E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes Mellitus with varying renal function from normal up to CKD3B |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
E.1.2 | System Organ Class | 100000004861 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess whether 1800 mg once daily metformin hydrochloride delayed-release tablets (Metformin Delayed-release [DR]) compared to placebo improves hemoglobin-specific A1c fraction (HbA1c) after 28 weeks of treatment in patients with T2DM with varying renal function from normal up to chronic kidney disease (CKD)3B.
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E.2.2 | Secondary objectives of the trial |
Double-blind: •Assess whether 1800 mg once daily Met DR is non-inferior to 1500 mg Met IR for changes in HbA1c after 28 weeks of treatment •Assess effect of 1800 mg once daily Met DR compared to placebo, and compared to 1500 mg Met IR, on other glycemic and non-glycemic parameters after 28 weeks of treatment •Assess effect of 1800 mg once daily Met DR compared to placebo, and compared to 1500 mg Met IR, on body weight after 28 weeks •Assess safety and tolerability of Met DR relative to placebo and Met IR •Assess Met DR PK endpoints over 28 weeks
Open-Label Extension: •Assess the effect of 1800 mg once daily Met DR on HbA1c after 52 weeks of treatment •Assess the effect of 1800 mg once daily Met DR on other glycemic and non-glycemic parameters after 52 weeks of treatment • Assess the effect of 1800 mg once daily Met DR on body weight after 52 weeks of treatment •Assess the long-term safety and tolerability of Met DR •Assess PK endpoints of Met DR over 52 weeks |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Note: Patients not eligible because of laboratory result(s) or blood pressure (BP) or electrocardiogram (ECG) assessments or weight being slightly over or under the required body mass index (BMI) may have these assessments repeated once during the screening period at the discretion of the investigator to determine eligibility. Each patient must meet the following criteria to be enrolled in this study: 1. Adult at least 18 years old 2. Has BMI 20.0 to 45.0 kg/m2 (inclusive) 3. Has T2DM 4. For patients on metformin at screening: has HbA1c of 7.0% to 9.5%, inclusive, at Visit 1A and HbA1c value of 7.0% to 10.5%, inclusive, at Week -2 (Visit 3/3A as applicable). For patients with CKD3B not on metformin at screening: HbA1c of 7.0% to 10.5%, inclusive, at Visit 1A and at Week -2 (Visit 1B/3) 5. For patients on metformin at screening: eGFR value of ≥30 mL/min/1.73 m2 based on the CKD-EPI equation at Visits 1A and 3/3A (Week -2). For patients with CKD3B not on metformin at screening: eGFR value of 30 to 44 mL/min/1.73 m2 based on the CKD-EPI equation at Visits 1A or 1B/3 (Week -2) 6. For patients on metformin at screening: stable treatment with a metformin preparation or a combination product containing metformin for 8 weeks prior to Visit 1A 7. If treated with the following medications, must be on a stable regimen for a minimum of 6 weeks prior to Visit 1B or 1B/3 and remain stable prior to randomization a. Drugs known to affect body weight, including prescription medications (e.g.,phentermine, phentermine/topiramate, orlistat, lorcaserin, bupropion/naltrexone, high dose GLP-1 agonists) and over-the-counter anti-obesity agents b. Hormone replacement therapy estrogen or testosterone c. Oral contraceptives (female patients) d. Antihypertensive agents including ACEi/ARB e. Lipid-lowering agents f. Thyroid replacement therapy g. Antidepressant agents 8. Ability to understand and willingness to adhere to protocol requirements. |
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E.4 | Principal exclusion criteria |
1. Currently on dialysis,has been on any dialysis within 1 year of Visit 1B or 1B/3, or is expected to undergo dialysis during the study 2. Has a history of lactic acidosis 3. Has a FPG value >240 mg/dL (>13.3 mmol/L) at Week -2 (Visit 3/3A or 1B/3 as applicable) 4. An alanine aminotransferase or aspartate aminotransferase result >2.5 × upper limit of normal (ULN) or a bilirubin result >1.5 × ULN at Visit 1B, 3/3A, or 1B/3 (except in case of documented Gilbert’s syndrome) 5. Has a fasting lactate value > 3 mmol/L at Visit 1B or 1B/3 6. Has a bicarbonate value <18 mEq/L at both Visits 1A and 1B or Visits 1A and 1B/3 7. History of >5% weight change within 12 weeks prior to Visit 1A 8. BP measurements >180 mmHg (systolic BP) or >100 mmHg (diastolic BP) at Visit 1A, 3/3A or 1B/3, which can be rechecked within 1 week 9. Oral antidiabetic agent,GLP-1 agonist or insulin use that is not stable for 6 weeks prior to randomization 10. Has been treated,is currently being treated,or is expected to require or undergo treatment with any of the following excluded medications: a. Prescribed metformin preparation after initiation of metformin washout following Visit 1B b. Greater than 10 consecutive days of systemic corticosteroids by oral, intravenous, or intramuscular route within 12 weeks of Visit 1B or 1B/3; inhaled,intranasal,ophthalmic,topical or intra-articular corticosteroids are not exclusionary c. Planned use of proton pump inhibitors after Visit 2 (for those patients who undergo metformin washout) or 1B/3 (for patients with CKD3B not on metformin); such use could potentially affect the DR and PK of Metformin DR. d. Planned use of systemically absorbed carbonic anhydrase inhibitors from Visit 3 onwards as they may increase the risk of lactic acidosis in the CKD3B population e. Cationic drugs that are eliminated by renal tubular secretion 1 week prior to Visit 3 or 1B/3 onwards, unless treatment is in accordance with the product label for the patient’s renal function. f. Iodinated contrast dye 1 week prior to Visit 3 or 1B/3 onwards g. Investigational drug within 8 weeks of the date of the first dose prior to randomized study medication h. Metformin DR or double-blind matching placebo for Metformin DR at any time prior to Visit 1B or 1B/3 i. Nephrotoxic medications and medications that are known to impact eGFR 11. Has a clinically significant medical condition as judged by the investigator that could potentially affect study participation and/or personal well-being 12. Known allergy or hypersensitivity to Metformin DR, Metformin IR,or placebo or any inactive component of study medication,active comparator,or placebo 13. History of diabetic ketoacidosis or hyperosmolar non-ketotic hyperglycemia within 1 year prior to Visit 1B or 1B/3 14. A physical,psychological,or historical finding that,in the investigator’s opinion,would make the patient unsuitable for the study 15. Any verified clinically significant abnormality identified on physical examination,laboratory tests,ECG, vital signs,or any AE at the time of Visit 1B through Visit 4 that,in the judgment of the investigator or any sub-investigator,would preclude safe completion of the study or constrains efficacy assessment 16. Currently abuses drugs or alcohol or has a known history of abuse that in the investigator’s opinion would cause the patient to be noncompliant with study procedures 17. Had a blood transfusion or experienced significant blood loss (i.e., >500 mL), including loss due to blood donation, within 8 weeks prior to Visit 1B or 1B/3, or is planning to donate blood or have a blood transfusion during the study 18. Prior or planned major surgery of any kind (requiring overnight hospitalization) within 6 months of Visit 1B or 1B/3 19. Patients insufficiently compliant with study medication during the placebo run-in phase ≤85% or ≥115%) as assessed at Visit 4 20. Is screening for the study at more than one clinical site or is participating in any other clinical study 21. Is currently pregnant (confirmed by serum pregnancy test at Visit 1B or 1B/3) or breastfeeding or plans to become pregnant during the course of the study 22. Women of childbearing potential not willing to use highly effective method(s) of birth control during the entire study, or who are unwilling or unable to be tested for pregnancy 23. If the patient has evidence of coronavirus disease 2019 (COVID-19) within 2 weeks prior to enrolment (a positive COVID-19 test or suspicion of COVID-19 infection), the patient cannot be enrolled in the study 24. Is employed by Anji Pharma (US) LLC or subsidiaries (that is an employee, contract worker, or designee of the company). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HbA1c from the double-blind treatment period baseline to Week 28 for Metformin DR compared to placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Efficacy
Double-Blind Treatment Period • HbA1c absolute value-based response (Yes/No) at Week 28 defined as HbA1c ≤7% for Metformin DR compared to placebo • Change in HbA1c from the double-blind treatment period baseline to Week 28 for Metformin DR compared to Metformin IR • HbA1c absolute value-based response (Yes/No) at Week 28 defined as HbA1c ≤7% for Metformin DR compared to Metformin IR. Other Secondary Efficacy Endpoints: • Change in FPG from the double-blind treatment period baseline to Week 28 for Metformin DR compared to placebo • Change in FPG from the double-blind treatment period baseline to Week 28 for Metformin DR compared to Metformin IR • C-average for the change in FPG concentrations from baseline to all subsequent visits over the first 28 weeks of treatment • Change in fasting glycated albumin from the double-blind treatment period baseline to Week 28 for Metformin DR compared to placebo • Change in fasting glycated albumin from the double-blind treatment period baseline to Week 28 for Metformin DR compared to Metformin IR • Percentage change in body weight from double-blind treatment period baseline to Week 28 for Metformin DR compared to placebo • Percentage change in body weight from double-blind treatment period baseline to Week 28 for Metformin DR compared to Metformin IR • Proportion of patients in each treatment group requiring rescue therapy and who discontinued treatment due to hyperglycemia or high HbA1c value, at any time during double-blind treatment period.
Open-Label Extension Period: • Change in HbA1c from the open-label extension period baseline to Week 52 for all Open-Label Extension Period: • Change in HbA1c from the open-label extension period baseline to Week 52 for all groups • HbA1c absolute value-based response (Yes/No) at Week 52 defined as HbA1c ≤7% for all groups • Change in FPG from the open-label extension period baseline to Week 52 for all groups • Change in fasting glycated albumin from the open-label extension period baseline to Week 52 for all groups • Percentage change in body weight from the open-label extension period baseline to Week 52 for all groups • Proportion of patients in each treatment group requiring rescue therapy and who discontinued treatment due to hyperglycemia or high HbA1c value, at any time during the open-label extension period.
Safety and Tolerability • Adverse events, with a focus on treatment-emergent AEs, including hypoglycemia, hyperlactatemia and metformin-associated lactic acidosis • Physical examination • 12-lead ECG • Vital signs (systolic BP, diastolic BP, heart rate) and body weight • Clinical laboratory parameters (serum chemistry including lactate and anion gap, hematology, lipids, and urinalysis).
Pharmacokinetics • Pre-dose plasma metformin concentration at Visits 5, 6, 7, 8, 9, and 10 • Post-dose (2 hours ± 15 minutes ) plasma metformin concentration at Visit 6A • Post-dose (4 hours ± 15 minutes) plasma metformin concentration at Visit 7A. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 28, Week 52 and at specified visits for PK |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Comparator-Controlled Study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Canada |
United States |
Russian Federation |
Ukraine |
Bulgaria |
Czechia |
Hungary |
Poland |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 26 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |