Comparison of the Efficacy and Safety of Two Insulin Intensification Strategies

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Comparison of Twice-Daily Insulin Lispro Low Mixture Versus Once-Daily Basal Insulin Glargine and Once-Daily Prandial Insulin Lispro as Insulin Intensification Strategies in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin Glargine and Metformin and/or Pioglitazone

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01175824
• Other study ID #: 13493
• Secondary ID: F3Z-CR-IOQE
• Status: Completed
• Phase: Phase 4
• First received: August 3, 2010
• Last updated: January 24, 2014
• Start date: April 2011
• Est. completion date: November 2012

Study information

• Verified date: January 2014
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaBrazil: Ministry of HealthEgypt: Ministry of Health, Drug Policy and Planning CenterIndia: Drugs Controller General of IndiaKorea: Food and Drug AdministrationRomania: National Medicines AgencyRussia: Ministry of Health of the Russian FederationSpain: Ministry of HealthTurkey: Ministry of HealthChina: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The study is a comparison of twice-daily insulin lispro low mixture versus once-daily basal insulin glargine and once-daily prandial insulin lispro, in participants with Type 2 Diabetes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 478
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Present with type 2 diabetes mellitus

• Have been taking metformin and/or pioglitazone

• Have received treatment with basal insulin glargine, injected once a day, for greater than or equal to 90 days

• Have glycosylated hemoglobin A1c (HbA1c) concentration between greater than or equal to 7.5% and less than or equal to 10.5

• Have a fasting plasma glucose concentration of less than or equal to 6.7 millimoles per liter [mmol/L, less than or equal to 121 milligrams per deciliter (mg/dL)], or greater than 6.7 mmol/L (greater than 121 mg/dL) if the investigator considers that further titration of basal insulin glargine is not possible for safety reasons

• Not pregnant or breastfeeding

Exclusion Criteria:

• Have Type 1 Diabetes

• Their stable dose of pioglitazone is greater than the maximum dose approved for use in combination with insulin in their country

• Have a body mass index (BMI) greater than 45 kilograms per square meter (kg/m2).

• Have a history of scheduled mealtime (prandial) insulin use within 12 weeks of the screening visit and the total duration of the prandial insulin treatment was greater than 2 weeks

• Have had more than one episode of severe hypoglycaemia within 24 weeks prior to entry into the study

• Have cardiac disease with a functional status that is Class III or IV

• Have a history of renal or liver disease

• Have had a blood transfusion or have a blood disorder

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:
• Insulin Lispro Low Mixture (LM)
Participant-dependent dose, administered subcutaneously for 24 weeks
• Insulin Glargine
Participant-dependent dose, administered subcutaneously for 24 weeks
• Prandial Insulin Lispro
Participant-dependent dose, administered subcutaneously for 24 weeks

Locations

Country	Name	City	State
Argentina	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.	Mar Del Plata
Argentina	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.	Ramos Mejia
Brazil	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.	Porto Alegre
Brazil	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.	São Paulo
China	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.	Changzhou
China	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.	Harbin
Egypt	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.	Alexandria
Egypt	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.	Cairo
India	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.	Jaipur
India	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.	Vishakhapatnam
Korea, Republic of	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.	Daegu
Korea, Republic of	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.	Goyang-Si
Korea, Republic of	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.	Kyunggi-Do
Korea, Republic of	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.	Seoul
Spain	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.	Málaga
Spain	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 Boi De Llobregat
Turkey	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.	Antalya
Turkey	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.	Istanbul

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

Argentina,  Brazil,  China,  Egypt,  India,  Korea, Republic of,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in HbA1c From Baseline to 24 Weeks Endpoint (Per Protocol Population)	The change from baseline to 24 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.	Baseline, 24 weeks	No
Primary	Change in HbA1c From Baseline to 24 Weeks Endpoint (Intention-to-Treat Population)	The change from baseline to 24 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.	Baseline, 24 weeks	No
Secondary	Change in the HbA1c Concentration From Baseline to 12 Weeks Endpoint	The change from baseline to 12 weeks in the percentage of glycosylated hemoglobin A1c (HbA1c) in plasma. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline HbA1c concentration as a covariate, treatment, country, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.	Baseline, 12 weeks	No
Secondary	Number of Participants Who Achieve a Target HbA1c Concentration of Less Than 7% or Less Than or Equal to 6.5% at 24 Weeks		24 weeks	No
Secondary	Change in the Fasting Plasma Glucose Concentration From Baseline to 12 Weeks and 24 Weeks	The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline fasting plasma glucose value as a covariate, treatment, country, baseline HbA1c stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.	Baseline, 12 weeks, and 24 weeks	No
Secondary	7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks	7-point Self-monitored Blood Glucose (SMBG) Profiles are measures of blood glucose taken 7 times a day at the morning pre-meal, morning 2-hours post-meal, midday pre-meal, midday 2-hours post-meal, evening pre-meal, evening 2-hours post-meal, and 0300 hour [3 am]. Each participant took measures on 3 non-consecutive days and the average was calculated for each of the 7 time points. The mean of the 7-point averages was calculated for all the participants at baseline, Weeks 12 and 24. The least squares (LS) mean was estimated from mixed-effects model with repeated measures that included the baseline value of the variable as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c)stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.	12 weeks, 24 weeks	No
Secondary	Glycemic Variability From the 7-point Self-Monitored Blood Glucose (SMBG) Profiles at 12 Weeks and 24 Weeks	The 7-point SMBG profile was calculated as the average blood glucose concentration across the 7 pre-specified time points in a day that was then averaged over 3 non-consecutive days in the 2 weeks prior to the 12 week visit and 24 week visit. Glycemic variability was calculated as the standard deviation of the 7-point SMBG profiles. Standard deviation was first calculated for each day and then averaged over 3 non-consecutive days for each visit. The least squares (LS) mean was estimated from mixed-effects model with repeated measures that included the baseline value of the variable as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c)stratification level, week of visit, and treatment-by-week interaction as fixed effects, and participant and error as random effects.	12 weeks, 24 weeks	No
Secondary	Daily Insulin Dose: Total, Basal, and Prandial at 12 Weeks and 24 Weeks		12 weeks, 24 weeks	No
Secondary	Change in Weight From Baseline to 12 Weeks and 24 Weeks	The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included baseline weight as a covariate, treatment, country, baseline glycosylated hemoglobin A1c (HbA1c) stratification level, week of visit, and the treatment-by-week interaction as fixed effects, and participant and error as random effects.	Baseline, 12 weeks, 24 weeks	No
Secondary	The Number of Participants With a Hypoglycemic Episodes (Incidence)	A hypoglycemic episode was defined as an event associated with 1) reported signs and symptoms of hypoglycemia, and/or 2) a documented blood glucose (BG) concentration of <= 70 milligrams per deciliter [mg/dL, 3.9 millimoles per liter (mmol/L)].	Baseline through 24 weeks	Yes
Secondary	Insulin Treatment Satisfaction Questionnaire (ITSQ) Score at 24 Weeks	ITSQ: validated instrument containing 22 items which are measured on a 7-point scale: 1 (no bother at all) to 7 (a tremendous bother) used to assess insulin treatment satisfaction. Items are divided into 5 domains: Inconvenience of Regimen (5 items: domain score range 5 to 35), Lifestyle Flexibility (3 items: domain score range 3 to 21), Glycemic Control (3 items: domain score range 3 to 21), Hypoglycemic Control (5 items: domain score range 5 to 35), Insulin Delivery Device (6 items: domain score range 6 to 42) lower scores reflect better outcome. ITSQ Total Overall Score ranged from 22 to 154. Raw domain scores transformed on 0-100 scale, where transformed domain score = 100×[(7-raw domain score)/6]. Higher scores indicate better treatment satisfaction. Least squares (LS) mean estimated from analysis of covariance (ANCOVA) model that included baseline score as covariate and treatment, glycosylated hemoglobin A1c (HbA1c) stratum, and country as fixed effects.	24 weeks	No
Secondary	Perceptions About Medications-Diabetes 21 (PAM-D21) Questionnaire Score at 24 Weeks	PAM-D21 is a validated questionnaire consisting of 21 items to assess a participant's perceptions about their diabetes treatment regimens and perceived emotional and physical side-effects. The PAM-D21 consists of 4 subscales: Convenience/Flexibility (items 1 to 3); Perceived Effectiveness (items 4 to 6); Emotional Effects (items 7 to 11); and Physical Effects (items 12 to 21). Item scores range from 1 (none of the time) to 4 (all of the time). Subscale scores were linearly transformed to a 0-100, with higher score corresponds to better perceptions about diabetes medications. The least squares (LS) mean was estimated from an analysis of covariance (ANCOVA) model that included baseline score as a covariate and treatment, glycosylated hemoglobin A1c (HbA1c) stratum, and country as fixed effects.	24 weeks	No
Secondary	The Rate of Hypoglycemic Episodes	The hypoglycemia rate per 30 days was calculated as the number of episodes reported for the interval between visits and during the study divided by the number of days in the given interval and multiplied by 30.	Baseline through 24 weeks	Yes
Secondary	The Number of Participants With Severe Hypoglycemic Episodes	The number of participants who had a severe hypoglycemic episode anytime during the study. Severe hypoglycemia was defined as any event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.	Baseline through 24 weeks	Yes