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A Study of LY2605541 in Participants With Type 1 Diabetes Mellitus (IMAGINE 7)

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ClinicalTrials.gov Identifier: NCT01792284
Recruitment Status : Completed
First Posted : February 15, 2013
Results First Posted : April 20, 2018
Last Update Posted : April 20, 2018
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Type 1 Diabetes Mellitus
Interventions Drug: LY2605541
Drug: Insulin Lispro
Enrollment 212
Recruitment Details  
Pre-assignment Details Participants completed a 12 week (wk) Lead-in Period during which insulin peglispro was administered at fixed time in the evening. Participants were then randomized to a fixed evening dose regimen or a variable time dose regimen for 12 wks (Randomization Period 1); after 12 wks, they crossed over to the alternate regimen (Randomization Period 2).
Arm/Group Title LY2605541 Fixed Time Dosing (All Participants) LY2605541 Fixed Time Dosing, LY2605541 Variable Time Dosing LY2605541 Variable Time Dosing, LY2605541 Fixed Time Dosing
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Lead-in Period: Participant-specific dose of LY2605541 administered subcutaneously (SQ) at approximately the same time every evening for 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Insulin dose and adjustments to insulin dose were determined by insulin algorithms based on self-monitored blood glucose (SMBG).

Target glucose values were as follows:

Preprandial and bedtime BG between 71 and 130 milligrams/deciliter (mg/dL) Insulin adjustment and glucose correction between 71 and 100 mg/dL.

Randomization Period 1: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Randomization Period 2: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Participants were dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday. Dosing schedules were to remain approximately the same throughout the 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Insulin dose and adjustments to insulin dose were determined by insulin algorithms based on SMBG. Target glucose values were as follows:

Preprandial and bedtime BG between 71 and 130 mg/dL Insulin adjustment and glucose correction between 71 and 100 mg/dL.

Randomization Period 1: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Participants were dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday. Dosing schedules were to remain approximately the same throughout the 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Randomization Period 2: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Insulin dose and adjustments to insulin dose were determined by insulin algorithms based on SMBG. Target glucose values were as follows:

Preprandial and bedtime BG between 71 and 130 mg/dL Insulin adjustment and glucose correction between 71 and 100 mg/dL.

Period Title: Lead-in Period
Started 212 0 0
Completed 182 [1] 0 0
Not Completed 30 0 0
Reason Not Completed
Adverse Event             15             0             0
Lost to Follow-up             2             0             0
Protocol Violation             1             0             0
Withdrawal by Subject             10             0             0
Physician Decision             1             0             0
Protocol Required Discontinuation             1             0             0
[1]
Participants that completed the Lead-in Period were randomized and entered Randomization Period 1.
Period Title: Randomization Period 1
Started 0 92 90
Received at Least 1 Dose of Study Drug 0 92 90
Completed 0 90 85
Not Completed 0 2 5
Reason Not Completed
Withdrawal by Subject             0             1             1
Physician Decision             0             1             1
Adverse Event             0             0             2
Lost to Follow-up             0             0             1
Period Title: Randomization Period 2
Started 0 90 85
Received at Least 1 Dose of Study Drug 0 90 85
Completed 0 87 85
Not Completed 0 3 0
Reason Not Completed
Protocol Violation             0             1             0
Withdrawal by Subject             0             2             0
Arm/Group Title All Enrolled Participants
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Participants entered a 12-week Lead-in Period where they received fixed time of dose of LY2605541 with bolus insulin lispro. Participants were then randomized to either a fixed time of dose or a variable time of dose regimen for 12 weeks administered with bolus insulin lispro; after 12 weeks, they crossed over to the alternate regimen. LY2605541 dose was adjusted using a dosing algorithm based on the participant’s BG values and documented hypoglycemia during the previous week. Insulin dose were determined by insulin algorithms based on SMBG.

Fixed time of dose: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks administered with bolus insulin lispro.

Variable time of dose: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks administered with bolus insulin lispro.

Overall Number of Baseline Participants 212
Hide Baseline Analysis Population Description
All enrolled participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 212 participants
43.08  (13.59)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 212 participants
Female 98
Male 114
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 212 participants
Hispanic or Latino 26
Not Hispanic or Latino 186
Unknown or Not Reported 0
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 212 participants
American Indian or Alaska Native 1
Asian 3
Native Hawaiian or Other Pacific Islander 0
Black or African American 4
White 203
More than one race 1
Unknown or Not Reported 0
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 212 participants
United States 199
Puerto Rico 13
1.Primary Outcome
Title Hemoglobin A1c (HbA1c) at 12 Weeks
Hide Description HbA1c is a test that measures a person's average blood glucose level over the past 2 to 3 months. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis including the following fixed effects: treatment, period, sequence, baseline HbA1c (last nonmissing value at or before randomization), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Week in Each Randomization Period
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Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HbA1c data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 180
Least Squares Mean (Standard Error)
Unit of Measure: percentage of HbA1c
6.87  (0.04) 6.93  (0.04)
2.Secondary Outcome
Title 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events
Hide Description Total hypoglycemic events (HE) include any event based on a blood glucose <=70 milligrams per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]), with or without signs/symptoms of hypoglycemia or an event associated with signs/symptoms of hypoglycemia but without a glucose measurement. Nocturnal HE include any total HE that occurred between bedtime and waking. Group Means are presented and were calculated from negative binomial regression models (number of episodes = treatment + period + treatment sequence + baseline HbA1c [<=8.0% or >8.0%], with log [exposure in days/30] as an offset variable). Group Mean (LS mean) is estimated by taking the inverse link function on individual participant covariates first and then averages over all participants.
Time Frame Baseline (Day 1) of Randomization Period through 24 Weeks (12 weeks in each Randomization Period)
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Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HE data during Randomization Periods.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 180
Least Squares Mean (Standard Error)
Unit of Measure: events/participant/30 days
Total HE 10.54  (0.67) 10.37  (0.62)
Nocturnal HE 1.52  (0.13) 1.34  (0.11)
3.Secondary Outcome
Title Percentage of Participants With Total and Nocturnal Hypoglycemic Events
Hide Description Total HE include any event based on a blood glucose <=70 mg/dL (3.9 mmol/L), with or without signs/symptoms of hypoglycemia or an event associated with signs/symptoms of hypoglycemia but without a glucose measurement. Nocturnal HE include any total HE that occurred between bedtime and waking. The percentage of participants was calculated by dividing the number of participants with hypoglycemic episodes by the total number of participants analyzed, multiplied by 100.
Time Frame Baseline (Day 1) of Randomization Period through 24 weeks (12 weeks in each Randomization Period)
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Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HE data during Randomization Periods
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 180
Measure Type: Number
Unit of Measure: percentage of participants
Total HE 98.2 97.8
Nocturnal HE 78.4 80.6
4.Secondary Outcome
Title Fasting Blood Glucose (FBG) Measured by Self-Monitored Blood Glucose
Hide Description FBG was measured by self-monitored blood glucose (SMBG). LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline FBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Weeks in Each Randomization Period
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Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable FBG data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 179
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
131.35  (2.86) 139.65  (2.87)
5.Secondary Outcome
Title Intra-Participant Variability of FBG at 12 Weeks
Hide Description FBG was measured by SMBG. Between-day glucose variability is measured by the standard deviation of FBG. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline intra-participant variability in FBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Weeks in Each Randomization Period
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable FBG data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 179
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
37.97  (1.73) 39.80  (1.73)
6.Secondary Outcome
Title Fasting Serum Glucose (FSG) at 12 Weeks
Hide Description LS means for FSG (obtained from clinical laboratory tests) were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline FSG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Weeks in Each Randomization Period
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Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable FSG data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 177
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
121.51  (4.27) 120.45  (4.25)
7.Secondary Outcome
Title Change From Randomization to 12 Weeks in 9-Point SMBG
Hide Description SMBG measurements were taken at 9 time points: pre-morning meal, 2 hours post-morning meal, pre-midday meal, 2 hours post-midday meal, pre-evening meal, 2 hours post-evening meal, bedtime, at approximately 0300 hours, and the subsequent morning prior to the morning meal. SMBG measures were assessed at Weeks 0, 4, 8, and 12 within each Randomization Period. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline SMBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame Randomization, 12 Weeks in Each Randomization Period
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Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 164 169
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
Pre-morning meal Number Analyzed 163 participants 168 participants
-7.77  (3.79) 0.07  (3.80)
2 hours post-morning meal Number Analyzed 163 participants 167 participants
-1.24  (4.03) 8.13  (4.04)
Pre-midday meal Number Analyzed 164 participants 168 participants
0.27  (3.55) 14.87  (3.57)
2 hours post-midday meal Number Analyzed 164 participants 167 participants
10.91  (3.93) 5.40  (3.95)
Pre-evening meal Number Analyzed 164 participants 169 participants
1.98  (3.81) -1.34  (3.84)
2 hours post-evening meal Number Analyzed 163 participants 167 participants
5.49  (4.06) 8.33  (4.03)
Bedtime Number Analyzed 163 participants 167 participants
8.40  (4.15) 5.36  (4.17)
0300 hours Number Analyzed 161 participants 164 participants
-7.05  (3.55) 4.71  (3.62)
Subsequent morning pre-meal Number Analyzed 162 participants 167 participants
-7.84  (3.20) -2.44  (3.22)
8.Secondary Outcome
Title Self-Monitored Blood Glucose (SMBG) at 12 Weeks
Hide Description SMBG measurements were taken at 9 time points: pre-morning meal, 2 hours post-morning meal, pre-midday meal, 2 hours post-midday meal, pre-evening meal, 2 hours post-evening meal, bedtime, at approximately 0300 hours, and the subsequent morning prior to the morning meal. SMBG measures were assessed at Weeks 0, 4, 8, and 12 within each Randomization Period. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline SMBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Week in Each Randomization Period
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Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 164 169
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
Pre-morning meal Number Analyzed 163 participants 168 participants
133.21  (3.79) 141.05  (3.80)
2 hours post-morning meal Number Analyzed 163 participants 167 participants
151.03  (4.03) 160.41  (4.04)
Pre-midday meal Number Analyzed 164 participants 168 participants
122.96  (3.55) 137.55  (3.57)
2 hours post-midday meal Number Analyzed 164 participants 167 participants
147.05  (3.93) 141.54  (3.95)
Pre-evening meal Number Analyzed 164 participants 169 participants
137.75  (3.81) 134.43  (3.84)
2 hours post-evening meal Number Analyzed 163 participants 167 participants
150.37  (4.06) 153.21  (4.03)
Bedtime Number Analyzed 163 participants 167 participants
153.81  (4.15) 150.77  (4.17)
0300 hours Number Analyzed 161 participants 164 participants
131.40  (3.55) 143.16  (3.62)
Subsequent morning pre-meal Number Analyzed 162 participants 167 participants
125.16  (3.20) 130.57  (3.22)
9.Secondary Outcome
Title Intra-participant Variability in SMBG at 12 Weeks
Hide Description A summary of glucose variability (intra-participant variability) as measured by the average of between-day standard deviations of individual SMBG time points. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline intra-participant variability in SMBG (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Week in Each Randomization Period
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG variability data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 154 153
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
34.82  (1.30) 36.21  (1.28)
10.Secondary Outcome
Title Change From Randomization to 12 Weeks in Body Weight
Hide Description LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline body weight (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame Randomization, 12 Weeks in Each Randomization Period
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Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable body weight data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 170 177
Least Squares Mean (Standard Error)
Unit of Measure: kilograms (kg)
-0.06  (0.19) 0.00  (0.19)
11.Secondary Outcome
Title Change From Day 1 of Lead-In Period to 36 Weeks in Body Weight
Hide Description LS means were calculated using MMRM analysis, including visit and baseline weight (last non-missing value at or before the beginning of Lead-in Period) as covariates.
Time Frame Day 1 of Lead-In Period, 36 Weeks
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All enrolled participants who completed the first visit of the Lead-in Period, received at least 1 dose of study drug, and had evaluable body weight data.
Arm/Group Title All Participants
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All enrolled participants entered a 12-week lead-in period where they received fixed time dosing of LY2605541. Participants were then randomized to a fixed evening dose regimen or a variable time dose regimen for 12 weeks; after 12 weeks, they crossed over to the alternate regimen.

Fixed-time dose regimen: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.

Variable-time dose regimen: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.

Overall Number of Participants Analyzed 210
Least Squares Mean (Standard Error)
Unit of Measure: kg
-1.16  (0.29)
12.Secondary Outcome
Title Change From Randomization to 12 Weeks in HbA1c
Hide Description LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline HbA1c (last nonmissing value at or before randomization), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame Randomization, 12 Weeks in Each Randomization Period
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HbA1c data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 180
Least Squares Mean (Standard Error)
Unit of Measure: percentage of HbA1c
0.10  (0.04) 0.18  (0.04)
13.Secondary Outcome
Title Participants With Treatment-Emergent Anti-LY2605541 Antibody Response
Hide Description The number of participants with a treatment emergent anti-LY2605541 antibody response (TEAR) is presented. Positive TEAR was defined as change from baseline to post-baseline in the anti-LY2605541 antibody level either from 1) undetectable to detectable or from 2) detectable to the value with at least 130% relative increase from baseline.
Time Frame Day 1 of Lead-in Period through 36 Weeks
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Hide Analysis Population Description
Participants who completed the first visit of the Lead-in Period, received at least 1 dose of study drug, and had evaluable anti-LY2605541 antibody data.
Arm/Group Title All Participants
Hide Arm/Group Description:

All enrolled participants entered a 12-week lead-in period where they received fixed time dosing of LY2605541. Participants were then randomized to a fixed evening dose regimen or a variable time dose regimen for 12 weeks; after 12 weeks, they crossed over to the alternate regimen.

Fixed-time dose regimen: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.

Variable-time dose regimen: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.

Overall Number of Participants Analyzed 210
Measure Type: Number
Unit of Measure: participants
80
14.Secondary Outcome
Title Basal, Bolus, and Total Insulin Doses at 12 Weeks
Hide Description LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline insulin dose (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Weeks in Each Randomization Period
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable insulin dose data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 180
Least Squares Mean (Standard Error)
Unit of Measure: units/kg/day
Basal 0.50  (0.01) 0.51  (0.01)
Bolus 0.20  (0.01) 0.20  (0.01)
Total Insulin 0.71  (0.01) 0.71  (0.01)
15.Secondary Outcome
Title Proportion of Bolus to Total Insulin Doses at 12 Weeks
Hide Description Proportion of bolus to total insulin dose is presented, where LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline proportion of bolus to total insulin dose (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Weeks in Each Randomization Period
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable bolus to total insulin dose data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 171 178
Least Squares Mean (Standard Error)
Unit of Measure: units/day
0.29  (0.01) 0.28  (0.01)
16.Secondary Outcome
Title 0300-Hour Blood Glucose to Fasting Blood Glucose Excursion
Hide Description Excursion results were calculated by subtracting the 0300 hours glucose value from the next day pre-morning glucose value within a single SMBG profile. LS means were calculated using MMRM analysis including the following fixed effects: treatment, period, sequence, baseline 0300-hour to next day pre-breakfast excursion (last nonmissing value at or before randomization), baseline HbA1c (<=8.0% or >8.0%), week (defined from the start of each Randomization Period), and treatment-by-week interaction.
Time Frame At 12 Week in Each Randomization Period
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG excursion data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 158 162
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
-6.41  (3.64) -15.24  (3.70)
17.Secondary Outcome
Title Change From Day 1 of Lead-in to 36 Weeks in Triglycerides, Total Cholesterol, Low-Density Lipoprotein Cholesterol (LDL-C), and High-Density Lipoprotein Cholesterol (HDL-C)
Hide Description LS means were calculated using MMRM analysis including visit and baseline lipid level (last nonmissing value at or before the beginning of Lead-in) as covariates.
Time Frame Day 1 of Lead-In Period, 36 Weeks
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Hide Analysis Population Description
All enrolled participants who completed the first visit of the Lead-in Period, received at least 1 dose of study drug, and had evaluable lipid data.
Arm/Group Title All Participants
Hide Arm/Group Description:

All enrolled participants entered a 12-week lead-in period where they received fixed time dosing of LY2605541. Participants were then randomized to a fixed evening dose regimen or a variable time dose regimen for 12 weeks; after 12 weeks, they crossed over to the alternate regimen.

Fixed-time dose regimen: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.

Variable-time dose regimen: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.

Overall Number of Participants Analyzed 202
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
Triglycerides Number Analyzed 186 participants
26.44  (3.83)
Total Cholesterol Number Analyzed 186 participants
3.75  (1.91)
LDL-C Number Analyzed 181 participants
4.45  (1.63)
HDL-C Number Analyzed 186 participants
-5.70  (0.82)
18.Secondary Outcome
Title Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks
Hide Description The percentage of participants was calculated by dividing the number of participants reaching target HbA1c by the total number of participants analyzed, multiplied by 100.
Time Frame At 12 Weeks in Each Randomization Period
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Hide Analysis Population Description
Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HbA1c data.
Arm/Group Title LY2605541 Fixed Time Dosing LY2605541 Variable Time Dosing
Hide Arm/Group Description:
Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks.
Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Dosing schedules were to remain approximately the same throughout the 12 weeks.
Overall Number of Participants Analyzed 167 167
Measure Type: Number
Unit of Measure: percentage of participants
HbA1c <7.0% 60.5 54.5
HbA1c <=6.5% 34.1 34.1
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title LY2605541 (All Participants) LY2605541 Fixed Time Dosing, LY2605541 Variable Time Dosing LY2605541 Variable Time Dosing, LY2605541 Fixed Time Dosing
Hide Arm/Group Description All participants who received at least 1 dose of LY2605541 during the Lead-In Period, Randomization Period 1, and Randomization Period 2.

Randomization Period 1: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Randomization Period 2: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Participants were dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday. Dosing schedules were to remain approximately the same throughout the 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Insulin dose and adjustments to insulin dose were determined by insulin algorithms based on SMBG. Target glucose values were as follows:

Preprandial and bedtime BG between 71 and 130 mg/dL Insulin adjustment and glucose correction between 71 and 100 mg/dL.

Randomization Period 1: Participant-specific dose of LY2605541 administered SQ on a variable schedule (8- and 40-hour dosing intervals) for 12 weeks. Participants were dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday. Dosing schedules were to remain approximately the same throughout the 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Randomization Period 2: Participant-specific dose of LY2605541 administered SQ at approximately the same time every evening for 12 weeks. Participant-specific dose of insulin lispro SQ when >20% of calories were consumed (pre-meal).

Insulin dose and adjustments to insulin dose were determined by insulin algorithms based on SMBG. Target glucose values were as follows:

Preprandial and bedtime BG between 71 and 130 mg/dL Insulin adjustment and glucose correction between 71 and 100 mg/dL.

All-Cause Mortality
LY2605541 (All Participants) LY2605541 Fixed Time Dosing, LY2605541 Variable Time Dosing LY2605541 Variable Time Dosing, LY2605541 Fixed Time Dosing
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
LY2605541 (All Participants) LY2605541 Fixed Time Dosing, LY2605541 Variable Time Dosing LY2605541 Variable Time Dosing, LY2605541 Fixed Time Dosing
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   30/212 (14.15%)      11/177 (6.21%)      7/180 (3.89%)    
Cardiac disorders       
Atrial fibrillation  1  1/212 (0.47%)  1 0/177 (0.00%)  0 0/180 (0.00%)  0
Coronary artery disease  1  1/212 (0.47%)  2 0/177 (0.00%)  0 1/180 (0.56%)  1
Gastrointestinal disorders       
Impaired gastric emptying  1  1/212 (0.47%)  2 0/177 (0.00%)  0 0/180 (0.00%)  0
Infections and infestations       
Cellulitis  1  1/212 (0.47%)  1 0/177 (0.00%)  0 0/180 (0.00%)  0
Osteomyelitis  1  1/212 (0.47%)  1 1/177 (0.56%)  1 0/180 (0.00%)  0
Injury, poisoning and procedural complications       
Road traffic accident  1  3/212 (1.42%)  4 0/177 (0.00%)  0 1/180 (0.56%)  1
Investigations       
Hepatic enzyme increased  1  1/212 (0.47%)  3 0/177 (0.00%)  0 1/180 (0.56%)  1
Metabolism and nutrition disorders       
Diabetic ketoacidosis  1  2/212 (0.94%)  2 0/177 (0.00%)  0 0/180 (0.00%)  0
Hypoglycaemia  1  24/212 (11.32%)  34 9/177 (5.08%)  9 6/180 (3.33%)  8
Nervous system disorders       
Convulsion  1  1/212 (0.47%)  1 0/177 (0.00%)  0 1/180 (0.56%)  1
Hypoglycaemic seizure  1  2/212 (0.94%)  2 1/177 (0.56%)  1 0/180 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
LY2605541 (All Participants) LY2605541 Fixed Time Dosing, LY2605541 Variable Time Dosing LY2605541 Variable Time Dosing, LY2605541 Fixed Time Dosing
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   166/212 (78.30%)      83/177 (46.89%)      88/180 (48.89%)    
Eye disorders       
Conjunctivitis  1  2/212 (0.94%)  2 2/177 (1.13%)  2 1/180 (0.56%)  1
Gastrointestinal disorders       
Constipation  1  3/212 (1.42%)  3 0/177 (0.00%)  0 0/180 (0.00%)  0
Diarrhoea  1  6/212 (2.83%)  7 1/177 (0.56%)  1 1/180 (0.56%)  2
Food poisoning  1  2/212 (0.94%)  2 2/177 (1.13%)  2 0/180 (0.00%)  0
Gastrooesophageal reflux disease  1  3/212 (1.42%)  3 1/177 (0.56%)  1 0/180 (0.00%)  0
Nausea  1  10/212 (4.72%)  10 3/177 (1.69%)  3 3/180 (1.67%)  3
Vomiting  1  6/212 (2.83%)  7 1/177 (0.56%)  1 2/180 (1.11%)  2
General disorders       
Fatigue  1  4/212 (1.89%)  4 2/177 (1.13%)  2 3/180 (1.67%)  3
Injection site pain  1  3/212 (1.42%)  3 1/177 (0.56%)  1 0/180 (0.00%)  0
Injection site swelling  1  10/212 (4.72%)  23 1/177 (0.56%)  1 2/180 (1.11%)  2
Local swelling  1  3/212 (1.42%)  4 1/177 (0.56%)  1 3/180 (1.67%)  4
Oedema peripheral  1  3/212 (1.42%)  3 2/177 (1.13%)  2 0/180 (0.00%)  0
Infections and infestations       
Bronchitis  1  6/212 (2.83%)  6 2/177 (1.13%)  2 3/180 (1.67%)  3
Gastroenteritis  1  9/212 (4.25%)  13 2/177 (1.13%)  2 2/180 (1.11%)  2
Gastroenteritis viral  1  7/212 (3.30%)  7 4/177 (2.26%)  4 1/180 (0.56%)  1
Hordeolum  1  3/212 (1.42%)  3 1/177 (0.56%)  1 0/180 (0.00%)  0
Influenza  1  13/212 (6.13%)  14 2/177 (1.13%)  3 2/180 (1.11%)  2
Nasopharyngitis  1  33/212 (15.57%)  47 11/177 (6.21%)  12 8/180 (4.44%)  8
Sinusitis  1  11/212 (5.19%)  12 3/177 (1.69%)  3 5/180 (2.78%)  5
Tooth infection  1  4/212 (1.89%)  4 1/177 (0.56%)  1 0/180 (0.00%)  0
Upper respiratory tract infection  1  30/212 (14.15%)  33 9/177 (5.08%)  9 10/180 (5.56%)  10
Urinary tract infection  1  5/212 (2.36%)  5 2/177 (1.13%)  2 2/180 (1.11%)  2
Injury, poisoning and procedural complications       
Contusion  1  2/212 (0.94%)  3 2/177 (1.13%)  2 0/180 (0.00%)  0
Corneal abrasion  1  4/212 (1.89%)  4 1/177 (0.56%)  1 1/180 (0.56%)  1
Laceration  1  4/212 (1.89%)  5 2/177 (1.13%)  2 2/180 (1.11%)  2
Investigations       
Alanine aminotransferase increased  1  4/212 (1.89%)  4 2/177 (1.13%)  2 3/180 (1.67%)  3
Aspartate aminotransferase increased  1  4/212 (1.89%)  4 2/177 (1.13%)  2 2/180 (1.11%)  2
Blood creatine phosphokinase increased  1  5/212 (2.36%)  5 1/177 (0.56%)  1 1/180 (0.56%)  1
Hepatic enzyme increased  1  5/212 (2.36%)  5 1/177 (0.56%)  1 2/180 (1.11%)  2
Liver function test abnormal  1  3/212 (1.42%)  3 0/177 (0.00%)  0 1/180 (0.56%)  1
Weight decreased  1  6/212 (2.83%)  6 3/177 (1.69%)  3 3/180 (1.67%)  3
Weight increased  1  3/212 (1.42%)  3 0/177 (0.00%)  0 1/180 (0.56%)  1
Metabolism and nutrition disorders       
Decreased appetite  1  2/212 (0.94%)  3 2/177 (1.13%)  2 1/180 (0.56%)  1
Musculoskeletal and connective tissue disorders       
Arthralgia  1  6/212 (2.83%)  6 2/177 (1.13%)  2 4/180 (2.22%)  4
Back pain  1  5/212 (2.36%)  6 2/177 (1.13%)  2 2/180 (1.11%)  2
Muscle spasms  1  3/212 (1.42%)  3 0/177 (0.00%)  0 1/180 (0.56%)  1
Musculoskeletal pain  1  4/212 (1.89%)  4 0/177 (0.00%)  0 0/180 (0.00%)  0
Myalgia  1  3/212 (1.42%)  3 0/177 (0.00%)  0 2/180 (1.11%)  2
Neck pain  1  3/212 (1.42%)  3 1/177 (0.56%)  1 2/180 (1.11%)  2
Pain in extremity  1  7/212 (3.30%)  7 3/177 (1.69%)  3 2/180 (1.11%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Lipoma  1  2/212 (0.94%)  2 2/177 (1.13%)  2 2/180 (1.11%)  2
Nervous system disorders       
Headache  1  7/212 (3.30%)  10 2/177 (1.13%)  3 4/180 (2.22%)  4
Respiratory, thoracic and mediastinal disorders       
Cough  1  8/212 (3.77%)  10 2/177 (1.13%)  2 2/180 (1.11%)  4
Nasal congestion  1  3/212 (1.42%)  3 2/177 (1.13%)  2 0/180 (0.00%)  0
Oropharyngeal pain  1  7/212 (3.30%)  9 2/177 (1.13%)  3 3/180 (1.67%)  3
Respiratory tract congestion  1  4/212 (1.89%)  4 2/177 (1.13%)  2 1/180 (0.56%)  1
Sinus congestion  1  13/212 (6.13%)  14 5/177 (2.82%)  5 1/180 (0.56%)  1
Skin and subcutaneous tissue disorders       
Lipohypertrophy  1  10/212 (4.72%)  15 3/177 (1.69%)  3 2/180 (1.11%)  2
Rash  1  4/212 (1.89%)  4 2/177 (1.13%)  2 2/180 (1.11%)  2
Vascular disorders       
Hypertension  1  4/212 (1.89%)  4 3/177 (1.69%)  3 3/180 (1.67%)  3
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
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Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01792284     History of Changes
Other Study ID Numbers: 14184
I2R-MC-BIAX ( Other Identifier: Eli Lilly and Company )
First Submitted: February 13, 2013
First Posted: February 15, 2013
Results First Submitted: March 17, 2018
Results First Posted: April 20, 2018
Last Update Posted: April 20, 2018