as a fixed classification effect, baseline FPG as linear covariate and age at randomisation as categorical covariate. The random error was assumed to be normally distributed. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. All available data as observed were included. Any values after start of rescue medication and any on- and post-treatment values were kept, baseline observations were carried forward to impute the missing data. Only patients with non-missing data were included.

End point type

Secondary

End point timeframe

Baseline (Day 1) and week 26.

End point values	Placebo - DINAMOᵀᴹ	Linagliptin 5 mg - DINAMOᵀᴹ	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	52	51	48	4	4	5
Units: Milligrams Per Deciliter (mg/dL)
least squares mean (confidence interval 95%)	15.70 (-0.53 to 31.93)	10.29 (-6.12 to 26.69)	-19.48 (-36.39 to -2.57)	-38.50 (-62.67 to -14.33)	0.12 (-23.67 to 23.91)	-18.45 (-40.00 to 3.10)

Statistical analysis 11

Statistical analysis description

Analysis of covariance (ANCOVA) model with treatment as a fixed classification effect, baseline FPG as linear covariate and age at randomisation as categorical covariate. The random error was assumed to be normally distributed.

Comparison groups

Placebo - DINAMOᵀᴹ v Linagliptin 5 mg - DINAMOᵀᴹ

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

^[10]

P-value

= 0.6438

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-5.41

Confidence interval

level

95%

sides

2-sided

lower limit

-28.49

upper limit

17.67

Notes
[10] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 12

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

^[11]

P-value

= 0.0035

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-35.18

Confidence interval

level

95%

sides

2-sided

lower limit

-58.61

upper limit

-11.74

Notes
[11] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 13

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Linagliptin 5 mg - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[12]

P-value

= 0.031

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

38.62

Confidence interval

level

95%

sides

2-sided

lower limit

4.54

upper limit

72.7

Notes
[12] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 14

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[13]

P-value

= 0.1994

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

20.05

Confidence interval

level

95%

sides

2-sided

lower limit

-13.01

upper limit

53.11

Notes
[13] - Mean difference calculated as [Treatment] - Placebo.

Secondary: Change in body weight (kg) from baseline to the end of 26 weeks

Top of page

End point title

Change in body weight (kg) from baseline to the end of 26 weeks

End point description

Change in body weight (kg) from baseline to the end of 26 weeks. Adjusted values taken from mixed model for repeated measures (MMRM) with 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 was treated as repeated measure with an unstructured covariance structure used to model the within-patient measurements. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. All available data as observed were included. Any values after start of rescue medication and any on- and post-treatment values were kept. Only patients with non-missing data were included.

End point type

Secondary

End point timeframe

Baseline (Day 1) and week 26.

End point values	Placebo - DINAMOᵀᴹ	Linagliptin 5 mg - DINAMOᵀᴹ	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	50	49	48	4	6	4
Units: kilogram (kg)
least squares mean (confidence interval 95%)	-0.04 (-1.40 to 1.32)	1.42 (0.04 to 2.81)	-0.79 (-2.17 to 0.59)	2.64 (-0.35 to 5.63)	2.69 (0.24 to 5.14)	1.29 (-1.75 to 4.33)

Statistical analysis 15

Statistical analysis description

Mixed model for repeated measures (MMRM) with 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 was treated as repeated measure with an unstructured covariance structure used to model the within-patient measurements.

Comparison groups

Placebo - DINAMOᵀᴹ v Linagliptin 5 mg - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[14]

P-value

= 0.1394

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.48

upper limit

3.41

Notes
[14] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 17

Statistical analysis description

Comparison groups

Linagliptin 5 mg - DINAMOᵀᴹ Mono v Placebo - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[15]

P-value

= 0.9789

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-3.8

upper limit

3.9

Notes
[15] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 18

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[16]

P-value

= 0.5092

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.35

Confidence interval

level

95%

sides

2-sided

lower limit

-5.68

upper limit

2.99

Notes
[16] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 16

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[17]

P-value

= 0.4476

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-2.68

upper limit

1.19

Notes
[17] - Mean difference calculated as [Treatment] - Placebo.

Secondary: Change in systolic blood pressure (SBP, mmHg) from baseline to the end of 26 weeks

Top of page

End point title

Change in systolic blood pressure (SBP, mmHg) from baseline to the end of 26 weeks

End point description

Change in systolic blood pressure (SBP, millimeters of mercury (mmHg)) from baseline to the end of 26 weeks. Adjusted values taken from mixed model for repeated measures (MMRM) with 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 was treated as repeated measure with an unstructured covariance structure used to model the within-patient measurements. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. All available data as observed were included. Any values after start of rescue medication and any on- and post-treatment values were kept. Only patients with non-missing data were included.

End point type

Secondary

End point timeframe

Baseline (Day 1) and week 26.

End point values	Placebo - DINAMOᵀᴹ	Linagliptin 5 mg - DINAMOᵀᴹ	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	50	49	48	4	6	4
Units: millimeters of mercury (mmHg)
least squares mean (confidence interval 95%)	1.30 (-1.01 to 3.61)	2.21 (-0.14 to 4.56)	-0.12 (-2.47 to 2.24)	2.63 (-4.07 to 9.34)	5.16 (-0.74 to 11.06)	2.63 (-4.86 to 10.12)

Statistical analysis 20

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[18]

P-value

= 0.3967

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.42

Confidence interval

level

95%

sides

2-sided

lower limit

-4.72

upper limit

1.88

Notes
[18] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 19

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Linagliptin 5 mg - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[19]

P-value

= 0.587

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

4.22

Notes
[19] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 22

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[20]

P-value

= 0.9995

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-10.13

upper limit

10.13

Notes
[20] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 21

Statistical analysis description

Comparison groups

Linagliptin 5 mg - DINAMOᵀᴹ Mono v Placebo - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[21]

P-value

= 0.5414

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

2.53

Confidence interval

level

95%

sides

2-sided

lower limit

-6.42

upper limit

11.47

Notes
[21] - Mean difference calculated as [Treatment] - Placebo.

Secondary: Change in diastolic blood pressure (DBP, mmHg) from baseline to the end of 26 weeks

Top of page

End point title

Change in diastolic blood pressure (DBP, mmHg) from baseline to the end of 26 weeks

End point description

Change in diastolic blood pressure (DBP, millimeters of mercury (mmHg)) from baseline to the end of 26 weeks. Adjusted values taken from mixed model for repeated measures (MMRM) with 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 was treated as repeated measure with an unstructured covariance structure used to model the within-patient measurements. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. All available data as observed were included. Any values after start of rescue medication and any on- and post-treatment values were kept. Only patients with non-missing data were included.

End point type

Secondary

End point timeframe

Baseline (Day 1) and week 26.

End point values	Placebo - DINAMOᵀᴹ	Linagliptin 5 mg - DINAMOᵀᴹ	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	50	49	48	4	6	4
Units: millimeters of mercury (mmHg)
least squares mean (confidence interval 95%)	0.76 (-1.01 to 2.53)	2.26 (0.46 to 4.05)	0.78 (-1.04 to 2.60)	3.42 (-4.92 to 11.75)	6.75 (0.14 to 13.35)	-3.20 (-10.10 to 3.69)

Statistical analysis 23

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Linagliptin 5 mg - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[22]

P-value

= 0.2433

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

4.02

Notes
[22] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 26

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[23]

P-value

= 0.2348

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-6.62

Confidence interval

level

95%

sides

2-sided

lower limit

-18.19

upper limit

4.95

Notes
[23] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 25

Statistical analysis description

Comparison groups

Linagliptin 5 mg - DINAMOᵀᴹ Mono v Placebo - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[24]

P-value

= 0.567

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

3.33

Confidence interval

level

95%

sides

2-sided

lower limit

-9

upper limit

15.65

Notes
[24] - Mean difference calculated as [Treatment] - Placebo.

Statistical analysis 24

Statistical analysis description

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[25]

P-value

= 0.9878

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-2.52

upper limit

2.56

Notes
[25] - Mean difference calculated as [Treatment] - Placebo.

Secondary: Percentage of patients who achieve HbA1c <6.5% at the end of 26 weeks

Top of page

End point title

Percentage of patients who achieve HbA1c <6.5% at the end of 26 weeks

End point description

Percentage of patients who achieve HbA1c <6.5% at the end of 26 weeks. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. Missing values were regarded as ‘failures’.

End point type

Secondary

End point timeframe

Baseline (Day 1) and week 26.

End point values	Placebo - DINAMOᵀᴹ	Linagliptin 5 mg - DINAMOᵀᴹ	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	5	8	11	2	1	1
Units: Percentage of subjects
number (not applicable)	9.4	15.4	21.2	40.0	16.7	16.7

Statistical analysis 27

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and two−sided Wald test.

Comparison groups

Placebo - DINAMOᵀᴹ v Linagliptin 5 mg - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[26]

P-value

= 0.3536

Method

Wald test

Parameter type

Rate difference (percentage)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7

upper limit

19.9

Notes
[26] - Difference calculated as [Treatment] - Placebo.

Statistical analysis 30

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and Fisher's exact test.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[27]

P-value

= 0.5455

Method

Fisher exact

Parameter type

Rate difference (percentage)

Point estimate

-23.3

Confidence interval

level

90%

sides

2-sided

lower limit

-67.9

upper limit

27.1

Notes
[27] - Difference calculated as [Treatment] - Placebo.

Statistical analysis 29

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and Fisher's exact test.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Linagliptin 5 mg - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[28]

P-value

= 0.5455

Method

Fisher exact

Parameter type

Rate difference (percentage)

Point estimate

-23.3

Confidence interval

level

90%

sides

2-sided

lower limit

-67.9

upper limit

27.1

Notes
[28] - Difference calculated as [Treatment] - Placebo.

Statistical analysis 28

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and two−sided Wald test.

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[29]

P-value

= 0.0914

Method

Wald test

Parameter type

Rate difference (percentage)

Point estimate

11.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

26.3

Notes
[29] - Difference calculated as [Treatment] - Placebo.

Secondary: Percentage of patients who achieve HbA1c <7.0% at the end of 26 weeks

Top of page

End point title

Percentage of patients who achieve HbA1c <7.0% at the end of 26 weeks

End point description

Percentage of patients who achieve HbA1c <7.0% at the end of 26 weeks. The modified intention-to-treat set (mITT) included all patients treated with at least 1 dose of trial medication who had a baseline HbA1c measurement. Missing values were regarded as ‘failures’.

End point type

Secondary

End point timeframe

Baseline (Day 1) and week 26.

End point values	Placebo - DINAMOᵀᴹ	Linagliptin 5 mg - DINAMOᵀᴹ	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ	Placebo - DINAMOᵀᴹ Mono	Linagliptin 5 mg - DINAMOᵀᴹ Mono	Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono
Number of subjects analysed	13	14	18	2	1	4
Units: Percentage of subjects
number (not applicable)	24.5	26.9	34.6	40.0	16.7	66.7

Statistical analysis 31

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and two−sided Wald test.

Comparison groups

Placebo - DINAMOᵀᴹ v Linagliptin 5 mg - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[30]

P-value

= 0.7789

Method

Wald test

Parameter type

Rate difference (percentage)

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-15.2

upper limit

19.5

Notes
[30] - Difference calculated as [Treatment] - Placebo.

Statistical analysis 32

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and two−sided Wald test.

Comparison groups

Placebo - DINAMOᵀᴹ v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[31]

P-value

= 0.2548

Method

Wald test

Parameter type

Rate difference (percentage)

Point estimate

10.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7

upper limit

28.1

Notes
[31] - Difference calculated as [Treatment] - Placebo.

Statistical analysis 33

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and Fisher's exact test.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Linagliptin 5 mg - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[32]

P-value

= 0.5455

Method

Fisher exact

Parameter type

Rate difference (percentage)

Point estimate

-23.3

Confidence interval

level

90%

sides

2-sided

lower limit

-67.9

upper limit

27.1

Notes
[32] - Difference calculated as [Treatment] - Placebo.

Statistical analysis 34

Statistical analysis description

The risk difference of active treatments versus placebo was determined and assessed by an exact 2-sided 95% confidence interval. Exact 95% CI by Chan and Zhang. Asymptotic and Fisher's exact test.

Comparison groups

Placebo - DINAMOᵀᴹ Mono v Empagliflozin pooled (10 mg and 25 mg) - DINAMOᵀᴹ Mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[33]

P-value

= 0.5671

Method

Fisher exact

Parameter type

Rate difference (percentage)

Point estimate

26.7

Confidence interval

level

90%

sides

2-sided

lower limit

-30.8

upper limit

70.8

Notes
[33] - Difference calculated as [Treatment] - Placebo.

Adverse events

Top of page

Timeframe for reporting adverse events

Date of first study drug intake until date of last active study drug intake + residual effect period (7 days), up to 402 days.

Adverse event reporting additional description

The treated set (TS) included all patients treated with at least 1 dose of randomised trial medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Placebo pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Patients from either DINAMOᵀᴹ or DINAMOᵀᴹ Mono randomized to Placebo.

Reporting group title

Empagliflozin 25 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Patients from either DINAMOᵀᴹ or DINAMOᵀᴹ Mono who were on Placebo and switched to 25 mg Empagliflozin following re-randomisation at week 26 or who were on 10 mg Empagliflozin and switched to 25 mg Empagliflozin following re-randomisation at week 14. 1 film-coated tablet of 25 mg empagliflozin, taken once daily, until end of treatment.

Reporting group title

Empagliflozin 10 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Patients from either DINAMOᵀᴹ or DINAMOᵀᴹ Mono who either started on 10 mg Empagliflozin or switched to 10 mg Empagliflozin from Placebo at week 26. 1 film-coated tablet of 10 milligram (mg) Empagliflozin once daily.

Reporting group title

Linagliptin 5 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono

Reporting group description

Patients from either DINAMOᵀᴹ or DINAMOᵀᴹ Mono who either started on Linagliptin or who switched to Linagliptin from Placebo at week 26. 1 film-coated tablet of 5 milligram (mg) Linagliptin once daily.

Serious adverse events	Placebo pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 25 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 10 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Linagliptin 5 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 58 (3.45%)	0 / 29 (0.00%)	4 / 74 (5.41%)	8 / 77 (10.39%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Investigations
Blood glucose increased
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	0 / 74 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	1 / 74 (1.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypovolaemic shock
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	1 / 74 (1.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Splenic vein thrombosis
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	1 / 74 (1.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	0 / 74 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	0 / 74 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	1 / 74 (1.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	1 / 74 (1.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	1 / 74 (1.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Chorioretinitis
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	0 / 74 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin candida
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	1 / 74 (1.35%)	0 / 77 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	0 / 74 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	2 / 77 (2.60%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	0 / 74 (0.00%)	1 / 77 (1.30%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 25 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Empagliflozin 10 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono	Linagliptin 5 mg pooled - DINAMOᵀᴹ & DINAMOᵀᴹ Mono
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 58 (51.72%)	14 / 29 (48.28%)	47 / 74 (63.51%)	45 / 77 (58.44%)
Investigations
Blood ketone body increased
subjects affected / exposed	2 / 58 (3.45%)	3 / 29 (10.34%)	5 / 74 (6.76%)	8 / 77 (10.39%)
occurrences all number	3	5	5	12
Urine albumin/creatinine ratio increased
subjects affected / exposed	2 / 58 (3.45%)	1 / 29 (3.45%)	1 / 74 (1.35%)	5 / 77 (6.49%)
occurrences all number	2	1	1	6
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 58 (5.17%)	0 / 29 (0.00%)	4 / 74 (5.41%)	1 / 77 (1.30%)
occurrences all number	3	0	4	2
Headache
subjects affected / exposed	9 / 58 (15.52%)	3 / 29 (10.34%)	12 / 74 (16.22%)	12 / 77 (15.58%)
occurrences all number	12	4	21	24
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	4 / 74 (5.41%)	0 / 77 (0.00%)
occurrences all number	0	0	4	0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	2 / 58 (3.45%)	2 / 29 (6.90%)	2 / 74 (2.70%)	2 / 77 (2.60%)
occurrences all number	2	2	2	2
Abdominal pain
subjects affected / exposed	4 / 58 (6.90%)	1 / 29 (3.45%)	4 / 74 (5.41%)	5 / 77 (6.49%)
occurrences all number	7	1	4	8
Nausea
subjects affected / exposed	3 / 58 (5.17%)	0 / 29 (0.00%)	3 / 74 (4.05%)	4 / 77 (5.19%)
occurrences all number	4	0	4	8
Diarrhoea
subjects affected / exposed	5 / 58 (8.62%)	2 / 29 (6.90%)	3 / 74 (4.05%)	7 / 77 (9.09%)
occurrences all number	9	2	4	8
Vomiting
subjects affected / exposed	2 / 58 (3.45%)	2 / 29 (6.90%)	5 / 74 (6.76%)	8 / 77 (10.39%)
occurrences all number	2	2	6	9
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 58 (0.00%)	1 / 29 (3.45%)	6 / 74 (8.11%)	2 / 77 (2.60%)
occurrences all number	0	1	8	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 58 (8.62%)	1 / 29 (3.45%)	4 / 74 (5.41%)	6 / 77 (7.79%)
occurrences all number	5	1	4	6
Oropharyngeal pain
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	5 / 74 (6.76%)	3 / 77 (3.90%)
occurrences all number	1	0	5	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 58 (1.72%)	0 / 29 (0.00%)	2 / 74 (2.70%)	4 / 77 (5.19%)
occurrences all number	1	0	2	4
Back pain
subjects affected / exposed	2 / 58 (3.45%)	0 / 29 (0.00%)	4 / 74 (5.41%)	4 / 77 (5.19%)
occurrences all number	2	0	4	4
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	0 / 58 (0.00%)	1 / 29 (3.45%)	5 / 74 (6.76%)	3 / 77 (3.90%)
occurrences all number	0	1	5	7
Urinary tract infection
subjects affected / exposed	1 / 58 (1.72%)	2 / 29 (6.90%)	5 / 74 (6.76%)	1 / 77 (1.30%)
occurrences all number	1	2	5	1
Nasopharyngitis
subjects affected / exposed	3 / 58 (5.17%)	1 / 29 (3.45%)	3 / 74 (4.05%)	6 / 77 (7.79%)
occurrences all number	3	1	3	7
Influenza
subjects affected / exposed	0 / 58 (0.00%)	0 / 29 (0.00%)	3 / 74 (4.05%)	4 / 77 (5.19%)
occurrences all number	0	0	3	4
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	2 / 58 (3.45%)	0 / 29 (0.00%)	3 / 74 (4.05%)	5 / 77 (6.49%)
occurrences all number	3	0	4	5
Hypoglycaemia
subjects affected / exposed	7 / 58 (12.07%)	5 / 29 (17.24%)	12 / 74 (16.22%)	16 / 77 (20.78%)
occurrences all number	22	52	66	77
Vitamin D deficiency
subjects affected / exposed	8 / 58 (13.79%)	2 / 29 (6.90%)	10 / 74 (13.51%)	6 / 77 (7.79%)
occurrences all number	8	2	10	6

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

03 Oct 2019

Streamlining and clarification of wording and inclusion of authority feedback (Food and Drug Administration (FDA) proposed pediatric study request, European Medicines Agency (EMA) paediatric investigational plan, and Medicine and Healthcare products Regulatory Agency in the United Kingdom (UK)) as follows: - Statistical method for primary endpoint changed from MMRM to pattern mixture model (jump-to-placebo and inverse probability weighting approach). The previous Mixed model for repeated measures (MMRM) became a sensitivity analysis - Number of patients increased in DINAMOᵀᴹ - Trial part with DINAMOᵀᴹ Mono added - Minor adaptions to the flow chart including additional interactions between patient and site - Exclusion criterion specified (acute metabolic decompensation) - Addition of further efficacy endpoint (proportion of patients who achieve HbA1c reduction of >0.5% at the end of 26 and 52 weeks) - Frequency for blood ketone bodies measurement adapted - Addition of Adverse event of special interest (AESIs) arthralgia, bullous pemphigoid, AEs related to reduced intravascular volume - Removal of hospitalisation for unstable angina and of pancreatic events from the adjudication process - New recommendations on diet and exercise for the patients by the site - Addition of Body mass index (BMI) as new subgroup

28 Sep 2020

Streamlining and clarification of wording, inclusion of authority feedback (FDA and EMA), and addition of measures related to the COVID-19 pandemic as follows: - Updated inclusion criteria: reduction in length of diagnosis of Type 2 diabetes mellitus (T2DM) from 12 to 8 weeks and addition of minimum daily metformin dosage - Change in primary endpoint analysis from pattern mixture model (‘jump-to-placebo’ and ‘inverse probability weighting’ approach) to ‘wash-out’ and ‘inverse probability weighting’ approach for primary and secondary hypotheses - Addition of measures related to the COVID-19 pandemic - Addition of remote visits - Guidance added for patients stopping prematurely (also related to Diabetic ketoacidosis (DKA)) - Addition of local instead of central laboratory testing - Shipment of trial medication directly to the patients - Possibility added to replace patients to keep a certain sample size despite the pandemic - Addition of alternative method for SAE report transmission in certain countries - Addition of sensitivity analysis for the primary endpoint - Rules implemented for remote source data verification during restricted on-site monitoring visits

14 Dec 2020

Administrative changes, streamlining of wording, and addition of further measures related to the COVID-19 pandemic as follows: - Reconsent could be done remotely due to the COVID-19 pandemic - Serum pregnancy test could be done at a local laboratory due to the COVID-19 pandemic

14 Jul 2021

This version was only submitted to the FDA and never implemented due to the requested changes. It included administrative changes, clarified wording, and incorporated feedback from the FDA on the previous global amendment. - Time reduced between rescreening visits (from 12 to 8 weeks) to allow earlier inclusion of patients - Clarification of maintaining the blinded conditions while the bioanalyst required access to the data when migrating from the main trial to the ancillary trial - If a centrally analysed, National Glycohemoglobin Standardization Program (NGSP)-certified Glycated haemoglobin (HbA1c) assay was unavailable (e.g. due to the COVID-19 pandemic), an HbA1c assay performed at a local laboratory was acceptable. Text added to specify the corresponding sensitivity analyses - Addition of an alternative means to measure blood glucose concentration - Clarification of the secondary hypotheses for the Analysis of covariance (ANCOVA)

28 Sep 2021

This amendment included administrative changes and incorporated feedback from the FDA: - Clarification that patients with a Continuous glucose monitoring (CGM) device could use relevant readings from that device to avoid additional finger pricks - Further clarification on secondary hypotheses for the ANCOVA

23 May 2022

This amendment mainly impacted the ancillary trial DINAMOᵀᴹ Mono which is still ongoing. Changes regarding DINAMOᵀᴹ included addition of bone fracture as further safety endpoint; bone fracture was already introduced via the initial Trial statistical analysis plan (TSAP) version.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
17 Mar 2020	Due to the COVID-19 pandemic, the enrolment 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.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in glycated haemoglobin (HbA1c) (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ

Primary: Change in glycated haemoglobin (HbA1c) (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ

Primary: Percentage of patients with treatment failure up to or at Week 26

Primary: Percentage of patients with treatment failure up to or at Week 26

Secondary: Change in HbA1c (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ Mono

Secondary: Change in HbA1c (%) from baseline to the end of 26 weeks - DINAMOᵀᴹ Mono

Secondary: Time to treatment failure

Secondary: Time to treatment failure

Secondary: Change in fasting plasma glucose (FPG, mg/dL) from baseline to the end of 26 weeks

Secondary: Change in fasting plasma glucose (FPG, mg/dL) from baseline to the end of 26 weeks

Secondary: Change in body weight (kg) from baseline to the end of 26 weeks

Secondary: Change in body weight (kg) from baseline to the end of 26 weeks

Secondary: Change in systolic blood pressure (SBP, mmHg) from baseline to the end of 26 weeks

Secondary: Change in systolic blood pressure (SBP, mmHg) from baseline to the end of 26 weeks

Secondary: Change in diastolic blood pressure (DBP, mmHg) from baseline to the end of 26 weeks

Secondary: Change in diastolic blood pressure (DBP, mmHg) from baseline to the end of 26 weeks

Secondary: Percentage of patients who achieve HbA1c <6.5% at the end of 26 weeks

Secondary: Percentage of patients who achieve HbA1c <6.5% at the end of 26 weeks

Secondary: Percentage of patients who achieve HbA1c <7.0% at the end of 26 weeks

Secondary: Percentage of patients who achieve HbA1c <7.0% at the end of 26 weeks

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA