A Comparison of Two Treatment Strategies in Older Participants With Type 2 Diabetes Mellitus (T2DM)

Study Overview
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Brief Summary
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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.

Official Title
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An Individualized treatMent aPproach for oldER patIents: A Randomized, Controlled stUdy in Type 2 Diabetes Mellitus (IMPERIUM)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Glimepiride
* Drug: Metformin
* Drug: Pioglitazone
* Drug: Acarbose
* Drug: Linagliptin
* Drug: Sitagliptin
* Drug: Liraglutide
* Drug: Insulin Glargine
* Drug: Exenatide once weekly (QW)
* Drug: Exenatide twice daily (BID)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Strategy A (Glucose-Dependent)<br>Participants may receive oral and injectable (glucagon-like peptide-1 receptor agonists [GLP-1 RA]) therapies 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. | Drug: Metformin<br>* Administered orally<br>Drug: Pioglitazone<br>* Administered orally<br>Drug: Acarbose<br>* Administered orally<br>Drug: Linagliptin<br>* Administered orally<br>Drug: Sitagliptin<br>* Administered orally<br>Drug: Liraglutide<br>* Administered subcutaneously (SC)<br>Drug: Exenatide once weekly (QW)<br>* Administered SC<br>Drug: Exenatide twice daily (BID)<br>* Administered SC<br>|
| Active Comparator: Strategy B (Reference)<br>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 is titrated according treatment algorithm. Treatment may last up to 72 weeks. | Drug: Glimepiride<br>* Administered orally<br>Drug: Metformin<br>* Administered orally<br>Drug: Pioglitazone<br>* Administered orally<br>Drug: Acarbose<br>* Administered orally<br>Drug: Linagliptin<br>* Administered orally<br>Drug: Sitagliptin<br>* Administered orally<br>Drug: Insulin Glargine<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to last participant visit (up to 72 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Requiring Alternative Treatment Due to Glycemic Failure of First Line Injectable Therapy |  | Baseline to last participant visit (up to 72 weeks) | 
| 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 | 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. | Baseline, Week 72 | 
| Change From Baseline in Body Mass Index (BMI) |  | Baseline, Week 72 | 
| 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. | Baseline, Week 72 |