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Clinical Trial Results:
A Randomized, Phase 3, Open-Label Trial Comparing the Effect of LY3298176 versus Titrated Insulin Degludec on Glycemic Control in Patients with Type 2 Diabetes

Summary
EudraCT number	2018-003422-84
Trial protocol	GR AT HU PL ES IT RO
Global end of trial date	04 Jan 2021

Results information
Results version number	v1(current)
This version publication date	18 Dec 2021
First version publication date	18 Dec 2021
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

I8F-MC-GPGH

ISRCTN number

US NCT number

NCT03882970

WHO universal trial number (UTN)

Other trial identifiers

Trial Number: 16997

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Public contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,

Scientific contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,

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

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?

Analysis stage

Final

Date of interim/final analysis

04 Jan 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Jan 2021

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to compare the effect of the study drug tirzepatide to insulin degludec on blood sugar levels in participants with type 2 diabetes. The study will last about 67 weeks and may include up to 22 visits.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Apr 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 224

Country: Number of subjects enrolled

Austria: 27

Country: Number of subjects enrolled

Greece: 137

Country: Number of subjects enrolled

Hungary: 147

Country: Number of subjects enrolled

Italy: 30

Country: Number of subjects enrolled

Poland: 132

Country: Number of subjects enrolled

Puerto Rico: 35

Country: Number of subjects enrolled

Romania: 214

Country: Number of subjects enrolled

Korea, Republic of: 36

Country: Number of subjects enrolled

Spain: 86

Country: Number of subjects enrolled

Taiwan: 36

Country: Number of subjects enrolled

Ukraine: 45

Country: Number of subjects enrolled

United States: 295

Worldwide total number of subjects

1444

EEA total number of subjects

773

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)

Adults (18-64 years)

1064

From 65 to 84 years

380

85 years and over

Subject disposition

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Recruitment details

No Text Available

Screening details

No Text Available

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

5 mg Tirzepatide

Arm description

5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.

Arm type

Experimental

Investigational medicinal product name

Tirzepatide

Investigational medicinal product code

Other name

LY3298176

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered SC

10 mg Tirzepatide

Arm description

10 mg tirzepatide administered SC once a week.

Arm type

Experimental

Investigational medicinal product name

Tirzepatide

Investigational medicinal product code

Other name

LY3298176

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered SC

15 mg Tirzepatide

Arm description

15 mg tirzepatide administered SC once a week SC.

Arm type

Experimental

Investigational medicinal product name

Tirzepatide

Investigational medicinal product code

Other name

LY3298176

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered SC

Insulin Degludec

Arm description

Insulin degludec administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin degludec was 10 IU/day ideally at bedtime, titrated to a fasting blood glucose (FBG) <90 milligram per Deciliter (mg/dL), following a treat-to-target (TTT) algorithm based on the last 3 FBG values.

Arm type

Active comparator

Investigational medicinal product name

Insulin Degludec

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered SC

Number of subjects in period 1	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Started	359	361	359	365
Received at least one dose of study drug	358	360	359	360
Completed	333	321	340	331
Not completed	26	40	19	34
Adverse event, serious fatal	1	2	1	1
Consent withdrawn by subject	8	17	7	22
Physician decision	-	2	2	2
Adverse event, non-fatal	5	7	3	1
Lost to follow-up	8	9	5	5
Personal Reason	2	3	1	3
Protocol deviation	2	-	-	-

Baseline characteristics

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Reporting group title

5 mg Tirzepatide

Reporting group description

5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.

Reporting group title

10 mg Tirzepatide

Reporting group description

10 mg tirzepatide administered SC once a week.

Reporting group title

15 mg Tirzepatide

Reporting group description

15 mg tirzepatide administered SC once a week SC.

Reporting group title

Insulin Degludec

Reporting group description

Reporting group values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec	Total
Number of subjects	359	361	359	365	1444
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	57.20 ( 10.13 )	57.40 ( 9.66 )	57.50 ( 10.24 )	57.50 ( 10.08 )	-
Gender categorical
Units: Subjects
Female	158	165	165	148	636
Male	201	196	194	217	808
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	109	108	96	108	421
Not Hispanic or Latino	247	253	259	256	1015
Unknown or Not Reported	3	0	4	1	8
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	1	2	4
Asian	20	19	20	19	78
Native Hawaiian or Other Pacific Islander	1	0	2	1	4
Black or African American	13	12	8	11	44
White	324	329	327	332	1312
More than one race	1	0	1	0	2
Unknown or Not Reported	0	0	0	0	0
Region of Enrollment
Units: Subjects
Argentina	57	54	56	57	224
Austria	7	8	4	8	27
Greece	33	35	35	34	137
Hungary	36	37	37	37	147
Italy	6	8	8	8	30
Poland	33	33	33	33	132
Puerto Rico	8	7	11	9	35
Romania	54	54	53	53	214
South Korea	9	10	8	9	36
Spain	21	21	22	22	86
Taiwan	9	8	10	9	36
Ukraine	11	11	12	11	45
United States	75	75	70	75	295
Hemoglobin A1c
Units: Percentage of HbA1c
arithmetic mean (standard deviation)	8.17 ( 0.89 )	8.18 ( 0.89 )	8.21 ( 0.94 )	8.12 ( 0.94 )	-

End points

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Reporting group title

5 mg Tirzepatide

Reporting group description

5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.

Reporting group title

10 mg Tirzepatide

Reporting group description

10 mg tirzepatide administered SC once a week.

Reporting group title

15 mg Tirzepatide

Reporting group description

15 mg tirzepatide administered SC once a week SC.

Reporting group title

Insulin Degludec

Reporting group description

Primary: Change from Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)

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End point title

Change from Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) ^[1]

End point description

HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates Baseline + Pooled Country + Baseline Oral Antihyperglycemic Medication (OAM) Use (Metformin (Met), Met plus SGLT-2i) + Treatment + Time + Treatment*Time (Type III sum of squares). Analysis Population Description: All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose date +7 days).

End point type

Primary

End point timeframe

Baseline, Week 52

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis were planned for 10 mg and 15 mg Tirzepatide arms only.

End point values	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	291	294	317
Units: Percentage of HbA1c
least squares mean (standard error)	-2.20 ( 0.051 )	-2.37 ( 0.050 )	-1.34 ( 0.049 )

Change from Baseline in Hemoglobin A1c (HbA1c)

Comparison groups

Insulin Degludec v 10 mg Tirzepatide

Number of subjects included in analysis

608

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.86

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

-0.72

Notes
[2] - The study was powered for superiority in HbA1c. The sample size provided >99% power to show noninferiority assuming a 0.3% NI boundary, 0.35% greater mean reduction in tirzepatide doses compared to insulin degludec, 1:1:1:1 randomization, a common SD of 1.1%, 1 sided significance level of 0.0125, and a dropout rate of 28%.

Change from Baseline in Hemoglobin A1c (HbA1c)

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

611

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-1.04

Confidence interval

level

95%

sides

2-sided

lower limit

-1.17

upper limit

-0.9

Notes
[3] - The study was powered for superiority in HbA1c. The sample size provided >99% power to show noninferiority assuming a 0.3% NI boundary, 0.35% greater mean reduction in tirzepatide doses compared to insulin degludec, 1:1:1:1 randomization, a common SD of 1.1%, 1 sided significance level of 0.0125, and a dropout rate of 28%.

Secondary: Change from Baseline in HbA1c (5 mg)

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End point title

Change from Baseline in HbA1c (5 mg) ^[4]

End point description

HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates Baseline + Pooled Country + Baseline OAM Use (Met, Met plus SGLT-2i) + Treatment + Time + Treatment*Time (Type III sum of squares). Analysis Population Description: All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose date +7 days).

End point type

Secondary

End point timeframe

Baseline, Week 52

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis were planned for 5 mg Tirzepatide arm only.

End point values	5 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	312	317
Units: Percentage of HbA1c
least squares mean (standard error)	-1.93 ( 0.050 )	-1.34 ( 0.049 )

Change from Baseline in Hemoglobin A1c (HbA1c)

Statistical analysis description

The study was powered for superiority in HbA1c. The sample size provided >99% power to show noninferiority assuming a 0.3% NI boundary, 0.35% greater mean reduction in tirzepatide doses compared to insulin degludec, 1:1:1:1 randomization, a common SD of 1.1%, 1 sided significance level of 0.0125, and a dropout rate of 28%.

Comparison groups

5 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

629

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-0.73

upper limit

-0.45

Secondary: Change from Baseline in Body Weight

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End point title

Change from Baseline in Body Weight

End point description

LS mean was determined by MMRM model with Baseline + Pooled Country + Baseline OAM Use (Met, Met plus SGLT-2i) + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares) as covariates. Analysis Population Description: All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose date +7 days).

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	310	291	295	317
Units: Kilograms (kg)
least squares mean (standard error)	-7.5 ( 0.37 )	-10.7 ( 0.37 )	-12.9 ( 0.37 )	2.3 ( 0.37 )

Change from Baseline in Body Weight

Comparison groups

5 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-9.8

Confidence interval

level

95%

sides

2-sided

lower limit

-10.8

upper limit

-8.8

Change from Baseline in Body Weight

Comparison groups

10 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

608

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-13

Confidence interval

level

95%

sides

2-sided

lower limit

-14

upper limit

-11.9

Change from Baseline in Body Weight

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

612

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-15.2

Confidence interval

level

95%

sides

2-sided

lower limit

-16.2

upper limit

-14.2

Secondary: Change from Baseline in Fasting Serum Glucose

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End point title

Change from Baseline in Fasting Serum Glucose

End point description

LS mean was determined by MMRM model with variables Baseline + Pooled Country + Baseline OAM Use (Met, Met plus SGLT-2i) + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares). Analysis Population Description: All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose date +7 days).

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	309	291	293	314
Units: milligram per Deciliter (mg/dL)
least squares mean (standard error)	-48.2 ( 1.82 )	-54.8 ( 1.86 )	-59.2 ( 1.85 )	-55.7 ( 1.81 )

Change from Baseline in Fasting Serum Glucose

Comparison groups

5 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

623

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

7.5

Confidence interval

level

95%

sides

2-sided

lower limit

2.4

upper limit

12.5

Change from Baseline in Fasting Serum Glucose

Comparison groups

10 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

605

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.751

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.3

upper limit

5.9

Change from Baseline in Fasting Serum Glucose

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

607

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.168

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-8.7

upper limit

1.5

Secondary: Percentage of Participants Achieving an HbA1cTarget Value of <7%

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End point title

Percentage of Participants Achieving an HbA1cTarget Value of <7%

End point description

Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Imputed data includes observed value and imputed value if endpoint measure is missing. Missing endpoint measures are imputed by predictions from an MMRM analysis model using observed data in the efficacy analysis set and adjusted for Baseline Value, Pooled Country, Baseline OAM Use (Met, Met plus SGLT-2i), Treatment, Visit and Visit*Treatment. Analysis Population Description: All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose date +7 days).

End point type

Secondary

End point timeframe

Week 52

End point values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	353	350	353	351
Units: percentage of participants
number (not applicable)	82.44	89.71	92.63	61.25

Participants Achieving HbA1c Target Value of <7%

Comparison groups

5 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.45

Confidence interval

level

95%

sides

2-sided

lower limit

2.38

upper limit

5.01

Participants Achieving HbA1c Target Value of <7%

Comparison groups

Insulin Degludec v 10 mg Tirzepatide

Number of subjects included in analysis

701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

7.02

Confidence interval

level

95%

sides

2-sided

lower limit

4.55

upper limit

10.84

Participants Achieving HbA1c Target Value of <7%

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

10.79

Confidence interval

level

95%

sides

2-sided

lower limit

6.65

upper limit

17.48

Secondary: Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

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End point title

Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

End point description

The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. LS mean was determined by mixed-model repeated measures (MMRM) model with variables Baseline + Baseline HbA1c Group (<=8.5%, >8.5%) + Pooled Country + Baseline OAM Use (Met, Met plus SGLT-2i) + Treatment + Time + Treatment*Time (Type III sum of squares). Analysis Population Description: All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose date +7 days).

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	281	263	274	288
Units: mg/dL
least squares mean (standard error)	-52.6 ( 1.20 )	-59.7 ( 1.22 )	-60.6 ( 1.20 )	-48.0 ( 1.18 )

No statistical analyses for this end point

Secondary: Percentage of Participants who Achieved WeightLoss ≥5%

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End point title

Percentage of Participants who Achieved WeightLoss ≥5%

End point description

Percentage of Participants who Achieved Weight Loss ≥5% Analysis Population Description: All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose date +7 days).

End point type

Secondary

End point timeframe

Week 52

End point values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	353	350	353	351
Units: percentage of participants
number (not applicable)	66.01	83.71	87.82	6.27

Percentage Participants who Achieved WeightLoss ≥5

Comparison groups

Insulin Degludec v 5 mg Tirzepatide

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

29.78

Confidence interval

level

95%

sides

2-sided

lower limit

18.35

upper limit

48.35

Percentage Participants who Achieved WeightLoss ≥5

Comparison groups

10 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

79.88

Confidence interval

level

95%

sides

2-sided

lower limit

47.56

upper limit

134.17

Percentage Participants who Achieved WeightLoss ≥5

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

110.77

Confidence interval

level

95%

sides

2-sided

lower limit

64.73

upper limit

189.55

Secondary: Diabetes Treatment Satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score

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End point title

Diabetes Treatment Satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score

End point description

DTSQc, an 8-item questionnaire, assesses relative change in treatment satisfaction perceived frequency of hyperglycemia, and perceived frequency of hypoglycemia from baseline to week 52 or early termination.The treatment satisfaction score ranges from -18 to 18 where the higher the score the greater the improvement in satisfaction with treatment. The lower the score the greater the deterioration in satisfaction with treatment. The hyperglycemia and hypoglycemia scores range from -3 to 3 where negative scores indicate fewer problems with blood glucose levels and positive scores indicate more problems than before. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline DTSQs + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline OAM Use (Met, Met plus SGLT-2i) + Treatment (Type III sum of squares).

End point type

Secondary

End point timeframe

Week 52

End point values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	306	293	292	313
Units: units on a scale
least squares mean (standard error)
Hyperglycemia	-1.4 ( 0.11 )	-1.4 ( 0.11 )	-1.6 ( 0.11 )	-1.1 ( 0.11 )
Hypoglycemia	-1.1 ( 0.12 )	-0.9 ( 0.12 )	-1.0 ( 0.12 )	-0.7 ( 0.12 )
Total Score	15.6 ( 0.27 )	15.5 ( 0.28 )	15.6 ( 0.28 )	12.6 ( 0.27 )

Hyperglycemia (5 mg Tirzepatide, Insulin Degludec)

Statistical analysis description

Hyperglycemia

Comparison groups

5 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

619

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.096

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.57

upper limit

0.05

Hyperglycemia (10mg Tirzepatide,Insulin Degludec)

Statistical analysis description

Hyperglycemia

Comparison groups

Insulin Degludec v 10 mg Tirzepatide

Number of subjects included in analysis

606

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.113

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.57

upper limit

0.06

Hyperglycemia (15 mg Tirzepatide,Insulin Degludec)

Statistical analysis description

Hyperglycemia

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

605

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.78

upper limit

-0.16

Hypoglycemia (5 mg Tirzepatide, Insulin Degludec)

Statistical analysis description

Hypoglycemia

Comparison groups

5 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

619

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-0.74

upper limit

-0.08

Hypoglycemia (10 mg Tirzepatide, Insulin Degludec)

Statistical analysis description

Hypoglycemia

Comparison groups

10 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

606

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.28

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.15

Hypoglycemia (15 mg Tirzepatide, Insulin Degludec)

Statistical analysis description

Hypoglycemia

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

605

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.129

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

0.07

Total Score (5 mg Tirzepatide, Insulin Degludec)

Statistical analysis description

Total Score

Comparison groups

5 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

619

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

3.01

Confidence interval

level

95%

sides

2-sided

lower limit

2.26

upper limit

3.75

Total Score (10 mg Tirzepatide, Insulin Degludec)

Statistical analysis description

Total Score

Comparison groups

10 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

606

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

2.15

upper limit

3.65

Total Score (15 mg Tirzepatide, Insulin Degludec)

Statistical analysis description

Total Score

Comparison groups

15 mg Tirzepatide v Insulin Degludec

Number of subjects included in analysis

605

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.99

Confidence interval

level

95%

sides

2-sided

lower limit

2.24

upper limit

3.74

Secondary: Rate of Hypoglycemia with Blood Glucose <54 milligram/deciliter (mg/dL) [<3.0 (millimole/liter (mmol/L))] or Severe Hypoglycemia

Top of page

End point title

Rate of Hypoglycemia with Blood Glucose <54 milligram/deciliter (mg/dL) [<3.0 (millimole/liter (mmol/L))] or Severe Hypoglycemia

End point description

Hypoglycemia events were defined by participant reported events with blood glucose<54mg/dL (<3.0 mmol/L) or severe hypoglycemia.Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma.The rate of postbaseline hypoglycemia was estimated by negative binomial model: Number of episodes = Pooled Country+Baseline OAM Use (Met, Met plus SGLT-2i)+Baseline HbA1c Group (<=8.5%, >8.5%)+Treatment,with log (exposure in days/365.25) as an offset variable. Randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or stopping study drug (last dose data + 7 days.

End point type

Secondary

End point timeframe

Baseline through Safety Follow-Up (Up to Week 56)

End point values	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Number of subjects analysed	356	360	359	358
Units: Episodes/participant/365.25 days
arithmetic mean (standard error)	0.0137 ( 0.0056 )	0.0108 ( 0.0044 )	0.0275 ( 0.0143 )	0.1020 ( 0.0568 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline Up To 56 Weeks

Adverse event reporting additional description

All participants who received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

5 mg Tirzepatide

Reporting group description

5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.

Reporting group title

10 mg Tirzepatide

Reporting group description

5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.

Reporting group title

15 mg Tirzepatide

Reporting group description

15 mg tirzepatide administered SC once a week SC.

Reporting group title

Insulin Degludec

Reporting group description

Serious adverse events	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Total subjects affected by serious adverse events
subjects affected / exposed	29 / 358 (8.10%)	20 / 360 (5.56%)	26 / 359 (7.24%)	22 / 360 (6.11%)
number of deaths (all causes)	1	2	1	1
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
adenocarcinoma of colon
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
cholangiocarcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
gastric neoplasm
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
invasive breast carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
invasive ductal breast carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
lung adenocarcinoma stage iv
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
metastases to liver
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
neoplasm skin
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
neuroendocrine carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pituitary tumour benign
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
squamous cell carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
testicular neoplasm
alternative dictionary used: MedDRA 23.1
subjects affected / exposed ^[1]	1 / 200 (0.50%)	0 / 195 (0.00%)	0 / 194 (0.00%)	0 / 213 (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
transitional cell carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
Vascular disorders
deep vein thrombosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
dry gangrene
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
Pregnancy, puerperium and perinatal conditions
abortion spontaneous
alternative dictionary used: MedDRA 23.1
subjects affected / exposed ^[2]	0 / 158 (0.00%)	1 / 165 (0.61%)	0 / 165 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
multiple organ dysfunction syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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 / 1
necrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
non-cardiac chest pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 358 (0.56%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
cervical dysplasia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed ^[3]	0 / 158 (0.00%)	0 / 165 (0.00%)	1 / 165 (0.61%)	0 / 147 (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
Respiratory, thoracic and mediastinal disorders
asthma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
pneumothorax
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pulmonary embolism
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
respiratory failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
Psychiatric disorders
alcohol abuse
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
depression suicidal
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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 / 1	0 / 0
major depression
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
suicide attempt
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
sars-cov-2 test positive
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
accident
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
ankle fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
craniocerebral injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
femur fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
foot fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
head injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
hip fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
limb traumatic amputation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
lumbar vertebral fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
maternal exposure during pregnancy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed ^[4]	0 / 158 (0.00%)	1 / 165 (0.61%)	0 / 165 (0.00%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
tendon injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
Congenital, familial and genetic disorders
arrhythmogenic right ventricular dysplasia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
Cardiac disorders
acute myocardial infarction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 358 (0.56%)	0 / 360 (0.00%)	0 / 359 (0.00%)	2 / 360 (0.56%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
atrial fibrillation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
atrial tachycardia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
cardiac arrest
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
cardiac failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	1 / 360 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
cardiac failure congestive
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
cardio-respiratory arrest
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
coronary artery disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	1 / 360 (0.28%)	0 / 359 (0.00%)	1 / 360 (0.28%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
myocardial infarction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	1 / 360 (0.28%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
ventricular tachycardia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
diabetic neuropathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
haemorrhagic stroke
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
hypoglycaemic unconsciousness
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
subarachnoid haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
syncope
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
transient ischaemic attack
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 358 (0.56%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
vertebrobasilar insufficiency
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
Blood and lymphatic system disorders
neutropenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
thrombocytopenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
Ear and labyrinth disorders
vertigo
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
Eye disorders
cataract
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
retinal detachment
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
constipation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
diarrhoea
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
diverticulum intestinal haemorrhagic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
dyspepsia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
gastric ulcer haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
gastritis alcoholic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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 haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
inguinal hernia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
lower gastrointestinal haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
pancreatitis acute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
segmental diverticular colitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
cholecystitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
cholelithiasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	1 / 360 (0.28%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
malignant biliary obstruction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
diabetic foot
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
skin ulcer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
Renal and urinary disorders
acute kidney injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
haematuria
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
nephrolithiasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	1 / 360 (0.28%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
renal colic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
inappropriate antidiuretic hormone secretion
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
lumbar spinal stenosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
rotator cuff syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
Infections and infestations
covid-19
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
covid-19 pneumonia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	1 / 360 (0.28%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
cellulitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
cellulitis orbital
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
colon gangrene
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
coronavirus infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
device related infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
diverticulitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	1 / 359 (0.28%)	1 / 360 (0.28%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
endocarditis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
gastroenteritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	1 / 360 (0.28%)	1 / 359 (0.28%)	0 / 360 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
hepatitis e
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 358 (0.28%)	0 / 360 (0.00%)	0 / 359 (0.00%)	0 / 360 (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
intervertebral discitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
osteomyelitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	1 / 360 (0.28%)	0 / 359 (0.00%)	1 / 360 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pneumonia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	2 / 359 (0.56%)	2 / 360 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
pyelonephritis acute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
sepsis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	1 / 359 (0.28%)	0 / 360 (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
septic shock
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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
systemic candida
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 358 (0.00%)	0 / 360 (0.00%)	0 / 359 (0.00%)	1 / 360 (0.28%)
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

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly

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

Non-serious adverse events	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Insulin Degludec
Total subjects affected by non serious adverse events
subjects affected / exposed	124 / 358 (34.64%)	157 / 360 (43.61%)	179 / 359 (49.86%)	66 / 360 (18.33%)
Investigations
lipase increased
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	21 / 358 (5.87%)	16 / 360 (4.44%)	20 / 359 (5.57%)	7 / 360 (1.94%)
occurrences all number	25	18	21	7
Vascular disorders
hypertension
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	11 / 358 (3.07%)	7 / 360 (1.94%)	11 / 359 (3.06%)	21 / 360 (5.83%)
occurrences all number	11	8	11	22
Gastrointestinal disorders
abdominal pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	7 / 358 (1.96%)	17 / 360 (4.72%)	23 / 359 (6.41%)	4 / 360 (1.11%)
occurrences all number	7	28	46	5
diarrhoea
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	55 / 358 (15.36%)	59 / 360 (16.39%)	56 / 359 (15.60%)	14 / 360 (3.89%)
occurrences all number	92	97	107	18
dyspepsia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	14 / 358 (3.91%)	32 / 360 (8.89%)	18 / 359 (5.01%)	0 / 360 (0.00%)
occurrences all number	14	39	28	0
nausea
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	41 / 358 (11.45%)	81 / 360 (22.50%)	85 / 359 (23.68%)	6 / 360 (1.67%)
occurrences all number	86	140	240	6
vomiting
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	21 / 358 (5.87%)	34 / 360 (9.44%)	36 / 359 (10.03%)	4 / 360 (1.11%)
occurrences all number	29	53	63	4
Infections and infestations
nasopharyngitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	11 / 358 (3.07%)	14 / 360 (3.89%)	15 / 359 (4.18%)	22 / 360 (6.11%)
occurrences all number	11	15	16	27
Metabolism and nutrition disorders
decreased appetite
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	22 / 358 (6.15%)	37 / 360 (10.28%)	43 / 359 (11.98%)	2 / 360 (0.56%)
occurrences all number	23	59	54	2

More information

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Were there any global substantial amendments to the protocol? Yes

30 Jul 2020

Mobile visits may be performed at patients’ homes when patients cannot travel to the site due to extenuating circumstances. This provides an option to conduct a clinical trial visit and all the applicable procedures in a mobile healthcare facility or at the home of a patient when the patient is not able or not willing to go to the site due to COVID-19 restrictions.

Were there any global interruptions to the trial? No

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

Clinical Trial Results:
A Randomized, Phase 3, Open-Label Trial Comparing the Effect of LY3298176 versus Titrated Insulin Degludec on Glycemic Control in Patients with Type 2 Diabetes

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)

Primary: Change from Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)

Secondary: Change from Baseline in HbA1c (5 mg)

Secondary: Change from Baseline in HbA1c (5 mg)

Secondary: Change from Baseline in Body Weight

Secondary: Change from Baseline in Body Weight

Secondary: Change from Baseline in Fasting Serum Glucose

Secondary: Change from Baseline in Fasting Serum Glucose

Secondary: Percentage of Participants Achieving an HbA1cTarget Value of <7%

Secondary: Percentage of Participants Achieving an HbA1cTarget Value of <7%

Secondary: Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

Secondary: Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

Secondary: Percentage of Participants who Achieved WeightLoss ≥5%

Secondary: Percentage of Participants who Achieved WeightLoss ≥5%

Secondary: Diabetes Treatment Satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score

Secondary: Diabetes Treatment Satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score

Secondary: Rate of Hypoglycemia with Blood Glucose <54 milligram/deciliter (mg/dL) [<3.0 (millimole/liter (mmol/L))] or Severe Hypoglycemia

Secondary: Rate of Hypoglycemia with Blood Glucose <54 milligram/deciliter (mg/dL) [<3.0 (millimole/liter (mmol/L))] or Severe Hypoglycemia

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
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Clinical trials

Clinical Trial Results: A Randomized, Phase 3, Open-Label Trial Comparing the Effect of LY3298176 versus Titrated Insulin Degludec on Glycemic Control in Patients with Type 2 Diabetes

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)

Primary: Change from Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)

Secondary: Change from Baseline in HbA1c (5 mg)

Secondary: Change from Baseline in HbA1c (5 mg)

Secondary: Change from Baseline in Body Weight

Secondary: Change from Baseline in Body Weight

Secondary: Change from Baseline in Fasting Serum Glucose

Secondary: Change from Baseline in Fasting Serum Glucose

Secondary: Percentage of Participants Achieving an HbA1cTarget Value of <7%

Secondary: Percentage of Participants Achieving an HbA1cTarget Value of <7%

Secondary: Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

Secondary: Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

Secondary: Percentage of Participants who Achieved WeightLoss ≥5%

Secondary: Percentage of Participants who Achieved WeightLoss ≥5%

Secondary: Diabetes Treatment Satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score

Secondary: Diabetes Treatment Satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire, change version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score

Secondary: Rate of Hypoglycemia with Blood Glucose <54 milligram/deciliter (mg/dL) [<3.0 (millimole/liter (mmol/L))] or Severe Hypoglycemia

Secondary: Rate of Hypoglycemia with Blood Glucose <54 milligram/deciliter (mg/dL) [<3.0 (millimole/liter (mmol/L))] or Severe Hypoglycemia

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Phase 3, Open-Label Trial Comparing the Effect of LY3298176 versus Titrated Insulin Degludec on Glycemic Control in Patients with Type 2 Diabetes