Trial Outcomes & Findings for An Administration Method Study of Human Regular U-500 Insulin (LY041001) in Participants With Type 2 Diabetes Mellitus (NCT NCT02561078)

Last Updated: 2020-05-20

Results Overview

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 baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

420 participants

Primary outcome timeframe

Baseline, 26 Weeks

Results posted on

2020-05-20

Participant Flow

Participant milestones

Participant milestones
Measure	Human Regular U-500 Insulin Administered by CSII Human regular U-500 insulin administered by continuous subcutaneous insulin infusion (CSII) and titrated based on blood glucose readings for 26 weeks with a 2-week multiple daily injections (MDI) lead-in.	Human Regular U-500 Insulin Administered by MDI Human regular U-500 insulin administered subcutaneously (SC) by multiple daily injections (MDI) three times a day and titrated based on blood glucose readings for 26 weeks.
Overall Study STARTED	209	211
Overall Study Received at Least 1 Dose of Study Drug	208	210
Overall Study COMPLETED	179	186
Overall Study NOT COMPLETED	30	25

Reasons for withdrawal

Reasons for withdrawal
Measure	Human Regular U-500 Insulin Administered by CSII Human regular U-500 insulin administered by continuous subcutaneous insulin infusion (CSII) and titrated based on blood glucose readings for 26 weeks with a 2-week multiple daily injections (MDI) lead-in.	Human Regular U-500 Insulin Administered by MDI Human regular U-500 insulin administered subcutaneously (SC) by multiple daily injections (MDI) three times a day and titrated based on blood glucose readings for 26 weeks.
Overall Study Adverse Event	5	2
Overall Study Death	2	1
Overall Study Lost to Follow-up	2	6
Overall Study Non-Compliance with Study Drug	6	3
Overall Study Physician Decision	2	3
Overall Study Withdrawal by Subject	13	10

Baseline Characteristics

An Administration Method Study of Human Regular U-500 Insulin (LY041001) in Participants With Type 2 Diabetes Mellitus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Human Regular U-500 Insulin Administered by CSII n=209 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=211 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.	Total n=420 Participants Total of all reporting groups
Age, Continuous	57.58 years STANDARD_DEVIATION 10.27 • n=5 Participants	56.66 years STANDARD_DEVIATION 10.12 • n=7 Participants	57.12 years STANDARD_DEVIATION 10.19 • n=5 Participants
Sex: Female, Male Female	105 Participants n=5 Participants	94 Participants n=7 Participants	199 Participants n=5 Participants
Sex: Female, Male Male	104 Participants n=5 Participants	117 Participants n=7 Participants	221 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	39 Participants n=5 Participants	49 Participants n=7 Participants	88 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	170 Participants n=5 Participants	162 Participants n=7 Participants	332 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Black or African American	19 Participants n=5 Participants	14 Participants n=7 Participants	33 Participants n=5 Participants
Race (NIH/OMB) White	160 Participants n=5 Participants	160 Participants n=7 Participants	320 Participants n=5 Participants
Race (NIH/OMB) More than one race	25 Participants n=5 Participants	26 Participants n=7 Participants	51 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment Puerto Rico	15 Participants n=5 Participants	21 Participants n=7 Participants	36 Participants n=5 Participants
Region of Enrollment United States	194 Participants n=5 Participants	190 Participants n=7 Participants	384 Participants n=5 Participants
Hemoglobin A1c (HbA1c)	8.75 Percentage of HbA1c STANDARD_DEVIATION 1.03 • n=5 Participants	8.77 Percentage of HbA1c STANDARD_DEVIATION 1.08 • n=7 Participants	8.76 Percentage of HbA1c STANDARD_DEVIATION 1.05 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline HbA1c measure.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=171 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=179 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Change From Baseline in Hemoglobin A1c (HbA1c)	-1.27 Percentage of HbA1c Standard Error 0.072	-0.85 Percentage of HbA1c Standard Error 0.070

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline fasting plasma glucose measure.

Fasting plasma glucose (FPG) is a test to determine how much glucose (sugar) is in a plasma sample after an overnight fast. Least Squares (LS) means was determined by MMRM methodology with baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=163 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=172 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Change From Baseline in Fasting Plasma Glucose (FPG)	-33.9 milligrams per deciliter (mg/dL) Standard Error 5.03	1.7 milligrams per deciliter (mg/dL) Standard Error 4.90

SECONDARY outcome

Timeframe: 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline HbA1c measure.

Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Longitudinal logistic regression was used to model the likelihood of having hbA1c\<7.0% at Week 26 with baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=171 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=179 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Percentage of Participants With HbA1c <7.0%	28.65 Percentage of participants	18.44 Percentage of participants

SECONDARY outcome

Timeframe: 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline HbA1c measure.

Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Longitudinal logistic regression was used to model the likelihood of having hbA1c\<7.5% at Week 26 with baseline of response, glucagon-like peptide-1 (GLP-1) or sodium-glucose cotransporter 2 (SGLT2) use, U-500R at entry, treatment, time and treatment by time interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=171 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=179 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Percentage of Participants With HbA1c <7.5%	52.63 Percentage of Participants	38.55 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline SMBG measure.

Seven-point SMBG are completed at the following timepoints: Before Morning Meal, 2 Hours After Morning Meal, Before Mid-Day Meal, 2 Hours After Mid-Day Meal, Before Evening Meal, Bed Time and 03:00 AM hours. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, time and treatment by time interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=140 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=151 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values Pre Morning Meal	-34.3 mg/dL Standard Error 3.53	-11.8 mg/dL Standard Error 3.41
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 2 Hours Post Morning Meal	-25.0 mg/dL Standard Error 4.58	-7.8 mg/dL Standard Error 4.50
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values Pre Mid-Day Meal	-19.8 mg/dL Standard Error 4.29	-10.9 mg/dL Standard Error 4.15
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 2 Hours Post Mid-Day Meal	-8.3 mg/dL Standard Error 4.20	-16.6 mg/dL Standard Error 4.08
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values Pre Evening Meal	-15.1 mg/dL Standard Error 4.11	-24.3 mg/dL Standard Error 3.99
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 2 HOURS POST EVENING MEAL	-14.6 mg/dL Standard Error 4.19	-31.3 mg/dL Standard Error 4.02
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values OVERNIGHT (3:00 AM)	-25.4 mg/dL Standard Error 3.71	-26.0 mg/dL Standard Error 3.58

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline TDD measure.

Baseline TDD was defined as the last prestudy insulin TDD prior to randomization to receiving the first dose of U-500 insulin post randomization. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, time and treatment by time interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=172 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=180 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Change From Baseline in Total Daily Dose (TDD)	2.8 units/day Standard Error 9.33	51.3 units/day Standard Error 9.14

SECONDARY outcome

Timeframe: 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline documented hypoglycemia.

The percentage of participants with hypoglycemic episodes (documented hypoglycemia) was calculated by dividing the number of participants with at least 1 hypoglycemic episode (documented hypoglycemia) over the 26-week treatment period by the total number of participants analyzed, multiplied by 100%. Logistic regression was used to estimate the odds ratio between the two treatments of at least 1 hypoglycemic episode (documented hypoglycemia) over 26 week treatment period adjusted for baseline documented hypoglycemia rate, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, time and treatment by time interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=209 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=210 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Percentage of Participants With Hypoglycemic Episodes (Documented Hypoglycemia With Blood Glucose <= 70 mg/dL)	95.69 Percentage of Participants	95.71 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline to 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline documented hypoglycemia.

Documented Hypoglycemic episodes with blood glucose\<=70mg/dL was used in this outcome measure. Hypoglycemia rate (documented hypoglycemia) per 30 days was summarized at each visit by treatment group. The rate of hypoglycemia (documented hypoglycemia) was analyzed using a generalized estimation equations model with a negative binomial distribution and a Log link. LS mean was determined by MMRM methodology with baseline documented hypoglycemia rate, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, with log of exposure in days divided by 30 as the offset, treatment, visit, and visit by treatment interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=209 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=210 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Rate of Hypoglycemic Episodes (Documented Hypoglycemia With Blood Glucose <= 70 mg/dL)	5.16 Episodes/participant/30 days Standard Error 0.380	4.27 Episodes/participant/30 days Standard Error 0.308

SECONDARY outcome

Timeframe: Baseline, 26 Weeks

Population: All randomized participants who received at least 1 dose of study drug with baseline and post-baseline body weight.

Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, GLP-1 or SGLT2 use, U-500R at entry, baseline HbA1C group, treatment, treatment by time interaction.

Outcome measures

Outcome measures
Measure	Human Regular U-500 Insulin Administered by CSII n=171 Participants Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=181 Participants Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Change From Baseline in Body Weight	4.2 Kilograms (kg) Standard Error 0.35	3.4 Kilograms (kg) Standard Error 0.34

Adverse Events

Human Regular U-500 Insulin Administered by CSII

Serious events: 34 serious events

Other events: 85 other events

Deaths: 2 deaths

Human Regular U-500 Insulin Administered by MDI

Serious events: 23 serious events

Other events: 84 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Human Regular U-500 Insulin Administered by CSII n=209 participants at risk Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=211 participants at risk Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Gastrointestinal disorders Diarrhoea	6.7% 14/209 • Number of events 18 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	8.1% 17/211 • Number of events 22 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Nausea	4.3% 9/209 • Number of events 9 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	8.1% 17/211 • Number of events 20 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Sinusitis	4.8% 10/209 • Number of events 10 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	6.2% 13/211 • Number of events 15 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection	8.1% 17/209 • Number of events 17 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	8.5% 18/211 • Number of events 19 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Urinary tract infection	1.4% 3/209 • Number of events 4 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	5.2% 11/211 • Number of events 11 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Viral upper respiratory tract infection	5.3% 11/209 • Number of events 12 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	8.5% 18/211 • Number of events 21 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Investigations Weight increased	6.7% 14/209 • Number of events 14 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	6.2% 13/211 • Number of events 13 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hyperglycaemia	5.3% 11/209 • Number of events 17 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	5.3% 11/209 • Number of events 11 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	6.2% 13/211 • Number of events 16 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Headache	4.3% 9/209 • Number of events 11 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	6.6% 14/211 • Number of events 18 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	3.3% 7/209 • Number of events 9 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	5.7% 12/211 • Number of events 15 • Up to 26 weeks All randomized participants who received at least one dose of study drug.

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Human Regular U-500 Insulin Administered by CSII n=209 participants at risk Human regular U-500 insulin administered by CSII and titrated based on blood glucose readings for 26 weeks with a 2-week MDI lead-in.	Human Regular U-500 Insulin Administered by MDI n=211 participants at risk Human regular U-500 insulin administered subcutaneously (SC) by MDI three times a day and titrated based on blood glucose readings for 26 weeks.
Cardiac disorders Acute coronary syndrome	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Acute myocardial infarction	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Angina pectoris	0.48% 1/209 • Number of events 2 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Angina unstable	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Atrial flutter	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Cardiac arrest	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure congestive	0.96% 2/209 • Number of events 2 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Cor pulmonale	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Coronary artery disease	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Left ventricular failure	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Myocardial infarction	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Myocardial ischaemia	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Cardiac disorders Ventricular tachycardia	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Eye disorders Diabetic retinopathy	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Eye disorders Retinal detachment	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Eye disorders Vitreous haemorrhage	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Colitis	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Enterocolitis	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Impaired gastric emptying	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
General disorders Asthenia	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
General disorders Non-cardiac chest pain	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.95% 2/211 • Number of events 2 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Bronchitis	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Cellulitis	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Gastroenteritis viral	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Infected skin ulcer	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Infection	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Influenza	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Osteomyelitis	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Perirectal abscess	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Pneumonia	1.9% 4/209 • Number of events 4 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.95% 2/211 • Number of events 2 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Pyelonephritis acute	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Sepsis	1.4% 3/209 • Number of events 3 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Urinary tract infection	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Infections and infestations Urosepsis	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Muscle strain	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Dehydration	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hypoglycaemia	4.8% 10/209 • Number of events 12 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	2.4% 5/211 • Number of events 5 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Obesity	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthropathy	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Compartment syndrome	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Cerebrovascular accident	0.96% 2/209 • Number of events 2 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Encephalopathy	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Hypoglycaemic seizure	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Loss of consciousness	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Lumbar radiculopathy	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Metabolic encephalopathy	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Moyamoya disease	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Peroneal nerve palsy	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Syncope	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Nervous system disorders Transient ischaemic attack	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Product Issues Device malfunction	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Psychiatric disorders Depression	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Psychiatric disorders Depression suicidal	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Renal and urinary disorders Acute kidney injury	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	1.4% 3/211 • Number of events 3 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Renal and urinary disorders Hydronephrosis	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Renal and urinary disorders Ureterolithiasis	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	1.4% 3/211 • Number of events 3 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/209 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.47% 1/211 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Diabetic foot	0.48% 1/209 • Number of events 1 • Up to 26 weeks All randomized participants who received at least one dose of study drug.	0.00% 0/211 • Up to 26 weeks All randomized participants who received at least one dose of study drug.