The DURABLE Trial: Evaluating the Durability of Starter Insulin Regimens in Patients With Type 2 Diabetes (IOOV)

Phase 4

Completed

Conditions: Diabetes Mellitus, Type 2

Interventions: Drug: Lispro Low Mix
Drug: Lispro Mid Mix
Drug: Insulin glargine
Drug: Lispro

Registration Number: NCT00279201

Lead Sponsor: Eli Lilly and Company

Brief Summary: This study will compare insulin lispro low mixture \[LM\] and insulin glargine both in combination with the patient's oral diabetes medicines, for their ability to control blood sugar in patients with type 2 diabetes and compare insulin lispro LM to insulin glargine with regard to the length of time that the overall blood sugar can be controlled.

This study will also determine whether the safety of insulin lispro LM and any side effects that might be associated with it are different from those observed with insulin glargine, both in combination with the patient's oral diabetes medications.

The addendum study (Intensification Addendum) will compare how different insulin treatments work to control blood sugar in patients whose diabetes could not be controlled by either insulin lispro LM or insulin glargine.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 2091

Inclusion Criteria

Must have type 2 diabetes.
Must be at least 30 and less than 80 years of age at the time of Visit 1.
Must be on at least two oral antidiabetes medications for at least 90 days.
Must have an HbA1c 1.2 to 2.0 times the upper limit of normal reference range at the local lab.

Exclusion Criteria

Must not have used insulin on a regular basis in the last 12 months.
Must not have had more than one episode of severe hypoglycemia in the last 24 weeks.
Must not have a body mass index (BMI) of greater than 45 (morbid obesity).
Must not have clinically significant hematologic, oncologic, renal, cardiac, hepatic, or gastrointestinal disease.
Must not be pregnant or intend to get pregnant during course of the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lispro Low Mix	Lispro Low Mix	Initiation Phase: Lispro Low Mix (LM) for 24 weeks Maintenance Phase: Up to an additional 2 years of Lispro LM if HbA1c less than or equal to 7.0 at 24 weeks.
Lispro Mid Mix prior Lispro Low Mix addendum	Lispro Mid Mix	Following Lispro LM Initiation Phase, if HbA1c greater than 7.0 after 24 weeks, then instead of entering Maintenance Phase, participants could be randomized to receive Lispro Mid Mix for 24 weeks in the Intensification Addendum Phase.
Lispro Low Mix prior Glargine addendum	Lispro Low Mix	Following Insulin Glargine Initiation Phase, if HbA1c greater than 7.0 after 24 weeks, then instead of entering Maintenance Phase, participants could be randomized to receive Lispro Low Mix for 24 weeks in the Intensification Addendum Phase
Basal bolus prior Lispro Low Mix addendum	Lispro	Following Lispro LM Initiation Phase, if HbA1c greater than 7.0 after 24 weeks, then instead of entering Maintenance Phase, participants could be randomized to receive Basal Bolus therapy (combination of insulin glargine and lispro) for 24 weeks in the Intensification Addendum Phase.
Basal bolus prior Glargine addendum	Lispro	Following Insulin Glargine Initiation Phase, if HbA1c greater than 7.0 after 24 weeks, then instead of entering Maintenance Phase, participants could be randomized to receive Basal Bolus therapy (combination of insulin glargine and lispro) for 24 weeks in the Intensification Addendum Phase.
Insulin glargine	Insulin glargine	Initiation Phase: Insulin glargine for 24 weeks Maintenance: Up to an additional 2 years of insulin glargine if glycosylated hemoglobin (HbA1c) less than or equal to 7.0 at 24 weeks.
Basal bolus prior Lispro Low Mix addendum	Insulin glargine	Following Lispro LM Initiation Phase, if HbA1c greater than 7.0 after 24 weeks, then instead of entering Maintenance Phase, participants could be randomized to receive Basal Bolus therapy (combination of insulin glargine and lispro) for 24 weeks in the Intensification Addendum Phase.
Basal bolus prior Glargine addendum	Insulin glargine	Following Insulin Glargine Initiation Phase, if HbA1c greater than 7.0 after 24 weeks, then instead of entering Maintenance Phase, participants could be randomized to receive Basal Bolus therapy (combination of insulin glargine and lispro) for 24 weeks in the Intensification Addendum Phase.

Primary Outcome Measures

Name	Time	Method
MAINTENANCE: Duration of Time HbA1c Maintained at Goal by Initiation Regimen (Insulin Glargine or Lispro Low Mix)	Endpoint (Last Observation Carried Forward [LOCF]) (Maintenance: up to 2.5 years)	HbA1c goal: HbA1c ≤7.0% or HbA1c \>7.0% but increased \<0.4% from last HbA1c ≤7.0%
INITIATION: 24-Week Endpoint Glycosylated Hemoglobin (HbA1c)	Endpoint (Initiation: Week 24)
ADDENDUM: 24-Week Endpoint HbA1c	Endpoint (Addendum) (24 weeks: Week 48)	HbA1c at 24-week endpoint in Intensification Addendum of the trial.

Secondary Outcome Measures

Name	Time	Method
INITIATION: Change in HbA1c From Baseline to 24 Weeks	Baseline (Initiation) to Endpoint (LOCF, Week 24)
INITIATION: Percentage of Participants With HbA1c < or = 7.0%, HbA1c <7.0%, and HbA1c < or = 6.5% at Endpoint	Endpoint (Initiation: Week 24)
INITIATION: HbA1c	Baseline (Initiation), Week 12, Week 24, Endpoint (LOCF)
INITIATION: 7-point Self-monitored Plasma Glucose (SMPG) Profiles and Postprandial Excursions	Endpoint (LOCF) (Initiation: Week 24)	Abbreviations: AM = morning; BG = blood glucose; PM = evening; PP = postprandial. A postprandial excursion is defined as: 2 hour postmeal plasma glucose-premeal plasma glucose.
INITIATION: Change From Baseline to Endpoint in 1,5 Anhydroglucitol (1,5 AG)	Baseline (Initiation), Endpoint (Week 24)
INITIATION: Incremental Change From Baseline in Body Weight	Baseline (Initiation), Weeks 6, 12, 18, 24, Endpoint (LOCF)
INITIATION: Body Weight	Baseline (Initiation), Weeks 6, 12, 18, 24, Endpoint (LOCF)
INITIATION: Percentage of Participants With Self-reported Hypoglycemic Episodes	Baseline (Initiation), Endpoint (Week 24), Overall (sum of frequencies of hypoglycemic episodes after baseline ([Week 0]).	Hypoglycemia = any time participant feels/person observes that the participant is experiencing a sign/symptom they associate with hypoglycemia (such as hunger, dizziness, shakiness, light-headedness, sweating, irritability, headache, fast heart beat, confusion, etc) or a glucose measurement ≤70 mg/dL (≤3.9 mmol/L). Severe hypoglycemia = participant requires assistance. Qualified medical staff instructed the participants about the signs and symptoms of hypoglycemia.
INITIATION: Rate of Self-reported Hypoglycemic Episodes	Endpoint (Initiation: Week 24), Overall (incidence of hypoglycemic episodes after baseline [Week 0])	Hypoglycemia = participant feels/person observes, that participant is experiencing a sign/symptom they associate with hypoglycemia (such as hunger, dizziness, shakiness, light-headedness, sweating, irritability, headache, fast heart beat, confusion, etc) or glucose measurement ≤70 mg/dL (≤3.9 mmol/L). Severe hypoglycemia = participant requires assistance. Qualified medical staff instructed the participants about the signs and symptoms of hypoglycemia.
INITIATION: Insulin Dose	Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, Endpoint (LOCF)
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal at Week 24 - Age	Endpoint (Initiation: Week 24)	Comparison of age at baseline between those participants who met their goal at Week 24 versus those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%).
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal at Week 24 - Origin	Endpoint (Initiation: Week 24)	Comparison of origin at baseline between those participants who met their goal at Week 24 versus those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%).
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal at Week 24 - Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)	Endpoint (Initiation: Week 24)	Comparison of HOMA-IR (surrogate markers of insulin resistance calculated from fasting insulin and glucose) at baseline between those participants who met their goal at Week 24 and those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%). HOMA-IR = fasting insulin (milliunits per milliliter) \* fasting plasma glucose (millimoles per liter) / 22.5.
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal at Week 24 - HbA1c	Endpoint (Initiation: Week 24)	Comparison of baseline HbA1c between those participants who met their goal at Week 24 versus those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%).
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal at Week 24 - Baseline HbA1c Percentage Group	Endpoint (Initiation: Week 24)	Comparison of baseline HbA1c percentage group (\<8.5,\>=8.5) between those participants who met their goal at Week 24 versus those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%).
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal at Week 24 - 1,5 AG	Endpoint (Initiation: Week 24)	Comparison of 1,5 AG between those participants who met their goal at Week 24 versus those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%).
MAINTENANCE: 7-point SMPG Profiles and Postprandial Excursions	Baseline (Maintenance: Week 24), Endpoint (LOCF) (up to 2.5 years)	Abbreviations: AM = morning; BG = blood glucose; PM = evening; PP = postprandial. A postprandial excursion is defined as: 2 hour postmeal plasma glucose-premeal plasma glucose.
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal at Week 24 - Pre Meals Blood Glucose, Post Meals Blood Glucose, Average of All Blood Glucose, and Fasting Blood Glucose	Endpoint (Initiation: Week 24)	Comparison of pre meals blood glucose, post meals blood glucose, average of all blood glucose, and fasting blood glucose between those participants who met their goal at Week 24 versus those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%).
INITIATION: Participant Demographics of Participants Who Did Versus Did Not Achieve HbA1c Goal - Oral Diabetes Medication at Baseline	Endpoint (Initiation: Week 24)	Comparison of oral diabetes medication at baseline between those participants who met their goal at Week 24 versus those who did not meet their goal at Week 24 (goal HbA1c ≤7.0%).
MAINTENANCE: HbA1c at Specified Visits and Endpoint	Baseline (Week 0), Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, Endpoint (LOCF) (up to 2.5 years)
MAINTENANCE: Rate of Increase in HbA1c	Endpoint (LOCF) (Maintenance: up to 2.5 years)	Rate of increase: HbA1c change/time period (month).
MAINTENANCE: Percentage of Participants With HbA1c < or = 7.0%, HbA1c <7.0, and HbA1c < or = 6.5%	Endpoint (LOCF) (Maintenance: up to 2.5 years)
MAINTENANCE: Incremental Change From Baseline in Body Weight	Baseline (Week 0), Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, Endpoint (LOCF) (Maintenance) (up to 2.5 years)
MAINTENANCE: Body Weight	Baseline (Week 0), Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, Endpoint (LOCF) (Maintenance) (up to 2.5 years)
MAINTENANCE: Insulin Dose	Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, Endpoint (LOCF) (Maintenance) (up to 2.5 years)
MAINTENANCE: Percentage of Participants With Self-reported Hypoglycemic Episodes	Endpoint (LOCF) (Maintenance) (up to 2.5 years), Overall (incidence of hypoglycemic episodes after baseline (Week 0)	Hypoglycemia = participant feels/person observes that the participant is experiencing a sign/symptom they associate with hypoglycemia (such as hunger, dizziness, shakiness, light-headedness, sweating, irritability, headache, fast heart beat, confusion, etc) or a glucose measurement ≤70 mg/dL (≤3.9 mmol/L). Severe hypoglycemia = participant requires assistance. Qualified medical staff instructed the participants about the signs and symptoms of hypoglycemia.
MAINTENANCE: Rate of Self-reported Hypoglycemic Episodes	Endpoint (LOCF) (Maintenance) (up to 2.5 years), Overall (incidence of hypoglycemic episodes after baseline [Week 0])	Hypoglycemia = participant feels/person observes that the participant is experiencing a sign/symptom they associate with hypoglycemia (such as hunger, dizziness, shakiness, light-headedness, sweating, irritability, headache, fast heart beat, confusion, etc) or a glucose measurement ≤70 mg/dL (≤3.9 mmol/L). Severe hypoglycemia = participant requires assistance. Qualified medical staff instructed the participants about the signs and symptoms of hypoglycemia.
MAINTENANCE: Change From Baseline in 1,5-Anhydroglucitol	Baseline (Maintenance: Week 24), Endpoint (LOCF) (up to 2.5 years)
MAINTENANCE: Change From Baseline to Endpoint in HbA1c	Baseline (Week 0), Week 24, Endpoint (LOCF) (Maintenance) (up to 2.5 years)
MAINTENANCE: Participant Demographics of Insulin Glargine Participants Who Did Versus Did Not Maintain HbA1c Goal - Duration of Diabetes	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of duration of diabetes at baseline between those participants taking insulin glargine that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Lispro LM Participants Who Did Versus Did Not Maintain HbA1c Goal - Duration of Diabetes	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of duration of diabetes at baseline between those participants taking lispro LM that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Insulin Glargine Participants Who Did Versus Did Not Maintain HbA1c Goal - Duration of Diabetes Group	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of duration of diabetes group (\<10, 10-\<20, \>=20 years) at baseline between those participants taking insulin glargine that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Lispro LM Participants Who Did Versus Did Not Maintain HbA1c Goal - Duration of Diabetes Group	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of duration of diabetes group (\<10, 10-\<20, \>=20 years) at baseline between those participants taking Lispro LM that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Insulin Glargine Participants Who Did Versus Did Not Maintain HbA1c Goal - Baseline HbA1c	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline HbA1c between those participants taking insulin glargine that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Lispro LM Participants Who Did Versus Did Not Maintain HbA1c Goal - Baseline HbA1c	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline HbA1c between those participants taking Lispro LM that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Insulin Glargine Participants Who Did Versus Did Not Maintain HbA1c Goal - Baseline HbA1c Group	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline HbA1c group (\<8.5,\>=8.5) between those participants taking insulin glargine that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Lispro LM Participants Who Did Versus Did Not Maintain HbA1c Goal - Baseline HbA1c Group	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline HbA1c group (\<8.5,\>=8.5) between those participants taking Lispro LM that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Insulin Glargine Participants Who Did Versus Did Not Maintain HbA1c Goal - Oral Diabetes Medicine at Baseline	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of oral diabetes medication at baseline between those participants taking insulin glargine that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Lispro LM Participants Who Did Versus Did Not Maintain HbA1c Goal - Oral Diabetes Medicine at Baseline	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of oral diabetes medication at baseline between those participants taking Lispro LM that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Insulin Glargine Participants Who Did Versus Did Not Maintain HbA1c Goal - 1,5 AG	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline 1,5 AG between those participants taking insulin glargine that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Lispro LM Participants Who Did Versus Did Not Maintain HbA1c Goal - 1,5 AG	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline 1,5 AG between those participants taking Lispro LM that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Insulin Glargine Participants Who Did Versus Did Not Maintain HbA1c Goal - Mean of Post Meals Blood Glucose and Average of All Blood Glucose	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline mean of post meals blood glucose and average of all blood glucose between those participants taking insulin glargine that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
MAINTENANCE: Participant Demographics of Lispro LM Participants Who Did Versus Did Not Maintain HbA1c Goal - Mean of Post Meals Blood Glucose and Average of All Blood Glucose	Endpoint (LOCF) (Maintenance) (up to 2.5 years)	Comparison of baseline mean of post meals blood glucose and average of all blood glucose between those participants taking Lispro LM that maintained their HbA1c goal and those that did not. Participants who maintained goal are those who did not fail during their duration on study. Failure is defined by HbA1c \> 7.0% with change \>= 0.4% from most recent HbA1c that was \<=7.0%.
ADDENDUM: Change in HbA1c From Point of Second Randomization (Addendum Baseline) to Endpoint	Baseline (Addendum: Week 24), Endpoint (24 weeks [Week 48])
ADDENDUM: Percentage of Participants With HbA1c < or = 7.0%, HbA1c < 7.0%, and < or = 6.5%	Endpoint (Addendum: 24 weeks [Week 48])
ADDENDUM: 7-point SMPG Profiles	Endpoint (Addendum: 24 weeks [Week 48])	Abbreviations: AM = morning; BG = blood glucose; PM = evening; PP = postprandial. A postprandial excursion is defined as: 2 hour postmeal plasma glucose-premeal plasma glucose.
ADDENDUM: Incremental Change From Baseline in Body Weight	Baseline (Addendum: Week 24), Weeks 6 (30 Weeks), 12 (36 Weeks), 24 (48 Weeks), Endpoint (LOCF)
ADDENDUM: Body Weight	Baseline (Addendum Week 24), Weeks 6 (30 weeks), 12 (36 weeks), 24 (48 weeks), Endpoint (LOCF)
ADDENDUM: Insulin Dose	Baseline (Addendum: Week 24), Weeks 1 (25 weeks), 2 (26 weeks), 3 (27 weeks), 4 (28 weeks), 5 (25 weeks), 6 (26 weeks), 8 (32 weeks), 10 (34 weeks), 12 (36 weeks), 24 (48 weeks), Endpoint (LOCF)
ADDENDUM: Percentage of Participants With Self-reported Hypoglycemic Episodes	Weeks 6 (Addendum: 30 weeks), 12 (36 weeks), 24 (48 weeks), Endpoint (LOCF)	Hypoglycemia = any time participant feels/person observes, that the participant is experiencing a sign/symptom they associate with hypoglycemia (such as hunger, dizziness, shakiness, light-headedness, sweating, irritability, headache, fast heart beat, confusion, etc) or a glucose measurement ≤70 mg/dL (≤3.9 mmol/L). Severe hypoglycemia = participant requires assistance. Qualified medical staff instructed the participants about the signs and symptoms of hypoglycemia.
ADDENDUM: Rate of Self-reported Hypoglycemic Episodes	Endpoint (Addendum 24 weeks), Overall (mean yearly rate of hypoglycemia during addendum phase	Hypoglycemia = participant feels/person observes, that the participant is experiencing a sign/symptom they associate with hypoglycemia (such as hunger, dizziness, shakiness, light-headedness, sweating, irritability, headache, fast heart beat, confusion, etc) or a glucose measurement ≤70 mg/dL (≤3.9 mmol/L). Severe hypoglycemia = participant requires assistance. Qualified medical staff instructed the participants about the signs and symptoms of hypoglycemia.
ADDENDUM: Change From Baseline in 1,5-Anhydroglucitol to Week 24	Baseline (addendum: 24 weeks), Endpoint (24 weeks: Week 48)
ADDENDUM: HbA1c at Specified Visits and Endpoint	Baseline (Addendum: 24 weeks), Weeks 12, 24, Endpoint (24 weeks: Week 48)

Trial Locations

Locations (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.
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Santander, Spain