Type 1 Diabetes Mellitus
Conditions
Brief summary
The primary purpose of participation in this study is to compare the safety and efficacy of different dosing schedules of LY2605541 and how different dosing schedules of LY2605541 affect Hemoglobin A1c (HbA1c). Participants will be treated for up to 36 weeks with LY2605541 (one 12-week Lead-in period and two 12-week Randomization periods) and will participate in a total of 42 weeks of total study enrollment, including a 2-week Screening period and a 4-week Follow-up period.
Detailed description
This study involved a comparison of LY2605541 regimens, each administered with bolus insulin lispro. Eligible participants were switched to a fixed evening LY2605541dosing regimen at the beginning of the 12-week lead-in period. LY2605541 was administered SQ once-daily using a prefilled insulin device. The LY2605541dose was adjusted using a dosing algorithm adapted from Bartley and Bolli (Bartley et al. 2008, Bolli et al. 2009) based on the participant's blood glucose (BG) values and documented hypoglycemia during the previous week. Participants not already receiving insulin lispro for prandial dosing were switched to insulin lispro at the beginning of the 12-week lead-in period. Adjustments to insulin lispro doses were based on the insulin dosing algorithms adapted from Riddle and Bergenstal (Riddle et al. 2003, Bergenstal et al. 2008). At the time of randomization, participants were randomized to begin either the fixed evening dosing regimen or the variable time dosing regimen. Each participant was crossed over to the alternate regimen after 12 weeks. The insulin device (prefilled pen) remained the same throughout the study.
Interventions
DRUGLY2605541
DRUGInsulin Lispro
All participants will be administering insulin lispro SQ as their pre-meal insulin during the course of the trial.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetes mellitus for at least 1 year * Have an HbA1c value \<9.0% * Have a body mass index (BMI) ≤35.0 kilogram per square meter (kg/m\^2) * Currently using basal/ bolus insulin * Women of childbearing potential are not breastfeeding and must use methods to prevent pregnancy
Exclusion criteria
* Have excessive insulin resistance * Are taking medications other than insulin for diabetes * High triglycerides * Have had more than 1 episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia as determined by the investigator) within 6 months prior to entry into the study * Have had 2 or more emergency room visits or hospitalizations due to poor glucose control (hyperglycemia or diabetic ketoacidosis) in the past 6 months * Have cardiac disease with functional status that is New York Heart Association (NYHA) Class III or IV (per NYHA Cardiac Disease Classification) * Have impaired renal function * Have impaired liver function * Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with HbA1c measurement * Have cancer, recent cancer, or risk of cancer * Have a known hypersensitivity or allergy to any of the study insulins or their excipients * Have chronic systemic glucocorticoid users * Have clinically significant diabetic autonomic neuropathy * Have irregular sleep/wake cycle * Have been treated with a drug within the last 30 days that has not received regulatory approval at the time of study entry * Prior study participation * Are using or have used niacin preparations as a lipid-lowering medication and/or bile acid sequestrants within 90 days prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin A1c (HbA1c) at 12 Weeks | At 12 Week in Each Randomization Period | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Total and Nocturnal Hypoglycemic Events | Baseline (Day 1) of Randomization Period through 24 weeks (12 weeks in each Randomization Period) | 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. |
| Fasting Blood Glucose (FBG) Measured by Self-Monitored Blood Glucose | At 12 Weeks in Each Randomization Period | 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. |
| Intra-Participant Variability of FBG at 12 Weeks | At 12 Weeks in Each Randomization Period | 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. |
| Fasting Serum Glucose (FSG) at 12 Weeks | At 12 Weeks in Each Randomization Period | 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. |
| Change From Randomization to 12 Weeks in 9-Point SMBG | Randomization, 12 Weeks in Each Randomization Period | 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. |
| Self-Monitored Blood Glucose (SMBG) at 12 Weeks | At 12 Week in Each Randomization Period | 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. |
| Intra-participant Variability in SMBG at 12 Weeks | At 12 Week in Each Randomization Period | 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. |
| Change From Randomization to 12 Weeks in Body Weight | Randomization, 12 Weeks in Each Randomization Period | 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. |
| 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Baseline (Day 1) of Randomization Period through 24 Weeks (12 weeks in each Randomization Period) | 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. |
| Change From Randomization to 12 Weeks in HbA1c | Randomization, 12 Weeks in Each Randomization Period | 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. |
| Participants With Treatment-Emergent Anti-LY2605541 Antibody Response | Day 1 of Lead-in Period through 36 Weeks | 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. |
| Basal, Bolus, and Total Insulin Doses at 12 Weeks | At 12 Weeks in Each Randomization Period | 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. |
| Proportion of Bolus to Total Insulin Doses at 12 Weeks | At 12 Weeks in Each Randomization Period | 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. |
| 0300-Hour Blood Glucose to Fasting Blood Glucose Excursion | At 12 Week in Each Randomization Period | 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. |
| 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) | Day 1 of Lead-In Period, 36 Weeks | 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. |
| Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks | At 12 Weeks in Each Randomization Period | 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. |
| Change From Day 1 of Lead-In Period to 36 Weeks in Body Weight | Day 1 of Lead-In Period, 36 Weeks | 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. |
Countries
Puerto Rico, United States
Participant flow
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).
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants 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. | 212 |
| Total | 212 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Lead-in Period | Adverse Event | 15 | 0 | 0 |
| Lead-in Period | Lost to Follow-up | 2 | 0 | 0 |
| Lead-in Period | Physician Decision | 1 | 0 | 0 |
| Lead-in Period | Protocol Required Discontinuation | 1 | 0 | 0 |
| Lead-in Period | Protocol Violation | 1 | 0 | 0 |
| Lead-in Period | Withdrawal by Subject | 10 | 0 | 0 |
| Randomization Period 1 | Adverse Event | 0 | 0 | 2 |
| Randomization Period 1 | Lost to Follow-up | 0 | 0 | 1 |
| Randomization Period 1 | Physician Decision | 0 | 1 | 1 |
| Randomization Period 1 | Withdrawal by Subject | 0 | 1 | 1 |
| Randomization Period 2 | Protocol Violation | 0 | 1 | 0 |
| Randomization Period 2 | Withdrawal by Subject | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | All Enrolled Participants |
|---|---|
| Age, Continuous | 43.08 years STANDARD_DEVIATION 13.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 186 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 203 Participants |
| Region of Enrollment Puerto Rico | 13 Participants |
| Region of Enrollment United States | 199 Participants |
| Sex: Female, Male Female | 98 Participants |
| Sex: Female, Male Male | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 166 / 212 | 83 / 177 | 88 / 180 |
| serious Total, serious adverse events | 30 / 212 | 11 / 177 | 7 / 180 |
Outcome results
Primary
Hemoglobin A1c (HbA1c) at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HbA1c data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Hemoglobin A1c (HbA1c) at 12 Weeks | 6.87 percentage of HbA1c | Standard Error 0.04 |
| LY2605541 Variable Time Dosing | Hemoglobin A1c (HbA1c) at 12 Weeks | 6.93 percentage of HbA1c | Standard Error 0.04 |
Secondary
0300-Hour Blood Glucose to Fasting Blood Glucose Excursion
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG excursion data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | 0300-Hour Blood Glucose to Fasting Blood Glucose Excursion | -6.41 mg/dL | Standard Error 3.64 |
| LY2605541 Variable Time Dosing | 0300-Hour Blood Glucose to Fasting Blood Glucose Excursion | -15.24 mg/dL | Standard Error 3.7 |
Secondary
30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events
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)
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HE data during Randomization Periods.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2605541 Fixed Time Dosing | 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Total HE | 10.54 events/participant/30 days | Standard Error 0.67 |
| LY2605541 Fixed Time Dosing | 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Nocturnal HE | 1.52 events/participant/30 days | Standard Error 0.13 |
| LY2605541 Variable Time Dosing | 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Total HE | 10.37 events/participant/30 days | Standard Error 0.62 |
| LY2605541 Variable Time Dosing | 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Nocturnal HE | 1.34 events/participant/30 days | Standard Error 0.11 |
Secondary
Basal, Bolus, and Total Insulin Doses at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable insulin dose data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2605541 Fixed Time Dosing | Basal, Bolus, and Total Insulin Doses at 12 Weeks | Basal | 0.50 units/kg/day | Standard Error 0.01 |
| LY2605541 Fixed Time Dosing | Basal, Bolus, and Total Insulin Doses at 12 Weeks | Bolus | 0.20 units/kg/day | Standard Error 0.01 |
| LY2605541 Fixed Time Dosing | Basal, Bolus, and Total Insulin Doses at 12 Weeks | Total Insulin | 0.71 units/kg/day | Standard Error 0.01 |
| LY2605541 Variable Time Dosing | Basal, Bolus, and Total Insulin Doses at 12 Weeks | Basal | 0.51 units/kg/day | Standard Error 0.01 |
| LY2605541 Variable Time Dosing | Basal, Bolus, and Total Insulin Doses at 12 Weeks | Bolus | 0.20 units/kg/day | Standard Error 0.01 |
| LY2605541 Variable Time Dosing | Basal, Bolus, and Total Insulin Doses at 12 Weeks | Total Insulin | 0.71 units/kg/day | Standard Error 0.01 |
Secondary
Change From Day 1 of Lead-In Period to 36 Weeks in Body Weight
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Change From Day 1 of Lead-In Period to 36 Weeks in Body Weight | -1.16 kg | Standard Error 0.29 |
Secondary
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)
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2605541 Fixed Time Dosing | 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) | Triglycerides | 26.44 mg/dL | Standard Error 3.83 |
| LY2605541 Fixed Time Dosing | 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) | Total Cholesterol | 3.75 mg/dL | Standard Error 1.91 |
| LY2605541 Fixed Time Dosing | 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) | LDL-C | 4.45 mg/dL | Standard Error 1.63 |
| LY2605541 Fixed Time Dosing | 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) | HDL-C | -5.70 mg/dL | Standard Error 0.82 |
Secondary
Change From Randomization to 12 Weeks in 9-Point SMBG
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 2 hours post-morning meal | -1.24 mg/dL | Standard Error 4.03 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 2 hours post-evening meal | 5.49 mg/dL | Standard Error 4.06 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 2 hours post-midday meal | 10.91 mg/dL | Standard Error 3.93 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Bedtime | 8.40 mg/dL | Standard Error 4.15 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Pre-midday meal | 0.27 mg/dL | Standard Error 3.55 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 0300 hours | -7.05 mg/dL | Standard Error 3.55 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Pre-evening meal | 1.98 mg/dL | Standard Error 3.81 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Subsequent morning pre-meal | -7.84 mg/dL | Standard Error 3.2 |
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Pre-morning meal | -7.77 mg/dL | Standard Error 3.79 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Subsequent morning pre-meal | -2.44 mg/dL | Standard Error 3.22 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Pre-morning meal | 0.07 mg/dL | Standard Error 3.8 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 2 hours post-morning meal | 8.13 mg/dL | Standard Error 4.04 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Pre-midday meal | 14.87 mg/dL | Standard Error 3.57 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 2 hours post-midday meal | 5.40 mg/dL | Standard Error 3.95 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Pre-evening meal | -1.34 mg/dL | Standard Error 3.84 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 2 hours post-evening meal | 8.33 mg/dL | Standard Error 4.03 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | Bedtime | 5.36 mg/dL | Standard Error 4.17 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in 9-Point SMBG | 0300 hours | 4.71 mg/dL | Standard Error 3.62 |
Secondary
Change From Randomization to 12 Weeks in Body Weight
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable body weight data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in Body Weight | -0.06 kilograms (kg) | Standard Error 0.19 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in Body Weight | 0.00 kilograms (kg) | Standard Error 0.19 |
Secondary
Change From Randomization to 12 Weeks in HbA1c
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HbA1c data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Change From Randomization to 12 Weeks in HbA1c | 0.10 percentage of HbA1c | Standard Error 0.04 |
| LY2605541 Variable Time Dosing | Change From Randomization to 12 Weeks in HbA1c | 0.18 percentage of HbA1c | Standard Error 0.04 |
Secondary
Fasting Blood Glucose (FBG) Measured by Self-Monitored Blood Glucose
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable FBG data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Fasting Blood Glucose (FBG) Measured by Self-Monitored Blood Glucose | 131.35 mg/dL | Standard Error 2.86 |
| LY2605541 Variable Time Dosing | Fasting Blood Glucose (FBG) Measured by Self-Monitored Blood Glucose | 139.65 mg/dL | Standard Error 2.87 |
Secondary
Fasting Serum Glucose (FSG) at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable FSG data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Fasting Serum Glucose (FSG) at 12 Weeks | 121.51 mg/dL | Standard Error 4.27 |
| LY2605541 Variable Time Dosing | Fasting Serum Glucose (FSG) at 12 Weeks | 120.45 mg/dL | Standard Error 4.25 |
Secondary
Intra-participant Variability in SMBG at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG variability data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Intra-participant Variability in SMBG at 12 Weeks | 34.82 mg/dL | Standard Error 1.3 |
| LY2605541 Variable Time Dosing | Intra-participant Variability in SMBG at 12 Weeks | 36.21 mg/dL | Standard Error 1.28 |
Secondary
Intra-Participant Variability of FBG at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable FBG data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Intra-Participant Variability of FBG at 12 Weeks | 37.97 mg/dL | Standard Error 1.73 |
| LY2605541 Variable Time Dosing | Intra-Participant Variability of FBG at 12 Weeks | 39.80 mg/dL | Standard Error 1.73 |
Secondary
Participants With Treatment-Emergent Anti-LY2605541 Antibody Response
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| LY2605541 Fixed Time Dosing | Participants With Treatment-Emergent Anti-LY2605541 Antibody Response | 80 participants |
Secondary
Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HbA1c data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks | HbA1c <7.0% | 60.5 percentage of participants |
| LY2605541 Fixed Time Dosing | Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks | HbA1c <=6.5% | 34.1 percentage of participants |
| LY2605541 Variable Time Dosing | Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks | HbA1c <7.0% | 54.5 percentage of participants |
| LY2605541 Variable Time Dosing | Percentage of Participants With HbA1c <7.0% and ≤6.5% at 12 Weeks | HbA1c <=6.5% | 34.1 percentage of participants |
Secondary
Percentage of Participants With Total and Nocturnal Hypoglycemic Events
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)
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable HE data during Randomization Periods
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Percentage of Participants With Total and Nocturnal Hypoglycemic Events | Total HE | 98.2 percentage of participants |
| LY2605541 Fixed Time Dosing | Percentage of Participants With Total and Nocturnal Hypoglycemic Events | Nocturnal HE | 78.4 percentage of participants |
| LY2605541 Variable Time Dosing | Percentage of Participants With Total and Nocturnal Hypoglycemic Events | Total HE | 97.8 percentage of participants |
| LY2605541 Variable Time Dosing | Percentage of Participants With Total and Nocturnal Hypoglycemic Events | Nocturnal HE | 80.6 percentage of participants |
Secondary
Proportion of Bolus to Total Insulin Doses at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable bolus to total insulin dose data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2605541 Fixed Time Dosing | Proportion of Bolus to Total Insulin Doses at 12 Weeks | 0.29 units/day | Standard Error 0.01 |
| LY2605541 Variable Time Dosing | Proportion of Bolus to Total Insulin Doses at 12 Weeks | 0.28 units/day | Standard Error 0.01 |
Secondary
Self-Monitored Blood Glucose (SMBG) at 12 Weeks
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
Population: Participants who were randomized, received at least 1 dose of study drug after randomization, and had evaluable SMBG data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 2 hours post-morning meal | 151.03 mg/dL | Standard Error 4.03 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 2 hours post-evening meal | 150.37 mg/dL | Standard Error 4.06 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 2 hours post-midday meal | 147.05 mg/dL | Standard Error 3.93 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Bedtime | 153.81 mg/dL | Standard Error 4.15 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Pre-midday meal | 122.96 mg/dL | Standard Error 3.55 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 0300 hours | 131.40 mg/dL | Standard Error 3.55 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Pre-evening meal | 137.75 mg/dL | Standard Error 3.81 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Subsequent morning pre-meal | 125.16 mg/dL | Standard Error 3.2 |
| LY2605541 Fixed Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Pre-morning meal | 133.21 mg/dL | Standard Error 3.79 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Subsequent morning pre-meal | 130.57 mg/dL | Standard Error 3.22 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Pre-morning meal | 141.05 mg/dL | Standard Error 3.8 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 2 hours post-morning meal | 160.41 mg/dL | Standard Error 4.04 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Pre-midday meal | 137.55 mg/dL | Standard Error 3.57 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 2 hours post-midday meal | 141.54 mg/dL | Standard Error 3.95 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Pre-evening meal | 134.43 mg/dL | Standard Error 3.84 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 2 hours post-evening meal | 153.21 mg/dL | Standard Error 4.03 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | Bedtime | 150.77 mg/dL | Standard Error 4.17 |
| LY2605541 Variable Time Dosing | Self-Monitored Blood Glucose (SMBG) at 12 Weeks | 0300 hours | 143.16 mg/dL | Standard Error 3.62 |