Trial Outcomes & Findings for Efficacy and Safety of Lixisenatide Versus Placebo on Top of Basal Insulin and/or Oral Antidiabetic Treatment in Older Type 2 Diabetic Patients (NCT NCT01798706)

Last Updated: 2017-04-18

Results Overview

Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last on-treatment observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Here, number of participants analyzed=participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

350 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2017-04-18

Participant Flow

The study was conducted at 83 centers in 13 countries. A total of 786 participants were screened between June 10, 2013 and July 09, 2014.

A total of 426 participants underwent 4 week placebo run-in period. 436 participants were screen failures and 76 were run-in failures; the most frequent reason for screen and run-in failure was glycosylated hemoglobin (HbA1c) criteria not met at end of the run-in phase. A total of 350 participants were randomized.

Participant milestones

Participant milestones
Measure	Lixisenatide Lixisenatide 10 mcg subcutaneously once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Overall Study STARTED	176	174
Overall Study COMPLETED	155	153
Overall Study NOT COMPLETED	21	21

Reasons for withdrawal

Reasons for withdrawal
Measure	Lixisenatide Lixisenatide 10 mcg subcutaneously once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Overall Study Adverse Event	15	10
Overall Study Lack of Efficacy	0	2
Overall Study Poor compliance to protocol	1	0
Overall Study Other than specified above	5	9

Baseline Characteristics

Efficacy and Safety of Lixisenatide Versus Placebo on Top of Basal Insulin and/or Oral Antidiabetic Treatment in Older Type 2 Diabetic Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lixisenatide n=176 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=174 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.	Total n=350 Participants Total of all reporting groups
Age, Continuous	74 years STANDARD_DEVIATION 4 • n=5 Participants	74.4 years STANDARD_DEVIATION 3.8 • n=7 Participants	74.2 years STANDARD_DEVIATION 3.9 • n=5 Participants
Sex: Female, Male Female	84 Participants n=5 Participants	84 Participants n=7 Participants	168 Participants n=5 Participants
Sex: Female, Male Male	92 Participants n=5 Participants	90 Participants n=7 Participants	182 Participants n=5 Participants
Race Caucasian/white	128 participants n=5 Participants	122 participants n=7 Participants	250 participants n=5 Participants
Race Black	3 participants n=5 Participants	0 participants n=7 Participants	3 participants n=5 Participants
Race Asian/Oriental	5 participants n=5 Participants	11 participants n=7 Participants	16 participants n=5 Participants
Race Other	40 participants n=5 Participants	41 participants n=7 Participants	81 participants n=5 Participants
Ethnicity Hispanic	51 participants n=5 Participants	48 participants n=7 Participants	99 participants n=5 Participants
Ethnicity Not Hispanic	125 participants n=5 Participants	126 participants n=7 Participants	251 participants n=5 Participants
Number of Participants with Categorical BMI <30 kg/m^2	102 participants n=5 Participants	96 participants n=7 Participants	198 participants n=5 Participants
Number of Participants with Categorical BMI ≥30 kg/m^2	74 participants n=5 Participants	78 participants n=7 Participants	152 participants n=5 Participants
Body Mass Index (BMI)	29.91 kg/m^2 STANDARD_DEVIATION 3.7 • n=5 Participants	30.09 kg/m^2 STANDARD_DEVIATION 4.53 • n=7 Participants	30.00 kg/m^2 STANDARD_DEVIATION 4.13 • n=5 Participants
Body Weight	80.81 kg STANDARD_DEVIATION 14.54 • n=5 Participants	80.08 kg STANDARD_DEVIATION 16.76 • n=7 Participants	80.45 kg STANDARD_DEVIATION 15.66 • n=5 Participants
HbA1c	8.04 Percentage of HbA1c STANDARD_DEVIATION 0.72 • n=5 Participants	8.05 Percentage of HbA1c STANDARD_DEVIATION 0.69 • n=7 Participants	8.04 Percentage of HbA1c STANDARD_DEVIATION 0.71 • n=5 Participants
Fasting Plasma Glucose (FPG)	8.83 mmol/L STANDARD_DEVIATION 2.38 • n=5 Participants	8.89 mmol/L STANDARD_DEVIATION 2.26 • n=7 Participants	8.86 mmol/L STANDARD_DEVIATION 2.32 • n=5 Participants
2-Hour Postprandial Plasma Glucose (PPG)	15.18 mmol/L STANDARD_DEVIATION 3.78 • n=5 Participants	14.87 mmol/L STANDARD_DEVIATION 3.69 • n=7 Participants	15.03 mmol/L STANDARD_DEVIATION 3.74 • n=5 Participants
Glucose Excursion	6.51 mmol/L STANDARD_DEVIATION 3.15 • n=5 Participants	6.02 mmol/L STANDARD_DEVIATION 3.17 • n=7 Participants	6.26 mmol/L STANDARD_DEVIATION 3.16 • n=5 Participants
7-Point Self-monitored Plasma Glucose (SMPG)	9.79 mmol/L STANDARD_DEVIATION 2.02 • n=5 Participants	9.97 mmol/L STANDARD_DEVIATION 1.98 • n=7 Participants	9.87 mmol/L STANDARD_DEVIATION 2.00 • n=5 Participants
Duration of Diabetes	13.63 years STANDARD_DEVIATION 7.34 • n=5 Participants	14.63 years STANDARD_DEVIATION 7.87 • n=7 Participants	14.13 years STANDARD_DEVIATION 7.62 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: Modified intent to treat (mITT) population: all randomized participants who received at least one dose of study drug; and had both baseline and at least one post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures.

Outcome measures

Outcome measures
Measure	Lixisenatide n=172 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=172 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Absolute Change in HbA1c From Baseline to Week 24	-0.57 percentage of hemoglobin Standard Error 0.075	0.06 percentage of hemoglobin Standard Error 0.072

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: mITT population. Here, number of participants analyzed=participants with 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 liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=147 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=144 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Change in 2-Hour PPG From Baseline to Week 24	-5.12 mmol/L Standard Error 0.392	-0.07 mmol/L Standard Error 0.393

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 three times in a week before baseline, before visit Week 12 and before visit week 26 and the average value across the profiles performed in the week 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. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=138 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=125 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Change in Average 7-point SMPG Profiles From Baseline to Week 24	-1.15 mmol/L Standard Error 0.186	-0.19 mmol/L Standard Error 0.189

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 up to 3 days after the last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=174 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=173 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Change in Body Weight From Baseline to Week 24	-1.47 kg Standard Error 0.241	-0.16 kg Standard Error 0.228

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. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=171 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=168 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Change in FPG From Baseline to Week 24	-0.3 mmol/L Standard Error 0.224	0.01 mmol/L Standard Error 0.218

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 exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG \>270 mg/dL (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG \>240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG \>200 mg/dL (11.1 mmol/L) or HbA1c \>9%.

Outcome measures

Outcome measures
Measure	Lixisenatide n=175 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=173 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Percentage of Participants Requiring Rescue Therapy During 24 Week Treatment Period	2.9 percentage of participants	10.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 24

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

Plasma glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the liquid standardized breakfast meal test, before study drug administration. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=145 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=143 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Change in Plasma Glucose Excursions From Baseline to Week 24	-4.71 mmol/L Standard Error 0.331	-0.25 mmol/L Standard Error 0.331

SECONDARY outcome

Timeframe: Baseline, Week 24

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

Change in basal insulin dose was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=54 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=55 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Change in Total Daily Basal Insulin Dose From Baseline to Week 24 (in Participants Who Took Basal Insulin as Background Therapy)	-2.97 units Standard Error 1.145	-1.3 units Standard Error 1.076

SECONDARY outcome

Timeframe: First dose of study drug up to 3 days after the last dose administration (maximum of 171 days)

Population: Analysis was performed on safety population defined as all randomized participants who received any amount of study drug.

Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the participant required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available.

Outcome measures

Outcome measures
Measure	Lixisenatide n=176 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=174 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Percentage of Participants With Symptomatic and Severe Symptomatic Hypoglycemia Severe symptomatic hypoglycemia	0.57 percentage of participants	0 percentage of participants
Percentage of Participants With Symptomatic and Severe Symptomatic Hypoglycemia Symptomatic hypoglycemia	7.4 percentage of participants	5.7 percentage of participants

SECONDARY outcome

Timeframe: Week 24

Population: mITT population. Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one symptomatic hypoglycemia. Otherwise, they were counted as missing.

The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=172 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=172 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Percentage of Participants With HbA1c Reduction >0.5% at Week 24 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia	57.6 percentage of participants	21.5 percentage of participants

SECONDARY outcome

Timeframe: Up to Day 171

Population: Analysis was performed on safety population.

Outcome measures

Outcome measures
Measure	Lixisenatide n=176 Participants Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.	Placebo n=174 Participants Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks.
Percentage of Participants With Gastrointestinal Disorders	40.3 percentage of participants	20.7 percentage of participants

Adverse Events

Lixisenatide

Serious events: 8 serious events

Other events: 89 other events

Deaths: 0 deaths

Placebo

Serious events: 10 serious events

Other events: 58 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Lixisenatide n=176 participants at risk Lixisenatide 10 mcg subcutaneously QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.(Median exposure: 169 days)	Placebo n=174 participants at risk Placebo (matched to lixisenatide) subcutaneously QD for 24 Weeks. (Median exposure: 169 days)
Gastrointestinal disorders Diarrhoea	10.8% 19/176 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).	7.5% 13/174 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).
Gastrointestinal disorders Nausea	25.0% 44/176 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).	7.5% 13/174 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).
Gastrointestinal disorders Vomiting	5.7% 10/176 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).	0.57% 1/174 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).
Infections and infestations Nasopharyngitis	8.5% 15/176 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).	12.6% 22/174 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).
Metabolism and nutrition disorders Hypoglycaemia	17.0% 30/176 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).	10.3% 18/174 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).
Nervous system disorders Headache	5.7% 10/176 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).	4.6% 8/174 • All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Day 171) regardless of seriousness or relationship to investigational medicinal product (IMP). Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug).

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