A Study to Compare and Measure the Effects of Insulin Peglispro (LY2605541) and Glargine on Meal Time Insulin Requirements

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02152384
• Collaborator: (none)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 6
• Patients Per Site Per Month: 4.7

Study Details

Study Description

Brief Summary

This study will look into how a base dose of insulin peglispro and insulin glargine will affect the meal time dose and efficacy of insulin lispro in type 1 diabetics.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Insulin Peglispro; Drug: Insulin Lispro; Drug: Insulin Glargine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Effect of Treatment With Basal Insulin Peglispro or Insulin Glargine on the Dose Response Effect of Prandial Insulin Lispro in Patients With Type 1 Diabetes Mellitus.
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Insulin peglispro (LY2605541, with Insulin Lispro) Insulin peglispro (LY2605541) once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required	Drug: Insulin Peglispro; Administered SC; Other Names: LY2605541 ; Drug: Insulin Lispro; Administered SC
Active Comparator: Insulin Glargine (with Insulin Lispro) Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required	Drug: Insulin Lispro; Administered SC; Drug: Insulin Glargine; Administered SC

Outcome Measures

Primary Outcome Measures

1. Pharmacodynamics (PD): Plasma Glucose Area Under the Concentration Curve Zero Through 5 Hours (AUC 0-5h), Above Pre Meal Baseline for Insulin Lispro [Day 30, 31, 32, 33, 34, pre-breakfast and10,20,30,40,50,60,90,120,150,180,210,240,270, 300 minutes (5 hours) post-breakfast]

   To quantitate the pharmacodynamic (PD) effect of a range of prandial insulin lispro doses after treatment with insulin peglispro (LY2605541) compared to insulin glargine during a meal tolerance test (MTT), with sequenced doses of insulin lispro ranging from 25% to 150% of each participant's normal dose. Data presented as hours times milligrams per deciliter (mg*h/dL)

Secondary Outcome Measures

1. Pharmacokinetics (PK): Under the Concentration Curve Zero Through 5 Hours (AUC 0-5h) for Prandial Insulin Lispro [Day 29: Pre-breakfast, and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast]

   Abbreviation for hours times picomol per liter (pmol*h/L)

2. Pharmacodynamics (PD): Average Glucose Infusion Rate From Euglycemic 2-step Hyperinsulinemic Clamp (M-value) [Day 35, last 60 minutes of euglycemic 2-step hyperinsulinemic clamp]

   Abbreviation for micro mole per kilogram per minute (µmol/kg/min). Both arms received insulin lispro in addition to their respective study drug. During the euglycemic 2-step hyperinsulinemic clamp, both low and high insulin was infused sequentially during the same procedure. The 2-step clamp procedure allowed insulin sensitivity to be measured in participants and uses a lower dose of insulin of which the effect is largely on the liver and a high dose of insulin at which the effect has reached 100% on liver and effects are largely on glucose uptake in peripheral tissues. Measurements for average glucose infusion rate are collected for both steps (low and high) of the clamp procedure.

3. Pharmacokinetics (PK): Area Under the Concentration Curve From Time Zero to Last Time (AUC [0 Tlast]) for Paracetamol [Day 29: Pre-breakfast, and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast]

4. Appetite and Satiety Ratings, as Measured Using Visual Analog Scale (VAS) on Day 29 [Day 29:Upon waking, pre-breakfast, 1 hour (hr), 2 hr, 3 hr, 4 hr and 5 hr post breakfast]

   VAS was scored from 0 - 100 millimeters (mm) as a perception of appetite and satiety (Flint et al. 2000), 0 being not hungry at all or nothing at all and 100 being extremely hungry and extremely large amount. The questions are abbreviated in table from: How hungry do you feel right now? to Hunger and How much food do you think you could eat right now? to Food amount. Day 29 and cumulative insulin lispro doses of 25%, 50%, 75%, 100% and 150 % of normal insulin lispro dose included.Scores were averaged will be presented and calculated by a sum of the scores dividing by the total by the number of scores reported for timepoints and reported in millimeters.

5. Pharmacodynamics (PD): Area Under the Concentration Zero Through 5 Hours (AUC 0-5h) for Triglycerides [Day 29, predose and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast]

6. Pharmacokinetics (PK): Area Under the Concentration Curve (AUC) for Insulin Lispro During Clamp [Day 35, insulin clearance during lispro infusion (dosing=infusion)]

   During the euglycemic 2-step hyperinsulinemic clamp, both low and high insulin was infused sequentially during the same procedure. The 2-step clamp procedure allowed insulin sensitivity to be measured in participants and uses a lower dose of insulin (Low) of which the effect is largely on the liver and a high dose of insulin (high) at which the effect has reached 100% on liver and effects are largely on glucose uptake in peripheral tissues. AUC is taking during infusion for this outcome measure.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Have a stable (within 0.5 percent (%) from last measure) glycated hemoglobin (HbA1c) <9.0%

• Have a stable (within 30%) basal insulin dose of 0.2 to 1.0 units per kilogram per day (U/kg/day) and a total daily insulin dose (basal + prandial/bolus) <1.5 units per kilogram (U/kg)

• Have C-peptide <0.3 nanomoles per liter (nmol/L)

• Are able and willing to eat the protocol specified standard breakfast and other meals as required

Exclusion Criteria:

• Have corrected QT interval (QTc) prolongation >500 milliseconds (ms) or have any other abnormality in the 12 lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study

• Have an abnormal blood pressure as determined by the investigator

• Have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine (apart from Type 1 Diabetes Mellitus [T1DM]), hematological, or neurological disorders

• Have fasting triglycerides (TGs) >400 milligrams per deciliter (mg/dL) (4.52 micromoles per liter [mmol/L])

• Have used systemic corticosteroids within 4 weeks prior to randomization

• Currently receive insulin pump or insulin degludec

• Have poorly controlled diabetes or are known to have poor awareness of hypoglycemia

• Have history of gastroparesis or gastrointestinal malabsorption

• Require treatment with any drug other than insulin to treat diabetes

• Have a previous history of proliferative retinopathy

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.	Neuss		Germany	41460

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

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT02152384
• Other Study ID Numbers: 15406; I2R-MC-BIDU
• First Posted: Jun 2, 2014
• Last Update Posted: Mar 1, 2019
• Last Verified: Oct 1, 2018

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

Study Results

Participant Flow

Arm/Group Title	Treatment Sequence A/B	Treatment Sequence B/A
Arm/Group Description	Treatment A: Insulin peglispro (LY2605541) once daily subcutaneous (SC). Insulin lispro given SC prandially or as bolus as required Treatment B: Insulin glargine once daily subcutaneous (SC). Insulin lispro given SC prandially or as bolus as required	Treatment B: Insulin glargine once daily subcutaneous (SC). Insulin lispro given SC prandially or as bolus as required Treatment A: Insulin peglispro (LY2605541) once daily subcutaneous (SC). Insulin lispro given SC prandially or as bolus as required
Period Title: Run In (1-5 Week Transition)
STARTED	14	14
COMPLETED	14	14
NOT COMPLETED	0	0
Period Title: Run In (1-5 Week Transition)
STARTED	14	14
Received at Least 1 Dose of Study Drug	14	14
COMPLETED	13	12
NOT COMPLETED	1	2
Period Title: Run In (1-5 Week Transition)
STARTED	13	12
COMPLETED	13	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All randomized participants who received at least 1 dose of study drug.
Overall Participants	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.2 (10.1)
Sex: Female, Male (Count of Participants)
Female	25 89.3%
Male	3 10.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	28 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	28 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
Germany	28 100%

Outcome Measures

1. Primary Outcome

Title	Pharmacodynamics (PD): Plasma Glucose Area Under the Concentration Curve Zero Through 5 Hours (AUC 0-5h), Above Pre Meal Baseline for Insulin Lispro
Description	To quantitate the pharmacodynamic (PD) effect of a range of prandial insulin lispro doses after treatment with insulin peglispro (LY2605541) compared to insulin glargine during a meal tolerance test (MTT), with sequenced doses of insulin lispro ranging from 25% to 150% of each participant's normal dose. Data presented as hours times milligrams per deciliter (mg*h/dL)
Time Frame	Day 30, 31, 32, 33, 34, pre-breakfast and10,20,30,40,50,60,90,120,150,180,210,240,270, 300 minutes (5 hours) post-breakfast

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had evaluable PD data.

Arm/Group Title	Insulin Peglispro (LY2605541)	Insulin Glargine
Arm/Group Description	Insulin peglispro (LY2605541) administered SC daily	Insulin glargine administered SC daily
Measure Participants	27	26
25% Normal Dose	677.84 (146.48)	716.52 (179.89)
50% Normal Dose	572.96 (149.76)	506.22 (188.54)
75% Normal Dose	393.28 (175.68)	369.08 (169.08)
100% Normal Dose	270.46 (201.73)	307.81 (204.27)
150% Normal Dose	174.38 (182.00)	123.97 (118.82)

2. Secondary Outcome

Title	Pharmacokinetics (PK): Under the Concentration Curve Zero Through 5 Hours (AUC 0-5h) for Prandial Insulin Lispro
Description	Abbreviation for hours times picomol per liter (pmol*h/L)
Time Frame	Day 29: Pre-breakfast, and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had evaluable PK data.

Arm/Group Title	Insulin Peglispro (LY2605541)	Insulin Glargine
Arm/Group Description	Insulin peglispro (LY2605541) administered SC daily	Insulin glargine administered SC daily
Measure Participants	23	21
Geometric Mean (Geometric Coefficient of Variation) [pmol*h/L]	850 (47)	852 (44)

3. Secondary Outcome

Title	Pharmacodynamics (PD): Average Glucose Infusion Rate From Euglycemic 2-step Hyperinsulinemic Clamp (M-value)
Description	Abbreviation for micro mole per kilogram per minute (µmol/kg/min). Both arms received insulin lispro in addition to their respective study drug. During the euglycemic 2-step hyperinsulinemic clamp, both low and high insulin was infused sequentially during the same procedure. The 2-step clamp procedure allowed insulin sensitivity to be measured in participants and uses a lower dose of insulin of which the effect is largely on the liver and a high dose of insulin at which the effect has reached 100% on liver and effects are largely on glucose uptake in peripheral tissues. Measurements for average glucose infusion rate are collected for both steps (low and high) of the clamp procedure.
Time Frame	Day 35, last 60 minutes of euglycemic 2-step hyperinsulinemic clamp

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had evaluable PD data.

Arm/Group Title	Insulin Peglispro (LY2605541, With Insulin Lispro)	Insulin Glargine (With Insulin Lispro)
Arm/Group Description	Insulin peglispro (LY2605541) once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required	Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required
Measure Participants	12	11
High Dose Insulin	52.756 (11.862)	56.321 (10.697)
Low Dose Insulin	13.908 (13.181)	18.765 (8.293)

4. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Curve From Time Zero to Last Time (AUC [0 Tlast]) for Paracetamol
Time Frame	Day 29: Pre-breakfast, and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had evaluable PK data.

Arm/Group Title	Insulin Peglispro (LY2605541, With Insulin Lispro)	Insulin Glargine (With Insulin Lispro)
Arm/Group Description	Insulin peglispro (LY2605541) once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required	Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required
Measure Participants	27	24
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	33400 (19)	33600 (22)

5. Secondary Outcome

Title	Appetite and Satiety Ratings, as Measured Using Visual Analog Scale (VAS) on Day 29
Description	VAS was scored from 0 - 100 millimeters (mm) as a perception of appetite and satiety (Flint et al. 2000), 0 being not hungry at all or nothing at all and 100 being extremely hungry and extremely large amount. The questions are abbreviated in table from: How hungry do you feel right now? to Hunger and How much food do you think you could eat right now? to Food amount. Day 29 and cumulative insulin lispro doses of 25%, 50%, 75%, 100% and 150 % of normal insulin lispro dose included.Scores were averaged will be presented and calculated by a sum of the scores dividing by the total by the number of scores reported for timepoints and reported in millimeters.
Time Frame	Day 29:Upon waking, pre-breakfast, 1 hour (hr), 2 hr, 3 hr, 4 hr and 5 hr post breakfast

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had VAS score.

Arm/Group Title	Insulin Peglispro (LY2605541, With Insulin Lispro)	Insulin Glargine (With Insulin Lispro)
Arm/Group Description	Insulin peglispro (LY2605541, once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required	Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required
Measure Participants	27	27
Day 29: Hunger, waking	27.1 (22.1)	32.1 (26.5)
Day 29: Hunger, 5 hours post breakfast	53.8 (27.9)	58.9 (24.6)
Day 29: Food amount, waking	32.5 (20.6)	37.7 (22.8)
Day 29: Food amount, 5 hours post-breakfast	31.8 (20.1)	38.1 (21.8)
Overall 25%: Hunger, waking	27.5 (30.4)	35.8 (28.5)
Overall 25%: Hunger, 5 hours post breakfast	56.1 (30.7)	58.0 (26.2)
Overall 25%: Food amount, waking	30.8 (28.9)	36.4 (27.6)
Overall 25%: Food amount, 5 hours post-breakfast	56.5 (28.0)	59.0 (24.9)
Overall 50%: Hunger, waking	36.0 (26.2)	28.2 (21.9)
Overall 50%: Hunger, 5 hours post breakfast	56.5 (26.7)	64.0 (25.0)
Overall 50%: Food amount, waking	37.1 (25.2)	31.7 (21.9)
Overall 50%: Food amount, 5 hours post-breakfast	55.0 (24.8)	64.2 (23.5)
Overall 75%: Hunger, waking	29.8 (25.4)	30.9 (27.5)
Overall 75%: Hunger, 5 hours post breakfast	55.5 (27.7)	62.5 (25.3)
Overall 75%: Food amount, waking	32.6 (24.6)	31.4 (55.3)
Overall 75%: Food amount, 5 hours post-breakfast	57.0 (27.1)	62.2 (24.0)
Overall 100%: Hunger, waking	28.9 (22.9)	29.6 (24.3)
Overall 100%: Hunger, 5 hours post breakfast	55.0 (30.2)	59.0 (26.9)
Overall 100%: Food amount, waking	32.3 (22.9)	35.7 (23.7)
Overall 100%: Food amount, 5 hours post-breakfast	55.3 (29.1)	58.6 (26.4)
Overall 150%: Hunger, waking	31.4 (20.4)	28.5 (16.9)
Overall 150%: Hunger, 5 hours post breakfast	52.2 (27.7)	58.6 (28.4)
Overall 150%: Food amount, waking	34.3 (17.6)	34.1 (17.1)
Overall 150%: Food amount, 5 hours post-breakfast	52.7 (25.9)	58.3 (26.1)

6. Secondary Outcome

Title	Pharmacodynamics (PD): Area Under the Concentration Zero Through 5 Hours (AUC 0-5h) for Triglycerides
Time Frame	Day 29, predose and 15, 30, 45, 60, 90, 120, 150,180,210,270, and 300 minutes (5 hours) post-breakfast

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had evaluable PD data.

Arm/Group Title	Insulin Peglispro (LY2605541), With Insulin Lispro)	Insulin Glargine (With Insulin Lispro)
Arm/Group Description	Insulin peglispro (LY2605541) once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required	Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required
Measure Participants	27	27
Mean (Standard Deviation) [ng*hr/mL]	6.85 (3.13)	6.01 (2.22)

7. Secondary Outcome

Title	Pharmacokinetics (PK): Area Under the Concentration Curve (AUC) for Insulin Lispro During Clamp
Description	During the euglycemic 2-step hyperinsulinemic clamp, both low and high insulin was infused sequentially during the same procedure. The 2-step clamp procedure allowed insulin sensitivity to be measured in participants and uses a lower dose of insulin (Low) of which the effect is largely on the liver and a high dose of insulin (high) at which the effect has reached 100% on liver and effects are largely on glucose uptake in peripheral tissues. AUC is taking during infusion for this outcome measure.
Time Frame	Day 35, insulin clearance during lispro infusion (dosing=infusion)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had evaluable PK data.

Arm/Group Title	Insulin Peglispro (LY2605541, With Insulin Lispro)	Insulin Glargine (With Insulin Lispro)
Arm/Group Description	Insulin peglispro (LY2605541) once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required	Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required
Measure Participants	27	25
Clamp Period 1-3 Hours	243 (78.9)	222 (84.7)
Clamp Period 4-6 Hours	926 (335)	897 (333)

Adverse Events

Adverse Event Reporting Description	All randomized participants.
Arm/Group Title	Insulin Peglispro (LY2605541, With Insulin Lispro)		Insulin Glargine (With Insulin Lispro)
Arm/Group Description	Insulin peglispro (LY2605541) once daily subcutaneous (SC) injection at bedtime. Insulin lispro given SC prandially or as bolus as required		Insulin glargine once daily SC injection at bedtime. Insulin lispro given SC prandially or as a bolus as required
All Cause Mortality
	Insulin Peglispro (LY2605541, With Insulin Lispro)		Insulin Glargine (With Insulin Lispro)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Insulin Peglispro (LY2605541, With Insulin Lispro)		Insulin Glargine (With Insulin Lispro)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		2/28 (7.1%)
Infections and infestations
Viral infection	0/27 (0%)	0	1/28 (3.6%)	1
Nervous system disorders
Neuralgic amyotrophy	0/27 (0%)	0	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	Insulin Peglispro (LY2605541, With Insulin Lispro)		Insulin Glargine (With Insulin Lispro)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/27 (25.9%)		7/28 (25%)
Gastrointestinal disorders
Nausea	0/27 (0%)	0	2/28 (7.1%)	2
General disorders
Fatigue	2/27 (7.4%)	2	0/28 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/27 (0%)	0	2/28 (7.1%)	2
Pain in extremity	2/27 (7.4%)	2	0/28 (0%)	0
Nervous system disorders
Headache	4/27 (14.8%)	7	4/28 (14.3%)	4
Vascular disorders
Phlebitis	2/27 (7.4%)	2	2/28 (7.1%)	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.