PRONTO-Pump: A Study of LY900014 and Insulin Lispro With an External Continuous Subcutaneous Insulin Infusion System in Adult Participants With Type 1 Diabetes

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03433677
• Collaborator: (none)
• Enrollment: 49
• Locations: 5
• Arms: 2
• Actual Duration (Months): 6.4
• Patients Per Site: 9.8
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the compatibility and safety of LY900014 and insulin lispro with an external continuous subcutaneous insulin infusion system in adult participants with type 1 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Type 1	Drug: LY900014; Drug: Insulin lispro	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized, Double-Blind, Crossover Comparison Evaluating Compatibility and Safety of LY900014 and Insulin Lispro With an External Continuous Subcutaneous Insulin Infusion System in Adult Patients With Type 1 Diabetes (PRONTO-Pump)
• Actual Study Start Date: Feb 21, 2018
• Actual Primary Completion Date: Sep 4, 2018
• Actual Study Completion Date: Sep 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY900014 100 units per milliliter (U/mL) LY900014 administered by individualized, continuous, subcutaneous insulin infusion (CSII)	Drug: LY900014; Administered by CSII; Other Names: Ultra-Rapid Lispro
Experimental: Insulin Lispro 100 U/mL insulin lispro (Humalog®) administered by individualized CSII	Drug: Insulin lispro; Administered by CSII; Other Names: Humalog

Outcome Measures

Primary Outcome Measures

1. Rate of Infusion Set Failures [6 Weeks]

   Infusion set failure events are defined as premature infusion set changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia with blood glucose (SMBG) >250 milligrams per deciliter (mg/dL) (13.9 millimoles per liter [mmol/L]) that does not decrease within 1 hour following a correction bolus delivered via the pump during the 6 week treatment period. Aggregate rate was calculated for each participant as the total number of events while the participant is on study treatment divided by the days of exposure [last dose date and time -first dose date and time -duration of pump or treatment interruption] times 30.

Secondary Outcome Measures

1. Percentage of Participants With at Least 1 Event of Infusion Set Failure [6 Weeks]

   Infusion set failures are defined as premature infusion set changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia with blood glucose (SMBG) >250mg/dL (13.9 mmol/L) that does not decrease within 1 hour following a correction bolus delivered via the pump.

2. Rate of Premature Infusion Set Changes [6 Weeks]

   Rate of premature infusion set changes.

3. Time Interval Until Infusion Set Change [6 Weeks]

   Time interval until infusion set change reflects the time interval in hours until infusion set change from first to last dose. MMRM model for post-baseline measures: Variable = Baseline + Period + Sequence + Strata(Region + Historical Use of SmartGuard/Threshold Suspend + HbA1c(<=7.3%, >7.3%)) + Treatment (Type III sum of squares).

4. Ratio of Bolus/Total Insulin Dose [6 Weeks]

   The bolus and total insulin doses for each visit was calculated as the mean of the doses for the last 3 days prior to the visit date that are entered in the eCRF. The bolus/total ratio was derived as the bolus dose divided by the total insulin dose at each visit.

5. Interstitial Glucose Reduction Rate From Hyperglycemia Following a Non-Meal-Related Correction Bolus Delivered Via the Pump [6 Weeks]

   Interstitial glucose reduction rate (glucose reduction [mg/dL] per minute) within 4 hours following a non-meal-related correction bolus via the pump, from hyperglycemia (interstitial glucose >180 mg/dL [10 mmol/L]) to recovery (interstitial glucose ≤180 mg/dL).

6. Number of Participants With Severe Hypoglycemic Events [6 Weeks]

   Number of participants with severe hypoglycemic events. Severe hypoglycemia was defined as participants with an altered mental status and could not assist in their own care, may have been semiconscious or unconscious, or experienced coma with or without seizures, and the event required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Blood glucose measurements may not have been available during such an event, but neurological recovery attributable to the restoration of BG concentration to normal was considered sufficient evidence that the event was induced by a low BG concentration (BG ≤70 mg/dL [3.9 mmol/L]).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosed with type 1 diabetes and have been using insulin continuously for at least 12 months.

• Using an insulin pump with 'rapid-acting insulin' for at least 6 months and using the same rapid-acting insulin for at least the past 30 days.

• Have experience using Continuous Glucose Monitoring (CGM) or Flash Glucose Monitoring (FGM) for at least 60 days during the past 12 months.

• Have hemoglobin A1c values ≤8.5%, as determined by the central laboratory at screening.

• Have a body mass index (BMI) of ≤35 kilograms per meter squared at screening.

• Have been using the MiniMed 530G or 630G (US) or the MiniMed 640G (EU) insulin pump for at least the past 30 days.

Exclusion Criteria:

• Have had more than 1 emergency treatment for very low blood glucose in the last 6 months.

• Have had more than 1 emergency treatment for poor glucose control (hyperglycemia or diabetic ketoacidosis) in the last 6 months.

• Have significant insulin resistance defined as having received a total daily dose of insulin >1.2 units per kilogram (U/kg) at screening, as determined by the average total daily insulin dose over the 3 days prior to screening divided by weight in kilograms based on investigator review of the participant's pump history.

• Have significant lipohypertrophy, lipoatrophy, or scars within the subcutaneous tissue in areas of infusion or have a history of abscess at an infusion site within the last 90 days prior to screening.

• Are receiving any oral or injectable medication intended for the treatment of diabetes mellitus other than rapid-acting analog insulin via CSII in the 90 days prior to screening. Occasional pen or syringe injection of insulin is allowed, for example, due to pump malfunction or unexplained hyperglycemia not responsive to pump correction bolus.

• Taking certain diabetes medications that are not allowed for study participation.

• Have major problems with heart, kidneys, liver, or have a blood disorder.

• Have had or are now being treated for certain types of cancer that prevents study participation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Valley Research	Fresno	California	United States	93720
2	Barbara Davis Center for Childhood Diabetes	Aurora	Colorado	United States	80045
3	Atlanta Diabetes Associates	Atlanta	Georgia	United States	30318
4	For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.	Sevilla		Spain	41009
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.	Seville		Spain	41003

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Jan 12, 2018
• Statistical Analysis Plan - Aug 29, 2018

More Information

Additional Information:

• A Study of LY900014 and Insulin Lispro With an External Continuous Subcutaneous Insulin Infusion System in Adult Participants With Type 1 Diabetes (PRONTO-Pump)

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT03433677
• Other Study ID Numbers: 16908; I8B-MC-ITSI; 2017-002374-39
• First Posted: Feb 14, 2018
• Last Update Posted: Oct 8, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eli Lilly and Company: insulin pump
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Lispro

Study Results

Participant Flow

Pre-assignment Detail	2-period crossover with no washout between periods and a 4 week safety follow-up.

Arm/Group Title	Sequence 1 (LY900014/Insulin Lispro)	Sequence 2 (Insulin Lispro/LY900014)
Arm/Group Description	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII) for six weeks 100 U/mL insulin lispro (Humalog®) administered by CSII for six weeks with no washout between periods	100 U/mL insulin lispro (Humalog®) administered by CSII for 6 weeks 100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII) for six weeks with no washout between periods
Period Title: Period 1
STARTED	24	25
Received at Least 1 Dose of Study Drug	24	25
COMPLETED	23	25
NOT COMPLETED	1	0
Period Title: Period 1
STARTED	23	25
Received at Least 1 Dose of Study Drug	23	25
COMPLETED	22	24
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Sequence 1 (LY900014/Insulin Lispro)	Sequence 2 (Insulin Lispro/LY900014)	Total
Arm/Group Description	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII) for six weeks 100 U/mL insulin lispro (Humalog®) administered by CSII for six weeks with no washout between periods	100 U/mL insulin lispro (Humalog®) administered by CSII for 6 weeks 100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII) for six weeks with no washout between periods	Total of all reporting groups
Overall Participants	24	25	49
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.50 (12.47)	36.72 (10.37)	39.55 (11.69)
Sex: Female, Male (Count of Participants)
Female	12 50%	14 56%	26 53.1%
Male	12 50%	11 44%	23 46.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.2%	0 0%	1 2%
Not Hispanic or Latino	23 95.8%	25 100%	48 98%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 4.2%	0 0%	1 2%
White	23 95.8%	25 100%	48 98%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	10 41.7%	11 44%	21 42.9%
Spain	14 58.3%	14 56%	28 57.1%

Outcome Measures

1. Primary Outcome

Title	Rate of Infusion Set Failures
Description	Infusion set failure events are defined as premature infusion set changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia with blood glucose (SMBG) >250 milligrams per deciliter (mg/dL) (13.9 millimoles per liter [mmol/L]) that does not decrease within 1 hour following a correction bolus delivered via the pump during the 6 week treatment period. Aggregate rate was calculated for each participant as the total number of events while the participant is on study treatment divided by the days of exposure [last dose date and time -first dose date and time -duration of pump or treatment interruption] times 30.
Time Frame	6 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Insulin Lispro (Humalog®)	LY900014
Arm/Group Description	100 U/mL insulin lispro (Humalog®) administered by CSII	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII)
Measure Participants	48	49
Number [events per 30 participant days]	0.05	0.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro (Humalog®), LY900014
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.375
	Comments
	Method	Wilcoxon signed-rank test
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With at Least 1 Event of Infusion Set Failure
Description	Infusion set failures are defined as premature infusion set changes, due to a pump occlusion alarm OR due to unexplained hyperglycemia with blood glucose (SMBG) >250mg/dL (13.9 mmol/L) that does not decrease within 1 hour following a correction bolus delivered via the pump.
Time Frame	6 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Insulin Lispro (Humalog®)	LY900014
Arm/Group Description	100 U/mL Insulin lispro (Humalog®) administered by CSII	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII)
Measure Participants	48	49
Number [percentage of participants]	6.3 26.3%	4.1 16.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro (Humalog®), LY900014
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.468
	Comments
	Method	Prescott's Exact test
	Comments

3. Secondary Outcome

Title	Rate of Premature Infusion Set Changes
Description	Rate of premature infusion set changes.
Time Frame	6 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Insulin Lispro (Humalog®)	LY900014
Arm/Group Description	100 U/mL insulin lispro (Humalog®) administered by CSII	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII)
Measure Participants	48	49
Number [events per 30 participant days]	0.78	1.13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro (Humalog®), LY900014
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Time Interval Until Infusion Set Change
Description	Time interval until infusion set change reflects the time interval in hours until infusion set change from first to last dose. MMRM model for post-baseline measures: Variable = Baseline + Period + Sequence + Strata(Region + Historical Use of SmartGuard/Threshold Suspend + HbA1c(<=7.3%, >7.3%)) + Treatment (Type III sum of squares).
Time Frame	6 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and non-missing baseline value and at least one non-missing post-baseline value.

Arm/Group Title	Insulin Lispro (Humalog®)	LY900014
Arm/Group Description	100 U/mL insulin lispro (Humalog®) administered by CSII	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII)
Measure Participants	46	47
Least Squares Mean (Standard Error) [hours]	76.1 (1.52)	74.3 (1.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro (Humalog®), LY900014
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.304
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean Difference
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -5.3 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Ratio of Bolus/Total Insulin Dose
Description	The bolus and total insulin doses for each visit was calculated as the mean of the doses for the last 3 days prior to the visit date that are entered in the eCRF. The bolus/total ratio was derived as the bolus dose divided by the total insulin dose at each visit.
Time Frame	6 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and non-missing baseline value and at least one non-missing post-baseline value.

Arm/Group Title	Insulin Lispro (Humalog®)	LY900014
Arm/Group Description	100 U/mL insulin lispro (Humalog®) administered by CSII	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII)
Measure Participants	47	46
Least Squares Mean (Standard Error) [percentage of total insulin dose]	46.6 (1.17)	44.2 (1.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro (Humalog®), LY900014
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.057
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMean Difference
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -4.8 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Interstitial Glucose Reduction Rate From Hyperglycemia Following a Non-Meal-Related Correction Bolus Delivered Via the Pump
Description	Interstitial glucose reduction rate (glucose reduction [mg/dL] per minute) within 4 hours following a non-meal-related correction bolus via the pump, from hyperglycemia (interstitial glucose >180 mg/dL [10 mmol/L]) to recovery (interstitial glucose ≤180 mg/dL).
Time Frame	6 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and non-missing baseline value and at least one non-missing post-baseline value of the response.

Arm/Group Title	Insulin Lispro (Humalog®)	LY900014
Arm/Group Description	100 U/mL insulin lispro (Humalog®) administered by CSII	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII)
Measure Participants	37	37
Least Squares Mean (Standard Error) [mg/dL/min]	0.71 (0.062)	0.82 (0.063)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Insulin Lispro (Humalog®), LY900014
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.177
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LSMeans
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	LSMean Difference

7. Secondary Outcome

Title	Number of Participants With Severe Hypoglycemic Events
Description	Number of participants with severe hypoglycemic events. Severe hypoglycemia was defined as participants with an altered mental status and could not assist in their own care, may have been semiconscious or unconscious, or experienced coma with or without seizures, and the event required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Blood glucose measurements may not have been available during such an event, but neurological recovery attributable to the restoration of BG concentration to normal was considered sufficient evidence that the event was induced by a low BG concentration (BG ≤70 mg/dL [3.9 mmol/L]).
Time Frame	6 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Insulin Lispro (Humalog®)	LY900014
Arm/Group Description	100 U/mL insulin lispro (Humalog®) administered by CSII	100 U/mL LY900014 administered by continuous subcutaneous insulin infusion (CSII)
Measure Participants	48	49
Number [participants]	1 4.2%	1 4%

Adverse Events

Time Frame	up to 12 weeks
Adverse Event Reporting Description	All randomized participants who received at least 1 dose of study drug.
Arm/Group Title	LY900014		Insulin Lispro (Humalog®)
Arm/Group Description	LY900014 administered by continuous subcutaneous insulin infusion (CSII)		Insulin lispro (Humalog®) administered by CSII
All Cause Mortality
	LY900014		Insulin Lispro (Humalog®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/48 (0%)
Serious Adverse Events
	LY900014		Insulin Lispro (Humalog®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/49 (2%)		1/48 (2.1%)
Metabolism and nutrition disorders
Hypoglycaemia	1/49 (2%)	1	1/48 (2.1%)	1
Other (Not Including Serious) Adverse Events
	LY900014		Insulin Lispro (Humalog®)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/49 (36.7%)		6/48 (12.5%)
General disorders
Infusion site pain	9/49 (18.4%)	11	2/48 (4.2%)	2
Infusion site reaction	9/49 (18.4%)	36	4/48 (8.3%)	5

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.