Type 1 Diabetes Mellitus
Conditions
Brief summary
The reason for this study is to compare the study drug LY900014 to insulin lispro (Humalog) when both are used in insulin pump therapy in adults with type 1 diabetes (T1D).
Interventions
DRUGUltra-Rapid Lispro
Administered SC
DRUGInsulin Lispro
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have been diagnosed with T1D and continuously using insulin for at least 1 year * Have been using CSII therapy for a minimum of 6 months * Currently treated with \<100 Units of one of following rapid-acting analog insulin via CSII for at least the past 30 days: insulin lispro U-100, insulin aspart, fast-acting insulin aspart, insulin glulisine * Must be using a MiniMed 530G (US), Paradigm Revel (US), or MiniMed 630G (US and Canada), MiniMed 640G or Paradigm Veo (select countries outside the US), insulin pump for at least the past 90 days
Exclusion criteria
* Have hypoglycemia unawareness * Have had more than 1 episode of severe hypoglycemia within 6 months prior to screening * Have had more than 1 emergency room visit or hospitalization due to poor glucose control (hyperglycemia or diabetic ketoacidosis) within 6 months prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 16 | Baseline, Week 16 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured 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 covariates: Baseline + Pooled Country + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares). The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour PPG During MMTT Efficacy Estimand at Week 16 | Baseline, Week 16 | A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 2-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. |
| Percentage of Time With Sensor Glucose Values Between 70 and 180 mg/dL Efficacy Estimand at Week 16 | Week 16 | Percentage of time with sensor glucose values between 70 and 180 mg/dL using continuous glucose monitoring (CGM). Least square (LS) mean difference will provided for CGM data normalized to a 24hrs period. Daytime: 0600 hours to midnight (06:00:00-23:59:59 on the 24-hour clock). Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Rate of Severe Hypoglycemia at Week 16 | Baseline through Week 16 | Severe hypoglycemia is defined as an event requiring assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. During these episodes, the participant has an altered mental status and cannot assist in his or her own care, or may be semiconscious or unconscious, or experience coma with or without seizures, and may require parenteral therapy. Rate of severe hypoglycemia events per 100 years during a defined period was calculated by total number of severe hypoglycemia episodes within the period divided by the cumulative days on treatment from all participants within a treatment group \*36525. |
| Rate of Documented Symptomatic Hypoglycemia at Week 16 | Baseline through Week 16 | Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are accompanied by blood glucose (BG) of \<54 mg/dL \[3.0 millimole per liter (mmol/L)\]. The rate of documented symptomatic hypoglycemia was estimated by negative binomial model: number of episodes = treatment with log (treatment exposure in days/365.25) as an offset variable. |
| Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 16 | Baseline, Week 16 | 1,5-anhydroglucitol (1,5-AG) is a marker of short-term glycemic control especially postprandial hyperglycemia. 1,5-AG accurately predicts rapid changes in glycemia and is tightly associated with glucose fluctuations and postprandial glucose. LS Mean was calculated using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data collected prior to permanent discontinuation of study drug. |
| Change From Baseline in 1-hour Postprandial Glucose (PPG) During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 16 | Baseline, Week 16 | A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 1-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. |
| Change From Baseline in Insulin Dose at Week 16 | Baseline, Week 16 | LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug. |
| Change From Baseline in Bolus/Total Insulin Dose Ratio at Week 16 | Baseline, Week 16 | The bolus/total ratio was derived as the bolus dose divided by the total insulin dose at each visit. LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug. |
| Percentage of Participants With HbA1c <7% | Week 16 | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. |
| Percentage of Participants With at Least 1 Pump Occlusion Alarm That Leads to an Unplanned Infusion Set Change | Baseline through Week 16 | Percentage of participants with at least 1 pump occlusion alarm that leads to an unplanned infusion set change was evaluated. |
| Percentage of Participants With at Least 1 Event of Unexplained Hyperglycemia >300 mg/dL Confirmed by SMBG That Leads to an Unplanned Infusion Set Change | Baseline through Week 16 | Percentage of participants with at least 1 event of unexplained hyperglycemia \>300 milligrams per deciliter (mg/dL) confirmed by SMBG that leads to an unplanned infusion set change was evaluated. |
| Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Baseline, Week 16 | SMBG 10-point profiles were measured at fasting, 1-hour post morning meal, 2-hours post morning meal, pre midday meal, 1-hour post midday meal, 2-hours post midday meal, pre evening meal, 1-hour post evening meal, 2-hours post evening meal, and bedtime. LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, HbA1c stratum : less than or equal to (≤)7.5%, greater than (\>)7.5% and participant's personal CGM or FGM use during the study), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The efficacy estimand included participant data when baseline and at least one post-baseline measurement prior to permanent discontinuation of study drug. |
Countries
Australia, Austria, Canada, France, Germany, Hungary, Israel, Italy, Puerto Rico, Spain, United States
Participant flow
Pre-assignment details
The purpose of the lead-in period was to assess basal rates and bolus calculator settings and adjust if needed prior to randomization. Participants (Pts) were then randomized to insulin lispro (Humalog) or ultra-rapid lispro as both basal and bolus insulin and delivered bolus doses 0 to 2 minutes prior to each meal (pre-meal).
Participants by arm
| Arm | Count |
|---|---|
| Insulin Lispro (Humalog) Participants received individual dose of 100 U/mL insulin lispro (Humalog) by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary. | 217 |
| Ultra-Rapid Lispro Participants received individual dose of 100 U/mL ultra rapid lispro by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary. | 215 |
| Total | 432 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Lead-in Period (2 Weeks) | Adverse Event | 2 | 0 |
| Lead-in Period (2 Weeks) | Not Met Eligibility Criteria | 6 | 0 |
| Lead-in Period (2 Weeks) | Physician Decision | 2 | 0 |
| Lead-in Period (2 Weeks) | Withdrawal by Subject | 29 | 0 |
| Treatment Period (16 Weeks) | Adverse Event | 1 | 7 |
| Treatment Period (16 Weeks) | Lost to Follow-up | 4 | 3 |
| Treatment Period (16 Weeks) | Physician Decision | 1 | 0 |
| Treatment Period (16 Weeks) | Sponsor Decision | 1 | 1 |
| Treatment Period (16 Weeks) | Withdrawal by Subject | 5 | 6 |
Baseline characteristics
| Characteristic | Total | Ultra-Rapid Lispro | Insulin Lispro (Humalog) |
|---|---|---|---|
| Age, Continuous | 46.4 years STANDARD_DEVIATION 15.3 | 48.2 years STANDARD_DEVIATION 15.4 | 44.7 years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 18 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 358 Participants | 178 Participants | 180 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 39 Participants | 19 Participants | 20 Participants |
| Hemoglobin A1c | 7.55 Percentage of HbA1c STANDARD_DEVIATION 0.58 | 7.56 Percentage of HbA1c STANDARD_DEVIATION 0.59 | 7.54 Percentage of HbA1c STANDARD_DEVIATION 0.58 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 409 Participants | 202 Participants | 207 Participants |
| Region of Enrollment Australia | 30 Participants | 15 Participants | 15 Participants |
| Region of Enrollment Austria | 16 Participants | 8 Participants | 8 Participants |
| Region of Enrollment Canada | 22 Participants | 11 Participants | 11 Participants |
| Region of Enrollment France | 14 Participants | 7 Participants | 7 Participants |
| Region of Enrollment Germany | 36 Participants | 19 Participants | 17 Participants |
| Region of Enrollment Hungary | 48 Participants | 24 Participants | 24 Participants |
| Region of Enrollment Israel | 41 Participants | 19 Participants | 22 Participants |
| Region of Enrollment Italy | 18 Participants | 9 Participants | 9 Participants |
| Region of Enrollment Puerto Rico | 5 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Spain | 32 Participants | 16 Participants | 16 Participants |
| Region of Enrollment United States | 170 Participants | 84 Participants | 86 Participants |
| Sex: Female, Male Female | 239 Participants | 120 Participants | 119 Participants |
| Sex: Female, Male Male | 193 Participants | 95 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 471 | 0 / 217 | 0 / 215 |
| other Total, other adverse events | 15 / 471 | 31 / 217 | 90 / 215 |
| serious Total, serious adverse events | 4 / 471 | 10 / 217 | 17 / 215 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 16
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured 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 covariates: Baseline + Pooled Country + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares). The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 16
Population: All randomized participants with baseline and at least one post-baseline HbA1c data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro (Humalog) | Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 16 | -0.09 Percentage of HbA1c | Standard Error 0.03 |
| Ultra-Rapid Lispro | Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 16 | -0.06 Percentage of HbA1c | Standard Error 0.031 |
p-value: 0.56595% CI: [-0.06, 0.11]Mixed Models Analysis
Secondary
Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16
SMBG 10-point profiles were measured at fasting, 1-hour post morning meal, 2-hours post morning meal, pre midday meal, 1-hour post midday meal, 2-hours post midday meal, pre evening meal, 1-hour post evening meal, 2-hours post evening meal, and bedtime. LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, HbA1c stratum : less than or equal to (≤)7.5%, greater than (\>)7.5% and participant's personal CGM or FGM use during the study), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The efficacy estimand included participant data when baseline and at least one post-baseline measurement prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 16
Population: All randomized participants with baseline and at least one post-baseline SMBG data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Morning Premeal | 0.2 mg/dL | Standard Error 2.76 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Morning 1-hour Postmeal | -3.1 mg/dL | Standard Error 3.15 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Morning 2-hour Postmeal | -2.7 mg/dL | Standard Error 3.04 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Midday Premeal | -0.6 mg/dL | Standard Error 2.82 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Midday 1-hour Postmeal | -4.2 mg/dL | Standard Error 2.85 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Midday 2-hour Postmeal | -0.2 mg/dL | Standard Error 3.14 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Evening Premeal | 3.8 mg/dL | Standard Error 3.28 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Evening 1-hour Postmeal | 2.6 mg/dL | Standard Error 3.21 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Evening 2-hour Postmeal | 6.3 mg/dL | Standard Error 3.36 |
| Insulin Lispro (Humalog) | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Bedtime | 8.6 mg/dL | Standard Error 6.37 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Evening 1-hour Postmeal | 8.6 mg/dL | Standard Error 3.41 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Morning Premeal | 0.5 mg/dL | Standard Error 2.89 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Midday 2-hour Postmeal | 4.4 mg/dL | Standard Error 3.31 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Morning 1-hour Postmeal | -12.9 mg/dL | Standard Error 3.31 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Bedtime | 19.0 mg/dL | Standard Error 6.58 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Morning 2-hour Postmeal | -2.9 mg/dL | Standard Error 3.21 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Evening Premeal | 17.5 mg/dL | Standard Error 3.41 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Midday Premeal | 4.9 mg/dL | Standard Error 2.98 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Evening 2-hour Postmeal | 12.2 mg/dL | Standard Error 3.54 |
| Ultra-Rapid Lispro | Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16 | Midday 1-hour Postmeal | -6.3 mg/dL | Standard Error 3.03 |
Secondary
Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 16
1,5-anhydroglucitol (1,5-AG) is a marker of short-term glycemic control especially postprandial hyperglycemia. 1,5-AG accurately predicts rapid changes in glycemia and is tightly associated with glucose fluctuations and postprandial glucose. LS Mean was calculated using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data collected prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 16
Population: All randomized participants with baseline and at least one post-baseline 1,5-AG data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro (Humalog) | Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 16 | 0.16 milligram per liter (mg/L) | Standard Error 0.116 |
| Ultra-Rapid Lispro | Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 16 | 0.11 milligram per liter (mg/L) | Standard Error 0.121 |
Secondary
Change From Baseline in 1-hour Postprandial Glucose (PPG) During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 16
A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 1-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 16
Population: All randomized participants with baseline and at least one post-baseline 1-hour PPG data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro (Humalog) | Change From Baseline in 1-hour Postprandial Glucose (PPG) During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 16 | -2.2 milligrams per deciliter (mg/dL) | Standard Error 5.02 |
| Ultra-Rapid Lispro | Change From Baseline in 1-hour Postprandial Glucose (PPG) During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 16 | -26.3 milligrams per deciliter (mg/dL) | Standard Error 5.33 |
p-value: <0.00195% CI: [-36, -12.2]ANCOVA
Secondary
Change From Baseline in 2-hour PPG During MMTT Efficacy Estimand at Week 16
A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 2-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 16
Population: All randomized participants with baseline and at least one post-baseline 2-hour PPG data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro (Humalog) | Change From Baseline in 2-hour PPG During MMTT Efficacy Estimand at Week 16 | -4.2 mg/dL | Standard Error 6.27 |
| Ultra-Rapid Lispro | Change From Baseline in 2-hour PPG During MMTT Efficacy Estimand at Week 16 | -32.0 mg/dL | Standard Error 6.59 |
p-value: <0.00195% CI: [-42.6, -13]ANCOVA
Secondary
Change From Baseline in Bolus/Total Insulin Dose Ratio at Week 16
The bolus/total ratio was derived as the bolus dose divided by the total insulin dose at each visit. LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 16
Population: All randomized participants with non-missing baseline value and at least one non-missing post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro (Humalog) | Change From Baseline in Bolus/Total Insulin Dose Ratio at Week 16 | 0.6 Percentage of bolus/total insulin dose | Standard Error 0.66 |
| Ultra-Rapid Lispro | Change From Baseline in Bolus/Total Insulin Dose Ratio at Week 16 | -1.3 Percentage of bolus/total insulin dose | Standard Error 0.68 |
Secondary
Change From Baseline in Insulin Dose at Week 16
LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug.
Time frame: Baseline, Week 16
Population: All randomized participants with baseline and at least one post-baseline basal insulin dose data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Lispro (Humalog) | Change From Baseline in Insulin Dose at Week 16 | Daily Basal Insulin Dose | -0.2 units per day (U/day) | Standard Error 0.43 |
| Insulin Lispro (Humalog) | Change From Baseline in Insulin Dose at Week 16 | Daily Bolus Insulin Dose | 0.8 units per day (U/day) | Standard Error 0.66 |
| Insulin Lispro (Humalog) | Change From Baseline in Insulin Dose at Week 16 | Total Daily Insulin Dose | 0.6 units per day (U/day) | Standard Error 0.8 |
| Ultra-Rapid Lispro | Change From Baseline in Insulin Dose at Week 16 | Daily Basal Insulin Dose | -0.1 units per day (U/day) | Standard Error 0.44 |
| Ultra-Rapid Lispro | Change From Baseline in Insulin Dose at Week 16 | Daily Bolus Insulin Dose | -1.0 units per day (U/day) | Standard Error 0.68 |
| Ultra-Rapid Lispro | Change From Baseline in Insulin Dose at Week 16 | Total Daily Insulin Dose | -1.1 units per day (U/day) | Standard Error 0.82 |
Secondary
Percentage of Participants With at Least 1 Event of Unexplained Hyperglycemia >300 mg/dL Confirmed by SMBG That Leads to an Unplanned Infusion Set Change
Percentage of participants with at least 1 event of unexplained hyperglycemia \>300 milligrams per deciliter (mg/dL) confirmed by SMBG that leads to an unplanned infusion set change was evaluated.
Time frame: Baseline through Week 16
Population: All randomized participants with baseline and at least one post-baseline value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Lispro (Humalog) | Percentage of Participants With at Least 1 Event of Unexplained Hyperglycemia >300 mg/dL Confirmed by SMBG That Leads to an Unplanned Infusion Set Change | 18.4 Percentage of participants |
| Ultra-Rapid Lispro | Percentage of Participants With at Least 1 Event of Unexplained Hyperglycemia >300 mg/dL Confirmed by SMBG That Leads to an Unplanned Infusion Set Change | 16.3 Percentage of participants |
Secondary
Percentage of Participants With at Least 1 Pump Occlusion Alarm That Leads to an Unplanned Infusion Set Change
Percentage of participants with at least 1 pump occlusion alarm that leads to an unplanned infusion set change was evaluated.
Time frame: Baseline through Week 16
Population: All randomized participants with baseline and at least one post-baseline value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Lispro (Humalog) | Percentage of Participants With at Least 1 Pump Occlusion Alarm That Leads to an Unplanned Infusion Set Change | 12.7 Percentage of participants |
| Ultra-Rapid Lispro | Percentage of Participants With at Least 1 Pump Occlusion Alarm That Leads to an Unplanned Infusion Set Change | 14.8 Percentage of participants |
Secondary
Percentage of Participants With HbA1c <7%
Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
Time frame: Week 16
Population: All randomized participants with baseline and at least one post-baseline HbA1c \<7% data. Missing endpoints were imputed by applying the Last Observation Carried Forward (LOCF) method to the post-baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Lispro (Humalog) | Percentage of Participants With HbA1c <7% | 20.77 Percentage of participants |
| Ultra-Rapid Lispro | Percentage of Participants With HbA1c <7% | 18.85 Percentage of participants |
Secondary
Percentage of Time With Sensor Glucose Values Between 70 and 180 mg/dL Efficacy Estimand at Week 16
Percentage of time with sensor glucose values between 70 and 180 mg/dL using continuous glucose monitoring (CGM). Least square (LS) mean difference will provided for CGM data normalized to a 24hrs period. Daytime: 0600 hours to midnight (06:00:00-23:59:59 on the 24-hour clock). Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Week 16
Population: All randomized participants with non-missing baseline value and at least one non-missing post-baseline value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Lispro (Humalog) | Percentage of Time With Sensor Glucose Values Between 70 and 180 mg/dL Efficacy Estimand at Week 16 | Daytime | 58.6 percentage of time | Standard Error 0.75 |
| Insulin Lispro (Humalog) | Percentage of Time With Sensor Glucose Values Between 70 and 180 mg/dL Efficacy Estimand at Week 16 | 24-Hour | 57.5 percentage of time | Standard Error 0.76 |
| Ultra-Rapid Lispro | Percentage of Time With Sensor Glucose Values Between 70 and 180 mg/dL Efficacy Estimand at Week 16 | Daytime | 59.3 percentage of time | Standard Error 0.77 |
| Ultra-Rapid Lispro | Percentage of Time With Sensor Glucose Values Between 70 and 180 mg/dL Efficacy Estimand at Week 16 | 24-Hour | 57.9 percentage of time | Standard Error 0.79 |
Comparison: Statistical analysis during daytime is reported.p-value: 0.53295% CI: [-1.4, 2.8]Mixed Models Analysis
Comparison: Statistical analysis during 24-hour period is reported.p-value: 0.73895% CI: [-1.8, 2.5]Mixed Models Analysis
Secondary
Rate of Documented Symptomatic Hypoglycemia at Week 16
Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are accompanied by blood glucose (BG) of \<54 mg/dL \[3.0 millimole per liter (mmol/L)\]. The rate of documented symptomatic hypoglycemia was estimated by negative binomial model: number of episodes = treatment with log (treatment exposure in days/365.25) as an offset variable.
Time frame: Baseline through Week 16
Population: All randomized participants with evaluable hypoglycemic data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro (Humalog) | Rate of Documented Symptomatic Hypoglycemia at Week 16 | 30.7 Events per participant per year | Standard Error 2.48 |
| Ultra-Rapid Lispro | Rate of Documented Symptomatic Hypoglycemia at Week 16 | 24.6 Events per participant per year | Standard Error 1.88 |
Secondary
Rate of Severe Hypoglycemia at Week 16
Severe hypoglycemia is defined as an event requiring assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. During these episodes, the participant has an altered mental status and cannot assist in his or her own care, or may be semiconscious or unconscious, or experience coma with or without seizures, and may require parenteral therapy. Rate of severe hypoglycemia events per 100 years during a defined period was calculated by total number of severe hypoglycemia episodes within the period divided by the cumulative days on treatment from all participants within a treatment group \*36525.
Time frame: Baseline through Week 16
Population: All randomized participants with evaluable hypoglycemic data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Lispro (Humalog) | Rate of Severe Hypoglycemia at Week 16 | 2.95 Events per 100 participant years |
| Ultra-Rapid Lispro | Rate of Severe Hypoglycemia at Week 16 | 6.36 Events per 100 participant years |