A Study Comparing Dulaglutide With Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes (T2D) and Moderate or Severe Chronic Kidney Disease (CKD)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the glycemic efficacy and safety of dulaglutide compared to insulin glargine in the treatment of participants with type 2 diabetes and moderate or severe chronic kidney disease.

Official Title
-----------------
A Randomized, Open-Label, Parallel-Arm Study Comparing the Effect of Once-weekly Dulaglutide With Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease

Conditions
-----------------
Type 2 Diabetes, Chronic Kidney Disease

Intervention / Treatment
-----------------
* Drug: Dulaglutide
* Drug: Insulin glargine
* Drug: Insulin lispro


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and non-pregnant women aged ≥18 years Hemoglobin A1c (HbA1c) ≥7.5% and ≤10.5% Type 2 diabetes on insulin or insulin + oral antihyperglycemic medication Participants with presumed diabetic kidney disease with or without hypertensive nephrosclerosis diagnosed with moderate or severe CKD with estimated glomerular filtration rate (eGFR) of ≥15 to <60 milliliters per minute (mL/min)/1.73 meter squared (m^2) Able and willing to perform multiple daily injections Body mass index (BMI) between 23 and 45 kilogram/square meter (kg/m^2) Exclusion Criteria: Stage 5 CKD as defined by eGFR <15 mL/min/1.73 m^2 OR having required dialysis Rapidly progressing renal dysfunction likely to require renal replacement History of a transplanted organ Type 1 diabetes mellitus At screening a systolic blood pressure of ≥150 mmHg or a diastolic blood pressure of ≥90 mmHg with or without antihypertensive medication An episode of ketoacidosis or hyperosmolar state/coma in the past 6 months or a history of severe hypoglycemia in the past 3 months prior to the Screening Visit Cardiovascular conditions within 12 weeks prior to randomization: acute myocardial infarction, New York Heart Association (NYHA) class III or class IV heart failure, or cerebrovascular accident (stroke) Acute or chronic hepatitis Signs and symptoms of chronic or acute pancreatitis, or were in the past diagnosed with pancreatitis Serum calcitonin ≥35 picograms per milliliter (pg/mL) at Screening Visit Self or family history of medullary C-cell hyperplasia, focal hyperplasia, or carcinoma Known history of untreated proliferative retinopathy

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Insulin glargine<br>Insulin glargine was administered subcutaneously (SC) at bedtime per a modified forced-titration treat-to-target algorithm. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day. | Drug: Insulin glargine<br>* Administered SC<br>Drug: Insulin lispro<br>* Administered SC<br>|
| Experimental: 0.75 mg Dulaglutide<br>0.75 milligram (mg) of dulaglutide was administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day. | Drug: Dulaglutide<br>* Administered SC<br>* Other names: LY2189265;Drug: Insulin lispro<br>* Administered SC<br>|
| Experimental: 1.5 mg Dulaglutide<br>1.5 mg of dulaglutide was administered once weekly as a SC injection. Participants were instructed to administer their titrated prandial insulin lispro dose SC with the three most significant meals of the day. | Drug: Dulaglutide<br>* Administered SC<br>* Other names: LY2189265;Drug: Insulin lispro<br>* Administered SC<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least square (LS) means in HbA1c were calculated using a restricted maximum likelihood (REML) based mixed-effects model for repeated measures (MMRM) with the change in HbA1c as the dependent variable and treatment, macroalbuminuria (MA) region, Baseline CKD Severity, week, treatment*week, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. | Baseline, 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Whose HbA1c Was <7.0% | Percentage of participants whose HbA1c was <7.0% based on last observation carried forward (LOCF). | 26 Weeks | 
| Percentage of Participants Whose HbA1c Was <8.0% | Percentage of Participants whose HbA1c was <8.0% based on last observation carried forward (LOCF). | 26 Weeks | 
| Change From Baseline in 8-Point Self-Monitored Plasma Glucose (SMPG) | The daily mean of 8-point SMPG profile at Week 26 is presented. Participants were required to perform two 8-point SMPG profiles over a 1-week period at 5 separate times throughout the study. LS means were calculated using the MMRM model including the corresponding baseline value as a continuous covariate, as well as baseline HbA1c, MA-region, treatment, week, treatment*week, baseline CKD severity, and log baseline eGFR (within CKD severity).The two 8-point SMPG profiles were collected on two non-consecutive days (pre-meal and 2-hour postprandial SMPG x [morning, midday, and evening meals in one day] + bedtime + 5 hours after bedtime). | Baseline, 26 Weeks | 
| Change From Baseline in Fasting Glucose (FG) | LS means were calculated using MMRM with the change in FG as the dependent variable and treatment, MA -region, Baseline CKD Severity, week, treatment*week, baseline FG, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured | Baseline, 26 Weeks | 
| Change From Baseline in Mean Daily Insulin Lispro Dose | The mean daily insulin was based on a 4-week interval prior to week 26 assessments. LS means were calculated using a REML based mixed-effects model for repeated measures (MMRM) with the change in mean daily insulin as the dependent variable and treatment, MA-region, Baseline HbA1c, baseline mean daily insulin, baseline CKD Severity, week, treatment*week, log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. | Baseline, 26 Weeks | 
| Percentage of Participants With Estimated Average Glucose <154 mg/dL | Percentage of Participants With Estimated Average Glucose <154 milligram/deciliter (mg/dL) was based on last observation carried forward (LOCF). | 26 Weeks | 
| Change From Baseline in Serum Creatinine (sCr) | Change from baseline in serum creatinine (sCr) levels after treatment. | Baseline, 26 Weeks | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | The change in estimated glomerular filtration rate (eGFR) by using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. | Baseline, 26 Weeks | 
| Change From Baseline in Estimated Creatinine Clearance (eCrCl) | Estimated creatinine clearance (eCrCl) was calculated by Cockcroft-Gault [Cockcroft and Gault 1976] equation using baseline estimated lean body weight. | Baseline, 26 Weeks | 
| Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) | The change from baseline in Urinary Albumin to Creatinine Ratio (UACR). | Baseline, 26 Weeks | 
| Change From Baseline in Body Weight | LS means were calculated from a REML based MMRM model: Change from Baseline = treatment, week, treatment*Week, MA-region, Baseline HbA1c (%), Baseline Body Weight (kg), Baseline CKD Severity, Log Baseline eGFR (within CKD severity), where participant enters the model as a random effect. Covariance structure = Unstructured. • | Baseline, 26 Weeks | 
| Percentage of Participants With Self-Reported Hypoglycemic Events (HE) | Hypoglycemic events (HE) were classified as severe (defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a plasma glucose level of ≤3.9 mmol/L (≤70 mg/dL), nocturnal (defined as any hypoglycemic event that occurs between bedtime and waking). The number of self-reported hypoglycemic events was summarized cumulatively at 26 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. | Baseline through 26 Weeks | 
| Rate of Hypoglycemic Events | Hypoglycemic events (HE) were classified as total HE rate, documented symptomatic hypoglycemia, severe hypoglycemia, and nocturnal. The 1-year adjusted rate of HEs was summarized cumulatively at 26 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. | Baseline through 26 Weeks | 
| Change From Baseline in HbA1c | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS means in HbA1c were calculated using a REML based mixed-effects model for repeated measures (MMRM) with the change in HbA1c as the dependent variable and treatment, MA region, Baseline CKD Severity, week, treatment*week, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. | Baseline, 52 Weeks | 
| Percentage of Participants Whose HbA1c is <7.0% | Percentage of participants whose HbA1c was <7.0% based on last observation carried forward (LOCF). | 52 Weeks | 
| Percentage of Participants Whose HbA1c is <8.0% | Percentage of participants whose HbA1c was <8.0% based on last observation carried forward (LOCF). | 52 Weeks | 
| Change From Baseline in 8-Point SMPG | The daily mean of 8-point SMPG profile at Week 52 is presented. Participants were required to perform two 8-point SMPG profiles over a 1-week period at 5 separate times throughout the study. LS means were calculated using the MMRM model including the corresponding baseline value as a continuous covariate, as well as baseline HbA1c, MA-region, treatment, week, treatment*week, baseline CKD severity, and log baseline eGFR (within CKD severity).The two 8-point SMPG profiles were collected on two non-consecutive days (pre-meal and 2-hour postprandial SMPG x [morning, midday, and evening meals in one day] + bedtime + 5 hours after bedtime). | Baseline, 52 Weeks | 
| Change From Baseline in FG | LS means were calculated using MMRM with the change in FG as the dependent variable and treatment, MA -region, Baseline CKD Severity, week, treatment*week, baseline FG, baseline HbA1c (%), log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured | Baseline, 52 Weeks | 
| Change in Mean Daily Insulin Lispro Dose | The mean daily insulin was based on a 4-week interval prior to week 52 assessments. LS means were calculated using a REML based mixed-effects model for repeated measures (MMRM) with the change in mean daily insulin as the dependent variable and treatment, MA-region, Baseline HbA1c, baseline mean daily insulin, baseline CKD Severity, week, treatment*week, log baseline eGFR (within CKD severity), and participant was the random effect. Covariance structure = Unstructured. | Baseline, 52 Weeks | 
| Percentage of Participants With Estimated Average Glucose <154 mg/dL | Percentage of Participants With Estimated Average Glucose <154 milligram/deciliter (mg/dL) was based on last observation carried forward (LOCF). | 52 Weeks | 
| Change From Baseline in sCr | Change from baseline in sCr levels after treatment. | Baseline, 52 Weeks | 
| Change From Baseline in eGFR | The change in eGFR by using CKD-EPI equation. | Baseline, 52 Weeks | 
| Change From Baseline in eCrCl | eCrCl was calculated by Cockcroft-Gault [Cockcroft and Gault 1976] equation using baseline estimated lean body weight. | Baseline, 52 Weeks | 
| Change From Baseline in UACR | The change from baseline in UACR | Baseline, 52 Weeks | 
| Change From Baseline in Body Weight | LS means were calculated from a REML based MMRM model: Change from Baseline = treatment , week, treatment*Week, MA-region, Baseline HbA1c (%), Baseline Body Weight (kg), Baseline CKD Severity, Log Baseline eGFR (within CKD severity), where participant enters the model as a random effect. Covariance structure = Unstructured. | Baseline, 52 Weeks | 
| Percentage of Participants With Self-Reported Hypoglycemic Events (HE) | Hypoglycemic events (HE) were classified as severe (defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a plasma glucose level of ≤3.9 mmol/L (≤70 mg/dL), nocturnal (defined as any hypoglycemic event that occurs between bedtime and waking). The number of self-reported hypoglycemic events was summarized cumulatively at 52 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. | Baseline through 52 Weeks | 
| Rate of Hypoglycemic Events (HE) | HE were classified as total HE rate, documented symptomatic hypoglycemia, severe hypoglycemia, and nocturnal. The 1-year adjusted rate of HEs was summarized cumulatively at 52 weeks. A summary of other nonserious AEs, and all SAEs, regardless of causality, is located in the Reported Adverse Events section. | Baseline through 52 Weeks | 
| Participants With Events of Allergic/Hypersensitivity Reactions | Participants with Events of Allergic/Hypersensitivity Reactions: Angioedema Standardized MedDRA Query (SMQ), Anaphylactic Reaction SMQ, or Severe Cutaneous Adverse Reactions SMQ | Baseline through 52 Weeks |