Diabetes Mellitus, Type 2
Conditions
Brief summary
The main purpose of this study is to compare the benefits and risks associated with the use of 2 treatment strategies to lower blood sugar in participants aged 65 and older with T2DM. One strategy is based on the use of oral and injectable medications that only reduce blood sugar (glucose) when it is high. The other strategy is based on non-glucose dependent agents. The trial will last up to 72 weeks for each participant.
Interventions
DRUGGlimepiride
Administered orally
DRUGMetformin
Administered orally
DRUGPioglitazone
Administered orally
DRUGAcarbose
Administered orally
DRUGLinagliptin
Administered orally
DRUGSitagliptin
Administered orally
DRUGLiraglutide
Administered subcutaneously (SC)
DRUGInsulin Glargine
Administered SC
DRUGExenatide once weekly (QW)
Administered SC
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have T2DM based on a history and clinical impression that is consistent with the World Health Organization (WHO) Classification of Diabetes * Have a Clinical Frailty Scale (CFS) score of 4 or above or Total Illness Burden Index (TIBI) score of 5 or above as assessed at screening * Have an A1c \>7.3% and \<10.9% at study entry and are not achieving desired glycemic control as evidenced by A1c measurement at least 0.4% higher than individualized treatment target set at screening. * Have been treated for at least 3 months prior to the study entry with any of the following treatment options: * Diet/exercise only (only if they have known contraindications to metformin treatment) * Any dose of sulfonylurea * Effective or maximally-tolerated doses of metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or acarbose used in monotherapy or in dual combination. The following doses are considered to be effective: * at least 1500 mg of metformin per day * At least 30 mg of pioglitazone per day * At least 4 mg of rosiglitazone per day * At least 75 mg of acarbose per day * Any marketed dose of DPP-4 inhibitor
Exclusion criteria
* Are currently enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Have participated, within the last 60 days in a clinical trial involving an investigational product other than the investigational product used in this study. If the previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed * Have previously completed or withdrawn from this study. This exclusion criterion does not apply to participants who are rescreened prior to randomization * At study entry, have contraindications to sulfonylurea, insulin, or GLP-1 RA * Have a history of pancreatitis, a personal or family history of medullary thyroid carcinoma, or have Multiple Endocrine Neoplasia syndrome type 2 * Have taken any injectable glucose-lowering agent, miglitol, meglitinide, Sodium/Glucose cotransporter-2 inhibitor, or other antihyperglycemia treatment that is not listed in the fourth inclusion criterion for more than 10 days within 3 months prior to the study entry * In the opinion of investigator should have an individualized A1c target set at 8% or higher * Have a body mass index (BMI) greater than 45 kg/m\^2 * Have had more than 1 episode of severe hypoglycemia within 24 weeks prior to the study * Have cardiac disease with functional status that is Class III or IV according to the New York Heart Association Cardiac Disease Classification * Have an estimated glomerular filtration rate (eGFR) \<30 milliliter/minute/1.73 m\^2 (mL/min/1.73 m\^2) or advanced renal disease including history of renal transplantation or currently receiving renal dialysis * Have obvious clinical signs or symptoms or laboratory evidence of liver disease (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \> 2.5 times the upper limit of the reference range) * Receive current therapy for a malignancy, other than basal-cell or squamous-cell skin cancer * Received systemic glucocorticoids within the 3 months prior to entry for more than 14 consecutive days * Have any other condition that precludes the participant from following and completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving and Maintaining Individualized Glycated Hemoglobin A1c (HbA1c) Targets Without Clinically Significant Hypoglycemia | Baseline to last participant visit (up to 72 weeks) | Failed to reach and maintain HbA1c target, without clinically significant hypoglycemia, is defined as having 2 consecutive HbA1c \> upper limit of HbA1c target over 12 weeks starting from Week 24 for participants with HbA1c data beyond Week 24, or Week 24 HbA1c \> upper limit of HbA1c target for participants without HbA1c data beyond Week 24. Clinically significant hypoglycemia is defined as any severe hypoglycemia or repeated hypoglycemia interrupting participants activities or sleep and associated with blood glucose ≤3.9 millimole per liter (mmol/L), or repeated asymptomatic hypoglycemia associated with blood glucose \<3.0 mmol/L. Success is defined as lacking of failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Baseline to last participant visit (up to 72 weeks) | — |
| Change From Baseline of Urinary Albumin to Creatinine Ratio | Baseline, Week 72 | The Urinary Albumin to Creatinine Ratio is used in addition to Estimated Glomerular Filtration Rate (eGFR) to measure the incidence and progression of diabetic kidney disease. |
| Change From Baseline in Body Mass Index (BMI) | Baseline, Week 72 | — |
| Change From Baseline of Estimated Glomerular Filtration Rate (eGFR) | Baseline, Week 72 | The eGFR is used in addition to the Urinary Albumin to Creatinine Ratio to measure the incidence and progression of diabetic kidney disease. |
| Percentage of Participants Requiring Alternative Treatment Due to Glycemic Failure of First Line Injectable Therapy | Baseline to last participant visit (up to 72 weeks) | — |
Other
| Measure | Time frame |
|---|---|
| Change From Baseline in Mini-mental State Examination (MMSE) Score | Baseline, Week 72 |
| Change From Baseline in European Quality of Life-5 Dimensions 5 Levels (EQ-5D-5L) Score | Baseline, Week 72 |
| Change From Baseline in Adult Low Blood Sugar Survey (ALBSS) Score | Baseline, Week 72 |
Countries
Austria, Germany, Puerto Rico, United Kingdom, United States
Participant flow
Pre-assignment details
Participants completed the first 24 weeks of the study at which time the study was stopped and interim analysis was triggered to assess feasibility. Treatment continued per protocol until study termination and participants discontinued at the next office study visit. Data was assessed from Baseline to last participant visit, up to 72 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Strategy A (Glucose-Dependent) Participants may receive oral and injectable therapies (glucagon-like peptide-1 receptor agonists \[GLP-1 RA\]) that exert a glucose-dependent mode of action. Medications allowed in this arm include: metformin, pioglitazone, acarbose, linagliptin, sitagliptin, liraglutide, exenatide once weekly (QW), and exenatide twice daily (BID). Choice of therapy is based on investigator's discretion. Treatment used in label. Treatment may last up to 72 weeks. | 99 |
| Strategy B (Reference) Participants will receive glimepiride and may receive basal insulin glargine as a first line injectable therapy. Medications allowed in this arm include: glimepiride, metformin, pioglitazone, acarbose, linagliptin, sitagliptin and basal insulin glargine. Choice of therapy is based on investigator's discretion. Treatment used in label. Insulin glargine dose is titrated according to treatment algorithm. Treatment may last up to 72 weeks. | 93 |
| Total | 192 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Lack of Efficacy | 18 | 29 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | No Reason Provided | 4 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 7 | 7 |
| Overall Study | Study Terminated by Sponsor | 43 | 30 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Strategy A (Glucose-Dependent) | Strategy B (Reference) | Total |
|---|---|---|---|
| Age, Continuous | 70.7 years STANDARD_DEVIATION 5.3 | 70.7 years STANDARD_DEVIATION 4.4 | 70.7 years STANDARD_DEVIATION 4.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 32 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 59 Participants | 122 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 10 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 93 Participants | 81 Participants | 174 Participants |
| Region of Enrollment Austria | 18 participants | 14 participants | 32 participants |
| Region of Enrollment Germany | 19 participants | 17 participants | 36 participants |
| Region of Enrollment Puerto Rico | 23 participants | 16 participants | 39 participants |
| Region of Enrollment United Kingdom | 10 participants | 11 participants | 21 participants |
| Region of Enrollment United States | 29 participants | 35 participants | 64 participants |
| Sex: Female, Male Female | 43 Participants | 34 Participants | 77 Participants |
| Sex: Female, Male Male | 56 Participants | 59 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 82 / 98 | 74 / 93 |
| serious Total, serious adverse events | 15 / 98 | 14 / 93 |
Outcome results
Primary
Percentage of Participants Achieving and Maintaining Individualized Glycated Hemoglobin A1c (HbA1c) Targets Without Clinically Significant Hypoglycemia
Failed to reach and maintain HbA1c target, without clinically significant hypoglycemia, is defined as having 2 consecutive HbA1c \> upper limit of HbA1c target over 12 weeks starting from Week 24 for participants with HbA1c data beyond Week 24, or Week 24 HbA1c \> upper limit of HbA1c target for participants without HbA1c data beyond Week 24. Clinically significant hypoglycemia is defined as any severe hypoglycemia or repeated hypoglycemia interrupting participants activities or sleep and associated with blood glucose ≤3.9 millimole per liter (mmol/L), or repeated asymptomatic hypoglycemia associated with blood glucose \<3.0 mmol/L. Success is defined as lacking of failure.
Time frame: Baseline to last participant visit (up to 72 weeks)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Strategy A (Glucose-Dependent) | Percentage of Participants Achieving and Maintaining Individualized Glycated Hemoglobin A1c (HbA1c) Targets Without Clinically Significant Hypoglycemia | 64.5 percentage of participants |
| Strategy B (Reference) | Percentage of Participants Achieving and Maintaining Individualized Glycated Hemoglobin A1c (HbA1c) Targets Without Clinically Significant Hypoglycemia | 54.9 percentage of participants |
Secondary
Change From Baseline in Body Mass Index (BMI)
Time frame: Baseline, Week 72
Population: All participants who received at least one dose of study drug and had evaluable baseline and post-baseline BMI data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Strategy A (Glucose-Dependent) | Change From Baseline in Body Mass Index (BMI) | -0.47 kilogram per square meter (kg/m^2) | Standard Deviation 1.56 |
| Strategy B (Reference) | Change From Baseline in Body Mass Index (BMI) | 0.20 kilogram per square meter (kg/m^2) | Standard Deviation 2.91 |
Secondary
Change From Baseline of Estimated Glomerular Filtration Rate (eGFR)
The eGFR is used in addition to the Urinary Albumin to Creatinine Ratio to measure the incidence and progression of diabetic kidney disease.
Time frame: Baseline, Week 72
Population: All participants who received at least one dose of study drug and had evaluable baseline and post-baseline eGFR data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Strategy A (Glucose-Dependent) | Change From Baseline of Estimated Glomerular Filtration Rate (eGFR) | -5.00 milliliter per minute/1.73 square meter | Standard Deviation 13.64 |
| Strategy B (Reference) | Change From Baseline of Estimated Glomerular Filtration Rate (eGFR) | -5.88 milliliter per minute/1.73 square meter | Standard Deviation 10.95 |
Secondary
Change From Baseline of Urinary Albumin to Creatinine Ratio
The Urinary Albumin to Creatinine Ratio is used in addition to Estimated Glomerular Filtration Rate (eGFR) to measure the incidence and progression of diabetic kidney disease.
Time frame: Baseline, Week 72
Population: All participants who received at least one dose of study drug and had evaluable baseline and post-baseline urinary albumin to creatinine ratio.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Strategy A (Glucose-Dependent) | Change From Baseline of Urinary Albumin to Creatinine Ratio | 1.85 milligram per millimole (mg/mmol) | Standard Deviation 22.99 |
| Strategy B (Reference) | Change From Baseline of Urinary Albumin to Creatinine Ratio | 1.85 milligram per millimole (mg/mmol) | Standard Deviation 16.46 |
Secondary
Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia
Time frame: Baseline to last participant visit (up to 72 weeks)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Total Hypoglycemia | 10 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Probable Symptomatic Hypoglycemia | 0 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Clinically Significant Hypoglycemia | 0 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Unspecified Hypoglycemia | 2 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Symptomatic Hypoglycemia | 5 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Relative Hypoglycemia | 1 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Severe Hypoglycemia | 0 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Nocturnal Hypoglycemia | 4 Participants |
| Strategy A (Glucose-Dependent) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Asymptomatic Hypoglycemia | 8 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Nocturnal Hypoglycemia | 10 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Total Hypoglycemia | 50 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Severe Hypoglycemia | 0 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Symptomatic Hypoglycemia | 34 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Asymptomatic Hypoglycemia | 30 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Probable Symptomatic Hypoglycemia | 7 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Unspecified Hypoglycemia | 7 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Relative Hypoglycemia | 6 Participants |
| Strategy B (Reference) | Number of Participants With Total Hypoglycemia and Other Categories of Hypoglycemia | Clinically Significant Hypoglycemia | 1 Participants |
Secondary
Percentage of Participants Requiring Alternative Treatment Due to Glycemic Failure of First Line Injectable Therapy
Time frame: Baseline to last participant visit (up to 72 weeks)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Strategy A (Glucose-Dependent) | Percentage of Participants Requiring Alternative Treatment Due to Glycemic Failure of First Line Injectable Therapy | 21 percentage of participants |
| Strategy B (Reference) | Percentage of Participants Requiring Alternative Treatment Due to Glycemic Failure of First Line Injectable Therapy | 13 percentage of participants |
Other Pre-specified
Change From Baseline in Adult Low Blood Sugar Survey (ALBSS) Score
Time frame: Baseline, Week 72
Population: Unable to conduct change from baseline analysis due to study closure and lack of endpoint data.
Other Pre-specified
Change From Baseline in European Quality of Life-5 Dimensions 5 Levels (EQ-5D-5L) Score
Time frame: Baseline, Week 72
Population: Unable to conduct change from baseline analysis due to study closure and lack of endpoint data.
Other Pre-specified
Change From Baseline in Mini-mental State Examination (MMSE) Score
Time frame: Baseline, Week 72
Population: Unable to conduct change from baseline analysis due to study closure and lack of endpoint data.