Trial Outcomes & Findings for A "Real World" Trial to Determine Efficacy and Health Outcomes of Toujeo (ACHIEVE CONTROL REAL LIFE STUDY PROGRAM) (NCT NCT02451137)

Last Updated: 2019-09-10

Results Overview

HEDIS criteria: Individualized HbA1c target \<8% if age \>= 65 years or presence of medical comorbidities, or otherwise \<7%. Severe hypoglycaemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Documented symptomatic hypoglycaemia was an event during which typical symptoms of hypoglycaemia were accompanied by a measured plasma glucose concentration of \<=70 milligrams per deciliter (mg/dL) (\<=3.9 millimoles per litre \[mmol/L\]). Analysis was performed using all post-baseline data available on the 6 month randomized period (defined as time from randomization up to Day 180 or discontinuation date, whichever comes earlier).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

3304 participants

Primary outcome timeframe

Baseline to Month 6

Results posted on

2019-09-10

Participant Flow

The study was conducted at 427 sites in 2 countries. A total of 4989 participants were screened between 16 June 2015 and 14 July 2017, of which 1684 were screen failures. Screen failures were mainly due to inclusion criteria not met.

Out of 3305 participants, 1 participant was not randomized, but received treatment; hence not included in any analysis (baseline, efficacy and safety). Assignment in arms was done centrally by interactive response technology (IRT) in 1:1 ratio.

Participant milestones

Participant milestones
Measure	Toujeo Toujeo® (Insulin glargine, 300 units per millilitre \[U/mL\]) subcutaneous (SC) injection administered once daily up to Month 12, with or without available participant support program.	Standard of Care Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Overall Study STARTED	1651	1653
Overall Study Treated	1632	1626
Overall Study Safety Population	1637	1621
Overall Study COMPLETED	1405	1355
Overall Study NOT COMPLETED	246	298

Reasons for withdrawal

Reasons for withdrawal
Measure	Toujeo Toujeo® (Insulin glargine, 300 units per millilitre \[U/mL\]) subcutaneous (SC) injection administered once daily up to Month 12, with or without available participant support program.	Standard of Care Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Overall Study Randomized but not treated	19	27
Overall Study Adverse Event	43	42
Overall Study Lack of Efficacy	4	9
Overall Study Participant decision:discontinue insulin	41	43
Overall Study Hypoglycemia	2	1
Overall Study Investigator's decision	23	19
Overall Study Lost to Follow-up	53	61
Overall Study Physician Decision	6	5
Overall Study Sponsor decision	13	25
Overall Study Withdrawal by Subject	40	63
Overall Study Other than specified above	2	3

Baseline Characteristics

Here, number analyzed = participants with available data for specified measure.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.	Total n=3304 Participants Total of all reporting groups
Age, Continuous	59.4 years STANDARD_DEVIATION 10.8 • n=1651 Participants	59.1 years STANDARD_DEVIATION 11.0 • n=1653 Participants	59.3 years STANDARD_DEVIATION 10.9 • n=3304 Participants
Sex: Female, Male Female	747 Participants n=1651 Participants	731 Participants n=1653 Participants	1478 Participants n=3304 Participants
Sex: Female, Male Male	904 Participants n=1651 Participants	922 Participants n=1653 Participants	1826 Participants n=3304 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	286 Participants n=1651 Participants	305 Participants n=1653 Participants	591 Participants n=3304 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1365 Participants n=1651 Participants	1348 Participants n=1653 Participants	2713 Participants n=3304 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=1651 Participants	0 Participants n=1653 Participants	0 Participants n=3304 Participants
Race/Ethnicity, Customized Caucasian/White	1283 Participants n=1651 Participants	1299 Participants n=1653 Participants	2582 Participants n=3304 Participants
Race/Ethnicity, Customized Black	262 Participants n=1651 Participants	238 Participants n=1653 Participants	500 Participants n=3304 Participants
Race/Ethnicity, Customized Asian/Oriental	83 Participants n=1651 Participants	95 Participants n=1653 Participants	178 Participants n=3304 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	15 Participants n=1651 Participants	12 Participants n=1653 Participants	27 Participants n=3304 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	6 Participants n=1651 Participants	4 Participants n=1653 Participants	10 Participants n=3304 Participants
Race/Ethnicity, Customized Other	12 Participants n=1651 Participants	14 Participants n=1653 Participants	26 Participants n=3304 Participants
Region of Enrollment Canada	82 Participants n=1651 Participants	85 Participants n=1653 Participants	167 Participants n=3304 Participants
Region of Enrollment United States	1569 Participants n=1651 Participants	1568 Participants n=1653 Participants	3137 Participants n=3304 Participants
Body Mass Index (BMI)	33.85 kg/m^2 STANDARD_DEVIATION 7.14 • n=1649 Participants • Here, number analyzed = participants with available data for specified measure.	33.70 kg/m^2 STANDARD_DEVIATION 7.29 • n=1652 Participants • Here, number analyzed = participants with available data for specified measure.	33.77 kg/m^2 STANDARD_DEVIATION 7.22 • n=3301 Participants • Here, number analyzed = participants with available data for specified measure.
Duration of Type 2 Diabetes Mellitus	11.43 years STANDARD_DEVIATION 7.43 • n=1651 Participants	11.16 years STANDARD_DEVIATION 7.31 • n=1653 Participants	11.30 years STANDARD_DEVIATION 7.37 • n=3304 Participants
Baseline glycated hemoglobin (HbA1c)	9.1 percentage of HbA1c STANDARD_DEVIATION 0.8 • n=1651 Participants	9.2 percentage of HbA1c STANDARD_DEVIATION 0.8 • n=1653 Participants	9.2 percentage of HbA1c STANDARD_DEVIATION 0.8 • n=3304 Participants

PRIMARY outcome

Timeframe: Baseline to Month 6

Population: Analysis was performed on Intent-to-Treat (ITT) population which comprised of all randomized participants, irrespective of the treatment actually received, and analyzed according to the treatment group allocated by randomization.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Percentage of Participants With Individualized Glycated Hemoglobin Target Attainment Per Healthcare Effectiveness Data and Information Set (HEDIS) Criteria Without Documented Symptomatic(Blood Glucose <=70 mg/dL [<=3.9 mmol/L]) and/or Severe Hypoglycemia	31.3 percentage of participants	27.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 12

Population: Analysis was performed on ITT population.

Change in HbA1c was calculated by subtracting baseline value from Month 6 and Month 12 values. Adjusted Least Squares (LS) means and Standard Errors (SE) were obtained using Mixed Effect Model with Repeated Measures (MMRM ) with fixed categorical effects of treatment arm, visit, treatment arm-by-visit interaction, randomization strata of HbA1c target (\<8% / \<7%), SU use (yes/no), GLP-1 RA use (yes/no), as well as baseline HbA1c (as continuous) and baseline HbA1c-by-visit interaction.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Change From Baseline in HbA1c at Month 6 and Month 12 Month 6	-1.40 percentage of HbA1c Standard Error 0.030	-1.36 percentage of HbA1c Standard Error 0.030
Change From Baseline in HbA1c at Month 6 and Month 12 Month 12	-1.29 percentage of HbA1c Standard Error 0.034	-1.24 percentage of HbA1c Standard Error 0.034

SECONDARY outcome

Timeframe: At Month 6 and Month 12

Population: Analysis was performed on safety population.

Treatment persistence was determined based on vendor claims database that would be responsible for managing and administration of the study drugs. Medication use was assessed by MPR and persistence measures based on data collected by the smart card vendor (date of fill or refill and quantity of medication dispensed for 30-day supply). The MPR was assessed based on total number of days of supply divided by the total number of days in 6 or 12 months period.

Outcome measures

Outcome measures
Measure	Toujeo n=1637 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1621 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Treatment Persistence Measured by Medication Possession Ratio (MPR) Month 6	62.06 Medication Possession ratio Standard Deviation 26.98	63.14 Medication Possession ratio Standard Deviation 28.42
Treatment Persistence Measured by Medication Possession Ratio (MPR) Month 12	58.21 Medication Possession ratio Standard Deviation 28.87	57.82 Medication Possession ratio Standard Deviation 29.97

SECONDARY outcome

Timeframe: Baseline to Month 6

Population: Analysis was performed on ITT population.

HEDIS criteria for Individualized HbA1c target: \<8% if age \>= 65 years or presence of medical comorbidities, or otherwise \<7%. Severe hypoglycaemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Documented symptomatic hypoglycaemia was an event during which typical symptoms of hypoglycaemia were accompanied by a measured plasma glucose concentration of \<54 mg/dL (3.0 mmol/L).

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Percentage of Participants Reaching Individualized HbA1c Target Without Documented Symptomatic <3.0 mmol/L (<54 mg/dL) and/or Severe Hypoglycemia During the 6-Month Randomized Period	37.3 percentage of participants	34.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Month 12

Population: Analysis was performed on ITT population.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Percentage of Participants Reaching Individualized HbA1c Target Without Documented Symptomatic <=3.9 mmol/L (<= 70 mg/dL) and <3.0 mmol/L (< 54 mg/dL) and/or Severe Hypoglycemia During the 12-Month Randomized Period Month 12: <=70 mg/dL	26.1 percentage of participants	23.7 percentage of participants
Percentage of Participants Reaching Individualized HbA1c Target Without Documented Symptomatic <=3.9 mmol/L (<= 70 mg/dL) and <3.0 mmol/L (< 54 mg/dL) and/or Severe Hypoglycemia During the 12-Month Randomized Period Month 12: <54 mg/dL	33.0 percentage of participants	29.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 12

Population: Analysis was performed on ITT population.

Change in FPG was calculated by subtracting baseline value from Month 6 and Month 12 values. Adjusted LS means and SE were obtained using MMRM model with fixed categorical effects of treatment arm, randomization strata of HbA1c target (\<8% / \<7%), SU use (yes/no), GLP-1 RA use (yes/no), as well as baseline FPG (as continuous) and baseline FPG-by-visit interaction.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Change From Baseline in Fasting Plasma Glucose (FPG) at Month 6 and Month 12 Month 6	-48.9 mg/dL Standard Error 1.56	-50.4 mg/dL Standard Error 1.58
Change From Baseline in Fasting Plasma Glucose (FPG) at Month 6 and Month 12 Month 12	-48.0 mg/dL Standard Error 1.66	-47.3 mg/dL Standard Error 1.69

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 12

Population: Analysis was performed on ITT population.

Adjusted LS means and SE were obtained using MMRM model with fixed categorical effects of treatment arm, visit, treatment arm-by-visit interaction, randomization strata of HbA1c target (\<8% / \<7%), SU use (yes/no), GLP-1 RA use (yes/no), as well as baseline weight (as continuous) and baseline weight-by-visit interaction.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Change From Baseline in Body Weight at Month 6 and Month 12 Month 6	1.02 kilogram (kg) Standard Error 0.109	1.14 kilogram (kg) Standard Error 0.110
Change From Baseline in Body Weight at Month 6 and Month 12 Month 12	1.51 kilogram (kg) Standard Error 0.140	1.40 kilogram (kg) Standard Error 0.142

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 12

Population: Analysis was performed on safety population. Here, 'Number analyzed' = participants with available data for each specified category.

Change in basal insulin dose was calculated by subtracting baseline value from Month 6 and Month 12 values.

Outcome measures

Outcome measures
Measure	Toujeo n=1637 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1621 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Change From Baseline in Basal Insulin Dose at Month 6 and Month 12 Month 6	0.179 Unit/kg (U/kg) Standard Deviation 0.212	0.183 Unit/kg (U/kg) Standard Deviation 0.218
Change From Baseline in Basal Insulin Dose at Month 6 and Month 12 Month 12	0.222 Unit/kg (U/kg) Standard Deviation 0.232	0.224 Unit/kg (U/kg) Standard Deviation 0.241

SECONDARY outcome

Timeframe: At Month 6, Month 12

Population: Analysis was performed on ITT population.

Participant and Physician (Provider) reported GES for this diabetes study. The GES assessed impact of treatment on scale ranges as: excellent (complete control of diabetes), good (marked improvement of diabetes), moderate (discernible, but limited improvement in diabetes), poor (no appreciable change in diabetes), or worsening of condition (worsening of diabetes). There was no score expressed by numbers and no change measured over the time of the study. Percentage of participants and providers who reported "excellent" or "good" on the GES at Month 6 and Month 12 are reported here.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Percentage of Responders (Participants and Provider) Who Reported "Excellent" or "Good" Responses to Global Effectiveness Scale (GES) Question at Month 6, and Month 12 Percentage of Participants: Month 6	67.2 percentage of responders	65.6 percentage of responders
Percentage of Responders (Participants and Provider) Who Reported "Excellent" or "Good" Responses to Global Effectiveness Scale (GES) Question at Month 6, and Month 12 Percentage of Providers: Month 6	62.1 percentage of responders	57.7 percentage of responders
Percentage of Responders (Participants and Provider) Who Reported "Excellent" or "Good" Responses to Global Effectiveness Scale (GES) Question at Month 6, and Month 12 Percentage of Participants: Month 12	64.7 percentage of responders	64.2 percentage of responders
Percentage of Responders (Participants and Provider) Who Reported "Excellent" or "Good" Responses to Global Effectiveness Scale (GES) Question at Month 6, and Month 12 Percentage of Providers: Month 12	58.8 percentage of responders	56.3 percentage of responders

SECONDARY outcome

Timeframe: At Baseline, Month 6, Month 12

Population: Analysis was performed on ITT population. Here, "number analyzed" = participants with available data for each specified category.

DTSQs is a validated questionnaire to assess participant's satisfaction with their diabetes treatment. It consists of 8 items, each answered on a Likert scale of 0 to 6. Responses of 6 questions (Items 1, 4, 5, 6, 7 and 8) were summarized to derive total treatment satisfaction score, such that a higher score was indicative of better satisfaction. Total treatment satisfaction score is the sum of items 1, 4-8 scores and ranged from 0 (no satisfaction) to 36 (improvement in treatment satisfaction). Item 2 and Item 3 scores were used for hyperglycemia perception and hypoglycemia perception respectively, where lower scores indicated better health outcome. Perceived frequency of hyperglycemia score (Item 2) and perceived frequency of hypoglycemia score (Item 3) range from 0 (none of the time) to 6 (most of time), where lower scores indicated more satisfaction/better health outcome.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Total treatment satisfaction score:Baseline	26.5 score on a scale Standard Deviation 7.0	26.4 score on a scale Standard Deviation 7.1
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Total treatment satisfaction score: Month 6	31.0 score on a scale Standard Deviation 5.5	31.1 score on a scale Standard Deviation 5.3
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Total treatment satisfaction score: Month 12	30.9 score on a scale Standard Deviation 6.0	30.7 score on a scale Standard Deviation 6.1
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Perceived frequencyof hyperglycemia score:Baseline	4.3 score on a scale Standard Deviation 1.7	4.3 score on a scale Standard Deviation 1.7
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Perceived frequency of hyperglycemia score:Month 6	2.8 score on a scale Standard Deviation 1.7	2.8 score on a scale Standard Deviation 1.7
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Perceived frequency of hyperglycemia score:Month12	2.6 score on a scale Standard Deviation 1.7	2.6 score on a scale Standard Deviation 1.7
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Perceived frequency of hypoglycemia score:Baseline	0.9 score on a scale Standard Deviation 1.4	0.8 score on a scale Standard Deviation 1.3
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Perceived frequency of hypoglycemia score: Month 6	0.9 score on a scale Standard Deviation 1.3	1.0 score on a scale Standard Deviation 1.4
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) at Baseline, Month 6, Month 12 Perceived frequency of hypoglycemia score:Month 12	0.9 score on a scale Standard Deviation 1.3	1.0 score on a scale Standard Deviation 1.4

SECONDARY outcome

Timeframe: At Month 12

Population: Analysis was performed on ITT population. Here, "number analyzed" = participants with available data for assessment during the 12 month randomized period.

DTSQc version evaluates the change in treatment satisfaction at Month 12 as compared to the start of the study . It consists of 8 items, each answered on a Likert scale from -3 to +3. The sum of treatment satisfaction scores (items 1, 4, 5, 6, 7,and 8) ranged from score -18 (deterioration in treatment satisfaction) to +18 (improvement in treatment satisfaction). Perceived frequency of hypoglycemia and perceived frequency of hyperglycemia score ranges from score -3 (fewer problems) to +3 (more problems).

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) at Month 12 Total satisfaction score	13.81 score on a scale Standard Error 0.15	13.79 score on a scale Standard Error 0.15
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) at Month 12 Perceived frequency of hyperglycemia score	0.14 score on a scale Standard Error 0.05	0.21 score on a scale Standard Error 0.05
Scores of Total Treatment Satisfaction, Hyperglycemia Perception, and Hypoglycemia Perception From Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) at Month 12 Perceived frequency of hypoglycemia	-0.82 score on a scale Standard Error 0.05	-0.82 score on a scale Standard Error 0.05

SECONDARY outcome

Timeframe: From Baseline to Month 6 and Month 12

Population: Analysis was performed on ITT population.

Percentage of participants with hospitalizations, emergency room visits, and specialty visits during the 6-month and 12-month randomized period were reported. The 12-month randomized period was defined as the time from randomization up to Day 365 or discontinuation date, whichever comes earlier.

Outcome measures

Outcome measures
Measure	Toujeo n=1651 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1653 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Percentage of Participants With Hospitalizations, Emergency Rooms and Specialty Visits From Baseline to Month 6 and Month 12 Hospitalizations: Month 6	8.1 percentage of participants	7.5 percentage of participants
Percentage of Participants With Hospitalizations, Emergency Rooms and Specialty Visits From Baseline to Month 6 and Month 12 Emergency Room Visits: Month 6	11.3 percentage of participants	10.3 percentage of participants
Percentage of Participants With Hospitalizations, Emergency Rooms and Specialty Visits From Baseline to Month 6 and Month 12 Specialty Visits: Month 6	78.3 percentage of participants	74.0 percentage of participants
Percentage of Participants With Hospitalizations, Emergency Rooms and Specialty Visits From Baseline to Month 6 and Month 12 Hospitalizations: Month 12	9.1 percentage of participants	8.0 percentage of participants
Percentage of Participants With Hospitalizations, Emergency Rooms and Specialty Visits From Baseline to Month 6 and Month 12 Emergency Room Visits: Month 12	12.7 percentage of participants	11.1 percentage of participants
Percentage of Participants With Hospitalizations, Emergency Rooms and Specialty Visits From Baseline to Month 6 and Month 12 Specialty Visits: Month 12	80.1 percentage of participants	75.9 percentage of participants

SECONDARY outcome

Timeframe: Up to Month 6 and Month 12

Population: Analysis was performed on safety population.

Severe hypoglycaemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Documented symptomatic hypoglycaemia was an event during which typical symptoms of hypoglycaemia were accompanied by a measured plasma glucose concentration of \<=70 mg/dL (\<=3.9 mmol/L) or \<54 mg/dL (3.0 mmol/L).

Outcome measures

Outcome measures
Measure	Toujeo n=1637 Participants Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care n=1621 Participants Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Any hypoglycemia: Any time: Month 6	28.9 percentage of participants	30.4 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Any hypoglycemia: Nocturnal: Month 6	8.9 percentage of participants	10.0 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Any hypoglycemia: Any time: Month 12	39.1 percentage of participants	41.8 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Any hypoglycemia: Nocturnal: Month 12	13.6 percentage of participants	14.9 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Severe hypoglycemia: Any time: Month 6	1.0 percentage of participants	1.0 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Severe hypoglycemia:Nocturnal: Month 6	0.5 percentage of participants	0.6 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic <=70 mg/dL:Any time:Month 6	13.9 percentage of participants	14.9 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic <54 mg/dL:Any time:Month 6	3.6 percentage of participants	3.1 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic <=70mg/dL:Nocturnal:Month 6	4.5 percentage of participants	5.6 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic <54 mg/dL:Nocturnal:Month 6	0.8 percentage of participants	0.8 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Severe hypoglycemia: Any time: Month 12	1.2 percentage of participants	1.9 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Severe hypoglycemia:Nocturnal: Month 12	0.5 percentage of participants	0.7 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic<=70 mg/dL:Any time:Month 12	19.9 percentage of participants	20.8 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic <54 mg/dL:Any time:Month 12	5.6 percentage of participants	5.6 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic<=70mg/dL:Nocturnal:Month 12	6.5 percentage of participants	8.3 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Hypoglycemia Event (Any Time of the Day, Nocturnal) Per Type of Hypoglycaemia During the Month 6 and Month 12 on Treatment Period Documented Symptomatic <54mg/dL:Nocturnal:Month 12	1.2 percentage of participants	1.7 percentage of participants

Adverse Events

Toujeo

Serious events: 161 serious events

Other events: 0 other events

Deaths: 7 deaths

Standard of Care Basal Insulin

Serious events: 165 serious events

Other events: 0 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Toujeo n=1637 participants at risk Toujeo® (Insulin glargine, 300 U/mL) SC injection once daily up to Month 12, with or without available participant support program.	Standard of Care Basal Insulin n=1621 participants at risk Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Blood and lymphatic system disorders Anaemia	0.12% 2/1637 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Febrile Neutropenia	0.12% 2/1637 • Number of events 3 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Haemorrhagic Anaemia	0.18% 3/1637 • Number of events 3 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.12% 2/1621 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Lymphadenitis	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Lymphadenopathy Mediastinal	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Neutropenia	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Normochromic Normocytic Anaemia	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Acute Left Ventricular Failure	0.18% 3/1637 • Number of events 3 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.12% 2/1621 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Acute Myocardial Infarction	0.49% 8/1637 • Number of events 8 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.25% 4/1621 • Number of events 4 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Angina Pectoris	0.37% 6/1637 • Number of events 7 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.19% 3/1621 • Number of events 3 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Angina Unstable	0.24% 4/1637 • Number of events 5 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.25% 4/1621 • Number of events 4 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Aortic Valve Stenosis	0.12% 2/1637 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Arrhythmia	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Arteriosclerosis Coronary Artery	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Atrial Fibrillation	0.49% 8/1637 • Number of events 8 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.37% 6/1621 • Number of events 6 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Atrial Flutter	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Atrioventricular Block Complete	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Bradycardia	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Bundle Branch Block Left	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Cardiac Arrest	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Cardiac Failure	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Cardiac Failure Acute	0.24% 4/1637 • Number of events 4 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.19% 3/1621 • Number of events 3 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Cardiac Failure Congestive	0.37% 6/1637 • Number of events 6 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.25% 4/1621 • Number of events 4 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Coronary Artery Disease	0.61% 10/1637 • Number of events 10 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.56% 9/1621 • Number of events 9 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Coronary Artery Stenosis	0.12% 2/1637 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Intracardiac Thrombus	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Ischaemic Cardiomyopathy	0.12% 2/1637 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Myocardial Infarction	0.18% 3/1637 • Number of events 3 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.19% 3/1621 • Number of events 3 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Supraventricular Tachycardia	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Ventricular Extrasystoles	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Cardiac disorders Ventricular Tachycardia	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Ear and labyrinth disorders Vertigo	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Endocrine disorders Autoimmune Thyroiditis	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Eye disorders Glaucoma	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Eye disorders Retinal Haemorrhage	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Eye disorders Vision Blurred	0.00% 0/1637 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.06% 1/1621 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Gastrointestinal disorders Abdominal Pain	0.12% 2/1637 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.12% 2/1621 • Number of events 2 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Gastrointestinal disorders Ascites	0.06% 1/1637 • Number of events 1 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.	0.00% 0/1621 • All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (12 months) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of investigational medicinal product (IMP) up to 1 day after the last injection of IMP). Analysis was performed on safety population.