A Study of LY900014 in Participants With Type 1 Diabetes

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the efficacy of the study drug LY900014 compared to insulin lispro, both in combination with insulin glargine or insulin degludec, in adults with type 1 diabetes (T1D).

Official Title
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A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro With an Open-Label Postprandial LY900014 Treatment Group, in Combination With Insulin Glargine or Insulin Degludec, in Adults With Type 1 Diabetes PRONTO-T1D

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: LY900014
* Drug: Insulin Lispro
* Drug: Insulin Glargine
* Drug: Insulin Degludec


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have T1D for at least 1 year prior to screening and continuously using insulin for at least 1 year. HbA1c of ≥7.0 and ≤9.5%. Use insulin lispro, insulin aspart, or insulin glulisine as prandial insulin. Use insulin glargine, insulin detemir, insulin degludec, or neutral protamine Hagedorn (NPH) insulin as basal insulin. Exclusion Criteria: Have used other antihyperglycemic medications or therapies (inhaled, oral or injectable) within 90-days of screening. Have had more than 1 severe hypoglycemic episode within 6 months of screening. Have had more than 1 hospitalization related to hyperglycemia or diabetic ketoacidosis within 6 months of screening. Have clinically significant gastrointestinal disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY900014<br>LY900014 given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | Drug: LY900014<br>* Administered SC<br>* Other names: Ultra-Rapid Lispro;Drug: Insulin Glargine<br>* Administered SC<br>Drug: Insulin Degludec<br>* Administered SC<br>|
| Active Comparator: Insulin Lispro (Humalog)<br>Insulin lispro given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | Drug: Insulin Lispro<br>* Administered SC<br>* Other names: Humalog;Drug: Insulin Glargine<br>* Administered SC<br>Drug: Insulin Degludec<br>* Administered SC<br>|
| Experimental: LY900014 Postmeal (Open Label)<br>LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. | Drug: LY900014<br>* Administered SC<br>* Other names: Ultra-Rapid Lispro;Drug: Insulin Glargine<br>* Administered SC<br>Drug: Insulin Degludec<br>* Administered SC<br>|
| Experimental: LY900014 - Maximum Extended Enrollment (MEE)<br>LY900014 given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | Drug: LY900014<br>* Administered SC<br>* Other names: Ultra-Rapid Lispro;Drug: Insulin Glargine<br>* Administered SC<br>Drug: Insulin Degludec<br>* Administered SC<br>|
| Active Comparator: Insulin Lispro (Humalog)-MEE<br>Insulin lispro given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. | Drug: Insulin Lispro<br>* Administered SC<br>* Other names: Humalog;Drug: Insulin Glargine<br>* Administered SC<br>Drug: Insulin Degludec<br>* Administered SC<br>|
| Experimental: LY900014 Postmeal (Open Label)-MEE<br>LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. | Drug: LY900014<br>* Administered SC<br>* Other names: Ultra-Rapid Lispro;Drug: Insulin Glargine<br>* Administered SC<br>Drug: Insulin Degludec<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26 | 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 strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26 | 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. 1-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. | Baseline, Week 26 | 
| Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26 | 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. 2-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. | Baseline, Week 26 | 
| Rate of Severe Hypoglycemia at Week 26 | 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. | Baseline through Week 26 | 
| Rate of Documented Symptomatic Hypoglycemia at Week 26 | 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. | Baseline through Week 26 | 
| Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26 | 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, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), 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. | Baseline, Week 26 | 
| Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 | 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, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), 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. | Baseline, Week 26 | 
| Change From Baseline in Insulin Dose at Week 26 | LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data prior to permanent discontinuation of study drug. | Baseline, Week 26 | 
| Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26 | ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the ANCOVA model with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug. | Baseline, Week 26 | 
| Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26 | ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the analysis of covariance (ANCOVA) with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug. | Baseline, Week 26 | 
| 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. | Week 26 | 
| Change From Baseline in HbA1c at Week 52 | 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 MMRM model with variables of baseline, pooled country, type of basal insulin during lead-in, prandial Insulin Dosing Plan, treatment (Type III sum of squares) as fixed factors. The analysis included data prior to permanent discontinuation of study drug. | Baseline, Week 52 |