A Study for Patients With Type 1 Diabetes

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01049412
• Collaborator: (none)
• Enrollment: 138
• Locations: 13
• Arms: 2
• Duration (Months): 12
• Patients Per Site: 10.6
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Comparison of blood glucose levels in patients with Type 1 diabetes when they take a new basal insulin analog and when they take insulin glargine

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: LY2605541; Drug: Insulin glargine	Phase 2

Detailed Description

Prestudy treatment for patients who enter this study will be once daily insulin glargine along with mealtime insulins. Patients will continue to use their mealtime insulins throughout the study. The study will consist of 16 weeks of treatment and 4 weeks of follow-up. The 16 weeks of treatment will consist of two 8-week periods (Periods 1 and 2) during which patients will receive insulin glargine for 8 weeks and LY2605541 for 8 weeks in a random sequence. During the 4-week follow-up period, patients will return to insulin glargine or another basal insulin recommended by the investigator.

Study Design

• Study Type: Interventional
• Actual Enrollment: 138 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of LY2605541 Compared With Insulin Glargine in the Treatment of Type 1 Diabetes Mellitus
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY2605541 First, Then Insulin Glargine Participants received LY2605541 for 8 weeks, followed by insulin glargine for 8 weeks.	Drug: LY2605541; Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.; Drug: Insulin glargine; Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.
Active Comparator: Insulin Glargine First, Then LY2605541 Participants received insulin glargine for 8 weeks, followed by LY2605541 for 8 weeks.	Drug: LY2605541; Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.; Drug: Insulin glargine; Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.

Outcome Measures

Primary Outcome Measures

1. Daily Average Blood Glucose (Avg. BG) at Week 8 Endpoint as Measured by the 8-Point Self-Monitored Blood Glucose (SMBG) Profiles [Week 8 of each treatment period]

   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.

Secondary Outcome Measures

1. Change From Baseline in Daily Average Blood Glucose (Avg. BG) at Week 8 Endpoint as Measured by the 8-Point Self-Monitored Blood Glucose (SMBG) Profiles [Baseline, Week 8 of each treatment period]

   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. LS mean of daily Avg. BG is from MMRM, which includes fixed effects of treatment (LY2605541, Glargine); Treatment Sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; a random effect for participant.

2. Change From Baseline in Hemoglobin (HbA1c) at Week 8 Endpoint of Period I [Baseline, Week 8 (Period I)]

   HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS mean of the change from baseline to 8-week at Period I is from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group); baseline HbA1c; visit; interaction between visit and treatment; and a random effect for participant.

3. Percentage of Participants With HbA1c <7.0% and HbA1c ≤6.5% at Week 8 Endpoint of Period I [Week 8 (Period I)]

   HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time.

4. Percentage of Participants With HbA1c <7.0% and HbA1c ≤6.5% at Week 8 Endpoint Who Did Not Experience a Hypoglycemic Episode During Treatment (Period I) [Week 8 (Period I)]

   HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 millimole/Liter (mmol/L) (≤70 milligram/deciliter [mg/dL]) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]).

5. 8-Point Self-Monitored Blood Glucose (SMBG) Measures at Week 8 Endpoint [Week 8 of each treatment period]

   8-point SMBG profiles are measured at morning fasting BG (FBG), midday pre-meal BG, evening pre-meal BG, 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; interaction between visit and treatment; and a random effect for participant.

6. Daily Basal Insulin Dose at Week 2 and Week 8 Endpoint [Week 2 and Week 8 of each treatment period]

   LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; interaction between visit and treatment; and a random effect for participant.

7. Pharmacokinetics - Drug (LY2605541) Concentration at Steady State (Css) at Week 8 Endpoint [Week 8 of each treatment period]

   The drug (LY2605541) concentration at steady state (Css) is calculated from the clearance (Liter/hour) and the final dose of the participants. Clearance was estimated using population-based approaches.

8. Percentage of Participants With Antibody Status Change From Baseline to Week 8, Week 16 and Week 20 [Week 8, Week 16 and Week 20]

   Negative is defined as either 'negative' from lab or percent binding <1.16%. Positive is defined as the percent binding is ≥1.16%. The antibody status change is from negative to positive or positive to negative.

9. Percentage of Participants With Hypoglycemia Baseline Through Week 8 [Baseline through Week 8 of each treatment period]

   Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 millimole per Liter (mmol/L) (≤70 milligram per deciliter [mg/dL]) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005].

10. Rate of Hypoglycemia Per 30 Days Baseline Through Week 8 [Baseline through Week 8 of each treatment period]

    Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 mmol/L (≤70 mg/dL) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]. Hypoglycemia rate per 30 days is calculated as the number of hypoglycemia/number of days at risk*30.

11. Glycemic Variability in Fasting Blood Glucose (FBG) at Week 8 Endpoint [Week 8 of each treatment period]

    Within-patient glycemic variability was assessed as the standard deviation of fasting blood glucose each day between Week 6 and Week 8. LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; interaction between visit and treatment; and a random effect for participant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 1 diabetes mellitus (T1DM) for at least 1 year and using insulin glargine for at least 6 months with a maximum daily dose of 1 unit per kilogram (U/kg).

• Hemoglobin A1c (HbA1c) of no greater than 10.5% before randomization

• Body mass index (BMI) 19 to 45 kilogram per square meter (kg/m²)

• Capable and willing to prepare and inject insulin with a syringe, monitor own blood glucose, complete the study diary, be receptive to diabetes education, comply with study requirements, and receive telephone calls during treatment

• Women of childbearing potential must test negative for pregnancy before receiving treatment and agree to use reliable birth control until completing the follow-up

Exclusion Criteria:

• Twice daily use of insulin glargine within 30 days prior to the study

• Use of any oral or injectable medication intended for the treatment of diabetes mellitus other than insulins in the 3 months prior to the study

• Use of an insulin pump

• More than 1 episode of severe hypoglycemia within 3 months prior to the study, or currently diagnosed as having hypoglycemia unawareness

• 2 or more emergency room visits or hospitalizations due to poor glucose control in the 6 months preceding the study

• Known hypersensitivity or allergy to any of the study insulins or their excipients

• Blood transfusion or severe blood loss within 3 months prior to the study or known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with the HbA1c methodology

• Irregular sleep/wake cycle

• Pregnant or intend to become pregnant during the study

• Women who are breastfeeding

• Use of prescription or over-the-counter medications to promote weight loss within 3 months prior to the study

• Current participation in a weight loss program or plans to do so during the study

• Use of chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy currently or within 4 weeks prior to the study

• Cardiac disease with a marked impact on physical functioning

• Clinically significant electrocardiogram (ECG) abnormalities at screening

• Fasting triglycerides greater than 500 milligram per deciliter (mg/dL)

• Liver disease

• History of renal transplantation, current renal dialysis, or creatinine greater than 2.0 mg/dL (177 micromole per liter [μmol/L])

• Malignancy other than basal cell or squamous cell skin cancer, currently or within the last 5 years

• Treatment with any antibody-based therapy within 6 months prior to the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Chula Vista	California	United States	91911
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Atlanta	Georgia	United States	30309
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Idaho Falls	Idaho	United States	83404
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Topeka	Kansas	United States	66606
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Metairie	Louisiana	United States	70006
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Baltimore	Maryland	United States	21204
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Minneapolis	Minnesota	United States	55416
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Austin	Texas	United States	78731
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Dallas	Texas	United States	75230
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Renton	Washington	United States	98057
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Holon		Israel	22100
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Petah Tiqva		Israel	49451
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tel Hashomer		Israel	52661

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

• Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9. Review.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01049412
• Other Study ID Numbers: 12151; I2R-MC-BIAD
• First Posted: Jan 14, 2010
• Last Update Posted: Apr 17, 2018
• Last Verified: Mar 1, 2018

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Glargine

Study Results

Participant Flow

Pre-assignment Detail	This is an open-label, randomized, 2-arm crossover study. The study consisted of two 8-week periods (Periods I and II) during which participants received Glargine for 8 weeks and LY2605541 for 8 weeks in a random sequence.

Arm/Group Title	LY2605541/Glargine	Glargine/LY2605541
Arm/Group Description	Participants took LY2605541 in Period I and Glargine in Period II	Participants took Glargine in Period I and LY2605541 in Period II
Period Title: Period I
STARTED	70	68
Took at Least One Dose of Study Drug	69	68
COMPLETED	62	55
NOT COMPLETED	8	13
Period Title: Period I
STARTED	62	55
COMPLETED	58	52
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	LY2605541/Glargine	Glargine/LY2605541	Total
Arm/Group Description	Participants took LY2605541 in Period I and Glargine in Period II	Participants took Glargine in Period I and LY2605541 in Period II	Total of all reporting groups
Overall Participants	69	68	137
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.82 (11.34)	39.53 (12.28)	38.17 (11.85)
Sex: Female, Male (Count of Participants)
Female	28 40.6%	23 33.8%	51 37.2%
Male	41 59.4%	45 66.2%	86 62.8%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.5%	1 0.7%
Asian	0 0%	1 1.5%	1 0.7%
Black or African American	3 4.3%	2 2.9%	5 3.6%
Multiple	1 1.4%	0 0%	1 0.7%
White	65 94.2%	64 94.1%	129 94.2%
Region of Enrollment (Count of Participants)
United States	62 89.9%	64 94.1%	126 92%
Israel	7 10.1%	4 5.9%	11 8%

Outcome Measures

1. Primary Outcome

Title	Daily Average Blood Glucose (Avg. BG) at Week 8 Endpoint as Measured by the 8-Point Self-Monitored Blood Glucose (SMBG) Profiles
Description	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.
Time Frame	Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	92	91
Least Squares Mean (Standard Error) [millimole per Liter (mmol/L)]	7.98 (0.32)	8.53 (0.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The statistical significance level is 0.10.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 90%; -0.81 to -0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Daily Average Blood Glucose (Avg. BG) at Week 8 Endpoint as Measured by the 8-Point Self-Monitored Blood Glucose (SMBG) Profiles
Description	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. LS mean of daily Avg. BG is from MMRM, which includes fixed effects of treatment (LY2605541, Glargine); Treatment Sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; a random effect for participant.
Time Frame	Baseline, Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	92	91
Least Squares Mean (Standard Error) [mmol/L]	-0.74 (0.40)	-0.18 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The statistical significance level is 0.10.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 90%; -0.83 to -0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Hemoglobin (HbA1c) at Week 8 Endpoint of Period I
Description	HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS mean of the change from baseline to 8-week at Period I is from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group); baseline HbA1c; visit; interaction between visit and treatment; and a random effect for participant.
Time Frame	Baseline, Week 8 (Period I)

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	62	54
Least Squares Mean (Standard Error) [percentage of glycated hemoglobin]	-0.45 (0.10)	-0.34 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.242
	Comments	The statistical significance level is 0.10.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 90%; -0.28 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With HbA1c <7.0% and HbA1c ≤6.5% at Week 8 Endpoint of Period I
Description	HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time.
Time Frame	Week 8 (Period I)

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value, last observation carried forward (LOCF).

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	65	60
HbA1c <7.0%	43.1 62.5%	33.3 49%
HbA1c ≤6.5%	24.6 35.7%	13.3 19.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.276
	Comments	The statistical significance level is 0.10. P-value is for HbA1c <7.0%.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments	The statistical significance level is 0.10. P-value is for HbA1c ≤6.5%.
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Percentage of Participants With HbA1c <7.0% and HbA1c ≤6.5% at Week 8 Endpoint Who Did Not Experience a Hypoglycemic Episode During Treatment (Period I)
Description	HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 millimole/Liter (mmol/L) (≤70 milligram/deciliter [mg/dL]) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]).
Time Frame	Week 8 (Period I)

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value, last observation carried forward (LOCF).

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	65	60
HbA1c <7.0%	1.5 2.2%	1.7 2.5%
HbA1c ≤6.5%	0 0%	0 0%

6. Secondary Outcome

Title	8-Point Self-Monitored Blood Glucose (SMBG) Measures at Week 8 Endpoint
Description	8-point SMBG profiles are measured at morning fasting BG (FBG), midday pre-meal BG, evening pre-meal BG, 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; interaction between visit and treatment; and a random effect for participant.
Time Frame	Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	124	130
0300 hours BG	8.97 (0.50)	8.67 (0.51)
Morning FBG	9.33 (0.45)	9.57 (0.49)
Morning 2-hr postprandial BG	8.27 (0.46)	8.76 (0.46)
Midday Pre-meal BG	6.98 (0.43)	7.52 (0.45)
Midday 2-hr postprandial BG	8.08 (0.44)	8.60 (0.47)
Evening Pre-meal BG	7.87 (0.38)	8.73 (0.41)
Evening 2-hr postprandial BG	8.37 (0.44)	9.26 (0.46)
Bed time BG	8.20 (0.45)	9.29 (0.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.392
	Comments	The statistical significance level is 0.10. P-value is for 0300 hour BG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 90%; -0.28 to 0.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.35
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.464
	Comments	The statistical significance level is 0.10. P-value is for morning FBG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 90%; -0.79 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.33
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.151
	Comments	The statistical significance level is 0.10. P-value is for morning 2-hr postprandial BG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 90%; -1.04 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.33
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.079
	Comments	The statistical significance level is 0.10. P-value is for midday pre-meal BG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.54
	Confidence Interval	(2-Sided) 90%; -1.05 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.30
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.070
	Comments	The statistical significance level is 0.10. P-value is for midday 2-hr postprandial BG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 90%; -0.99 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	The statistical significance level is 0.10. P-value is for evening pre-meal BG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.86
	Confidence Interval	(2-Sided) 90%; -1.39 to -0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.32
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	The statistical significance level is 0.10. P-value is for evening 2-hr postprandial BG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.89
	Confidence Interval	(2-Sided) 90%; -1.38 to -0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.29
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	The statistical significance level is 0.10. P-value is for bed time BG.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-1.10
	Confidence Interval	(2-Sided) 90%; -1.64 to -0.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.33
	Estimation Comments

7. Secondary Outcome

Title	Daily Basal Insulin Dose at Week 2 and Week 8 Endpoint
Description	LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; interaction between visit and treatment; and a random effect for participant.
Time Frame	Week 2 and Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with at least one non-missing value of the response variable at any of the subsequent weeks.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	124	130
Week 2	3.35 (0.16)	2.58 (0.16)
Week 8	4.12 (0.18)	2.86 (0.16)

8. Secondary Outcome

Title	Pharmacokinetics - Drug (LY2605541) Concentration at Steady State (Css) at Week 8 Endpoint
Description	The drug (LY2605541) concentration at steady state (Css) is calculated from the clearance (Liter/hour) and the final dose of the participants. Clearance was estimated using population-based approaches.
Time Frame	Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

Participants who took at least one dose of study drug and had measurements at Week 8.

Arm/Group Title	LY2605541
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	115
Geometric Mean (Geometric Coefficient of Variation) [picomoles per liter (pMol/L)]	2873 (54.9)

9. Secondary Outcome

Title	Percentage of Participants With Antibody Status Change From Baseline to Week 8, Week 16 and Week 20
Description	Negative is defined as either 'negative' from lab or percent binding <1.16%. Positive is defined as the percent binding is ≥1.16%. The antibody status change is from negative to positive or positive to negative.
Time Frame	Week 8, Week 16 and Week 20

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with both baseline and endpoint antibody measurements.

Arm/Group Title	LY2605541/Glargine	Glargine/LY2605541
Arm/Group Description	Participants took LY2605541 in Period I and Glargine in Period II	Participants took Glargine in Period I and LY2605541 in Period II
Measure Participants	69	68
Week 8 (Period I) from negative to positive	8.3 12%	3.3 4.9%
Week 8 (Period I) from positive to negative	3.3 4.8%	5.0 7.4%
Week 16 (Period II) from negative to positive	12.5 18.1%	7.4 10.9%
Week 16 (Period II) from positive to negative	1.8 2.6%	7.4 10.9%
Week 20 (follow up) from negative to positive	14.8 21.4%	11.5 16.9%
Week 20 (follow up) from positive to negative	1.9 2.8%	3.8 5.6%

10. Secondary Outcome

Title	Percentage of Participants With Hypoglycemia Baseline Through Week 8
Description	Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 millimole per Liter (mmol/L) (≤70 milligram per deciliter [mg/dL]) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005].
Time Frame	Baseline through Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	124	130
Number [percentage of participants]	92.7 134.3%	90.0 132.4%

11. Secondary Outcome

Title	Rate of Hypoglycemia Per 30 Days Baseline Through Week 8
Description	Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 mmol/L (≤70 mg/dL) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]. Hypoglycemia rate per 30 days is calculated as the number of hypoglycemia/number of days at risk*30.
Time Frame	Baseline through Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	124	130
Mean (Standard Deviation) [number of hypoglycemia episodes/30 days]	8.74 (7.70)	7.36 (6.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.037
	Comments	The statistical significance level is 0.10.
	Method	Negative Binomial Model
	Comments

12. Secondary Outcome

Title	Glycemic Variability in Fasting Blood Glucose (FBG) at Week 8 Endpoint
Description	Within-patient glycemic variability was assessed as the standard deviation of fasting blood glucose each day between Week 6 and Week 8. LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; interaction between visit and treatment; and a random effect for participant.
Time Frame	Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug with non-missing baseline value and at least one non-missing post-baseline value.

Arm/Group Title	LY2605541	Glargine
Arm/Group Description	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods	Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods
Measure Participants	107	107
Least Squares Mean (Standard Error) [mmol/L]	3.13 (0.23)	3.60 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2605541, Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The statistical significance level is 0.10.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Final)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 90%; -0.69 to -0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Adverse Events

Arm/Group Title	LY2605541		Glargine
Arm/Group Description	Participants took LY2605541 administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks		Participants took Glargine administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks
All Cause Mortality
	LY2605541		Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2605541		Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/125 (4.8%)		4/130 (3.1%)
Infections and infestations
Urosepsis	0/125 (0%)	0	1/130 (0.8%)	1
Injury, poisoning and procedural complications
Facial bones fracture	1/125 (0.8%)	1	0/130 (0%)	0
Fall	1/125 (0.8%)	1	0/130 (0%)	0
Metabolism and nutrition disorders
Severe hypoglycaemia	5/125 (4%)	6	3/130 (2.3%)	6
Other (Not Including Serious) Adverse Events
	LY2605541		Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/125 (52.8%)		59/130 (45.4%)
Blood and lymphatic system disorders
Anaemia	2/125 (1.6%)	2	2/130 (1.5%)	2
Lymphadenopathy	2/125 (1.6%)	2	1/130 (0.8%)	1
Gastrointestinal disorders
Abdominal distension	4/125 (3.2%)	5	0/130 (0%)	0
Dyspepsia	4/125 (3.2%)	4	1/130 (0.8%)	1
Nausea	4/125 (3.2%)	4	1/130 (0.8%)	1
Toothache	2/125 (1.6%)	2	1/130 (0.8%)	1
General disorders
Chest pain	2/125 (1.6%)	2	0/130 (0%)	0
Fatigue	2/125 (1.6%)	2	0/130 (0%)	0
Pyrexia	1/125 (0.8%)	1	3/130 (2.3%)	3
Infections and infestations
Influenza	1/125 (0.8%)	1	2/130 (1.5%)	2
Localised infection	2/125 (1.6%)	2	0/130 (0%)	0
Nasopharyngitis	4/125 (3.2%)	4	3/130 (2.3%)	3
Onychomycosis	2/125 (1.6%)	2	2/130 (1.5%)	2
Pharyngitis streptococcal	2/125 (1.6%)	2	2/130 (1.5%)	2
Sinusitis	0/125 (0%)	0	4/130 (3.1%)	4
Upper respiratory tract infection	8/125 (6.4%)	8	7/130 (5.4%)	7
Urinary tract infection	1/125 (0.8%)	1	3/130 (2.3%)	4
Metabolism and nutrition disorders
Decreased appetite	2/125 (1.6%)	2	2/130 (1.5%)	2
Hypoglycaemia	3/125 (2.4%)	3	4/130 (3.1%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	3/125 (2.4%)	3	1/130 (0.8%)	1
Back pain	2/125 (1.6%)	2	2/130 (1.5%)	2
Musculoskeletal discomfort	1/125 (0.8%)	1	2/130 (1.5%)	2
Musculoskeletal stiffness	2/125 (1.6%)	2	2/130 (1.5%)	2
Myalgia	0/125 (0%)	0	2/130 (1.5%)	2
Pain in extremity	5/125 (4%)	5	3/130 (2.3%)	3
Nervous system disorders
Dizziness	0/125 (0%)	0	2/130 (1.5%)	2
Headache	6/125 (4.8%)	7	7/130 (5.4%)	7
Reproductive system and breast disorders
Dysmenorrhoea	2/125 (1.6%)	2	1/130 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/125 (0.8%)	1	2/130 (1.5%)	2
Oropharyngeal pain	2/125 (1.6%)	2	3/130 (2.3%)	3
Sinus congestion	0/125 (0%)	0	2/130 (1.5%)	2
Skin and subcutaneous tissue disorders
Pruritus	2/125 (1.6%)	2	1/130 (0.8%)	1
Rash	2/125 (1.6%)	2	0/130 (0%)	0
Vascular disorders
Hypertension	3/125 (2.4%)	3	2/130 (1.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.