Clinical study to evaluate the efficacy and safety of Pioglitazone co-administration in patients with type II diabetes with insufficient glycemic control with Metformin and Empagliflozin combination therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celltrion Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

20 Aug 2024 → 4 May 2026

Decision date (initial)

2024-05-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Celltrion Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

1) Part 1: To evaluate the efficacy of combination therapy of Metformin, Empagliflozin 10 mg, and Pioglitazone compared with Metformin and Empagliflozin 10 mg in type 2 diabetes mellitus (T2DM) subjects with inadequate glycemic control on a regimen of Metformin and Empagliflozin 10 mg.
2) Part 2: To evaluate the efficacy of combination therapy of Metformin, Empagliflozin 25 mg, and Pioglitazone compared with Metformin and Empagliflozin 25 mg in T2DM subjects with inadequate glycemic control on a regimen of Metformin and Empaglifozin 25 mg

Secondary objectives 1

1. To evaluate the safety of combination therapy of Metformin, Empagliflozin, and Pioglitazone compared with Metformin and Empagliflozin in T2DM subjects with inadequate glycemic control on a regimen of Metformin and Empagliflozin, in each part.

Conditions and MedDRA coding

Type 2 diabetes mellitus (T2DM)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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 and older in Korea and Poland, respectively.
2. Diagnosed with T2DM
3. 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.
4. 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
5. Body mass index (BMI) ≤ 45.0 kg/m2 at Visit 1 and Visit 3
6. Compliance of overall medication in between 70% and 120% inclusive, at each Visit 2 and Visit 3
7. Signed the written ICF voluntarily after being fully informed of the objectives, methods, and effects of the study
8. 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 39

1. Diagnosed with other types of diabetes than T2DM (type 1 diabetes, secondary diabetes, or congenital nephrogenic diabetes insipidus, etc.)
2. Immune deficiency syndrome (AIDS) or history of positive HIV-1
3. History of gross hematuria or current symptom of clinically significant hematuria
4. Hypopituitarism or adrenal insufficiency
5. History of genetic disorders, including galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, etc.
6. 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
7. 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.
8. 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.]
9. 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)
10. History of acute or chronic metabolic acidosis including lactic acidosis and diabetic ketoacidosis within 12 weeks of Visit 1
11. 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.)
12. History of diabetic coma or precoma within 1 year of Visit 1
13. 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
14. 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.)
15. 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
16. Any acute or chronic diseases that can cause tissue hypoxia, such as pulmonary infarction, severe pulmonary dysfunction, shock, etc
17. Change in body weight more than 10% within 3 months of Visit 1 and currently have symptoms of polyuria or polydipsia
18. Pregnant or lactating women
19. 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.
20. 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.)
21. Other cases considered as not eligible at the discretion of the investigator
22. Measured as FPG > 270 mg/dL by study site at Visit 1 or Visit 2
23. 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
24. Uncontrolled hypertension (SBP > 180 mmHg or DBP > 110 mmHg)
25. History of alcohol or drug abuse within 1 year of Visit 1
26. 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.)
27. 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.
28. 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
29. Modification of excl 1:Diagnosed with other types of diabetes than T2DM (type 1 diabetes, secondary diabetes, or congenital renal glycosuria, etc.)
30. 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
31. 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
32. Mod excl 8:Uncontrolled hypertension (SBP > 180 mmHg or DBP > 110 mmHg) at Visit 1 or Visit 2
33. Mod excl 10: History of uninvestigated macroscopic hematuria or current symptom of clinically significant hematuria
34. 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
35. 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.
36. 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
37. 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.)
38. 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.
39. 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.)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from Baseline in HbA1c at Week 24 of the Treatment

Secondary endpoints 12

1. Change from Baseline in HbA1c at Week 12 of the Treatment
2. Change from Baseline in fasting plasma glucose (FPG) at Week 12 and 24 of the Treatment
3. Proportion (%) of subjects who achieved HbA1c < 6.5% at Week 24 of the Treatment
4. Proportion (%) of subjects who achieved HbA1c < 7.0% at Week 24 of the Treatment
5. Change from Baseline in lipid profile (total cholesterol, LDL-C, HDL-C, and TG) levels at Week 12 and 24 of the Treatment
6. Change from Baseline in insulin resistance (HOMA-IR) and insulin secretion ability (HOMA-β) at Week 12 and 24 of the Treatment
7. Change from Baseline in liver function indicators (AST, ALT) at Week 12 and 24 of the Treatment
8. Proportion (%) of subjects who received a rescue medication at Week 12 and 24 of the Treatment
9. Change from Baseline in body weight at Week 12 and 24 of the Treatment
10. Change from Baseline in blood pressure (SBP, DBP) at Week 12 and 24 of the Treatment
11. Change from Baseline in heart rate at Week 12 and 24 of the Treatment
12. Change from Baseline in waist circumference at Week 12 and 24 of the Treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Celltrion Inc.

Sponsor organisation

Celltrion Inc.

Address

23 Academy-Ro, Yeonsu-Gu Yeonsu-Gu

City

Incheon

Postcode

22014

Country

Korea, Republic of

Scientific contact point

Organisation

Celltrion Inc.

Contact name

Jeongbin (Justine) Yoon

Public contact point

Organisation

Celltrion Inc.

Contact name

Jeongbin (Justine) Yoon

Third parties 3

Locations

1 EU/EEA country · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications