A Study to Evaluate the Effect of add-on Pioglitazone or Dapagliflozin in Participants With Type 2 Diabetes Mellitus Inadequately Controlled by DPP-4 Inhibitor and Metformin Therapy

Study Overview
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Brief Summary
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The purpose of this study is to assess the pioglitazone plus alogliptin plus metformin is non-inferior to dapagliflozin plus alogliptin plus metformin on glycosylated haemoglobin (HbA1c) change from baseline at Week 26.

Detailed Description
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The drug being tested in this study is Alogliptin Benzoate and Pioglitazone Hydrochloride FDC. This study will assess the efficacy of pioglitazone or dapagliflozin in participants with type 2 diabetes mellitus. The study will enroll approximately 156 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups. Pioglitazone 15 mg + Alogliptin 25 mg + Metformin >=500 mg Dapagliflozin 10 mg + Alogliptin 25 mg + Metformin >=500 mg Based on investigators opinion at Week 12, if participant has HbA1c >=7.5%, dose of pioglitazone can be titrated up to 30 mg. This multi-center trial will be conducted in Republic of Korea. The overall time to participate in this study is up to 36 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 14 days after their last dose of drug for a follow-up assessment.

Official Title
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A Multicenter, Randomized, Open-label, Two-arm, Phase 4 Study to Evaluate the Effect of Add-on Pioglitazone or Dapagliflozin in Subjects With Type 2 Diabetes Mellitus Inadequately Controlled by Dipeptidyl Peptidase-4 Inhibitor and Metformin Therapy

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Pioglitazone + Alogliptin
* Drug: Alogliptin
* Drug: Metformin
* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is a regular outpatient with an has a historical diagnosis of type 2 diabetes. The subject has metabolic syndrome as jointly defined by the International Diabetes Federation (IDF); National Heart, Lung, and Blood Institute (NHLBI) / American Heart Association (AHA); and International Association for the Study of Obesity (IASO). If any 3 of the following 5 risk factors are present, metabolic syndrome can be considered: High waist circumference: male ≥ 90 cm, female ≥ 85 cm. High TGs (drug treatment for high TGs is an alternate indicator): ≥ 150 mg/dL (1.7 mmol/L). Low HDL-C (drug treatment for low HDL-C is an alternate indicator): < 40 mg/dL(1.0 mmol/L) in males, < 50 mg/dL (1.3 mmol/L) in females. High blood pressure (antihypertensive drug treatment in a subject with a history of hypertension is an alternate indicator): Systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg. High fasting glucose (drug treatment of high glucose is an alternate indicator): ≥ 100 mg/dL. The subject has been receiving a stable dose of DPP-4 inhibitor + metformin therapy with diet and exercise for ≥ 3 months prior to Randomization. The subject has a HbA1c value between 7.0 and 11% inclusively within 28 days of Randomization via central laboratory test or after run-in period for 4 weeks via central laboratory test. Exclusion Criteria: The subject has type 1 diabetes, diabetic ketoacidosis, diabetic coma or diabetic precoma. The subject has an active bladder cancer or a history of bladder cancer. The use of any medications ie, oral or systemically injected glucocorticoids (including intra-articular injection), weight-loss drugs, insulin or other anti-diabetic drugs except DPP-4 inhibitor and metformin, within 3 months prior to randomization. Strong Cytochrome P450 2C8 (CYP2C8) inhibitors (eg, gemfibrozil, montelukast, quercetin, phenelzine) and CYP2C8 inducers (eg, rifampin) that in the opinion of the Investigator or Sponsor require treatment contraindicated during the study. The diuretics, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) -inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) are to be used per product label with close monitoring under Investigator's supervision. Has genetic problems such as galactose intolerance, Lapp lactose dehydrogenase deficiency or glucose-galactose uptake disorder, etc. Has a history of alcohol abuse within 2 years prior to randomization.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 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: Pioglitazone + Alogliptin + Metformin (PAM)<br>Pioglitazone 15 milligram (mg) and alogliptin 25 mg in fixed dose combination (FDC) tablet (SYR-322-4833), orally once daily and metformin greater than or equal to (>=) 500 mg, tablet, orally, twice a day for up to 26 weeks. At Week 12, if participants has HbA1c >=7.5%, pioglitazone dose will be titrated up to 30 mg based on investigator's opinion and up-titrated dose will be maintained up to Week 26. | Drug: Pioglitazone + Alogliptin<br>* Pioglitazone and Alogliptin FDC tablets<br>* Other names: SYR-322-4833;Drug: Metformin<br>* Metformin tablets.<br>|
| Active Comparator: Dapagliflozin + Alogliptin + Metformin (DAM)<br>Dapagliflozin 10 mg, tablet, orally, once daily with alogliptin 25 mg, tablet, orally, once daily, and metformin >=500 mg, tablet, orally, twice a day, for up to Week 26. | Drug: Alogliptin<br>* Alogliptin tablets.<br>Drug: Metformin<br>* Metformin tablets.<br>Drug: Dapagliflozin<br>* Dapagliflozin tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change from Baseline in HbA1c at Week 26 |  | Baseline and Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change from Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at Week 26 | HOMA IR measures insulin resistance based on fasting glucose and insulin measurements: HOMA IR equal to (=) fasting insulin (micro unit per milliliter [mcU/mL])*fasting glucose (millimole per milliliter [mmol/mL])/22.5. A higher number indicates a greater insulin resistance. | Baseline and Week 26 | 
| Mean Change from Baseline in Serum Lipids at Week 26 | The change from baseline in serum lipids (Total Cholesterol [TC], Low-density Lipoprotein Cholesterol [LDL-C], High-density Lipoprotein Cholesterol [HDL-C], Triglycerides [TGs]) will be analyzed using mixed model repeated measures (MMRM) model. | Baseline and Week 26 | 
| Number of Participants who Achieved an HbA1c Goal Target of Less than (<) 6.5 Percent (%) at Week 26 |  | Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy