Insulin Lispro 6 Days Versus Insulin Aspart 6 Days in Pump Use

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01109316
• Collaborator: (none)
• Enrollment: 132
• Locations: 11
• Arms: 3
• Duration (Months): 16
• Patients Per Site: 12
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This is a 6-sequence, 3-period (8 weeks each), 3-arm, 24-week crossover study. The purpose of this study is to provide information on the use of insulin lispro in insulin pumps (Continuous Subcutaneous Insulin Infusion [CSII]) compared to insulin aspart over 6 days of pump reservoir in-use. The study will also compare the in-use characteristics of insulin lispro infused at 6 days with insulin lispro infused at 2 days.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Insulin lispro 2 day reservoir in-use; Drug: Insulin lispro 6 day reservoir in-use; Drug: Insulin aspart 6 day reservoir in-use	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 132 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Randomized, Crossover Trial of CSII Reservoir In-use Comparing Insulin Lispro Formulation to Insulin Aspart in Patients With Type 1 Diabetes Mellitus
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Insulin Lispro 2 Day	Drug: Insulin lispro 2 day reservoir in-use; Insulin lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.; Other Names: LY275585 Humalog
Experimental: Insulin Lispro 6 Day	Drug: Insulin lispro 6 day reservoir in-use; Insulin lispro 6 Day (L6D) administered by infusion pump for 8 week treatment period.; Other Names: LY275585 Humalog
Active Comparator: Insulin Aspart 6 Day	Drug: Insulin aspart 6 day reservoir in-use; Insulin aspart 6 Day (A6D) administered by infusion pump for 8 week treatment period.

Outcome Measures

Primary Outcome Measures

1. Mean of Last Five 7-point Self Monitored Blood Glucose (SMBG) Taken on Day 6 for Insulin Lispro 6D and Day 2 for Insulin Lispro 2D and Day 6 for Insulin Aspart 6D Pump Reservoir In-use [8 weeks of each treatment]

Secondary Outcome Measures

1. Mean SMBG [8 weeks for each treatment]

   Mean SMBG for combined periods; all reported SMBG values on days 1-6 for Insulin Lispro 6 Day and Insulin Aspart 6 Day, and days 1-2 for Insulin Lispro 2 Day.

2. Mean Daily Insulin Dose (Total, Basal, and Bolus) [8 weeks for each treatment]

3. Change From Baseline to 8 Weeks Endpoint for Each Treatment in Hemoglobin A1c (HbA1c) Values [Baseline, 8 weeks for each treatment]

4. Number of Participants Who Achieve or Maintain an HbA1c Less Than or Equal to 6.5% and Less Than 7% [8 weeks for each treatment]

5. Percentage of Participants With Hyperglycemia [8 weeks for each treatment]

   Hyperglycemia was defined as an event with (1) a measured blood glucose concentration >250 milligrams per deciliter (mg/dL) (13.9 mmol/L) and ≥3 hours after eating, or (2) a measured blood glucose concentration >300 mg/dL (16.7 mmol/L) and <3 hours after eating.

6. Hyperglycemic Episode Rate Per 30 Days [8 weeks for each treatment]

   Hyperglycemia was defined as an episode with (1) a measured blood glucose concentration >250 milligrams per deciliter (mg/dL) (13.9 mmol/L) and ≥3 hours after eating, or (2) a measured blood glucose concentration >300 mg/dL (16.7 mmol/L) and <3 hours after eating. Rate is presented as the number of hyperglycemic episodes adjusted for 30 days.

7. Percentage of Participants With Pump Complications [8 weeks for each treatment]

   Overall Pump Complications were any combination of: tubing clogged, kinked, disconnected, pulled out, blood in tubing; too much heat, too much cold, empty reservoir, low battery, occlusion alarm, no delivery alarm; at site - skin abscess, excessive redness, swelling (not nodule), bleeding, bruising; reservoir change (infusion set change reason only); and other. When either a reservoir change or an infusion set change was reported, participants were questioned whether change was early (prior to 6 days for L6D or A6D, or prior to 2 days for L2D). If 'yes', then recorded as premature change.

8. Pump Complication Rate Per 30 Days [8 weeks for each treatment]

   Overall Pump Complications were any combination of: tubing clogged, kinked, disconnected, pulled out, blood in tubing; too much heat, too much cold, empty reservoir, low battery, occlusion alarm, no delivery alarm; at site - skin abscess, excessive redness, swelling (not nodule), bleeding, bruising; reservoir change (infusion set change reason only); and other. When either a reservoir change or an infusion set change was reported, participants were questioned whether change was early (prior to 6 days for L6D or A6D, or prior to 2 days for L2D). If 'yes', then recorded as premature change.

9. Percentage of Participants With Hypoglycemia [8 weeks for each treatment]

   Hypoglycemia was defined as an event which was associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of ≤ 70 mg/dL (3.9 mmol/L).

10. Hypoglycemia Episode Rate Per 30 Days [8 weeks for each treatment]

    Hypoglycemia was defined as an event which was associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of ≤ 70 mg/dL (3.9 mmol/L). Rate is presented as the number of hypoglycemic episodes adjusted for 30 days.

11. Change From Baseline to 8 Weeks Endpoint for Each Treatment in Weight [Baseline, 8 weeks for each treatment]

12. Change From Baseline to 8 Weeks Endpoint for Each Treatment in Blood Pressure [Baseline, 8 weeks for each treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosed with type 1 diabetes (World Health Organization criteria) for at least 24 months.

• Treated with continuous subcutaneous insulin infusion therapy for the previous 6 months.

• Mean total daily insulin dose for 3 days prior to screening equal to or less than 46 units/day using a 300-unit reservoir or less than or equal to 26 units/day using a 180 unit reservoir.

• Baseline body mass index (BMI) less than or equal to 35.0 kg/m^2.

• Baseline glycosylated hemoglobin (HbA1c) 5% to 9%.

Exclusion Criteria:

• Impaired renal function (serum creatinine greater than or equal to 2.0 milligrams per deciliter [mg/dL]).

• Legal blindness.

• Have had any episode of hypoglycemic coma, seizures, or disorientation in the 12 months prior to screening.

• Have had hypoglycemia unawareness (routinely asymptomatic at blood glucose (BG) less than 45 mg/dL) in the 12 months prior to screening.

• Have had any emergency room visits or hospitalizations due to poor glucose control in the 12 months prior to screening.

• Have had a pump-related infusion site abscess in the 12 months prior to screening.

• Have had multiple, clinically significant occlusions as judged by the investigator.

• Have had any infection with staphylococcus aureus in the past 5 years.

• Have one of the following concomitant diseases: presence of clinically significant hematologic, oncologic, renal, cardiac, hepatic, or gastrointestinal disease, or any other serious disease considered by the investigator to be exclusionary.

• Patients with malignancy other than basal cell or squamous cell skin cancer who have not yet been treated, are currently being treated, or who were diagnosed less than 5 years ago.

• Have had a blood transfusion or severe blood loss within 3 months prior to screening, or have known hemoglobinopathy, hemolytic anemia or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with HbA1c methodology.

• Are receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intra-articular, intraocular and inhaled prescriptions), or have received such therapy within the 4 weeks immediately preceding screening.

• Have an irregular sleep/wake cycle (for example, patients who sleep during the day and work during the night), in the investigator's opinion.

• Have known hypersensitivity or allergy to any of the study insulins or their excipients.

• Are breastfeeding or pregnant, or intend to become pregnant during the course of the study, or are sexually active women of childbearing potential not actively practicing birth control by a method determined by the investigator to be medically acceptable.

• Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

• Have previously completed or withdrawn from this study after having signed the informed consent document (ICD).

• Are unwilling or unable to comply with the use of a data collection device to directly record data from the patient.

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.	Concord	California	United States	94520
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.	Aurora	Colorado	United States	80045
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.	Hollywood	Florida	United States	33021
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.	West Palm Beach	Florida	United States	33401
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.	Idaho Falls	Idaho	United States	83404
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.	Topeka	Kansas	United States	66606
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.	Nashua	New Hampshire	United States	03063
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.	Albany	New York	United States	12206
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.	Syracuse	New York	United States	13210
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.	Asheville	North Carolina	United States	28803
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.	Austin	Texas	United States	78731

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 9am - 5pm Eastern (UTC/GMT - 5hrs, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01109316
• Other Study ID Numbers: 12174; F3Z-MC-IOPV
• First Posted: Apr 23, 2010
• Last Update Posted: Mar 27, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin Lispro

Study Results

Participant Flow

Arm/Group Title	Sequence A (L2D/L6D/A6D)	Sequence B (L2D/A6D/L6D)	Sequence C (L6D/L2D/A6D)	Sequence D (L6D/A6D/L2D)	Sequence E (A6D/L2D/L6D)	Sequence F (A6D/L6D/L2D)
Arm/Group Description	Participants received Insulin Lispro 2D (L2D (Days)), Insulin Lispro 6D (L6D) and Insulin Aspart 6D (A6D) as per below dosing schedule Period 1: Lispro 2D, Period 2: Lispro 6D and Period 3: Insulin Aspart 6D	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Lispro 2D, Period 2: Insulin Aspart 6D and Period 3: Insulin Lispro 6D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Lispro 6D, Period 2: Insulin Lispro 2D and Period 3: Insulin Aspart 6D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Lispro 6D, Period 2: Insulin Aspart 6D and Period 3: Insulin Lispro 2D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Aspart 6D, Period 2: Insulin Lispro 2D and Period 3: Insulin Lispro 6D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Aspart 6D, Period 2: Insulin Lispro 6D and Period 3: Insulin Lispro 2D.
Period Title: Study Period 1
STARTED	22	22	22	22	22	22
Received at Least One Dose of Study Drug	22	22	22	22	22	20
COMPLETED	22	22	19	21	20	20
NOT COMPLETED	0	0	3	1	2	2
Period Title: Study Period 1
STARTED	22	22	19	21	20	20
COMPLETED	21	21	18	20	20	19
NOT COMPLETED	1	1	1	1	0	1
Period Title: Study Period 1
STARTED	21	21	18	20	20	19
COMPLETED	20	21	18	20	18	19
NOT COMPLETED	1	0	0	0	2	0

Baseline Characteristics

Arm/Group Title	Sequence A (L2D/L6D/A6D)	Sequence B (L2D/A6D/L6D)	Sequence C (L6D/L2D/A6D)	Sequence D (L6D/A6D/L2D)	Sequence E (A6D/L2D/L6D)	Sequence F (A6D/L6D/L2D)	Total
Arm/Group Description	Participants received Insulin Lispro 2D (2 Days), Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Lispro 2D, Period 2: Lispro 6D and Period 3: Insulin Aspart 6D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Lispro 2D, Period 2: Insulin Aspart 6D and Period 3: Insulin Lispro 6D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Lispro 6D, Period 2: Insulin Lispro 2D and Period 3: Insulin Aspart 6D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Lispro 6D, Period 2: Insulin Aspart 6D and Period 3: Insulin Lispro 2D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Aspart 6D, Period 2: Insulin Lispro 2D and Period 3: Insulin Lispro 6D.	Participants received Insulin Lispro 2D, Insulin Lispro 6D and Insulin Aspart 6D as per below dosing schedule Period 1: Insulin Aspart 6D, Period 2: Insulin Lispro 6D and Period 3: Insulin Lispro 2D.	Total of all reporting groups
Overall Participants	22	22	22	22	22	22	132
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.28 (19.62)	36.61 (14.07)	42.63 (17.39)	47.23 (18.78)	41.15 (14.22)	38.34 (14.93)	41.37 (16.68)
Sex: Female, Male (Count of Participants)
Female	15 68.2%	16 72.7%	15 68.2%	14 63.6%	18 81.8%	18 81.8%	96 72.7%
Male	7 31.8%	6 27.3%	7 31.8%	8 36.4%	4 18.2%	4 18.2%	36 27.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.5%	4 18.2%	1 4.5%	0 0%	3 13.6%	3 13.6%	12 9.1%
Not Hispanic or Latino	21 95.5%	18 81.8%	21 95.5%	22 100%	19 86.4%	19 86.4%	120 90.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 4.5%	0 0%	0 0%	0 0%	0 0%	1 0.8%
White	22 100%	21 95.5%	22 100%	21 95.5%	22 100%	21 95.5%	129 97.7%
More than one race	0 0%	0 0%	0 0%	1 4.5%	0 0%	1 4.5%	2 1.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	22 100%	22 100%	22 100%	22 100%	22 100%	22 100%	132 100%

Outcome Measures

1. Primary Outcome

Title	Mean of Last Five 7-point Self Monitored Blood Glucose (SMBG) Taken on Day 6 for Insulin Lispro 6D and Day 2 for Insulin Lispro 2D and Day 6 for Insulin Aspart 6D Pump Reservoir In-use
Time Frame	8 weeks of each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who completed at least one post-randomization visit. Those included in the Primary analysis had to have at least one reservoir in-use cycle with an SMBG measurement on Day 6 during the pre-specified collection period.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	119	116	117
Mean (Standard Deviation) [millimoles per liter (mmol/L)]	9.03 (2.17)	9.33 (2.31)	8.72 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments	This was the primary gated analysis.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority margin of 0.6 mmol/L was used.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 95%; 0.20 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Age stratum + Baseline HbA1c.

2. Secondary Outcome

Title	Mean SMBG
Description	Mean SMBG for combined periods; all reported SMBG values on days 1-6 for Insulin Lispro 6 Day and Insulin Aspart 6 Day, and days 1-2 for Insulin Lispro 2 Day.
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who completed at least one post-randomization visit and one SMBG measurement on Day 2 for insulin lispro 2 day or Day 6 for the respective treatment arm: insulin lispro 6 day and insulin aspart 6 day.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	122	122	122
Mean (Standard Deviation) [mmol/L]	8.79 (2.73)	9.01 (2.87)	8.83 (2.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority margin of 0.6 mmol/L was used.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Age Stratum + Baseline HbA1c; where participant is treated as a random effect.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority margin of 0.6 mmol/L was used.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Age Stratum + Baseline HbA1c; where participant is treated as a random effect.

3. Secondary Outcome

Title	Mean Daily Insulin Dose (Total, Basal, and Bolus)
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who completed at least one post-randomization visit. Participants included in insulin analyses are only those for whom data existed regarding insulin dose.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	117	117	117
Daily Bolus Insulin	14.33 (5.88)	14.51 (6.33)	14.44 (6.11)
Daily Basal Insulin	18.62 (9.32)	18.77 (8.89)	18.34 (8.72)
Daily Total Insulin	32.36 (10.28)	32.37 (10.12)	31.99 (10.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference of Daily Bolus Insulin = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Baseline Insulin Basal/Bolus/Total Dose + Age Stratum.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference of Daily Bolus Insulin = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Baseline Insulin Basal/Bolus/Total Dose + Age Stratum.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference of Daily Bolus Insulin = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Baseline Insulin Basal/Bolus/Total Dose + Age Stratum.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference of Daily Bolus Insulin = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Baseline Insulin Basal/Bolus/Total Dose + Age Stratum.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference of Daily Bolus Insulin = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Baseline Insulin Basal/Bolus/Total Dose + Age Stratum.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.85 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference of Daily Bolus Insulin = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Sequence + Period + Baseline Insulin Basal/Bolus/Total Dose + Age Stratum.

4. Secondary Outcome

Title	Change From Baseline to 8 Weeks Endpoint for Each Treatment in Hemoglobin A1c (HbA1c) Values
Time Frame	Baseline, 8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who completed at least one post-randomization visit, and had a baseline and a post-randomization HbA1c measurement for the respective treatment period. Last Observation Carried Forward (LOCF) method was utilized in this analysis.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	121	120	121
Mean (Standard Deviation) [percentage of glycosylated hemoglobin]	-0.04 (0.59)	0.06 (0.56)	0.00 (0.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Period + Sequence + Baseline HbA1c.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Insulin Lispro 6 Day minus Insulin Aspart 6 Day; adjusted for Treatment + Period + Sequence + Baseline HbA1c.

5. Secondary Outcome

Title	Number of Participants Who Achieve or Maintain an HbA1c Less Than or Equal to 6.5% and Less Than 7%
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who completed a post-randomization visit and had an HbA1c measurement for the respective treatment period.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	121	120	121
HbA1c ≤6.5%	21 95.5%	16 72.7%	18 81.8%
HbA1c <7%	40 181.8%	38 172.7%	44 200%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio of HbA1c ≤6.5% for Insulin Lispro 6 Day versus Insulin Aspart 6 Day.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.29 to 1.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio of HbA1c ≤6.5% for Insulin Lispro 6 Day versus Insulin Lispro 2 Day.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio of HbA1c <7% for Insulin Lispro 6 Day versus Insulin Aspart 6 Day.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio of HbA1c <7% for Insulin Lispro 6 Day versus Insulin Lispro 2 Day.

6. Secondary Outcome

Title	Percentage of Participants With Hyperglycemia
Description	Hyperglycemia was defined as an event with (1) a measured blood glucose concentration >250 milligrams per deciliter (mg/dL) (13.9 mmol/L) and ≥3 hours after eating, or (2) a measured blood glucose concentration >300 mg/dL (16.7 mmol/L) and <3 hours after eating.
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug. Participants included in hyperglycemia analyses are only those for whom data existed regarding hyperglycemia.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	122	127	124
Number [percentage of participants]	99.2 450.9%	98.4 447.3%	98.4 447.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	P-value computed using Treatment comparison Gart's Test. Participants represented in both treatment groups and with non-missing incidence value in each treatment period are used for p-value calculation.
	Method	Gart's Test
	Comments

7. Secondary Outcome

Title	Hyperglycemic Episode Rate Per 30 Days
Description	Hyperglycemia was defined as an episode with (1) a measured blood glucose concentration >250 milligrams per deciliter (mg/dL) (13.9 mmol/L) and ≥3 hours after eating, or (2) a measured blood glucose concentration >300 mg/dL (16.7 mmol/L) and <3 hours after eating. Rate is presented as the number of hyperglycemic episodes adjusted for 30 days.
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug. Participants included in hyperglycemia analyses are only those for whom data existed regarding hyperglycemia.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	122	127	124
Mean (Standard Deviation) [hyperglycemic episodes per 30 days]	15.91 (12.78)	16.91 (13.98)	15.76 (12.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.164
	Comments	P-value computed using a negative binomial test including factors for treatment, period, and sequence.
	Method	Negative Binomial Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.185
	Comments	P-value computed using a negative binomial test including factors for treatment, period, and sequence.
	Method	Negative Binomial Test
	Comments

8. Secondary Outcome

Title	Percentage of Participants With Pump Complications
Description	Overall Pump Complications were any combination of: tubing clogged, kinked, disconnected, pulled out, blood in tubing; too much heat, too much cold, empty reservoir, low battery, occlusion alarm, no delivery alarm; at site - skin abscess, excessive redness, swelling (not nodule), bleeding, bruising; reservoir change (infusion set change reason only); and other. When either a reservoir change or an infusion set change was reported, participants were questioned whether change was early (prior to 6 days for L6D or A6D, or prior to 2 days for L2D). If 'yes', then recorded as premature change.
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who completed at least one post-randomization visit. Participants included in pump complication analyses are only those for whom data existed regarding pump complications.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	122	127	124
Pump Complication: Premature Reservoir Change	23.8 108.2%	38.6 175.5%	36.3 165%
Pump Complication: Premature Infusion Set Change	42.6 193.6%	59.1 268.6%	56.5 256.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.736
	Comments	P-value for Premature Reservoir Change. P-value computed using Treatment comparison Gart's Test. Participants represented in both treatment groups and with non-missing incidence value in each treatment period are used for p-value calculation.
	Method	Gart's Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	P-value for Premature Reservoir Change. P-value computed using Treatment comparison Gart's Test. Participants represented in both treatment groups and with non-missing incidence value in each treatment period are used for p-value calculation.
	Method	Gart's Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	P-value for Premature Infusion Set Change. P-value computed using Treatment comparison Gart's Test. Participants represented in both treatment groups and with non-missing incidence value in each treatment period are used for p-value calculation.
	Method	Gart's Test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	P-value for Premature Infusion Set Change. P-value computed using Treatment comparison Gart's Test. Participants represented in both treatment groups and with non-missing incidence value in each treatment period are used for p-value calculation.
	Method	Gart's Test
	Comments

9. Secondary Outcome

Title	Pump Complication Rate Per 30 Days
Description	Overall Pump Complications were any combination of: tubing clogged, kinked, disconnected, pulled out, blood in tubing; too much heat, too much cold, empty reservoir, low battery, occlusion alarm, no delivery alarm; at site - skin abscess, excessive redness, swelling (not nodule), bleeding, bruising; reservoir change (infusion set change reason only); and other. When either a reservoir change or an infusion set change was reported, participants were questioned whether change was early (prior to 6 days for L6D or A6D, or prior to 2 days for L2D). If 'yes', then recorded as premature change.
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who completed at least one post-randomization visit. Participants included in pump complication analyses are only those for whom data existed regarding pump complications.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	122	127	124
Pump Complication: Premature Reservoir Change	0.16 (0.34)	0.40 (0.76)	0.51 (1.05)
Pump Complication: Premature Infusion Set Change	0.44 (0.65)	0.84 (1.18)	0.94 (1.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.471
	Comments	P-value for Premature Reservoir Change. P-value is computed using negative binomial test including factors for treatment, period and sequence.
	Method	Negative Binomial Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value for Premature Reservoir Change. P-value is computed using negative binomial test including factors for treatment, period and sequence.
	Method	Negative Binomial Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.737
	Comments	P-value for Premature Infusion Set Change. P-value is computed using negative binomial test including factors for treatment, period and sequence.
	Method	Negative Binomial Test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value for Premature Infusion Set Change. P-value is computed using negative binomial test including factors for treatment, period and sequence.
	Method	Negative Binomial Test
	Comments

10. Secondary Outcome

Title	Percentage of Participants With Hypoglycemia
Description	Hypoglycemia was defined as an event which was associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of ≤ 70 mg/dL (3.9 mmol/L).
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug. Participants included in hypoglycemia analyses are only those for whom data existed regarding hypoglycemia.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	122	127	124
Number [percentage of participants]	100.0 454.5%	100.0 454.5%	99.2 450.9%

11. Secondary Outcome

Title	Hypoglycemia Episode Rate Per 30 Days
Description	Hypoglycemia was defined as an event which was associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of ≤ 70 mg/dL (3.9 mmol/L). Rate is presented as the number of hypoglycemic episodes adjusted for 30 days.
Time Frame	8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug. Participants included in hypoglycemia analyses are only those for whom data existed regarding hypoglycemia.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	122	127	124
Mean (Standard Deviation) [hypoglycemic episodes per 30 days]	17.90 (11.13)	15.66 (12.29)	17.52 (11.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	P-value is computed using negative binomial test including factors for treatment, period and sequence.
	Method	Negative Binomial Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	P-value is computed using negative binomial test including factors for treatment, period and sequence.
	Method	Negative Binomial Test
	Comments

12. Secondary Outcome

Title	Change From Baseline to 8 Weeks Endpoint for Each Treatment in Weight
Time Frame	Baseline, 8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had both baseline and post-baseline weight measurements for the respective treatment period.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	121	122	122
Mean (Standard Deviation) [kilograms (kg)]	0.44 (2.13)	0.34 (2.04)	0.65 (2.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments	P-value computed using crossover model. Response = Treatment + Sequence + Period + Age stratum + Baseline Body Weight.
	Method	Crossover Model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.486
	Comments	P-value computed using crossover model. Response = Treatment + Sequence + Period + Age stratum + Baseline Body Weight.
	Method	Crossover Model
	Comments

13. Secondary Outcome

Title	Change From Baseline to 8 Weeks Endpoint for Each Treatment in Blood Pressure
Time Frame	Baseline, 8 weeks for each treatment

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had both baseline and post-baseline blood pressure measurements for the respective treatment period.

Arm/Group Title	Insulin Lispro 2 Day	Insulin Lispro 6 Day	Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.	Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.	Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
Measure Participants	121	122	123
Systolic Blood Pressure (SBP)	0.80 (12.82)	0.80 (12.52)	-1.07 (12.06)
Diastolic Blood Pressure (DBP)	-0.14 (8.24)	1.37 (7.62)	-0.33 (7.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments	P-value is for Systolic Blood Pressure. P-value computed using crossover model. Response = Treatment + Sequence + Period + Age stratum + Baseline Systolic Blood Pressure.
	Method	Crossover Model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.805
	Comments	P-value is for Systolic Blood Pressure. P-value computed using crossover model. Response = Treatment + Sequence + Period + Age stratum + Baseline Systolic Blood Pressure.
	Method	Crossover Model
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 6 Day, Insulin Aspart 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	P-value is for Diastolic Blood Pressure. P-value computed using crossover model. Response = Treatment + Sequence + Period + Age stratum + Baseline Diastolic Blood Pressure.
	Method	Crossover Model
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro 2 Day, Insulin Lispro 6 Day
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments	P-value is for Diastolic Blood Pressure. P-value computed using crossover model. Response = Treatment + Sequence + Period + Age stratum + Baseline Diastolic Blood Pressure.
	Method	Crossover Model
	Comments

Adverse Events

Time Frame	Up To 8 weeks
Adverse Event Reporting Description	There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
Arm/Group Title	Insulin Lispro 2 Day		Insulin Lispro 6 Day		Insulin Aspart 6 Day
Arm/Group Description	Insulin Lispro 2 Day (L2D) administered by infusion pump for 8 week treatment period.		Insulin Lispro 6 Day (L6D) administered by infusion pump for 8 weeks.		Insulin Aspart 6 Day (A6D) administered by infusion pump for 8 weeks.
All Cause Mortality
	Insulin Lispro 2 Day		Insulin Lispro 6 Day		Insulin Aspart 6 Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin Lispro 2 Day		Insulin Lispro 6 Day		Insulin Aspart 6 Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/122 (2.5%)		8/127 (6.3%)		10/124 (8.1%)
Gastrointestinal disorders
Oesophagitis	0/122 (0%)	0	1/127 (0.8%)	1	0/124 (0%)	0
Injury, poisoning and procedural complications
Sternal fracture	0/122 (0%)	0	1/127 (0.8%)	1	0/124 (0%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/122 (0%)	0	3/127 (2.4%)	4	0/124 (0%)	0
Hypoglycaemia	2/122 (1.6%)	2	4/127 (3.1%)	5	9/124 (7.3%)	11
Nervous system disorders
Cervical myelopathy	1/122 (0.8%)	1	0/127 (0%)	0	0/124 (0%)	0
Hydrocephalus	0/122 (0%)	0	1/127 (0.8%)	1	0/124 (0%)	0
Reproductive system and breast disorders
Ovarian cyst	0/90 (0%)	0	0/93 (0%)	0	1/90 (1.1%)	1
Other (Not Including Serious) Adverse Events
	Insulin Lispro 2 Day		Insulin Lispro 6 Day		Insulin Aspart 6 Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/122 (58.2%)		68/127 (53.5%)		71/124 (57.3%)
Gastrointestinal disorders
Diarrhoea	1/122 (0.8%)	1	0/127 (0%)	0	2/124 (1.6%)	2
Nausea	4/122 (3.3%)	4	3/127 (2.4%)	3	4/124 (3.2%)	4
Toothache	0/122 (0%)	0	0/127 (0%)	0	2/124 (1.6%)	2
Vomiting	5/122 (4.1%)	5	2/127 (1.6%)	2	4/124 (3.2%)	4
General disorders
Asthenia	0/122 (0%)	0	2/127 (1.6%)	2	1/124 (0.8%)	1
Chills	2/122 (1.6%)	2	0/127 (0%)	0	1/124 (0.8%)	1
Infusion site erythema	1/122 (0.8%)	1	1/127 (0.8%)	1	2/124 (1.6%)	2
Infusion site haemorrhage	1/122 (0.8%)	1	1/127 (0.8%)	1	2/124 (1.6%)	3
Infusion site mass	1/122 (0.8%)	1	1/127 (0.8%)	1	2/124 (1.6%)	2
Pyrexia	2/122 (1.6%)	2	5/127 (3.9%)	5	2/124 (1.6%)	2
Infections and infestations
Ear infection	1/122 (0.8%)	1	3/127 (2.4%)	3	1/124 (0.8%)	1
Fungal infection	2/122 (1.6%)	3	2/127 (1.6%)	2	0/124 (0%)	0
Gastroenteritis viral	5/122 (4.1%)	5	2/127 (1.6%)	2	3/124 (2.4%)	3
Influenza	1/122 (0.8%)	1	1/127 (0.8%)	1	2/124 (1.6%)	2
Nasopharyngitis	10/122 (8.2%)	11	11/127 (8.7%)	12	13/124 (10.5%)	14
Pharyngitis	0/122 (0%)	0	2/127 (1.6%)	2	0/124 (0%)	0
Pharyngitis streptococcal	0/122 (0%)	0	2/127 (1.6%)	2	0/124 (0%)	0
Sinusitis	4/122 (3.3%)	4	1/127 (0.8%)	1	3/124 (2.4%)	3
Upper respiratory tract infection	10/122 (8.2%)	10	6/127 (4.7%)	6	9/124 (7.3%)	10
Urinary tract infection	1/122 (0.8%)	1	2/127 (1.6%)	2	3/124 (2.4%)	4
Viral infection	1/122 (0.8%)	1	2/127 (1.6%)	2	1/124 (0.8%)	1
Vulvovaginal Mycotic Infection	0/90 (0%)	0	0/93 (0%)	0	1/90 (1.1%)	1
Smear Cervix Abnormal	0/90 (0%)	0	1/93 (1.1%)	1	0/90 (0%)	0
Injury, poisoning and procedural complications
Contusion	2/122 (1.6%)	2	1/127 (0.8%)	1	1/124 (0.8%)	1
Investigations
Urine ketone body present	0/122 (0%)	0	1/127 (0.8%)	1	2/124 (1.6%)	3
Metabolism and nutrition disorders
Hyperlipidaemia	2/122 (1.6%)	2	1/127 (0.8%)	1	1/124 (0.8%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/122 (1.6%)	2	4/127 (3.1%)	4	3/124 (2.4%)	3
Back pain	2/122 (1.6%)	2	2/127 (1.6%)	2	2/124 (1.6%)	2
Muscle spasms	3/122 (2.5%)	3	0/127 (0%)	0	0/124 (0%)	0
Musculoskeletal pain	0/122 (0%)	0	2/127 (1.6%)	3	0/124 (0%)	0
Myalgia	0/122 (0%)	0	2/127 (1.6%)	2	0/124 (0%)	0
Neck pain	1/122 (0.8%)	1	2/127 (1.6%)	2	1/124 (0.8%)	1
Rotator cuff syndrome	1/122 (0.8%)	1	2/127 (1.6%)	2	2/124 (1.6%)	2
Tendonitis	2/122 (1.6%)	2	2/127 (1.6%)	2	1/124 (0.8%)	1
Nervous system disorders
Dizziness	1/122 (0.8%)	1	1/127 (0.8%)	1	3/124 (2.4%)	3
Headache	6/122 (4.9%)	7	3/127 (2.4%)	3	3/124 (2.4%)	3
Psychiatric disorders
Depression	2/122 (1.6%)	2	2/127 (1.6%)	2	2/124 (1.6%)	2
Respiratory, thoracic and mediastinal disorders
Cough	5/122 (4.1%)	5	3/127 (2.4%)	3	1/124 (0.8%)	1
Dyspnoea	3/122 (2.5%)	3	0/127 (0%)	0	0/124 (0%)	0
Nasal congestion	1/122 (0.8%)	1	3/127 (2.4%)	3	1/124 (0.8%)	1
Oropharyngeal pain	5/122 (4.1%)	5	4/127 (3.1%)	4	5/124 (4%)	5
Paranasal sinus hypersecretion	2/122 (1.6%)	2	0/127 (0%)	0	1/124 (0.8%)	1
Rhinitis seasonal	2/122 (1.6%)	2	2/127 (1.6%)	2	2/124 (1.6%)	2
Sinus congestion	3/122 (2.5%)	3	4/127 (3.1%)	4	3/124 (2.4%)	3
Throat irritation	2/122 (1.6%)	2	0/127 (0%)	0	0/124 (0%)	0
Skin and subcutaneous tissue disorders
Subcutaneous nodule	1/122 (0.8%)	1	1/127 (0.8%)	1	2/124 (1.6%)	2

Limitations/Caveats

Input to primary endpoint measurements (SMBG) contained approximately 40% missing data. Several analyses to account for missing data have been conducted and results from these additional analyses were consistent with results of original analysis.

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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.