A Study of LY900014 Compared to Insulin Lispro in Participants With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare LY900014 to insulin lispro, both in combination with insulin glargine or insulin degludec, in participants with type 2 diabetes (T2D).

Official Title
-----------------
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro, Both in Combination With Insulin Glargine or Insulin Degludec in Adults With Type 2 Diabetes PRONTO-T2D

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: LY900014
* Drug: Insulin Lispro
* Drug: Insulin Glargine
* Drug: Insulin Degludec
* Drug: Metformin
* Drug: SGLT2 inhibitor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have been diagnosed (clinically) with T2D, based on the World Health Organization (WHO) classification for at least 1 year prior to screening. Have been treated for at least 90 days prior to screening with: Basal insulin (insulin glargine U-100 [Basaglar/Abasaglar or LANTUS] or U-300, insulin detemir, insulin degludec U-100 or U-200, or neutral protamine Hagedorn [NPH] insulin) in combination with at least 1 prandial injection of bolus insulin (insulin lispro U-100 or U-200, insulin aspart, insulin glulisine, or regular insulin) Or Premixed analog or human insulin regimens with any basal and bolus insulin combination injected at least twice daily Participants may be treated with up to 3 of the following oral antihyperglycemic medications (OAMs) in accordance with local regulations: Metformin Dipeptidyl peptidase-4 (DPP-4) inhibitor Sodium glucose cotransporter 2 (SGLT2) inhibitor Sulfonylurea Meglitinide Alpha-glucoside inhibitor Have an HbA1c value between ≥7.0 and ≤10.0%, according to the central laboratory at the time of screening. Have a body mass index (BMI) of ≤45.0 kilograms per meter squared at screening. Exclusion Criteria: Have been diagnosed, at any time, with type 1 diabetes (T1D) or Latent Autoimmune Diabetes in Adults. Have hypoglycemia unawareness as judged by the investigator. Have had any episode of severe hypoglycemia within the 6 months prior to screening. Have had 1 or more episodes of diabetic ketoacidosis or hyperglycemic hyperosmolar state within the 6 months prior to screening. Have used thiazolidinediones, Glucagon-Like Peptide 1 (GLP-1) receptor agonist, or pramlintide within 90 days prior to screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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) with each meal with either 100 U/mL (U-100) basal insulin glargine given SC once or twice daily or U-100 or 200 U/mL (U-200) 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>Drug: Metformin<br>* Administered orally.<br>Drug: SGLT2 inhibitor<br>* Administered orally.<br>|
| Active Comparator: Insulin Lispro (Humalog)<br>Insulin lispro given SC with each meal with either U-100 basal insulin glargine given SC once or twice daily or U-100 or U-200 insulin degludec given SC once daily. Prandial 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>Drug: Metformin<br>* Administered orally.<br>Drug: SGLT2 inhibitor<br>* Administered orally.<br>|
| Experimental: LY900014 Maximum Extended Enrollment (MEE)<br>LY900014 given subcutaneously (SC) with each meal with either U-100 basal insulin glargine given SC once or twice daily or U-100 or U-200 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>Drug: Metformin<br>* Administered orally.<br>Drug: SGLT2 inhibitor<br>* Administered orally.<br>|
| Active Comparator: Insulin Lispro (Humalog) MEE<br>Insulin lispro given SC with each meal with either U-100 basal insulin glargine given SC once or twice daily or U-100 or U-200 insulin degludec given SC once daily. Prandial 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>Drug: Metformin<br>* Administered orally.<br>Drug: SGLT2 inhibitor<br>* Administered orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26 | Change from baseline in HbA1c was performed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, 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 were available prior to permanent discontinuation of study drug. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand | 1-hour PPG excursion during MMTT uses the analysis of covariance (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 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. | Week 26 | 
| 2-hour PPG Excursion During MMTT Efficacy Estimand | 2-hour PPG excursion during MMTT uses 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 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. | Week 26 | 
| Rate of Severe Hypoglycemia | 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. 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 com with or without seizures, and may require parenteral therapy. | Baseline through Week 26 | 
| Rate of Documented Symptomatic Hypoglycemia | 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 | Change from baseline in 1,5-AG 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 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 | Change from baseline in 10-point SMBG values 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 | Change from baseline in insulin dose 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. Change from baseline in ITSQ regimen inconvenience domain score 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. | 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. Change from baseline in ITSQ lifestyle flexibility domain score 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. | Baseline, Week 26 | 
| Number of Participants With HbA1c <7% | Number of participants with HbA1c <7% at Week 26. | Week 26 |