Trial Outcomes & Findings for A Study of LY2963016 Compared to LANTUS® in Adult Participants With Type 2 Diabetes Mellitus (NCT NCT02302716)

Last Updated: 2017-10-24

Results Overview

HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline of response, treatment (LY2963016, LANTUS), pooled country, basal insulin at entry (yes/no), sulfonylurea (SU) use (yes/no), visit, treatment and visit\*treatment in the model.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

493 participants

Primary outcome timeframe

Baseline, 24 weeks

Results posted on

2017-10-24

Participant Flow

Participant milestones

Participant milestones
Measure	LY2963016 Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Overall Study STARTED	249	244
Overall Study Received at Least 1 Dose of Study Drug	249	244
Overall Study COMPLETED	230	225
Overall Study NOT COMPLETED	19	19

Reasons for withdrawal

Reasons for withdrawal
Measure	LY2963016 Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Overall Study Adverse Event	1	1
Overall Study Death	0	1
Overall Study Lack of Efficacy	0	1
Overall Study Lost to Follow-up	2	4
Overall Study Physician Decision	3	4
Overall Study Withdrawal by Subject	13	7
Overall Study Protocol Violation	0	1

Baseline Characteristics

A Study of LY2963016 Compared to LANTUS® in Adult Participants With Type 2 Diabetes Mellitus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LY2963016 n=249 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=244 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	Total n=493 Participants Total of all reporting groups
Age, Continuous	57.82 years STANDARD_DEVIATION 8.83 • n=5 Participants	56.98 years STANDARD_DEVIATION 9.86 • n=7 Participants	57.40 years STANDARD_DEVIATION 9.35 • n=5 Participants
Sex: Female, Male Female	118 Participants n=5 Participants	118 Participants n=7 Participants	236 Participants n=5 Participants
Sex: Female, Male Male	131 Participants n=5 Participants	126 Participants n=7 Participants	257 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	116 Participants n=5 Participants	118 Participants n=7 Participants	234 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	15 Participants n=5 Participants	15 Participants n=7 Participants	30 Participants n=5 Participants
Race (NIH/OMB) White	115 Participants n=5 Participants	110 Participants n=7 Participants	225 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment South Korea	47 Participants n=5 Participants	45 Participants n=7 Participants	92 Participants n=5 Participants
Region of Enrollment Puerto Rico	29 Participants n=5 Participants	33 Participants n=7 Participants	62 Participants n=5 Participants
Region of Enrollment Turkey	15 Participants n=5 Participants	10 Participants n=7 Participants	25 Participants n=5 Participants
Region of Enrollment United States	60 Participants n=5 Participants	57 Participants n=7 Participants	117 Participants n=5 Participants
Region of Enrollment Taiwan	20 Participants n=5 Participants	22 Participants n=7 Participants	42 Participants n=5 Participants
Region of Enrollment India	49 Participants n=5 Participants	51 Participants n=7 Participants	100 Participants n=5 Participants
Region of Enrollment Russia	29 Participants n=5 Participants	26 Participants n=7 Participants	55 Participants n=5 Participants
Baseline Hemoglobin A1c (HbA1c)	8.66 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.09 • n=5 Participants	8.56 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.02 • n=7 Participants	8.61 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.06 • n=5 Participants
Sulfonylurea Group Yes, did use sulfonylurea	207 Participants n=5 Participants	207 Participants n=7 Participants	414 Participants n=5 Participants
Sulfonylurea Group No, did not use sulfonylurea	42 Participants n=5 Participants	37 Participants n=7 Participants	79 Participants n=5 Participants
Duration of Diabetes	11.59 years STANDARD_DEVIATION 6.34 • n=5 Participants	12.26 years STANDARD_DEVIATION 6.45 • n=7 Participants	11.92 years STANDARD_DEVIATION 6.40 • n=5 Participants
Time of basal insulin injection Daytime	99 Participants n=5 Participants	96 Participants n=7 Participants	195 Participants n=5 Participants
Time of basal insulin injection Evening/Bedtime	150 Participants n=5 Participants	148 Participants n=7 Participants	298 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 24 weeks

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

Outcome measures

Outcome measures
Measure	LY2963016 n=226 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=223 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Change From Baseline to 24 Weeks in Hemoglobin A1c (HbA1c)	-1.25 Percentage of glycosylated hemoglobin Standard Error 0.066	-1.22 Percentage of glycosylated hemoglobin Standard Error 0.067

SECONDARY outcome

Timeframe: Endpoint [up to 24 weeks]

Population: All randomized participants who received at least 1 dose of study drug with Baseline and at least 1 post-Baseline HbA1c measure; last observation carried forward (LOCF).

Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time.

Outcome measures

Outcome measures
Measure	LY2963016 n=240 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=240 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Percentage of Participants With HbA1c <7% and ≤6.5% HbA1c- at 24 week endpoint (LOCF) < 7.0%	35.0 Percentage of participants	38.3 Percentage of participants
Percentage of Participants With HbA1c <7% and ≤6.5% HbA1c- at 24 week endpoint (LOCF) <= 6.5%	20.8 Percentage of participants	18.8 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 24

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

Seven-point SMBG are completed at the following timepoints: Before Morning Meal, 2 Hours After Morning Meal, Before Mid-Day Meal, 2 Hours After Mid-Day Meal, Before Evening Meal, Bed Time and 03:00 AM hours. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit\*treatment in the model.

Outcome measures

Outcome measures
Measure	LY2963016 n=198 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=198 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 24 week- Before Morning Meal	-2.37 Millimoles per liter (mmol/L) Standard Error 0.083	-2.69 Millimoles per liter (mmol/L) Standard Error 0.083
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 24 week- 2 Hours After Morning Meal	-2.78 Millimoles per liter (mmol/L) Standard Error 0.161	-3.00 Millimoles per liter (mmol/L) Standard Error 0.160
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 24 week-Before Mid-Day Meal	-2.14 Millimoles per liter (mmol/L) Standard Error 0.135	-2.20 Millimoles per liter (mmol/L) Standard Error 0.132
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 24 weeks- 2 Hours After Mid-Day Meal	-2.26 Millimoles per liter (mmol/L) Standard Error 0.158	-2.42 Millimoles per liter (mmol/L) Standard Error 0.156
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 24 weeks-Before Evening Meal	-1.84 Millimoles per liter (mmol/L) Standard Error 0.156	-2.25 Millimoles per liter (mmol/L) Standard Error 0.154
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 24 weeks- Bed Time	-2.14 Millimoles per liter (mmol/L) Standard Error 0.157	-2.40 Millimoles per liter (mmol/L) Standard Error 0.156
Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values 24 weeks- 3:00 AM hrs	-2.09 Millimoles per liter (mmol/L) Standard Error 0.124	-2.09 Millimoles per liter (mmol/L) Standard Error 0.122

SECONDARY outcome

Timeframe: Week 24

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

Fasting blood glucose (FBG) is a test to determine how much glucose (sugar) is in a blood sample after an overnight fast. Intra-Participant FBG variability was calculated based on the standard deviation (SD) of the morning pre-meal BG value. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit\*treatment in the model.

Outcome measures

Outcome measures
Measure	LY2963016 n=184 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=183 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Intra-Participant Variability in Fasting Blood Glucose (FBG)	0.81 mmol/L Standard Error 0.049	0.79 mmol/L Standard Error 0.049

SECONDARY outcome

Timeframe: Week 24

Population: All randomized participants who received at least 1 dose of study drug with Baseline and at least 1 post-Baseline Basal Insulin Dose.

Units of Basal Insulin dose taken per day (U/day). Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit\*treatment in the model.

Outcome measures

Outcome measures
Measure	LY2963016 n=231 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=225 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Basal Insulin Dose Units Per Day	49.8 Units per day (U/day) Standard Error 2.16	49.7 Units per day (U/day) Standard Error 2.17

SECONDARY outcome

Timeframe: Week 24

Population: All randomized participants who received at least 1 dose of study drug with Baseline and at least 1 post-Baseline Basal Insulin Dose per Body Weight measure.

Basal Insulin dose in units (U) per body weight in kilograms (kg) per day. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit\*treatment in the model.

Outcome measures

Outcome measures
Measure	LY2963016 n=229 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=225 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Basal Insulin Dose Per Body Weight (U/kg/Day)	0.58 units per kilogram per day (U/kg/day) Standard Error 0.024	0.61 units per kilogram per day (U/kg/day) Standard Error 0.024

SECONDARY outcome

Timeframe: Baseline, 24 Weeks

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

Change from baseline in body weight. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit\*treatment in the model.

Outcome measures

Outcome measures
Measure	LY2963016 n=229 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=225 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Change From Baseline to 24 Weeks in Body Weight	2.3 Kilogram (kg) Standard Error 0.28	1.7 Kilogram (kg) Standard Error 0.29

SECONDARY outcome

Timeframe: Week 4 and Week 24

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

ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. Items divided into 5 domains of satisfaction: Inconvenience of Regimen \[(IR) 5 items: domain scores range (DSR) 5-35\], Lifestyle Flexibility \[(LF) 3 items: DSR 3-21\], Glycemic Control \[(GC) 3 items: DSR 3-21\], Hypoglycemic Control \[(HC) 5 items: DSR 5-35\], Insulin Delivery Device \[(IDD) 6 items: DSR 6-42\]. All items measured on a 7-point scale: 1 (no bother at all) to 7 (a tremendous bother), with lower scores reflecting better outcomes. ITSQ Total Overall Raw Scores range from 22-154. Both raw domain and overall scores are transformed on a scale of 0-100, where transformed score=100\*\[(7-mean raw score)/6\]. Higher scores indicate better treatment satisfaction. LS means was determined by MMRM with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit\*treatment in the model.

Outcome measures

Outcome measures
Measure	LY2963016 n=234 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=235 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score IR-Week 4	85.79 units on a scale Standard Error 1.32	84.92 units on a scale Standard Error 1.33
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score IR-Week 24	84.75 units on a scale Standard Error 1.26	84.91 units on a scale Standard Error 1.28
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score LF-Week 4	71.43 units on a scale Standard Error 1.87	69.11 units on a scale Standard Error 1.89
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score LF-Week 24	72.44 units on a scale Standard Error 1.77	70.87 units on a scale Standard Error 1.80
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score HC-Week 4	77.82 units on a scale Standard Error 1.50	76.98 units on a scale Standard Error 1.52
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score HC-Week 24	76.18 units on a scale Standard Error 1.46	76.52 units on a scale Standard Error 1.48
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score GC-Week 4	79.24 units on a scale Standard Error 1.45	78.87 units on a scale Standard Error 1.46
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score GC-Week 24	82.14 units on a scale Standard Error 1.36	81.30 units on a scale Standard Error 1.38
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score IDD-Week 4	82.21 units on a scale Standard Error 1.23	82.37 units on a scale Standard Error 1.25
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score IDD-Week 24	82.12 units on a scale Standard Error 1.29	82.01 units on a scale Standard Error 1.31
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score ITSQ Overall Total-Week 4	80.15 units on a scale Standard Error 1.12	79.40 units on a scale Standard Error 1.13
Insulin Treatment Satisfaction Questionnaire (ITSQ) Score ITSQ Overall Total-Week 24	80.01 units on a scale Standard Error 1.13	79.76 units on a scale Standard Error 1.14

SECONDARY outcome

Timeframe: Endpoint [up to 24 weeks]

Population: All randomized participants who received at least 1 dose of study drug and with a Baseline and at least 1 post-Baseline with detectable anti-drug antibodies; last observation carried forward (LOCF).

The percentage of participants with detected insulin antibodies were summarized as counts and percentages at baseline, at each visit, at the 24-week endpoint (LOCF), and overall for the 24-week treatment period.

Outcome measures

Outcome measures
Measure	LY2963016 n=234 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=239 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Percentage of Participants With Detectable Anti-Drug Antibodies to LY2963016 or LANTUS®	14.5 Percentage of participants	17.2 Percentage of participants

SECONDARY outcome

Timeframe: Baseline through Endpoint [up to 24 weeks]

Population: All randomized participants who received at 1 dose of study drug with Baseline at least 1 post-Baseline hypoglycemic event; last observation carried forward (LOCF).

The rate of hypoglycemic events were analyzed at baseline, titration, maintenance, and overall study periods and at endpoint using the Wilcoxon test. In addition, a negative binomial model was used as a sensitivity analysis. A hypoglycemic event is defined as any time a participant has a blood glucose (BG) level of ≤70 milligrams per deciliter (mg/dL) even if the event was not associated with signs, symptoms, or treatment consistent with current guidelines (American Diabetes Association 2005). Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between bedtime and waking. Severe hypoglycemia is defined as a hypoglycemic event requiring assistance of another person to actively administer carbohydrates, glucagons, or other resuscitative actions. Severe Hypoglycemic events may or may not have a reported BG ≤70 mg/dL. These events may be associated with sufficient neuroglycopenia to induce seizure or coma.

Outcome measures

Outcome measures
Measure	LY2963016 n=246 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=243 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Rate of Hypoglycemic Events Adjusted Per 1 Year Total Hypoglycemia with BG ≤70 mg/dL	16.95 Hypoglycemic events per 1 year Standard Deviation 23.444	23.37 Hypoglycemic events per 1 year Standard Deviation 35.809
Rate of Hypoglycemic Events Adjusted Per 1 Year Severe Hypoglycemia	0.00 Hypoglycemic events per 1 year Standard Deviation 0.00	0.00 Hypoglycemic events per 1 year Standard Deviation 0.02
Rate of Hypoglycemic Events Adjusted Per 1 Year Nocturnal Hypoglycemia with BG ≤70 mg/dL	6.64 Hypoglycemic events per 1 year Standard Deviation 11.650	7.94 Hypoglycemic events per 1 year Standard Deviation 17.882

SECONDARY outcome

Timeframe: Endpoint [up to 24 weeks]

Population: All randomized participants who had a post-baseline measurement for Hypoglycemic Events; last observation carried forward (LOCF).

The percentage of participants (with at least 1 hypoglycemic event (total, severe, nocturnal, and others) or incidence during the study was analyzed using Fisher's exact test. A hypoglycemic event is defined as any time a participant has a blood glucose (BG) level of ≤70 milligrams per deciliter (mg/dL) even if the event was not associated with signs, symptoms, or treatment consistent with current guidelines (American Diabetes Association 2005). Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between bedtime and waking. Severe hypoglycemia is defined as a hypoglycemic event requiring assistance of another person to actively administer carbohydrates, glucagons, or other resuscitative actions. Severe Hypoglycemic events may or may not have a reported BG ≤70 mg/dL. These events may be associated with sufficient neuroglycopenia to induce seizure or coma.

Outcome measures

Outcome measures
Measure	LY2963016 n=249 Participants Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=244 Participants Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Percentage of Participants With Hypoglycemic Events Total hypoglycemia with BG ≤70 mg/dL	68.7 Percentage of participants	69.1 Percentage of participants
Percentage of Participants With Hypoglycemic Events Severe hypoglycemia	0 Percentage of participants	0.8 Percentage of participants
Percentage of Participants With Hypoglycemic Events Nocturnal hypoglycemia with BG ≤70 mg/dL	49.6 Percentage of participants	46.1 Percentage of participants
Percentage of Participants With Hypoglycemic Events Non-nocturnal hypoglycemia with BG ≤70 mg/dL	59.4 Percentage of participants	63.0 Percentage of participants

Adverse Events

LY2963016

Serious events: 10 serious events

Other events: 75 other events

Deaths: 0 deaths

LANTUS®

Serious events: 12 serious events

Other events: 87 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	LY2963016 n=249 participants at risk Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=244 participants at risk Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Cardiac disorders Acute myocardial infarction	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Cardiac disorders Cardiogenic shock	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Cardiac disorders Myocardial infarction	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Cardiac disorders Supraventricular tachycardia	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Eye disorders Macular hole	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Bronchitis	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Cellulitis	0.40% 1/249 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Diverticulitis	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Gastroenteritis	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Pneumonia	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.82% 2/244 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Pyelonephritis	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Urinary tract infection	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Injury, poisoning and procedural complications Head injury	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Metabolism and nutrition disorders Hyperglycaemia	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Metabolism and nutrition disorders Hypoglycaemia	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.82% 2/244 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic myeloid leukaemia	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Nervous system disorders Encephalopathy	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Nervous system disorders Intracranial pressure increased	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Nervous system disorders Presyncope	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Nervous system disorders Syncope	0.00% 0/249 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Renal and urinary disorders Acute kidney injury	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Vascular disorders Hypertensive crisis	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.

Measure	LY2963016 n=249 participants at risk Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine Hagedorn (NPH) QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day (BID) were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).	LANTUS® n=244 participants at risk Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD were started at the same dose SC. Participants entering on insulin detemir or NPH twice a day were started at 80% of the total daily dose SC. Participants-driven titration was followed to include the addition of 1 U/day until the fasting blood glucose (FBG) level reaches ≤100 mg/dL (5.6 mmol/L). Participants were allowed to continue oral antihyperglycemic medication (OAM).
Cardiac disorders Palpitations	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.00% 0/244 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Gastrointestinal disorders Constipation	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.2% 3/244 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Gastrointestinal disorders Diarrhoea	0.80% 2/249 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.2% 3/244 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Gastrointestinal disorders Dyspepsia	1.2% 3/249 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Gastrointestinal disorders Gastritis	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.2% 3/244 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Gastrointestinal disorders Gastrooesophageal reflux disease	1.6% 4/249 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Gastrointestinal disorders Vomiting	0.80% 2/249 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.6% 4/244 • Number of events 5 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
General disorders Fatigue	0.80% 2/249 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.2% 3/244 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
General disorders Injection site pain	0.80% 2/249 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	2.9% 7/244 • Number of events 11 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
General disorders Pyrexia	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.6% 4/244 • Number of events 5 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Bronchitis	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.2% 3/244 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Nasopharyngitis	7.2% 18/249 • Number of events 23 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	9.8% 24/244 • Number of events 26 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Upper respiratory tract infection	4.0% 10/249 • Number of events 10 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	3.7% 9/244 • Number of events 10 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Urinary tract infection	1.6% 4/249 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.2% 3/244 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Infections and infestations Viral infection	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.82% 2/244 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Injury, poisoning and procedural complications Laceration	1.2% 3/249 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Investigations Weight increased	3.2% 8/249 • Number of events 9 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.6% 4/244 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Metabolism and nutrition disorders Abnormal weight gain	2.8% 7/249 • Number of events 9 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	2.0% 5/244 • Number of events 7 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Metabolism and nutrition disorders Vitamin d deficiency	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.6% 4/244 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Musculoskeletal and connective tissue disorders Arthralgia	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	2.9% 7/244 • Number of events 7 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	2.0% 5/244 • Number of events 5 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Musculoskeletal and connective tissue disorders Osteoarthritis	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Nervous system disorders Dizziness	1.2% 3/249 • Number of events 3 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	0.41% 1/244 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Nervous system disorders Headache	1.6% 4/249 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	2.0% 5/244 • Number of events 8 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Respiratory, thoracic and mediastinal disorders Cough	0.80% 2/249 • Number of events 2 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.6% 4/244 • Number of events 5 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.40% 1/249 • Number of events 1 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	2.0% 5/244 • Number of events 6 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.
Vascular disorders Hypertension	1.2% 3/249 • Number of events 4 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.	1.6% 4/244 • Number of events 5 • Up to 28 weeks All the randomized participants who received at least one dose of the study drug.