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Clinical Trial Results:
A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Degludec in Insulin Naïve Adults With Type 2 Diabetes

Summary
EudraCT number	2021-005891-21
Trial protocol	GR
Global end of trial date	10 Apr 2024

Results information
Results version number	v1(current)
This version publication date	23 Apr 2025
First version publication date	23 Apr 2025
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

I8H-MC-BDCX

ISRCTN number

US NCT number

NCT05362058

WHO universal trial number (UTN)

Other trial identifiers

Trial Number: 18262

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

10 Apr 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Apr 2024

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to determine the effect and safety of insulin efsitora alfa (LY3209590) compared to degludec in adult participants with type 2 diabetes who are starting basal insulin for the first time.The study consists of a 1-week screening period, a 2-week lead-in period, a 52-week treatment period, and a 5-week safety follow-up period. The study will last up to 60 weeks.

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

03 Jun 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 83

Country: Number of subjects enrolled

Canada: 41

Country: Number of subjects enrolled

China: 134

Country: Number of subjects enrolled

Czechia: 98

Country: Number of subjects enrolled

Germany: 57

Country: Number of subjects enrolled

Greece: 32

Country: Number of subjects enrolled

Japan: 144

Country: Number of subjects enrolled

Mexico: 99

Country: Number of subjects enrolled

Korea, Republic of: 19

Country: Number of subjects enrolled

United States: 221

Worldwide total number of subjects

928

EEA total number of subjects

187

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)

672

From 65 to 84 years

256

85 years and over

Subject disposition

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Recruitment details

Participants continued their protocol-specified stable therapy with 1 to 3 non-insulin antihyperglycemic medications, including glucagon-like peptide-1 (GLP-1) receptor agonists (RA), as well as non-GLP-1 receptor agonists such as dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, (Continued..)

Screening details

biguanides (e.g., metformin), alpha-glucosidase inhibitors, sulfonylureas (SUs), or thiazolidinediones throughout the study, at the discretion of the investigator.

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

500 U/mL - Insulin Efsitora Alfa

Arm description

Participants received 500 units per milliliter (U/mL) of insulin efsitora alfa administered subcutaneously (SC) once weekly (QW) over a 52-week treatment period, followed by a 5-week safety follow-up period.

Arm type

Experimental

Investigational medicinal product name

Insulin Efsitora Alfa

Investigational medicinal product code

Other name

LY3209590, Basal Insulin-FC

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 500 U/mL insulin efsitora alfa administered SC QW.

100 U/mL - Insulin Degludec

Arm description

Participants received 100 U/mL insulin degludec administered SC once daily (QD) over a 52-week treatment period, followed by a 5-week safety follow-up period.

Arm type

Active comparator

Investigational medicinal product name

Insulin Degludec

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 100 U/mL insulin degludec administered SC QD.

Number of subjects in period 1	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Started	466	462
Participants Using GLP-1 RA	232	232
Participants Not Using GLP-1 RA	234	230
Received at least 1 dose of study drug	466	462
Completed	441	439
Not completed	25	23
Assigned treatment by mistake	3	4
Physician decision	1	-
Consent withdrawn by subject	10	11
Adverse event, non-fatal	3	3
Death	1	1
Non-compliance with study drug	-	1
Lost to follow-up	6	3
Protocol deviation	1	-

Period 2 title

Follow-Up Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

500 U/mL - Insulin Efsitora Alfa

Arm description

Participants who received 500 U/mL insulin efsitora alfa administered SC QW in the treatment period were required to complete a safety follow-up period, and participants who discontinued the study treatment prematurely were encouraged to remain in the study for safety monitoring.

Arm type

Experimental

Investigational medicinal product name

Insulin Efsitora Alfa

Investigational medicinal product code

Other name

LY3209590, Basal Insulin-FC

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 500 U/mL insulin efsitora alfa administered SC QW.

100 U/mL - Insulin Degludec

Arm description

Participants who received 100 U/mL insulin degludec administered SC QD in the treatment period were required to complete a safety follow-up period and participants who discontinued the study treatment prematurely were encouraged to remain in the study for safety monitoring.

Arm type

Active comparator

Investigational medicinal product name

Insulin Degludec

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received 100 U/mL insulin degludec administered SC QD.

Number of subjects in period 2	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Started	445	444
Completed	441	439
Not completed	4	5
Consent withdrawn by subject	-	3
Death	1	-
Lost to follow-up	2	1
Protocol deviation	1	1

Baseline characteristics

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Reporting group title

500 U/mL - Insulin Efsitora Alfa

Reporting group description

Reporting group title

100 U/mL - Insulin Degludec

Reporting group description

Participants received 100 U/mL insulin degludec administered SC once daily (QD) over a 52-week treatment period, followed by a 5-week safety follow-up period.

Reporting group values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec	Total
Number of subjects	466	462	928
Age categorical
Analysis Population Description (APD): All randomized participants.
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	331	341	672
From 65-84 years	135	121	256
85 years and over	0	0	0
Gender categorical
Units: Subjects
Female	185	197	382
Male	281	265	546
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	119	123	242
Not Hispanic or Latino	345	335	680
Unknown or Not Reported	2	4	6
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	34	36	70
Asian	163	164	327
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	31	27	58
White	235	233	468
More than one race	3	2	5
Unknown or Not Reported	0	0	0
Region of Enrollment
Units: Subjects
Brazil	40	43	83
Canada	18	23	41
China	67	67	134
Czechia	48	50	98
Germany	30	27	57
Greece	17	15	32
Japan	71	73	144
Mexico	50	49	99
South Korea	11	8	19
United States	114	107	221
HemoglobinA1c (HbA1c)
HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time.
Units: Percentage of HbA1c
arithmetic mean (standard deviation)	8.21 ( 0.96 )	8.23 ( 0.96 )	-

End points

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Reporting group title

500 U/mL - Insulin Efsitora Alfa

Reporting group description

Reporting group title

100 U/mL - Insulin Degludec

Reporting group description

Participants received 100 U/mL insulin degludec administered SC once daily (QD) over a 52-week treatment period, followed by a 5-week safety follow-up period.

Reporting group title

500 U/mL - Insulin Efsitora Alfa

Reporting group description

Reporting group title

100 U/mL - Insulin Degludec

Reporting group description

Primary: Change From Baseline in HbA1c at Week 52 [Noninferiority Analysis]

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End point title

Change From Baseline in HbA1c at Week 52 [Noninferiority Analysis]

End point description

HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time.Least Squares (LS) mean was determined using Analysis of Covariance (ANCOVA) model with Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment (Type III sum of squares) as variables. Missing data at Week 52 were imputed by return-to-baseline multiple imputations approach. APD:All randomized participants who received at least one dose of the study drug and had HbA1c measurement at baseline or Week 52. Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Primary

End point timeframe

Baseline, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	463	458
Units: millimoles per mole (mmol/mol)
least squares mean (standard error)	-13.75 ( 0.514 )	-12.79 ( 0.517 )

Statistical Analysis 1

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.96

Confidence interval

level

95%

sides

2-sided

lower limit

-2.39

upper limit

0.47

Notes
[1] - The noninferiority margin (NIM) of 0.4% is equivalent to a NIM of 4.372 mmol/mol.

Secondary: Change From Baseline in HbA1c at Week 52 in Participants Using GLP-1 Receptor Agonists [Noninferiority Analysis]

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End point title

Change From Baseline in HbA1c at Week 52 in Participants Using GLP-1 Receptor Agonists [Noninferiority Analysis]

End point description

HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time.LS mean was determined using ANCOVA model with Baseline + Country + SU Use at Randomization Flag + Treatment (Type III sum of squares) as variables. Missing data at Week 52 were imputed by return-to-baseline multiple imputations approach. APD:All randomized participants who continued using GLP-1 receptor agonists and received at least one dose of the study drug, had HbA1c measurement at baseline or Week 52. Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	230	231
Units: millimoles per mole (mmol/mol)
least squares mean (standard error)	-13.73 ( 0.764 )	-13.04 ( 0.761 )

Statistical Analysis 1

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

461

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.69

Confidence interval

level

95%

sides

2-sided

lower limit

-2.81

upper limit

1.42

Notes
[2] - The noninferiority margin (NIM) of 0.4% is equivalent to a NIM of 4.372 mmol/mol.

Secondary: Change From Baseline in HbA1c at Week 52 in Participants Not Using GLP-1 Receptor Agonists [Noninferiority Analysis]

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End point title

Change From Baseline in HbA1c at Week 52 in Participants Not Using GLP-1 Receptor Agonists [Noninferiority Analysis]

End point description

HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined using ANCOVA model with Baseline + Country + SU Use at Randomization Flag + Treatment (Type III sum of squares) as variables. Missing data at Week 52 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who were not using GLP-1 receptor agonists and received at least one dose of the study drug, had HbA1c measurement at baseline or Week 52. Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	233	227
Units: millimoles per mole (mmol/mol)
least squares mean (standard error)	-13.74 ( 0.686 )	-12.55 ( 0.698 )

Statistical Analysis 1

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.11

upper limit

0.72

Notes
[3] - The noninferiority margin (NIM) of 0.4% is equivalent to a NIM of 4.372 mmol/mol.

Secondary: Change From Baseline in HbA1c at Week 52 [Superiority Analysis]

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End point title

Change From Baseline in HbA1c at Week 52 [Superiority Analysis]

End point description

HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined using ANCOVA model with Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment (Type III sum of squares) as variables. Missing data at Week 52 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had HbA1c measurement at baseline or Week 52. Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	463	458
Units: millimoles per mole (mmol/mol)
least squares mean (standard error)	-13.75 ( 0.514 )	-12.79 ( 0.517 )

Statistical Analysis 1

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.188

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.96

Confidence interval

level

95%

sides

2-sided

lower limit

-2.39

upper limit

0.47

Secondary: Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 48 to Week 52

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End point title

Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 48 to Week 52

End point description

Percentage of time spent within the blood glucose range of 70 to 180 milligrams per deciliter (mg/dL) [3.9 to 10.0 millimoles per liter (mmol/L)], as measured during the continuous glucose monitoring (CGM) session over a 24-hour period, from Week 48 to Week 52. APD: All randomized participants who took at least 1 dose of the study drug and had evaluable data for this outcome at baseline or Week 48-52 were included. Participants who discontinued the study drug due to inadvertent enrollment were excluded. Data from participants at China sites were assessed separately due to the use of a different CGM device (Freestyle Libre H), while the rest of the world used the Dexcom G6. The device differences prevented pooling the data for analysis.

End point type

Secondary

End point timeframe

Week 48 to Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	387	381
Units: Percentage of time
least squares mean (standard error)	64.27 ( 1.076 )	61.18 ( 1.085 )

Statistical Analysis 1

Statistical analysis description

LS mean was determined using ANCOVA model with Baseline + Country + HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization + SU Use at Randomization + Treatment (Type III sum of squares) as variables. Missing data at baseline were imputed using multiple imputation under the assumption of missing at random, while missing data at Week 48-52 were imputed using a return-to-baseline multiple imputation approach.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

768

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.043

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

3.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

6.08

Secondary: Change From Baseline in HbA1c at Week 26 [Superiority Analysis]

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End point title

Change From Baseline in HbA1c at Week 26 [Superiority Analysis]

End point description

HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined using ANCOVA model with Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment (Type III sum of squares) as variables. Missing data at Week 26 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had HbA1c measurement at baseline or Week 26. Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	463	458
Units: millimoles per mole (mmol/mol)
least squares mean (standard error)	-14.95 ( 0.431 )	-14.26 ( 0.434 )

Statistical Analysis 1

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

921

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.26

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.69

Confidence interval

level

95%

sides

2-sided

lower limit

-1.89

upper limit

0.51

Secondary: Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 22 to Week 26

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End point title

Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 22 to Week 26

End point description

Percentage of time spent within the blood glucose range of 70 to 180 mg/dL (3.9 to 10.0 mmol/L), as measured during the CGM session over a 24-hour period, from Week 22 to Week 26. APD: All randomized participants who took at least 1 dose of the study drug and had evaluable data for this outcome at baseline or Week 22-26 were included. Participants who discontinued the study drug due to inadvertent enrollment were excluded. Data from participants at China sites were assessed separately due to the use of a different CGM device (Freestyle Libre H), while the rest of the world used the Dexcom G6. The device differences prevented pooling the data for analysis.

End point type

Secondary

End point timeframe

Week 22 to Week 26

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	385	382
Units: Percentage of time
least squares mean (standard error)	66.12 ( 0.991 )	65.85 ( 0.990 )

Statistical Analysis 1

Statistical analysis description

LS mean was determined using ANCOVA model with Baseline + Country + HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization + SU Use at Randomization + Treatment (Type III sum of squares) as variables. Missing data at baseline were imputed using multiple imputation under the assumption of missing at random, while missing data at Week 22-26 were imputed using a return-to-baseline multiple imputation approach.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

767

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.848

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-2.48

upper limit

3.02

Secondary: Change From Baseline in Fasting Blood Glucose (FBG)

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End point title

Change From Baseline in Fasting Blood Glucose (FBG)

End point description

Change from baseline in fasting blood glucose measured by self-monitoring blood glucose (SMBG). APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome at Baseline, Week 26, or Week 52 were included in the analysis. For the Week 26 analysis, data from Baseline and Week 26 were considered, while for the Week 52 analysis, data from Baseline and Week 52 were included. Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 26, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	458 ^[4]	451 ^[5]
Units: millimoles per liter (mmol/L)
least squares mean (standard error)
Week 26	-3.21 ( 0.083 )	-3.50 ( 0.083 )
Week 52	-3.32 ( 0.078 )	-3.33 ( 0.078 )

Notes
[4] - Number of subjects analysed (n) at Week 26 = 458 and Week 52 = 458
[5] - Number of subjects analysed (n) at Week 26 = 451 and Week 52 = 448

Statistical Analysis 1

Statistical analysis description

Week 26 (Statistical Analysis) - LS mean was determined using ANCOVA model with Baseline + Country + HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization + SU Use at Randomization + Treatment (Type III sum of squares) as variables. Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data at week 26 were imputed by return-to-baseline multiple imputations approach.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

909

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

0.52

Statistical Analysis 2

Statistical analysis description

Week 52 (Statistical Analysis) - Total number of subjects analysed (N) for this outcome = 906. LS mean was determined using ANCOVA model with Baseline + Country + HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization + SU Use at Randomization + Treatment (Type III sum of squares) as variables. Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data at week 52 were imputed by return-to-baseline multiple imputations approach.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

909

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.918

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.23

Secondary: Glucose Variability

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End point title

Glucose Variability

End point description

Glucose variability measured as coefficient of variation (CV) for blood glucose during the CGM session over a 24-hour period, between Week 22 to Week 26 and Week 48 to Week 52 was reported.LS mean was determined using Mixed Model Repeated Measures (MMRM) model with Baseline + Country +HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. APD:All randomized participants who took at least 1 dose of the study drug and had a baseline and at least one post- baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded. Data from participants at China sites were assessed separately due to the use of a different CGM device (Freestyle Libre H), while the rest of the world used the Dexcom G6. The device differences prevented pooling the data for analysis.

End point type

Secondary

End point timeframe

Week 22 to Week 26 and Week 48 to Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	368	360
Units: Percentage of CV
least squares mean (standard error)
Week 22 to Week 26	26.31 ( 0.250 )	26.67 ( 0.251 )
Week 48 to Week 52	26.29 ( 0.243 )	26.81 ( 0.246 )

Statistical Analysis 1

Statistical analysis description

Week 22 to Week 26 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.31

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-1.06

upper limit

0.34

Statistical Analysis 2

Statistical analysis description

Week 48 to Week 52 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.138

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-1.19

upper limit

0.17

Secondary: Basal Insulin Dose

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End point title

Basal Insulin Dose

End point description

The insulin dose was calculated based on the participant's entry of daily or weekly insulin doses in an electronic diary. The average weekly basal insulin dose at Week 26 and Week 52 was reported. LS mean was determined using MMRM model with Country + HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. APD: All randomized participants who received at least one dose of the study drug and had a baseline and at least one post-baseline value for this outcome.Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Week 26 and Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	463	457
Units: Units per week (U/week)
least squares mean (standard error)
Week 26	292.8 ( 6.30 )	305.9 ( 6.17 )
Week 52	314.7 ( 6.25 )	334.4 ( 6.22 )

Statistical Analysis 1

Statistical analysis description

Week 26 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

920

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.136

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-13.2

Confidence interval

level

95%

sides

2-sided

lower limit

-30.5

upper limit

4.1

Statistical Analysis 2

Statistical analysis description

Week 52 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

920

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-19.7

Confidence interval

level

95%

sides

2-sided

lower limit

-37

upper limit

-2.4

Secondary: Hypoglycemia Event Rate

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End point title

Hypoglycemia Event Rate

End point description

A hypoglycemic event with blood glucose (BG) levels of less than (<) 54 mg/dL (3.0 mmol/L) [Level 2] or Severe Hypoglycemia [Level 3] was reported. A severe hypoglycemic event was characterized by altered mental or physical status, requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions for the treatment of hypoglycemia. Group mean was reported and determined by Negative binomial model using Number of episodes = HbA1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as an offset variable. APD:All randomized participants who received at least one dose of the study drug.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	466	462
Units: Events per participant-year of exposure
arithmetic mean (standard error)	0.58 ( 0.062 )	0.45 ( 0.058 )

Statistical Analysis 1

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

928

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.111

Method

Negative binomial model

Parameter type

Relative Rate

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.78

Secondary: Nocturnal Hypoglycemia Event Rate

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End point title

Nocturnal Hypoglycemia Event Rate

End point description

The event rate of participant-reported clinically significant nocturnal hypoglycemia (defined as blood glucose level <54 mg/dL (3.0 mmol/L) or severe hypoglycemia and occurs at night and presumably during sleep between midnight and 6:00 AM), measured during treatment phase up to week 52. Group mean was reported and determined by Negative binomial model using Number of episodes = HbA1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as an offset variable. APD: All randomized participants who received at least one dose of the study drug.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	466	462
Units: Events per participant-year of exposure
arithmetic mean (standard error)	0.08 ( 0.018 )	0.08 ( 0.018 )

Statistical Analysis 1

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

928

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.983

Method

Negative binomial model

Parameter type

Relative Rate

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.89

Secondary: Change From Baseline in Body Weight

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End point title

Change From Baseline in Body Weight

End point description

Change from baseline in body weight was reported. LS mean was determined by MMRM model with Baseline + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. APD:All randomized participants who received at least one dose of the study drug, had a baseline and at least one post- baseline value for this outcome were included.

End point type

Secondary

End point timeframe

Baseline, Week 26, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	465	461
Units: Kilogram (kg)
least squares mean (standard error)
Change from Baseline at Week 26	3.16 ( 0.158 )	2.66 ( 0.158 )
Change from Baseline at Week 52	3.60 ( 0.158 )	3.54 ( 0.159 )

Statistical Analysis 1

Statistical analysis description

Change from Baseline at Week 26 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

926

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.064

upper limit

0.94

Statistical Analysis 2

Statistical analysis description

Change from Baseline at Week 52 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

926

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.801

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

0.5

Secondary: Percentage of Time in Hypoglycemia Range With Blood Glucose <70 mg/dL (3.9 mmol/L)

Top of page

End point title

Percentage of Time in Hypoglycemia Range With Blood Glucose <70 mg/dL (3.9 mmol/L)

End point description

Percentage of time spent in the hypoglycemia range with blood glucose <70 mg/dL (3.9 mmol/L), as measured during the CGM session over a 24-hour period from Week 8 to Week 12, Week 22 to Week 26, and Week 48 to Week 52 was reported.LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. APD: All randomized participants who took at least 1 dose of the study drug and had a baseline and at least one post- baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded. Data from participants at China sites were assessed separately due to the use of a different CGM device (Freestyle Libre H), while the rest of the world used the Dexcom G6. The device differences prevented pooling the data for analysis.

End point type

Secondary

End point timeframe

Week 8 to Week 12, Week 22 to Week 26 and Week 48 to Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	368	360
Units: Percentage of time
least squares mean (standard error)
Week 8 to Week 12	1.06 ( 0.101 )	0.93 ( 0.103 )
Week 22 to Week 26	1.55 ( 0.137 )	1.25 ( 0.137 )
Week 48 to Week 52	1.49 ( 0.150 )	1.19 ( 0.152 )

Statistical Analysis 1

Statistical analysis description

Week 8 to Week 12 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.374

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.41

Statistical Analysis 2

Statistical analysis description

Week 22 to Week 26 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.67

Statistical Analysis 3

Statistical analysis description

Week 48 to Week 52 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.162

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.12

upper limit

0.72

Secondary: Percentage of Time in Hypoglycemia Range With Blood Glucose <54 mg/dL (3.0 mmol/L)

Top of page

End point title

Percentage of Time in Hypoglycemia Range With Blood Glucose <54 mg/dL (3.0 mmol/L)

End point description

Percentage of time spent in the hypoglycemia range with blood glucose < 54 mg/dL (3.0 mmol/L), as measured during the CGM session over a 24-hour period from Week 8 to Week 12, Week 22 to Week 26, and Week 48 to Week 52, was reported.LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. APD:All randomized participants who took at least 1 dose of the study drug and had a baseline and at least one post- baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded. Data from participants at China sites were assessed separately due to the use of a different CGM device (Freestyle Libre H), while the rest of the world used the Dexcom G6. The device differences prevented pooling the data for analysis.

End point type

Secondary

End point timeframe

Week 8 to Week 12, Week 22 to Week 26 and Week 48 to Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	368	360
Units: Percentage of time
least squares mean (standard error)
Week 8 to Week 12	0.24 ( 0.041 )	0.27 ( 0.041 )
Week 22 to Week 26	0.33 ( 0.037 )	0.28 ( 0.037 )
Week 48 to Week 52	0.32 ( 0.043 )	0.30 ( 0.043 )

Statistical Analysis 1

Statistical analysis description

Week 8 to Week 12 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.594

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.08

Statistical Analysis 2

Statistical analysis description

Week 22 to Week 26 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.266

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.16

Statistical Analysis 3

Statistical analysis description

Week 48 to Week 52 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.791

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.14

Secondary: Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L)

Top of page

End point title

Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L)

End point description

Percentage of time spent in the hyperglycemia range with blood glucose greater than (>) 180 mg/dL (10.0 mmol/L), as measured during the CGM session over a 24-hour period from Week 8 to Week 12, Week 22 to Week 26, and Week 48 to Week 52 was reported. LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. APD: All randomized participants who took at least 1 dose of the study drug and had a baseline and at least one post- baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded. Data from participants at China sites were assessed separately due to the use of a different CGM device (Freestyle Libre H), while the rest of the world used the Dexcom G6. The device differences prevented pooling the data for analysis.

End point type

Secondary

End point timeframe

Week 8 to Week 12, Week 22 to Week 26 and Week 48 to Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	368	360
Units: Percentage of time
least squares mean (standard error)
Week 8 to Week 12	31.99 ( 0.925 )	32.40 ( 0.939 )
Week 22 to Week 26	28.93 ( 0.999 )	29.87 ( 1.007 )
Week 48 to Week 52	29.66 ( 1.074 )	33.05 ( 1.086 )

Statistical Analysis 1

Statistical analysis description

Week 8 to Week 12 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.757

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

2.18

Statistical Analysis 2

Statistical analysis description

Week 22 to Week 26 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.511

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.93

Confidence interval

level

95%

sides

2-sided

lower limit

-3.72

upper limit

1.85

Statistical Analysis 3

Statistical analysis description

Week 48 to Week 52 (Statistical Analysis)

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.027

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-3.39

Confidence interval

level

95%

sides

2-sided

lower limit

-6.39

upper limit

-0.39

Secondary: Change From Baseline in Treatment-Related Impact Measures for Diabetes (TRIM-D) -Total Score at Week 26 and Week 52

Top of page

End point title

Change From Baseline in Treatment-Related Impact Measures for Diabetes (TRIM-D) -Total Score at Week 26 and Week 52

End point description

The TRIM-D is a participant-reported measure designed to assess the impact of diabetes treatment on individuals' functioning and well-being across different diabetes treatments. The questionnaire includes 28 items grouped into 5 sub-domains: treatment burden, daily life, diabetes management, compliance, and psychological health. Each item is assessed on a 5-point scale, with higher scores indicating better health status. All items were summed to obtain a total raw score, which was transformed to a scale of 0 to 100 to obtain a total score. The total score range is 0-100, with a higher total score indicating better overall health and well-being, while a lower total score indicates worse health or well-being. APD:All randomized participants who received at least one dose of the study drug, had a baseline and at least one post- baseline value for this outcome.Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 26, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	444	445
Units: score on a scale
least squares mean (standard error)
Week 26	8.84 ( 0.507 )	7.18 ( 0.507 )
Week 52	8.82 ( 0.519 )	6.81 ( 0.517 )

Statistical Analysis 1

Statistical analysis description

Week 26 (Statistical Analysis) -LS mean was determined using MMRM model with Baseline + Country + HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

889

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.021

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

1.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

3.07

Statistical Analysis 2

Statistical analysis description

Week 52 (Statistical Analysis) -LS mean was determined using MMRM model with Baseline + Country + HbA1c Stratum at Baseline + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

889

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

3.44

Secondary: Change From Baseline in Short Form-36 Health Survey Version 2 (SF-36v2) Acute Form (Physical-Component and Mental-Component) Scores at Week 26 and Week 52

Top of page

End point title

Change From Baseline in Short Form-36 Health Survey Version 2 (SF-36v2) Acute Form (Physical-Component and Mental-Component) Scores at Week 26 and Week 52

End point description

The SF-36v2 is a participant-reported measure designed to assess health status using 36 items across 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Each domain is scored individually, and information from these 8 domains is further aggregated into 2 health component summary scores, the Physical Component Summary and Mental Component Summary. Scoring of each domain and both summary scores are norm based and presented in the form of T-scores, with a mean of 50 and a standard deviation of 10. Higher scores indicate better levels of function and/or better health. Range cannot be specified in norm-based scores. APD:All randomized participants who received at least one dose of the study drug, had a baseline and at least one post- baseline value for this outcome.Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 26, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	431	434
Units: T-score
least squares mean (standard error)
Physical Component Score at Week 26	0.29 ( 0.344 )	0.49 ( 0.345 )
Mental Component Score at Week 26	0.018 ( 0.380 )	0.34 ( 0.381 )
Physical Component Score at Week 52	0.027 ( 0.349 )	-0.14 ( 0.351 )
Mental Component Score at Week 52	0.014 ( 0.386 )	0.25 ( 0.389 )

Statistical Analysis 1

Statistical analysis description

Physical Component Score at Week 26 (Statistical Analysis) -LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

865

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.638

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

0.63

Statistical Analysis 2

Statistical analysis description

Mental Component Score at Week 26 (Statistical Analysis) - LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

865

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.499

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-1.24

upper limit

0.6

Statistical Analysis 3

Statistical analysis description

Physical Component Score at Week 52 (Statistical Analysis) - LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

865

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.695

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

1.01

Statistical Analysis 4

Statistical analysis description

Mental Component Score at Week 52 (Statistical Analysis) -LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use at Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

865

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.626

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-1.17

upper limit

0.71

Secondary: Change from Baseline in EuroQuality of Life (EuroQol) -5 Dimensions-5 Levels (EQ-5D-5L) Health State Index and EQ visual analog scale (VAS) Scores at Week 26 and Week 52

Top of page

End point title

Change from Baseline in EuroQuality of Life (EuroQol) -5 Dimensions-5 Levels (EQ-5D-5L) Health State Index and EQ visual analog scale (VAS) Scores at Week 26 and Week 52

End point description

The EQ-5D-5L is a multidimensional, health-related, quality-of-life instrument. It includes 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that are assessed at 5 levels of response (no problems, slight problems, moderate problems, severe problems, and unable to perform or extreme problems). A single health- state index value was derived, which ranges from less than 0 (health state equivalent to death, negative values are valued as worse than death) to 1 (perfect health). The EQ VAS rates the participants’ perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health). This score provides a composite picture of the respondent’s health status. APD:All randomized participants who received at least one dose of the study drug, had a baseline and at least one post- baseline value for this outcome.Participants who discontinued the study drug due to inadvertent enrollment were excluded.

End point type

Secondary

End point timeframe

Baseline, Week 26, Week 52

End point values	500 U/mL - Insulin Efsitora Alfa	100 U/mL - Insulin Degludec
Number of subjects analysed	430	434
Units: Score on a scale
least squares mean (standard error)
EQ-5D-5L Health State Index Score at Week 26	-0.018 ( 0.0078 )	-0.004 ( 0.0078 )
EQ VAS Score at Week 26	1.07 ( 0.701 )	2.18 ( 0.699 )
EQ-5D-5L Health State Index Score at Week 52	-0.018 ( 0.0077 )	-0.008 ( 0.0077 )
EQ VAS Score at Week 52	1.56 ( 0.733 )	1.91 ( 0.739 )

Statistical Analysis 1

Statistical analysis description

EQ-5D-5L Health State Index Score at Week 26 (Statistical Analysis) - LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

864

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.128

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.034

upper limit

0.004

Statistical Analysis 2

Statistical analysis description

EQ VAS Score at Week 26 (Statistical Analysis) - LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

864

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.196

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-2.8

upper limit

0.58

Statistical Analysis 3

Statistical analysis description

EQ-5D-5L Health State Index Score at Week 52 (Statistical Analysis) - LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

864

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.285

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.029

upper limit

0.008

Statistical Analysis 4

Statistical analysis description

EQ VAS Score at Week 52 (Statistical Analysis) - LS mean was determined using MMRM model with Baseline + HbA1c Stratum at Baseline + Country + GLP-1 RA Use Randomization Flag + SU Use at Randomization Flag + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

Comparison groups

500 U/mL - Insulin Efsitora Alfa v 100 U/mL - Insulin Degludec

Number of subjects included in analysis

864

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.701

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-2.15

upper limit

1.44

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline to end of follow-up (up to 57 weeks)

Adverse event reporting additional description

All randomized participants who received at least one dose of study drug. Participants were analyzed based on the actual treatment they received. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

100 U/mL - Insulin Degludec

Reporting group description

Participants received 100 U/mL insulin degludec administered SC QD over a 52-week treatment period, followed by a 5-week safety follow-up period.

Reporting group title

500 U/mL - Insulin Efsitora Alfa

Reporting group description

Participants received 500 U/mL insulin efsitora alfa administered SC QW over a 52-week treatment period, followed by a 5-week safety follow-up period.

Serious adverse events	100 U/mL - Insulin Degludec	500 U/mL - Insulin Efsitora Alfa
Total subjects affected by serious adverse events
subjects affected / exposed	38 / 462 (8.23%)	41 / 466 (8.80%)
number of deaths (all causes)	1	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
bladder cancer
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
benign spleen tumour
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
basal cell carcinoma
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
clear cell renal cell carcinoma
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
colorectal adenocarcinoma
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
diffuse large b-cell lymphoma
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
hormone receptor positive breast cancer
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
rectal adenocarcinoma
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
pancreatic neoplasm
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
pancreatic carcinoma metastatic
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
hypertension
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	2 / 462 (0.43%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
phlebitis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
peripheral arterial occlusive disease
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
varicose vein
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
cardiac pacemaker insertion
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
cholecystectomy
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
coronary artery bypass
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
chest pain
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	2 / 462 (0.43%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
death
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
impaired healing
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
abnormal uterine bleeding
alternative dictionary used: MedDRA 27.0
subjects affected / exposed ^[1]	0 / 197 (0.00%)	1 / 185 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
benign prostatic hyperplasia
alternative dictionary used: MedDRA 27.0
subjects affected / exposed ^[2]	0 / 265 (0.00%)	1 / 281 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
endometrial hyperplasia
alternative dictionary used: MedDRA 27.0
subjects affected / exposed ^[3]	0 / 197 (0.00%)	1 / 185 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
dyspnoea
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
cervical vertebral fracture
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
clavicle fracture
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ligament sprain
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
lumbar vertebral fracture
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
meniscus injury
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	2 / 462 (0.43%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
traumatic renal injury
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
tibia fracture
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
road traffic accident
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
rib fracture
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
angina unstable
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
angina pectoris
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
acute myocardial infarction
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	2 / 462 (0.43%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
arteriosclerosis coronary artery
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	3 / 462 (0.65%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
cardiac arrest
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
cardiac failure
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
cardiac ventricular thrombosis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
atrioventricular block complete
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
coronary artery disease
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
coronary artery stenosis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
microvascular coronary artery disease
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
myocardial infarction
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	2 / 466 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
hypoglycaemic coma
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
intracranial aneurysm
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ischaemic stroke
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
peripheral nerve lesion
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
transient ischaemic attack
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
vertebrobasilar insufficiency
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
vertigo positional
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
glaucoma
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
rhegmatogenous retinal detachment
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
retinal ischaemia
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
gastrooesophageal reflux disease
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	3 / 462 (0.65%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
intestinal polyp
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
large intestine polyp
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
cholecystitis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
cholelithiasis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	2 / 466 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
cholecystitis acute
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	2 / 462 (0.43%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
calculus urinary
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
cervical spinal stenosis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
chondropathy
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
intervertebral disc protrusion
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
lumbar spinal stenosis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
osteoarthritis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	4 / 462 (0.87%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
osteonecrosis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
spinal stenosis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
appendicitis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
cellulitis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
covid-19 pneumonia
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
arthritis bacterial
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
chronic tonsillitis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
diverticulitis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
pyelonephritis acute
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
pyelonephritis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
postoperative wound infection
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
pneumonia bacterial
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
pneumonia
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
pilonidal disease
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	1 / 462 (0.22%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
urosepsis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	0 / 462 (0.00%)	1 / 466 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
hypoglycaemia
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	5 / 462 (1.08%)	0 / 466 (0.00%)
occurrences causally related to treatment / all	5 / 5	0 / 0
deaths causally related to treatment / all	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: Gender-specific events occurring only in female participants have had the number of participants at risk 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: Gender-specific events occurring only in male participants have had the number of participants at risk 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: Gender-specific events occurring only in female participants have had the number of participants at risk adjusted accordingly.

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

Non-serious adverse events	100 U/mL - Insulin Degludec	500 U/mL - Insulin Efsitora Alfa
Total subjects affected by non serious adverse events
subjects affected / exposed	224 / 462 (48.48%)	195 / 466 (41.85%)
Investigations
weight increased
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	20 / 462 (4.33%)	28 / 466 (6.01%)
occurrences all number	20	30
Injury, poisoning and procedural complications
drug titration error
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	55 / 462 (11.90%)	33 / 466 (7.08%)
occurrences all number	86	58
Nervous system disorders
headache
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	28 / 462 (6.06%)	21 / 466 (4.51%)
occurrences all number	47	30
Gastrointestinal disorders
diarrhoea
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	32 / 462 (6.93%)	31 / 466 (6.65%)
occurrences all number	48	36
nausea
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	26 / 462 (5.63%)	26 / 466 (5.58%)
occurrences all number	29	27
Infections and infestations
covid-19
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	51 / 462 (11.04%)	37 / 466 (7.94%)
occurrences all number	51	38
influenza
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	26 / 462 (5.63%)	18 / 466 (3.86%)
occurrences all number	31	22
nasopharyngitis
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	41 / 462 (8.87%)	43 / 466 (9.23%)
occurrences all number	50	50
upper respiratory tract infection
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	46 / 462 (9.96%)	37 / 466 (7.94%)
occurrences all number	63	52
urinary tract infection
alternative dictionary used: MedDRA 27.0
subjects affected / exposed	29 / 462 (6.28%)	17 / 466 (3.65%)
occurrences all number	35	20

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Were there any global substantial amendments to the protocol? No

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.

Glucose monitoring endpoint data from Chinese sites were not reported due to the use of a different CGM device (Freestyle Libre H) compared to the Dexcom G6 used at other sites. The device differences prevented data pooling for analysis.

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Clinical trials

Clinical Trial Results: A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Degludec in Insulin Naïve Adults 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 HbA1c at Week 52 [Noninferiority Analysis]

Primary: Change From Baseline in HbA1c at Week 52 [Noninferiority Analysis]

Secondary: Change From Baseline in HbA1c at Week 52 in Participants Using GLP-1 Receptor Agonists [Noninferiority Analysis]

Secondary: Change From Baseline in HbA1c at Week 52 in Participants Using GLP-1 Receptor Agonists [Noninferiority Analysis]

Secondary: Change From Baseline in HbA1c at Week 52 in Participants Not Using GLP-1 Receptor Agonists [Noninferiority Analysis]

Secondary: Change From Baseline in HbA1c at Week 52 in Participants Not Using GLP-1 Receptor Agonists [Noninferiority Analysis]

Secondary: Change From Baseline in HbA1c at Week 52 [Superiority Analysis]

Secondary: Change From Baseline in HbA1c at Week 52 [Superiority Analysis]

Secondary: Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 48 to Week 52

Secondary: Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 48 to Week 52

Secondary: Change From Baseline in HbA1c at Week 26 [Superiority Analysis]

Secondary: Change From Baseline in HbA1c at Week 26 [Superiority Analysis]

Secondary: Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 22 to Week 26

Secondary: Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L] - Week 22 to Week 26

Secondary: Change From Baseline in Fasting Blood Glucose (FBG)

Secondary: Change From Baseline in Fasting Blood Glucose (FBG)

Secondary: Glucose Variability

Secondary: Glucose Variability

Secondary: Basal Insulin Dose

Secondary: Basal Insulin Dose

Secondary: Hypoglycemia Event Rate

Secondary: Hypoglycemia Event Rate

Secondary: Nocturnal Hypoglycemia Event Rate

Secondary: Nocturnal Hypoglycemia Event Rate

Secondary: Change From Baseline in Body Weight

Secondary: Change From Baseline in Body Weight

Secondary: Percentage of Time in Hypoglycemia Range With Blood Glucose <70 mg/dL (3.9 mmol/L)

Secondary: Percentage of Time in Hypoglycemia Range With Blood Glucose <70 mg/dL (3.9 mmol/L)

Secondary: Percentage of Time in Hypoglycemia Range With Blood Glucose <54 mg/dL (3.0 mmol/L)

Secondary: Percentage of Time in Hypoglycemia Range With Blood Glucose <54 mg/dL (3.0 mmol/L)

Secondary: Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L)

Secondary: Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L)

Secondary: Change From Baseline in Treatment-Related Impact Measures for Diabetes (TRIM-D) -Total Score at Week 26 and Week 52

Secondary: Change From Baseline in Treatment-Related Impact Measures for Diabetes (TRIM-D) -Total Score at Week 26 and Week 52

Secondary: Change From Baseline in Short Form-36 Health Survey Version 2 (SF-36v2) Acute Form (Physical-Component and Mental-Component) Scores at Week 26 and Week 52

Secondary: Change From Baseline in Short Form-36 Health Survey Version 2 (SF-36v2) Acute Form (Physical-Component and Mental-Component) Scores at Week 26 and Week 52

Secondary: Change from Baseline in EuroQuality of Life (EuroQol) -5 Dimensions-5 Levels (EQ-5D-5L) Health State Index and EQ visual analog scale (VAS) Scores at Week 26 and Week 52

Secondary: Change from Baseline in EuroQuality of Life (EuroQol) -5 Dimensions-5 Levels (EQ-5D-5L) Health State Index and EQ visual analog scale (VAS) Scores at Week 26 and Week 52

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Degludec in Insulin Naïve Adults With Type 2 Diabetes