Trial Outcomes & Findings for Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Combination Versus Insulin Glargine Alone on Top of Metformin in Type 2 Diabetic Patients (NCT NCT01476475)

Results Overview

Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

323 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2017-02-10

Participant Flow

The study was conducted at 70 centers in 13 countries. A total of 520 participants were screened between November 21, 2011 and June 08, 2012. Out of 520 participants, 197 were screen failure; main reason for screen failure was that glycosylated hemoglobin (HbA1c) values were out of the protocol defined range.

A total of 323 participants were randomized in 1:1 ratio to insulin glargine/lixisenatide fixed ratio combination (FRC) and insulin glargine arms, stratified by screening HbA1c values (\<8% or ≥8%) and screening body mass index (BMI) values (\<30 kg/m\^2, ≥30 kg/m\^2).

Participant milestones

Participant milestones
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination FRC injected subcutaneously once daily (QD) for 24 weeks. Dose individually adjusted.	Insulin Glargine Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Overall Study STARTED	161	162
Overall Study COMPLETED	150	159
Overall Study NOT COMPLETED	11	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination FRC injected subcutaneously once daily (QD) for 24 weeks. Dose individually adjusted.	Insulin Glargine Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Overall Study Adverse Event	6	0
Overall Study Poor compliance to protocol	1	1
Overall Study Other reasons	4	2

Baseline Characteristics

Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Combination Versus Insulin Glargine Alone on Top of Metformin in Type 2 Diabetic Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=161 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=162 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Total n=323 Participants Total of all reporting groups
Age, Continuous	56.9 years STANDARD_DEVIATION 9.5 • n=93 Participants	56.6 years STANDARD_DEVIATION 9.4 • n=4 Participants	56.7 years STANDARD_DEVIATION 9.4 • n=27 Participants
Gender Female	81 Participants n=93 Participants	77 Participants n=4 Participants	158 Participants n=27 Participants
Gender Male	80 Participants n=93 Participants	85 Participants n=4 Participants	165 Participants n=27 Participants
Race Caucasian/White	158 participants n=93 Participants	160 participants n=4 Participants	318 participants n=27 Participants
Race Black	2 participants n=93 Participants	1 participants n=4 Participants	3 participants n=27 Participants
Race Asian/Oriental	1 participants n=93 Participants	1 participants n=4 Participants	2 participants n=27 Participants
Ethnicity Hispanic	35 participants n=93 Participants	30 participants n=4 Participants	65 participants n=27 Participants
Ethnicity Non Hispanic	126 participants n=93 Participants	132 participants n=4 Participants	258 participants n=27 Participants
Screening HbA1c	8.12 percentage of haemoglobin STANDARD_DEVIATION 0.80 • n=93 Participants	8.08 percentage of haemoglobin STANDARD_DEVIATION 0.77 • n=4 Participants	8.10 percentage of haemoglobin STANDARD_DEVIATION 0.78 • n=27 Participants
Baseline BMI	32.24 kg/m^2 STANDARD_DEVIATION 4.75 • n=93 Participants	32.02 kg/m^2 STANDARD_DEVIATION 4.35 • n=4 Participants	32.13 kg/m^2 STANDARD_DEVIATION 4.55 • n=27 Participants
Duration of Diabetes	6.29 years STANDARD_DEVIATION 4.29 • n=93 Participants	7.10 years STANDARD_DEVIATION 5.27 • n=4 Participants	6.69 years STANDARD_DEVIATION 4.82 • n=27 Participants
Daily Dose of Metformin	2075.8 mg STANDARD_DEVIATION 440.7 • n=93 Participants	2093.7 mg STANDARD_DEVIATION 415.5 • n=4 Participants	2084.8 mg STANDARD_DEVIATION 427.7 • n=27 Participants
Fasting Plasma Glucose (FPG)	9.76 mmol/L STANDARD_DEVIATION 2.19 • n=93 Participants	9.46 mmol/L STANDARD_DEVIATION 2.16 • n=4 Participants	9.61 mmol/L STANDARD_DEVIATION 2.18 • n=27 Participants

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: Modified intent-to-treat (mITT) population consisted of all randomized participants received at least 1 dose of IMP and had both baseline and at least 1 post-baseline efficacy assessment. Number of participants analyzed = participants with both baseline and at least one post-baseline HbA1c assessment during on-treatment period.

Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP).

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=160 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=161 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in HbA1c From Baseline to Week 24	-1.82 percentage of hemoglobin Standard Error 0.058	-1.64 percentage of hemoglobin Standard Error 0.057

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population.Here, number of participants analyzed = participants with both baseline and at least one post-baseline 2-hour PPG assessment during on-treatment period.

The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=151 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=153 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24	-7.49 mmol/L Standard Error 0.283	-4.33 mmol/L Standard Error 0.274

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of participants analyzed = participants with both baseline and at least one post-baseline plasma glucose excursion assessment during on-treatment period.

2-hour plasma glucose excursion = 2-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=151 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=152 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24	-3.91 mmol/L Standard Error 0.277	-0.67 mmol/L Standard Error 0.269

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline 7-point SMPG assessment during on-treatment period.

Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, over a single day, once in a week before baseline, before visit Week 12 and before visit Week 24 and the average value across the profiles performed in the week before a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=149 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=155 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24	-3.23 mmol/L Standard Error 0.104	-2.93 mmol/L Standard Error 0.101

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during on-treatment period.

Change in body weight was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 3 days after the last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=159 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=160 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in Body Weight From Baseline to Week 24	-0.97 kg Standard Error 0.289	0.48 kg Standard Error 0.282

SECONDARY outcome

Timeframe: Week 24

Population: mITT population. Here, number of participants analyzed = participants with insulin glargine dose measured during on-treatment period

Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=161 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=162 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Average Daily Insulin Glargine Dose at Week 24	36.08 Units (U) Standard Error 1.415	39.32 Units (U) Standard Error 1.384

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline FPG assessment during on-treatment period.

Change in FPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 1 day after the last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=159 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=160 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in FPG From Baseline to Week 24	-3.35 mmol/L Standard Error 0.130	-3.51 mmol/L Standard Error 0.128

SECONDARY outcome

Timeframe: Baseline up to Week 24

Population: mITT population.

Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceed the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values from Week 8 to Week 12: fasting SMPG/FPG \>240 mg/dL (13.3 mmol/L), and from Week 12 to Week 30: fasting SMPG/FPG \>200 mg/dL (11.1 mmol/L) or HbA1c \>8%.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=161 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=162 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Percentage of Participants Requiring Rescue Therapy During 24-week Treatment Period	0 percentage of participants	0.6 percentage of participants

SECONDARY outcome

Timeframe: Week 24

Population: mITT population. Here, number of participants analyzed = participants with at least one post-baseline HbA1c assessment during on-treatment period.

On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=160 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=161 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 HbA1c <7.0%	84.4 percentage of participants	78.3 percentage of participants
Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 HbA1c ≤6.5%	71.9 percentage of participants	64.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline PPG assessment during on-treatment period. Here, 'n' signifies number of participants with available data for specified category.

The 30 minute and 1-hour PPG test measured blood glucose 30 minutes and 1-hour after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=151 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=153 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in 30-minute and 1-hour PPG From Baseline to Week 24 30-minute PPG (n=151, 153)	-5.01 mmol/L Standard Error 0.194	-3.76 mmol/L Standard Error 0.187
Change in 30-minute and 1-hour PPG From Baseline to Week 24 1-hour PPG (n=150, 153)	-5.94 mmol/L Standard Error 0.246	-4.10 mmol/L Standard Error 0.239

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline plasma glucose excursion assessment during on-treatment period.

30-minute and 1-hour plasma glucose excursion = 30-minute and 1-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=151 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=152 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 30-minute plasma glucose excursion (n=151, 152)	-1.47 mmol/L Standard Error 0.156	-0.05 mmol/L Standard Error 0.151
Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 1-hour plasma glucose excursion (n=150, 152)	-2.34 mmol/L Standard Error 0.233	-0.44 mmol/L Standard Error 0.226

SECONDARY outcome

Timeframe: Baseline up to Week 24

Population: mITT population. Here, number of participants analyzed = participants with at least one post-baseline HbA1c assessment during on-treatment period.

Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L). Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one documented symptomatic hypoglycemia before the introduction of rescue medication and up to 1 day after the last injection of IMP. Otherwise, they were counted as missing data. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=160 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=161 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period	67.5 percentage of participants	59.0 percentage of participants

SECONDARY outcome

Timeframe: Week 24

Population: mITT population. Here, number of participants analyzed = participants with any post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart or with one of the components (for HbA1c and body weight) showing non-response based on the last post-baseline on-treatment value.

Participants without any post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (for HbA1c and body weight) was available and showed non-response. Otherwise, they were counted as missing data.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=160 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=161 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24	56.3 percentage of participants	37.3 percentage of participants

SECONDARY outcome

Timeframe: First dose of study drug up to 3 days after the last dose administration (maximum of 219 days)

Population: Safety population that included all randomized participants who received at least 1 dose of study medication regardless of the amount of treatment administered.

Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L).Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes were associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. All episodes in which neurological impairment was severe enough to prevent self-treatment and which were thought to place participants at risk for injury to themselves or others.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=161 Participants FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted.	Insulin Glargine n=162 Participants Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted.
Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia Documented symptomatic hypoglycemia	21.7 percentage of participants	22.8 percentage of participants
Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia Severe Symptomatic Hypoglycemia	0.0 percentage of participants	0.0 percentage of participants

Adverse Events

Insulin Glargine/Lixisenatide Fixed Ratio Combination

Serious events: 9 serious events

Other events: 26 other events

Deaths: 0 deaths

Insulin Glargine

Serious events: 6 serious events

Other events: 21 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=161 participants at risk FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted (median exposure: 169 days).	Insulin Glargine n=162 participants at risk Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted (median exposure: 169 days).
Infections and infestations Nasopharyngitis	5.6% 9/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	5.6% 9/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Nervous system disorders Headache	5.0% 8/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	7.4% 12/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Gastrointestinal disorders Nausea	7.5% 12/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).

Additional Information

Trial Transparency Team

Sanofi

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

Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination n=161 participants at risk FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted (median exposure: 169 days).	Insulin Glargine n=162 participants at risk Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted (median exposure: 169 days).
Infections and infestations Cellulitis	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Infections and infestations Urinary tract infection	0.00% 0/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.62% 1/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Psychiatric disorders Depression	0.00% 0/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.62% 1/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Nervous system disorders Diabetic neuropathy	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Nervous system disorders Sciatica	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Nervous system disorders Presyncope	0.00% 0/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.62% 1/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Cardiac disorders Angina pectoris	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Cardiac disorders Angina unstable	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Cardiac disorders Bradycardia	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Cardiac disorders Atrial fibrillation	0.00% 0/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.62% 1/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Musculoskeletal and connective tissue disorders Pain in extremity	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.62% 1/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Renal and urinary disorders Calculus ureteric	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Investigations ECG signs of myocardial ischaemia	0.00% 0/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.62% 1/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).
Injury, poisoning and procedural complications Radius fracture	0.62% 1/161 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).	0.00% 0/162 • All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product. Reported adverse events are treatment-emergent AEs that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of open-label IMP up to 3 days after the last injection of IMP, regardless of the introduction of rescue therapy).