| 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 |
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. 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)
5. Has an eGFR value of ≥30 mL/min/1.73 m2 based on the CKD-EPI equation at Visit 1A and Visit 3/3A as applicable (Week -2)
6. 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
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 (female patients) and testosterone (male patients)
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 |
Exclusion Criteria:
1. Currently on dialysis, has been on any dialysis within 1 year of Visit 1B, 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 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 or Visit 3/3A (Week -2)
5. Has a fasting lactate value > 2 mmol/L at Visit 1B
6. Has a bicarbonate value < 20 mEq/L at both Visit 1A and 1B
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 or Visit 3/3A, which can be rechecked within 1 week
9. Oral antidiabetic agent 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; inhaled, intranasal, ophthalmic, topical, or intra-articular corticosteroids are not exclusionary
c. Planned use of proton pump inhibitors after Visit 2; such use could potentially affect the DR and PK of Metformin DR. Proton pump inhibitor treatment may be replaced by other treatment (such as H2-receptor antagonists [excluding ranitidine], or calcium carbonate antacids) prior to Visit 4
d. Cationic drugs that are eliminated by renal tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, flecainide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) within 1 week of Visit 3
e. Iodinated contrast dye within 1 week prior to Visit 3
f. Investigational drug within 8 weeks of the date of the first dose of randomized study medication
g. Metformin DR or double-blind matching placebo for Metformin DR at any time prior to Visit 1B
11. Has a clinically significant medical condition as judged by the investigator that could potentially affect study participation and/or personal well-being, including but not limited to the following conditions:
a. Hepatic disease
b. Gastrointestinal disease
c. Endocrine disorder other than T2DM or hypothyroidism on replacement therapy
d. Cardiovascular disease, including history of stroke, decompensated heart failure New York Heart Association Class III or IV, myocardial infarction, unstable angina pectoris, or coronary arterial bypass graft or angioplasty within 3 months prior to Visit 1A
e. Central nervous system diseases such as epilepsy
f. Psychiatric or neurological disorders that in the investigator’s opinion would cause the patient to be noncompliant with study procedures
g. Organ transplantation
h. Chronic or acute infection requiring systemic antibiotic treatment
i. Orthostatic hypotension or syncope
j. Active malignancy within the past 5 years with exception of basal cell and squamous cell carcinoma
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
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 is planning to donate blood or have a blood transfusion during the study
18. Prior or planned major surgery of any kind within 6 months of Visit 1B
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 or breastfeeding or plans to become pregnant during 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. Patient has evidence of COVID-19 within 2 weeks prior to enrolment
24. Is employed by Anji Pharma |
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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 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 | 8 |
| 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 |
| Brazil |
| Canada |
| Russian Federation |
| Ukraine |
| United States |
| Bulgaria |
| Hungary |
| Poland |
| Spain |
| Czechia |
| Argentina |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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