Study of Human Regular U-500 Insulin in Adult Participants With Type 2 Diabetes

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Two Treatment Approaches for Human Regular U-500 Insulin (Thrice-Daily Versus Twice-Daily) in Subjects With Type 2 Diabetes Mellitus Not Achieving Adequate Glycemic Control on High-Dose U-100 Insulin Therapy With or Without Oral Agents: A Randomized, Open-Label, Parallel Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01774968
• Other study ID #: 14838
• Secondary ID: B5K-US-IBHC
• Status: Completed
• Phase: Phase 4
• First received: January 22, 2013
• Last updated: September 3, 2015
• Start date: February 2013
• Est. completion date: May 2014

Study information

• Verified date: September 2015
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The main purpose of this study is to compare the effectiveness of Human Regular U-500 Insulin three times a day versus twice a day.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 325
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Major Inclusion Criteria:

• Have type 2 diabetes mellitus (World Health Organization [WHO] Classification of Diabetes)

• Have a body mass index (BMI) =25 kilogram per square meter (kg/m^2)

• Have Glycated Hemoglobin A1c (HbA1c) =7.5% and =12.0%, as measured by the central laboratory at entry

• Current U-100 insulin/analogue users on >200 and =600 units per day for =3 months at study entry and reconfirmed at randomization

• Have a history of stable body weight for at least 3 months prior to study entry

• Concomitant medications may include metformin (MET), dipeptidyl peptidase-4 (DPP-4) inhibitors approved for use with insulin at time of study entry (for example, sitagliptin, saxagliptin, and linagliptin), pioglitazone, and/or sulfonylureas (SUs)/glinides (repaglinide or nateglinide). Participant's oral antihyperglycemic drug (OAD) dose(s) must have been stable for =3 months

Major Exclusion Criteria:

• Have type 1 diabetes mellitus or other types of diabetes mellitus apart from type 2 diabetes mellitus

• Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransferase or aspartate aminotransferase levels =3 times the upper limit of the reference range

• Have chronic kidney disease stage 4 and higher or history of renal transplantation

• Have history of more than 1 episode of severe hypoglycemia within the 6 months prior to study entry

• Have received insulin by continuous subcutaneous insulin infusion in the 3 months prior to study entry

• Have received U-500R in the 3 months prior to study entry

• Have had a blood transfusion or severe blood loss within 3 months prior to study entry or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia

• Are taking chronic systemic glucocorticoid therapy or have received such therapy within the 4 weeks immediately prior to study entry

• Have an irregular sleep/wake cycle

• Have used rosiglitazone, once- or twice-daily glucagon-like peptide-1 (GLP-1) receptor agents, pramlintide, or other injectable or oral antihyperglycemic therapy not listed in the inclusion criteria in the 3 months prior to study entry. Participants may not have used once-weekly GLP-1 receptor agents in the 4 months prior to study entry

• Have used any weight loss drugs in the 3 months prior to study entry

• Have a history of bariatric surgery

• Have a history of malignancy other than basal cell or squamous cell skin cancer

• Have New York Heart Association (NYHA) Class III or IV per NYHA Cardiac Disease Functional Classification

• 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Human Regular U-500 Insulin

Locations

Country	Name	City	State
Puerto Rico	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.	Bayamon
Puerto Rico	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.	Las Lomas
Puerto Rico	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.	Manati
Puerto Rico	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.	San Juan
United States	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Baltimore	Maryland
United States	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.	Bangor	Maine
United States	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.	Beaumont	Texas
United States	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.	Chattanooga	Tennessee
United States	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.	Columbia	Missouri
United States	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	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.	Crystal Lake	Illinois
United States	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Dallas	Texas
United States	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.	Des Moines	Iowa
United States	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.	Durham	North Carolina
United States	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.	Federal Way	Washington
United States	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.	Fresno	California
United States	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.	Greenville	North Carolina
United States	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.	Honolulu	Hawaii
United States	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	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.	Jacksonville	Florida
United States	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.	Las Vegas	Nevada
United States	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.	Little Rock	Arkansas
United States	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.	Louisville	Kentucky
United States	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.	Mobile	Alabama
United States	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	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.	Nashville	Tennessee
United States	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.	Norfolk	Virginia
United States	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.	Oklahoma City	Oklahoma
United States	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.	Olympia	Washington
United States	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.	Omaha	Nebraska
United States	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.	Philadelphia	Pennsylvania
United States	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.	Pittsburgh	Pennsylvania
United States	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Renton	Washington
United States	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.	Spokane	Washington
United States	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.	Springfield	Missouri
United States	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.	Tacoma	Washington
United States	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.	Tampa	Florida
United States	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	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

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 24 in Glycated Hemoglobin A1c (HbA1c)	Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with investigator, baseline total daily dose (TDD; =300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline HbA1c as a covariate.	Baseline, Week 24	No
Secondary	Percentage of Participants Achieving HbA1c of =6.5%, <7.0%, <7.5%, and <8.0% at Week 24	The percentage of participants achieving an HbA1c of =6.5%, <7.0%, <7.5%, and <8.0% at Week 24 was calculated by the dividing the number of participants meeting the criteria by the total number of participants analyzed, multiplied by 100.	Week 24	No
Secondary	30-Day Adjusted Rate of Hypoglycemic Events	Hypoglycemic events (HE) were classified as severe (an event requiring assistance from another person [accompanied by neurologic/cognitive impairment]), documented symptomatic (an event which is associated with signs/symptoms of hypoglycemia and plasma glucose [PG] =70 milligrams per deciliter [mg/dL]), documented symptomatic nocturnal (any documented symptomatic HE that occurred between bedtime and waking), or asymptomatic (any measured PG =70 mg/dL not accompanied by hypoglycemic signs/symptoms). The 30-day adjusted rate of HE is summarized cumulatively at 24 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline through Week 24	Yes
Secondary	Change From Baseline to Week 24 in Body Weight	LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (=8% or >8%), baseline TDD (=300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline body weight as a covariate.	Baseline, Week 24	Yes
Secondary	Change From Baseline to Week 24 in Total Daily Dose (TDD; Units) of Insulin	Baseline TDD was defined as the last U-100 insulin TDD prior to receiving the first dose of U-500R insulin. LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (=8% or >8%), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline TDD as a covariate.	Baseline, Week 24	No
Secondary	Change From Baseline to Week 24 in Total Daily Dose (TDD; Units/kg) of Insulin	Baseline TDD was defined as the last U-100 insulin TDD prior to receiving the first dose of U-500R insulin. LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (=8% or >8%), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline TDD as a covariate.	Baseline, Week 24	No
Secondary	Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) Levels	LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (=8% or >8%), baseline TDD (=300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline FPG as a covariate.	Baseline, Week 24	No
Secondary	Time to Reach HbA1c Target Values	The cumulative number of participants achieving an HbA1c of =6.5%, <7.0%, <7.5%, and <8.0% is summarized at Weeks 6, 12, 18, and 24. The number of participants at risk (n) is also provided for each target value and timepoint.	Baseline through 6, 12, 18, and 24 weeks.	No
Secondary	Percentage of Participants With Hypoglycemic Events	Hypoglycemic events (HE) were classified as severe (an event requiring assistance from another person [accompanied by neurologic/cognitive impairment]), documented symptomatic (an event which is associated with signs/symptoms of hypoglycemia and plasma glucose [PG] =70 milligrams per deciliter [mg/dL]), documented symptomatic nocturnal (any documented symptomatic HE that occurred between bedtime and waking), or asymptomatic (any measured PG =70 mg/dL not accompanied by hypoglycemic signs/symptoms). The percentage of participants with HE at 24 weeks was calculated by the dividing the number of participants meeting the criteria by the total number of participants analyzed, multiplied by 100. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline through Week 24	Yes
Secondary	Change From Baseline to Week 24 in Number of Insulin Injections	The number of insulin injections per day at baseline (Week 0) and at Week 24 are presented.	Baseline, Week 24	No
Secondary	Mean Change From Baseline to Week 24 in 7-Point Self-Monitored Blood Glucose (SMBG)	The 7-point SMBG is a participant self-administered blood glucose test which utilizes measurements at specific time points over a 24-hour period, including pre-morning meal (fasting), 2 hours after morning meal, pre-midday meal, 2 hours after midday meal, pre-evening meal, 2 hours after evening meal, and 3 AM. LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (=8% or >8%), baseline TDD (=300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline SMBG as a covariate.	Baseline, Week 24	No
Secondary	Change From Baseline to Week 24 in HbA1c Based on Baseline TDD Insulin =2.0 Units/kg and >2.0 Units/kg	Participants were stratified by their baseline TDD insulin (=2.0 units/kg or >2.0 units/kg). LS means of change from baseline were calculated using MMRM with investigator, baseline TDD (=300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline HbA1c as a covariate.	Baseline, Week 24	No
Secondary	Change From Baseline to Week 24 in 30-Day Adjusted Rate of Hypoglycemic Events Based on Baseline TDD Insulin =2.0 Units/kg and >2.0 Units/kg	Participants were stratified by their baseline TDD insulin (=2.0 units/kg or >2.0 units/kg). Hypoglycemic events (HE) were classified as severe (an event requiring assistance from another person [accompanied by neurologic/cognitive impairment]), documented symptomatic (DS; an event which is associated with signs/symptoms of hypoglycemia and plasma glucose [PG] =70 milligrams per deciliter [mg/dL]), or nocturnal (Noc; any documented symptomatic HE that occurred between bedtime and waking). The 30-day adjusted rate of HE is summarized cumulatively at 24 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline, Week 24	Yes
Secondary	Change From Baseline to Week 24 in Percentage of Participants With Hypoglycemic Events Based on Baseline TDD Insulin =2.0 Units/kg and <2.0 Units/kg	Participants were stratified by their baseline TDD insulin (=2.0 units (U)/kg or >2.0 U/kg). The percentage of participants at risk of developing hypoglycemia (including documented symptomatic, asymptomatic, probable symptomatic, unspecified, or severe hypoglycemia) is presented at Baseline and at Week 24 and was calculated using MMRM fit with options of the binomial distribution and log link function including treatment, TDD (>300 units or =300 units), pioglitazone use (yes or no), visit, and treatment-by-visit interaction as fixed effects, and baseline HbA1c value as a covariate.	Baseline, Week 24	Yes
Secondary	Change From Baseline to Week 24 in Body Weight Based on Baseline TDD Insulin =2.0 Units/kg and <2.0 Units/kg	Participants were stratified by their baseline TDD insulin (=2.0 units/kg or >2.0 units/kg). LS means of change from baseline were calculated using MMRM with investigator, baseline HbA1c (=8% or >8%), baseline TDD (=300 or >300 units), treatment (TID or BID), visit, and treatment-by-visit interaction as fixed effects and baseline body weight as a covariate.	Baseline, Week 24	Yes