Efficacy and Safety Evaluation of Pioglitazone with Metformin and Empagliflozin in Type 2 Diabetes Mellitus Patients with Inadequate Glycemic Control
- Trial ID
- 2023-508924-36-00
- Protocol
- CT-L03-301
- Sponsor
- Celltrion Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of a combination therapy involving Metformin, Empagliflozin, and Pioglitazone in patients with **type 2 diabetes mellitus (T2DM)** who exhibit inadequate glycemic control while on a regimen of Metformin and Empagliflozin. This evaluation is conducted in two parts: Part 1 assesses the efficacy of Metformin, Empagliflozin 10 mg, and Pioglitazone compared to Metformin and Empagliflozin 10 mg, while Part 2 compares Metformin, Empagliflozin 25 mg, and Pioglitazone to Metformin and Empagliflozin 25 mg. The clinical relevance of this objective lies in its potential to improve glycemic control in T2DM patients, thereby reducing the risk of diabetes-related complications.
The secondary objective is to evaluate the **safety** of the combination therapy of Metformin, Empagliflozin, and Pioglitazone compared to Metformin and Empagliflozin in T2DM subjects with inadequate glycemic control. This assessment is crucial for determining the risk-benefit profile of the combination therapy, ensuring that any improvements in glycemic control do not come at the expense of patient safety.
Participants
The clinical trial involves a total of **358 participants** diagnosed with **Type 2 diabetes mellitus (T2DM)**. The study population includes both male and female adults, with the age of majority being 19 years or older, except in Korea and Poland where it is 18 years or older. Participants were selected based on their inadequate glycemic control while on a regimen of Metformin and Empagliflozin. The trial does not include a vulnerable population. Key lifestyle considerations include maintaining a body mass index (BMI) of 45.0 kg/m² or less. Participants are required to have a compliance rate with overall medication between 70% and 120%. The selection criteria ensure that participants have not changed their background therapy dosage or administration method during the stabilization and washout period. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **Pioglitazone** co-administration in patients with **type 2 diabetes mellitus** (T2DM) who have insufficient glycemic control with a combination therapy of **Metformin** and **Empagliflozin**. The trial is structured in two parts, each assessing different dosages of Empagliflozin (10 mg and 25 mg) in combination with Metformin and Pioglitazone. The primary objective is to evaluate the change from baseline in HbA1c at Week 24 of treatment. Secondary endpoints include changes in fasting plasma glucose, lipid profiles, insulin resistance, liver function indicators, body weight, blood pressure, heart rate, and waist circumference at Weeks 12 and 24.
The trial is expected to commence recruitment on May 1, 2024, and conclude by May 31, 2026. Participants will be involved in the study for a maximum of 34 weeks, depending on their treatment regimen. The study includes several key visits: an initial screening visit to confirm eligibility, followed by a stabilization and washout period for certain participants. Subsequent visits will occur at regular intervals to monitor treatment efficacy and safety, with a final end-of-study visit to assess overall outcomes and collect final data.
Inclusion criteria require participants to be adults diagnosed with T2DM, with specific HbA1c levels depending on their prior treatment regimen. Participants must maintain a body mass index (BMI) of ≤ 45.0 kg/m² and demonstrate compliance with medication protocols. Conditions for early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and data integrity.
Treatment
The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy and safety in patients with type 2 diabetes mellitus (T2DM) who have insufficient glycemic control. **Metformin Hydrochloride** is utilized in the study in two pharmaceutical forms: prolonged-release tablets and film-coated tablets. The maximum daily dose of Metformin Hydrochloride is 2000 mg, with a maximum treatment period of 34 weeks. The route of administration is oral, and the medication is classified as a chemical substance. Participant compliance is monitored to ensure adherence to the dosing schedule.
**Pioglitazone** is another experimental medication used in the trial, provided in tablet form. The maximum daily dose is 30 mg, with a treatment period of up to 24 weeks. Pioglitazone is administered orally and is also classified as a chemical substance. The study aims to assess the co-administration of Pioglitazone with Metformin and Empagliflozin to improve glycemic control in T2DM patients.
**Empagliflozin** is included in the trial in the form of film-coated tablets. It is administered orally with a maximum daily dose of either 10 mg or 25 mg, depending on the study part, and a treatment period of 34 weeks. Empagliflozin is a chemical substance, and its efficacy in combination with Metformin and Pioglitazone is evaluated.
Additional medications used in the study include **Glipizide**, **Gliquidone**, **Glimepiride**, and **Gliclazide**, all administered in tablet form with oral use. These medications have varying maximum daily doses and treatment periods, ranging from 4 to 34 weeks. Each of these medications is classified as a chemical substance and is used to support the primary treatment regimen.
A **placebo** is also utilized in the trial as a comparator to evaluate the efficacy of the active treatments. The placebo is designed to match the appearance of the active tablets but contains no active pharmaceutical ingredients. The use of a placebo helps to maintain the double-blind nature of the study, ensuring unbiased results.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in **HbA1c** at Week 24 of the treatment. Secondary endpoints include changes from baseline in **HbA1c** at Week 12, fasting plasma glucose (FPG) at Weeks 12 and 24, and the proportion of subjects achieving **HbA1c** levels below 6.5% and 7.0% at Week 24. Additional secondary endpoints involve changes in lipid profiles, insulin resistance (HOMA-IR), insulin secretion ability (HOMA-β), liver function indicators (AST, ALT), body weight, blood pressure (SBP, DBP), heart rate, and waist circumference at Weeks 12 and 24. The proportion of subjects requiring rescue medication at Weeks 12 and 24 will also be evaluated.
Measurements will be collected at specified time points, including baseline, Week 12, and Week 24, using validated laboratory tests and patient assessments. The analysis will focus on comparing the efficacy of the combination therapy of Metformin, Empagliflozin, and Pioglitazone against the regimen of Metformin and Empagliflozin alone in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control. The trial is designed as a multicenter, randomized, double-blind, placebo-controlled phase III study, ensuring rigorous evaluation of the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults* at the time of signing the Informed Consent Form (ICF) * The age of majority is different in countries, and the current country-specific requirements apply. Currently, the age of majority is 19 years or older and 18 years and older in Korea and Poland, respectively.
- Diagnosed with T2DM
- Following HbA1c concentration* at Visit 1 ① Drug-naïve** or prior treatment with Metformin*** monotherapy: 7.5% ≤ HbA1c ≤ 11% ② Prior treatment with co-administration of Metformin*** and other oral hypoglycemic agents****: 7.0% ≤ HbA1c ≤ 11% * Based on the test result performed by the study site at Visit 1 (the test result performed by the study site within 2 weeks is allowed.) ** Subjects who have not received any oral hypoglycemic agents within 12 weeks of Visit 1. *** Subjects who have not received Metformin or who have received less than 1,000 mg as a fixed-dose combination (FDC) or combination therapy at Visit 1 may participate in this study if it is appropriate to prescribe Metformin 1,000 mg as a new dose or to increase the dose above 1,000 mg, at the discretion of the Investigator. In this case, subjects need to enter an 8- week stabilization and washout period with the increased dosage. However, if subjects have received Metformin over 1,000 mg, they may maintain the existing dose administered prior to the Screening. If subjects need to change the dosage of Metformin, they need to enter stabilization and washout period. **** Subjects who have received oral hypoglycemic agents (except oral GLP-1 analogues) or with components or drugs of the same class as the IP or the background therapy (biguanides, SGLT2 inhibitors, and thiazolidinediones) may participate in the study after the stabilization and washout period and the run-in period if they meet the inclusion/exclusion criteria.
- Subjects who meet the following at Visit 2 ① Subjects who have received the background therapy without change in the dosage, administration method, and dosage form during the stabilization and washout period (12 weeks for drug naïve, 8 weeks for the others) ② Subjects who do not need to change the background therapy at the discretion of the investigator ③ Measured as 7.0% ≤ HbA1c ≤ 11% by the central laboratory at Visit 2
- Body mass index (BMI) ≤ 45.0 kg/m2 at Visit 1 and Visit 3
- Compliance of overall medication in between 70% and 120% inclusive, at each Visit 2 and Visit 3
- Signed the written ICF voluntarily after being fully informed of the objectives, methods, and effects of the study
- Correction of Incl crit 1. Adults* at the time of signing the Informed Consent Form (ICF) * The age of majority is different in countries, and the current country-specific requirements apply. Currently, the age of majority is 19 years or older and 18 years or older in Korea and Poland, respectively
Exclusion Criteria
- Diagnosed with other types of diabetes than T2DM (type 1 diabetes, secondary diabetes, or congenital nephrogenic diabetes insipidus, etc.)
- Immune deficiency syndrome (AIDS) or history of positive HIV-1
- History of gross hematuria or current symptom of clinically significant hematuria
- Hypopituitarism or adrenal insufficiency
- History of genetic disorders, including galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, etc.
- Following conditions with a clinically significant liver disease: ① AST or ALT > 3 times the upper limit of normal ② Total bilirubin > 2 times the upper limit of normal ③ Hepatitis requiring antiviral treatment ④ Liver cirrhosis or liver failure
- Following conditions with a clinically significant kidney disease: ① eGFR* < 45 ml/min/1.73 m2 ② eGFR* < 60 ml/min/1.73 m2: For those who received more than Metformin 1,000 mg at Visit 1 * eGFR can be calculated using either the Modification of Diet in Renal Disease (MDRD) equation or the equation of the study site.
- Uncontrolled severe complications of diabetes (e.g., proliferative diabetic retinopathy that is uncontrolled by medication, and severe diabetic neuropathy) [Exception: If subjects are stable (e.g., can be controlled with a stable dose of medication), they may be enrolled at the discretion of the investigator.]
- History of hypersensitivity reaction to the components or drugs of the same class as the IP or the background therapy (biguanides, SGLT2 inhibitors, and thiazolidinediones)
- History of acute or chronic metabolic acidosis including lactic acidosis and diabetic ketoacidosis within 12 weeks of Visit 1
- History of cardiovascular diseases of New York Heart Association (NYHA) Class II or higher (e.g., heart failure, unstable angina, arrhythmia, myocardial infarction, transient ischemic attack, and stroke, coronary artery bypass graft, or coronary intervention) within 6 months of Visit 1 (Exception: If subjects have the history of heart failure longer than 6 months, they may participate, only under the full recovery or in stable condition currently. However, if subjects have the history of heart failure of NYHA Class II or higher, they will be excluded even if the event occurred before 6 months ago.)
- History of diabetic coma or precoma within 1 year of Visit 1
- Following conditions with a history of gastrointestinal disorders or surgical operation which may affect the absorption, distribution, metabolism, and excretion of the IP: ① Active gastritis or gastric ulcer uncontrolled with medications ② Gastrointestinal/rectal bleeding, biliary obstruction or cessation of bile secretion, urinary tract obstruction ③ Acute or chronic pancreatitis ④ Active inflammatory bowel diseases (e.g., Crohn’s disease, and ulcerative colitis) within 12 months of Visit 1 ⑤ History of any types of bariatric surgery within 2 years of Visit 1 ⑥ History of any major gastrointestinal surgery such as total gastrectomy, total proctocolectomy, enterectomy, gastroenterostomy, and gastric bypass surgery ⑦ History of pancreatectomy ⑧ Conditions requiring treatment for dehydration due to persistent diarrhea, vomiting, etc., or at risk of body fluid depletion
- History of surgery requiring general anesthesia (except for surgery not requiring dietary restrictions) within 4 weeks of Visit 1, or plan for such surgery within 4 weeks after the end of study (Exception: Surgeries that do not have a significant impact on systemic metabolism, such as endoscopic surgery, dental surgery, and dermatologic surgery, are allowed.)
- Any severe infections and infestations considered as clinically significant by investigator’s discretion (e.g., severe infection requiring continued antibiotics or immunotherapy) or severe trauma
- Any acute or chronic diseases that can cause tissue hypoxia, such as pulmonary infarction, severe pulmonary dysfunction, shock, etc
- Change in body weight more than 10% within 3 months of Visit 1 and currently have symptoms of polyuria or polydipsia
- Pregnant or lactating women
- Plans to become pregnant up to 30 days after the last IP administration or not to consent to use medically acceptable methods of contraception* among those of childbearing potential * Subjects must use one of the following contraceptive methods. ① Single contraceptive method: Intrauterine device (e.g., copper loop, and hormone-containing intrauterine device), sterilization (e.g., tubal ligation, and vasectomy), progesterone-only oral contraceptive without estrogen, combined hormone patch, vaginal ring, subcutaneous implant (under the skin), injectables, and etc. ② Dual-barrier methods: Use of cervical cap or contraceptive diaphragm in combination with male condom ③ Combined contraceptive methods: Use of parenteral hormonal contraceptives or spermicides in combination with barrier methods, or use of contraceptive sponges in combination with spermicides Complete abstinence is allowed in this study; however, periodic abstinence (e.g., ovulation cycle, symptothermal, or post-ovulation methods) and withdrawal are not acceptable.
- Participation in investigational clinical trials other than this study, or receipt of IP from other studies within 4 weeks of Visit 1 (Exception: Observational studies or retrospective studies that investigator considered no impact on efficacy and safety will be allowed.)
- Other cases considered as not eligible at the discretion of the investigator
- Measured as FPG > 270 mg/dL by study site at Visit 1 or Visit 2
- Received an intra-arterial injection of an iodinated contrast agent or received an examination with intravenous injection of an iodinated contrast agent under the condition of eGFR < 60 ml/min/1.73 m2 (e.g., intravenous urography, intravenous cholangiography, computed tomography using contrast agent, etc.), within 48 hours of Visit 1
- Uncontrolled hypertension (SBP > 180 mmHg or DBP > 110 mmHg)
- History of alcohol or drug abuse within 1 year of Visit 1
- Those who require drug treatment for thyroid dysfunction (Exception: If subjects have received a stable dose and administration method of thyroid drugs for 6 weeks (4 weeks for thyroid hormones) or longer prior to Visit 1, they may be enrolled at the discretion of the investigator.)
- History of malignancy within 5 years of Visit 1 ① Those who have a history of bladder cancer cannot participate, even if it has been 5 years or longer. ② However, if subjects have a history of basal cell carcinoma, squamous cell carcinoma of the skin, thyroid cancer, or carcinoma in situ in other areas, they may participate even the history is within 5 years. Only if, the disease has been evaluated as complete remission and no recurrence for at least 3 years.
- History of the following drug administration or expected to continue the administration during the study ① Systemic (injection, oral, inhalation) steroids administration (above the equivalent dosage of Prednisolone 30 mg/day) within 2 weeks of Visit 1 ② Chronic (longer than 14 consecutive days) administration of corticosteroids within 8 weeks of Visit 1 (Exception: Topical administration such as external preparation, eye drops, intranasal, and intra-articular cavity is permitted regardless of the period.) ③ Weight loss drugs (e.g., Orlistat) within 12 weeks of Visit 1 ④ Insulin or GLP-1 analogues (oral or injection) within 4 weeks of Visit 1 ⑤ Require administration of hypoglycemic agents or prohibited treatments other than the IP, background therapy, and rescue medication
- Modification of excl 1:Diagnosed with other types of diabetes than T2DM (type 1 diabetes, secondary diabetes, or congenital renal glycosuria, etc.)
- Mod of excl 2: Severe progressive complications of diabetes (e.g., proliferative diabetic retinopathy that is uncontrolled by medication, and severe diabetic neuropathy) [Exception: If subjects are stable (e.g., can be controlled with a stable dose of medication), they may be enrolled at the discretion of the Investigator
- Mod excl 7: Received an examination with an intra-arterial injection of an iodinated contrast agent, or received an examination with intravenous injection of an iodinated contrast agent under the condition of eGFR < 60 ml/min/1.73 m2 (e.g., intravenous urography, intravenous cholangiography, computed tomography using contrast agent, etc.), within 48 hours of Visit 1
- Mod excl 8:Uncontrolled hypertension (SBP > 180 mmHg or DBP > 110 mmHg) at Visit 1 or Visit 2
- Mod excl 10: History of uninvestigated macroscopic hematuria or current symptom of clinically significant hematuria
- Mod excl 13:Following conditions with a clinically significant liver disease at Visit 1 or Visit 2: ① AST or ALT > 2.5 times the upper limit of normal ② Total bilirubin > 2 times the upper limit of normal ③ Hepatitis requiring antiviral treatment ④ Liver cirrhosis or liver failure
- Mod excl 14) Following conditions with a clinically significant kidney disease at Visit 1 or Visit 2: ① eGFR* < 45 ml/min/1.73 m2 ② eGFR* < 60 ml/min/1.73 m2: For those who received more than Metformin 1,000 mg/day at Visit 1 * eGFR can be calculated using either the Modification of Diet in Renal Disease (MDRD) equation or the equation of the study site.
- Mod excl 17) History of the following drug administration or expected to continue the administration during the study ① Systemic (injection, oral, inhalation) steroids administration (above the equivalent dosage of Prednisolone 30 mg/day) within 2 weeks of Visit 1 ② Chronic (longer than 14 consecutive days) administration of systemic corticosteroids within 8 weeks of Visit 1 (Exception: Topical administration such as external preparation, eye drops, intranasal, and intra-articular cavity is permitted regardless of the period.) ③ Weight loss drugs (e.g., Orlistat) within 12 weeks of Visit 1 ④ Insulin or GLP-1 analogues (oral or injection) within 4 weeks of Visit 1 ⑤ Require administration of hypoglycemic agents or prohibited treatments other than the IP, background therapy, and rescue medication
- Mod excl 19) History of cardiovascular diseases (e.g., heart failure of New York Heart Association (NYHA) Class II or higher (e.g. unstable angina, arrhythmia, myocardial infarction, transient ischemic attack, stroke, coronary artery bypass graft, or coronary intervention) within 6 months of Visit 1 (Exception: Subjects who have the history of heart failure of NYHA Class II or higher, need to be excluded even if the event occurred before 6 months ago. However, subjects who have the history of other cardiovascular diseases mentioned above (except heart failure of NYHA Class II or higher) longer than 6 months ago, they may participate, only under the full recovery or in stable condition currently.)
- Mod excl 26) Plans to become pregnant up to 30 days after the last IP administration or not to consent to use medically acceptable methods of contraception* among those of childbearing potential * Subjects must use one of the following country-specific contraceptive methods in Appendix 1.
- Mod excl 27) Participation in investigational clinical trials other than this study, or administration of IP from other studies within 4 weeks of Visit 1 (Exception: Observational studies or retrospective studies that iInvestigator considered no impact on efficacy and safety will be allowed.)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 01 May 2024 | 224 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Pioglitazone | Test | TABLET | ORAL USE | 30 | 24 | PRD10993851 |
EMPAGLIFLOZIN | Other | — | ORAL USE | 25 | 34 | SUB35915 |
METFORMIN HYDROCHLORIDE | Other | — | ORAL USE | 2000 | 34 | SUB03200MIG |
GLIMEPIRIDE | Other | — | ORAL USE | 6 | 4 | SUB07925MIG |
GLICLAZIDE | Other | — | ORAL USE | 120 | 4 | SUB07921MIG |
METFORMIN HYDROCHLORIDE | Other | — | ORAL USE | 2000 | 34 | SUB03200MIG |
GLIPIZIDE | Other | — | ORAL USE | 20 | 4 | SUB07927MIG |
METFORMIN HYDROCHLORIDE | Other | — | ORAL | 2000 | 34 | SUB03200MIG |
EMPAGLIFLOZIN | Other | — | ORAL | 10 | 34 | SUB35915 |
GLIQUIDONE | Other | — | ORAL USE | 120 | 4 | SUB07928MIG |