Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
LY2605541 · 14 trials · 5 indications
Glycosylated hemoglobin A1 (HbA1c) is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. Least Squares (LS) means were calculated by mixed model repeated measures (MMRM) using treatment, stratification factors (country, sulfonylureas/meglitinide use \[Yes/No\]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects.
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.
HbA1c is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for stratification factors (country, baseline low-density lipoprotein cholesterol \[LDL-C, \<100 milligrams per deciliter (mg/dL) and ≥100 mg/dL\], and sulfonylurea (SU) or meglitinide use), visit, treatment, visit-by-treatment interaction, and baseline HbA1c.
HbA1c is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for stratification factors (country, low-density lipoprotein cholesterol \[LDL-C, \<100 milligrams per deciliter (mg/dL) and ≥100 mg/dL\], and number of insulin injections at baseline \[1, 2, or ≥3\]), visit, treatment, visit-by-treatment interaction, and baseline HbA1c.
8-point SMBG profiles are measured at morning FBG, midday and evening pre-meal blood glucose (BG), 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. Least squares (LS) mean of the FBG is from mixed-model repeated measures (MMRM) approach, which includes fixed effects of treatment (LY2605541 algorithm 1 and 2, glargine); dose conversion (pre-interim analysis \[IA\], post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline hemoglobin A1c \[HbA1c\] group); visit; visit and treatment interaction; random effect for participant.
It is the Avg. of the 8-point SMBG profiles, BG of morning fasting, midday \& evening pre-meal, 2-hour postprandial after each of the 3 main meals, bedtime, 0300 hours. Least squares (LS) mean of daily Avg. BG is from mixed-model repeated measures (MMRM), which includes fixed effects of treatment (LY2605541, Glargine); Treatment Sequence; treatment period; dose conversion (pre-interim analysis \[IA\], post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline Hemoglobin \[HbA1c\] group); visit; visit and treatment interaction; a random effect for participant.
Lipid or glucose metabolism was assessed by the measurement of respiratory quotient (RQ) during sleep using whole room calorimetry. RQ is a calculation of basal metabolic rate (BMR) when estimated from carbon dioxide production. It is calculated from the ratio of carbon dioxide produced by the body to oxygen consumed by the body using whole room calorimetry (WRC).
LY2605541 exposure in terms of AUC from time 0 extrapolated to infinity (AUC\[0-inf\]) is summarized for each PEG source (LY1, LY2, or LY3).
The maximum observed drug concentration (Cmax) of LY2605541 is summarized for each PEG source (LY1, LY2, or LY3).
AUC from time zero to infinity (AUC(0-∞)) of LY2605541 was evaluated across injection sites (abdominal wall, arm, and thigh).
Cmax of LY2605541 was evaluated across injection sites (abdominal wall, arm, and thigh).
AUC(0-∞) for LY2605541 was evaluated.
Cmax of LY2605541 was evaluated.
Epinephrine levels are presented. Each participant's measurements at 30, 15, and 0 minutes preclamp on the day of the clamp were averaged for the baseline value, and measurements at blood glucose (BG) level attainment and +10, 20, and 30 minutes were averaged for the BG nadir value.
Venous blood samples for pharmacokinetic analysis were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.
Venous blood samples for pharmacokinetic analysis were collected during the euglycemic glucose clamps during Part A. The intra-participant percentage of coefficient of variation (%CV) is presented. %CV was calculated by dividing the standard deviation by the mean, multiplied by 100.
The percent suppression from baseline in endogenous glucose production (EGP) is presented. Percent EGP change from baseline was calculated by (1-\[last 2 hours of EGP/basal EGP\])\*100. The duration of the clamp procedure was 10 hours for the LY2605541 74.1 mU/min dose in Part B. The duration of the clamp procedures performed at the 15.3 mU/min LY2605541 dose and both of the insulin glargine doses was 8 hours.
The fold change from baseline in glucose disappearance rate (GDR) is presented. The fold GDR increase from baseline was calculated by last 2 hours of GDR/basal GDR. The duration of the clamp procedure was 10 hours for the LY2605541 74.1 mU/min dose in Part B. The duration of the clamp procedures performed at the 15.3 mU/min LY2605541 dose and both of the insulin glargine doses was 8 hours.
The maximum rate of glucose disposal (Rdmax) is presented. The duration of the clamp procedure was 10 hours for the LY2605541 74.1 mU/min dose in Part B. The duration of the clamp procedures performed at the 15.3 mU/min LY2605541 dose and both of the insulin glargine doses was 8 hours.
| Arm | Type | Description |
|---|---|---|
| LY2605541 | EXPERIMENTAL | Administered by subcutaneous (SC) injection once daily in the morning or at bedtime. Initial dose is 10 units (or less for some of the participants in Korea) and is adjusted weekly based on Fasting Blood Glucose (FBG). LY2605541 will be given alone or in combination with up to 3 pre-study oral antihyperglycemic medications \[OAM(s)\] whose use is not excluded in combination with insulin. Treatment may last up to 26 weeks. |
| Human Insulin NPH | ACTIVE_COMPARATOR | Administered by SC injection once daily at bedtime. Initial dose is 10 units (or less for some of the participants in Korea) and is adjusted weekly based on FBG. Human insulin NPH will be used alone or in combination with up to 3 pre-study OAM(s) whose use is not excluded in combination with insulin. Treatment may last up to 26 weeks. Some participants who are unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may be asked to add a second injection prior to the morning meal. |
| LY2605541 Fixed Time Dosing | EXPERIMENTAL | Participant-specific dose of LY2605541 administered subcutaneously (SQ) at approximately the same time every evening for 12 weeks in the Lead-in Period and in Randomization Period 1 or Randomization Period 2. 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. |
| LY2605541 Variable Time Dosing | EXPERIMENTAL | Participant-specific dose of LY2605541 administered SQ on a variable time schedule (8- and 40-hour dosing intervals) for 12 weeks in Randomization Period 1 or Randomization Period 2. 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. |
| Insulin glargine | ACTIVE_COMPARATOR | Administered by SQ injection once daily at bedtime. Initial dose based on dose of prestudy basal insulin and adjusted based on FBG. Insulin glargine will be used alone or in combination with up to 3 pre-study OAMs whose use is not excluded in combination with insulin. Treatment may last up to 52 weeks. |
| Insulin Glargine + Insulin Lispro | ACTIVE_COMPARATOR | Participant-specific dose of Insulin Glargine will be administered subcutaneously (SC) once daily at bedtime for 26 weeks. Participant-specific dose of Insulin Lispro will be administered SC for preprandial (pre-meal) and supplemental doses for 26 weeks. |
| LY2605541 + Insulin Lispro | EXPERIMENTAL | Participant-specific dose of LY2605541 will be administered SC once daily at bedtime for 26 weeks. Participant-specific dose of Insulin Lispro will be administered SC for preprandial and supplemental doses for 26 weeks. |
| LY2605541 Dosing Algorithm 1 | EXPERIMENTAL | Participants took both LY2605541 and their pre-study insulin for first several days |
| LY2605541 Dosing Algorithm 2 | EXPERIMENTAL | Participants took only LY2605541 with first dose doubled |
| LY2605541 First, Then Insulin Glargine | EXPERIMENTAL | Participants received LY2605541 for 8 weeks, followed by insulin glargine for 8 weeks. |
| Insulin Glargine First, Then LY2605541 | ACTIVE_COMPARATOR | Participants received insulin glargine for 8 weeks, followed by LY2605541 for 8 weeks. |
| Insulin Peglispro/Insulin Glargine | EXPERIMENTAL | Insulin peglispro (LY2605541) administered to participants with T1DM subcutaneously (SQ) once daily (QD) for 28 to 35 days in one of two treatment periods. Dose is based on participant's prestudy basal insulin dosing regimen. Insulin glargine administered to participants with T1DM SQ QD for 28 to 35 days in one of two treatment periods. Dose is based on participant's prestudy basal insulin dosing regimen. Participants continue to use mealtime insulin. |
| Insulin Glargine/Insulin Peglispro | ACTIVE_COMPARATOR | Insulin glargine administered to participants with T1DM SQ QD for 28 to 35 days in one of two treatment periods. Dose is based on participant's prestudy basal insulin dosing regimen. Participants continue to use mealtime insulin. Insulin peglispro (LY2605541) administered to participants with T1DM subcutaneously (SQ) once daily (QD) for 28 to 35 days in one of two treatment periods. Dose is based on participant's prestudy basal insulin dosing regimen. |
| Control | NO_INTERVENTION | Control Arm. Untreated healthy participants. |
| LY2605541-Part A | EXPERIMENTAL | 1.42 units per kilogram (U/kg) of LY2605541 given once daily (QD) for 1 day, subcutaneously (SQ) in 1 of 4 treatment periods. |
| Insulin Lispro-Part A | ACTIVE_COMPARATOR | Single dose 0.36 U/kg of insulin lispro given QD for 1 day, SQ in 1 of 4 treatment periods. |
| LY2605541/Lispro Mix 1-Part A | EXPERIMENTAL | Single dose 0.54 U/kg of LY2605541 and 0.36 U/kg insulin lispro mixture given QD for 1 day, SQ in 1 of 4 treatment periods. |
| LY2605541/Lispro Mix 2-Part A | EXPERIMENTAL | Single dose 1.42 U/kg of LY2605541 and 0.36 insulin lispro mixture given QD for 1 day, SQ in 1 of 4 treatment periods. |
| Insulin Lispro-Part B | ACTIVE_COMPARATOR | 0.18 U/kg insulin lispro given twice daily (BID) for 1 day, SQ in 1 of 4 treatment periods. Part B is contingent on data from Part A. |
| LY2605541/Lispro Mix-Part B | EXPERIMENTAL | 0.71 U/kg LY2605541 and 0.18 U/kg insulin lispro mixture given BID for 1 day, SQ in 1 of 4 treatment periods. Part B is contingent on data from Part A. |
| LY2605541 QD-Part B | EXPERIMENTAL | 0.54 U/kg of LY2605541 given QD for 1 day, SQ in 1 of 4 treatment periods. Part B is contingent on data from Part A. |
| LY2605541 BID-Part B | EXPERIMENTAL | 0.71 U/kg of LY2605541 given BID for 1 day SQ in 1 of 4 treatment periods. Part B is contingent on data from Part A. |
| LY2605541 - Source 1 | EXPERIMENTAL | Each healthy participant will receive a single subcutaneous (SC) injection of 0.5 units per kilogram (U/kg) of LY2605541 on Day 1 of 1 of 3 treatment periods |
| LY2605541 - Source 2 | EXPERIMENTAL | Each healthy participant will receive single SC injection of 0.5 U/kg of LY2605541 on Day 1 of 1of 3 treatment periods |
| LY2605541 - Source 3 | EXPERIMENTAL | Each healthy participant will receive single SC injection of 0.5 U/kg of LY2605541 on Day 1 of 1 of 3 treatment periods |
| LY2605541: Cohort A (Injection site: Abdomen) | EXPERIMENTAL | Participants ≤55 years of age will receive 1 subcutaneous (SC) injection of 0.5 Units per kilogram (U/kg) of LY2605541 in the abdominal wall on Day 1 in 1 of 3 treatment periods. There was a washout period of 16-28 days between each treatment period. |
| LY2605541: Cohort A (Injection site: Upper Arm) | EXPERIMENTAL | Participants ≤55 years of age will receive 1 SC injection of 0.5 U/kg of LY2605541 in the upper arm on Day 1 in 1 of 3 treatment periods. There was a washout period of 16-28 days between each treatment period. |
| LY2605541: Cohort A (Injection site: Thigh) | EXPERIMENTAL | Participants ≤55 years of age will receive 1 SC injection of 0.5 U/kg of LY2605541 in the thigh on Day 1 in 1 of 3 treatment periods. There was a washout period of 16-28 days between each treatment period. |
| LY2605541: Cohort B (Injection site: Abdomen) | EXPERIMENTAL | Participants ≥65 years of age will receive 1 SC injection of 0.5 U/kg of LY2605541 in the abdominal wall on Day 1. |
| LY2605541 (Part A) | EXPERIMENTAL | 0.5 units per kilogram (U/kg) LY2605541 subcutaneously (SC) once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14. Participants remained on their regular physician-prescribed mealtime insulin. |
| Glargine (Part A) | ACTIVE_COMPARATOR | 0.5 U/kg insulin glargine SC once daily for 15 days. Part A involved 3 clamp procedures on Days 8, 11, and 14. Participants remained on their regular physician-prescribed mealtime insulin. |
| First LY2605541 + Exercise,Then LY2605541 Alone (Part B) | EXPERIMENTAL | 0.5 U/kg LY2605541 SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 17 (no exercise on Day 20).Participants remained on their regular physician-prescribed mealtime insulin. |
| First LY2605541 Alone, Then LY2605541 + Exercise (Part B) | EXPERIMENTAL | 0.5 U/kg LY2605541 SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 20 (no exercise on Day 17). Participants remained on their regular physician-prescribed mealtime insulin. |
| First Glargine + Exercise, Then Glargine Alone (Part B) | ACTIVE_COMPARATOR | 0.5 U/kg insulin glargine SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 17 (no exercise on Day 20). Participants remained on their regular physician-prescribed mealtime insulin. |
| First Glargine Alone, Then Glargine + Exercise (Part B) | ACTIVE_COMPARATOR | 0.5 U/kg insulin glargine SC once daily for an additional 6 days, beginning on Day 16. Exercise challenge on Day 20 (no exercise on Day 17). |
| LY2605541-Normal Hepatic Function | EXPERIMENTAL | Participants with normal hepatic function will receive a single subcutaneous (SC) dose of 0.075 milligrams per kilogram (mg/kg) LY2605541 |
| LY2605541-Mild Hepatic Impairment | EXPERIMENTAL | Participants with mild hepatic impairment will receive a single SC dose of 0.075 mg/kg LY2605541 |
| LY2605541-Moderate Hepatic Impairment | EXPERIMENTAL | Participants with moderate hepatic impairment will receive a single SC dose of 0.075 mg/kg LY2605541 |
| LY2605541-Severe Hepatic Impairment | EXPERIMENTAL | Participants with severe hepatic impairment will receive a single SC dose of 0.075 mg/kg LY2605541 |
| Part A, Cohort A; LY2605541 | EXPERIMENTAL | Healthy participants received 5.1 milliunits/minute (mU/min) in Period 1, 10.2 mU/min in Period 2, and 15.3 mU/min in Period 3, administered intravenously (IV) over 8 hours. All periods were separated by a minimum 6-day washout period |
| Part A, Cohort A; Insulin Glargine | ACTIVE_COMPARATOR | Healthy participants received insulin glargine (30 milliunits/meter squared/minute \[mU/m\^2/min\]) administered IV over 8 hours in Period 4. All periods were separated by a minimum 6-day washout period |
| Part A, Cohort B; LY2605541 | EXPERIMENTAL | Healthy participants received 15.3 mU/min in Period 1, 37.0 mU/min in Period 2, and 74.1 mU/min in Period 3, administered IV over 8 hours. All periods were separated by a minimum 6-day washout period. |
| Part A, Cohort B; Insulin Glargine | ACTIVE_COMPARATOR | Healthy participants received insulin glargine (60 mU/m\^2/min) administered IV over 8 hours in Period 4. All periods were separated by a minimum 6-day washout period. |
| Part B; LY2605541 | EXPERIMENTAL | Participants with T1DM received 15.3 mU/min in 1 of 4 study periods, administered IV up to 8 hours and received 74.1 mU/min in 1 of 4 Periods, administered IV up to 10 hours. Each dose was separated by a minimum 6-day washout period. |
| Part B; Insulin Glargine | ACTIVE_COMPARATOR | Participants with T1DM received 1 insulin glargine dose per study period (10 and 20 mU/m\^2/min) administered IV over 8 hours in 2 of 4 study periods. Each dose was separated by a minimum 6-day washout period. |
| Name | Type | Description |
|---|---|---|
| LY2605541 | DRUG | - |
| Human Insulin NPH | DRUG | - |
| Oral Antihyperglycemic Medications (OAM) | DRUG | - |
| Insulin Lispro | DRUG | All participants will be administering insulin lispro SQ as their pre-meal insulin during the course of the trial. |
| Insulin glargine | DRUG | - |
Inclusion Criteria: * Have had type 2 diabetes mellitus for at least 1 year, not treated with insulin * Have been receiving 2 or more OAMs for at least 3 months prior to the study * Have a hemoglobin A1c (HbA1c) of 7.0% to 11.0%, inclusive, at screening * Have a body mass index (BMI) less than or e...