Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of the study is to compare the glycemic effects of delayed-release metformin (Met DR) to placebo in subjects with type 2 diabetes mellitus (T2DM) over 16 weeks. The study is designed to evaluate several doses of Met DR (600 to 1500 mg once daily in the morning \[qAM\]) compared to placebo. A single-blind reference treatment of 2000 mg metformin immediate-release (Met IR) per day administered as equal divided doses (1000 mg Met IR BID) will also be included.
Interventions
Sponsors
Elcelyx Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Is at least 25 years old at Visit 1 (Screening). 2. Is male, or is female and meets all of the following criteria: 1. Not breastfeeding 2. Negative pregnancy test result at Visit 1 (not applicable to post-menopausal or surgically sterile females) 3. Surgically sterile, postmenopausal, or if of childbearing potential, must practice and be willing to continue to practice appropriate birth control during the entire duration of the study. 3. Body mass index (BMI) 20.0 to 45.0 kg/m² (inclusive) at Visit 1 (Screening). 4. Has a physical examination with no clinically significant abnormalities as judged by the investigator. 5. Has T2DM and an HbA1c of 7.5% to 10.5%, inclusive, at Visit 1. 6. Has an estimated glomerular filtration rate (eGFR) value of ≥60 mL/min/1.73 m² based on the Modification of Diet in Renal Disease (MDRD) equation. 7. Either is not treated with or has been on a stable treatment regimen with any of the following medications for a minimum of 3 months prior to Visit 1: 1. Thiazolidinedione, sulfonylurea, dipeptidyl peptidase-4 inhibitors, and alpha-glucosidase inhibitors 2. Hormone replacement therapy (female subjects) and testosterone (male subjects) 3. Oral contraceptives (female subjects) 4. Antihypertensive agents 5. Lipid-lowering agents 6. Thyroid replacement therapy 7. Antidepressant agents 8. Ability to understand and willingness to adhere to protocol requirements.
Exclusion criteria
1. 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: 1. Hepatic disease 2. Gastrointestinal disease 3. Endocrine disorder (T2DM is allowed) 4. Cardiovascular disease 5. Central nervous system diseases 6. Psychiatric or neurological disorders 7. Organ transplantation 8. Chronic or acute infection 9. Orthostatic hypotension, fainting spells or blackouts 10. Allergy or hypersensitivity. 2. A history of diabetic ketoacidosis or hyperosmolar non-ketotic hyperglycemia within the past year. 3. Prior major surgery of any kind within 6 months of Visit 1. 4. A history of \>3% weight change within 3 months of Visit 1. 5. A clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormality, other than that related to T2DM, judged by the investigator to be clinically significant at Visit 1. 6. An alanine aminotransferase or aspartate aminotransferase result \>2.5 × upper limit of normal (ULN) or a bilirubin result \>1.5 × ULN. 7. A physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study. 8. Has been treated, is currently being treated, or is expected to require or undergo treatment with any of the following excluded medications: 1. Metformin within 2 months of Visit 1 (Screening) 2. Insulin within 2 weeks of Visit 1 (Screening) or for more than 1 week within 3 months of Visit 1 (Screening) 3. Glucagon-like peptide-1 receptor agonists or sodium-glucose co-transporter 2 inhibitors within 3 months of Visit 1 4. Drugs known to affect body weight, including prescription medications and over-the-counter anti obesity agents within 3 months of Visit 1. 5. Systemic corticosteroids by oral, intravenous, or intramuscular route; or potent, inhaled, or intrapulmonary steroids known to have a high rate of systemic absorption within 3 months of Visit 1 6. Planned use of any drug treatment that affects gastric pH (prescription or over-the-counter), such as H2-receptor antagonists and proton pump inhibitors, after Visit 2 (Week -2), or planned chronic use of any antacids (i.e., more than twice per week) after Visit 2 (Week -2) 7. Cationic drugs that are eliminated by renal tubular secretion within 1 week of Visit 1. 8. Iodinated contrast dye within 1 week prior to Visit 1. 9. Investigational drug within 2 months (or five half-lives of the investigational drug, whichever is greater) of the date of the first dose of randomized study medication. 10. Met DR or double-blind matching placebo for Met DR at any time prior to Visit 1 (Screening) 9. Currently abuses drugs or alcohol or has a history of abuse that in the investigator's opinion would cause the individual to be noncompliant with study procedures. 10. Had a blood transfusion or experienced significant blood loss (i.e., \>500 mL), including loss due to blood donation, within 2 months prior to Visit 1 (Screening), or is planning to donate blood during the study. 11. Has known immune system based allergies or hypersensitivity to any component of study treatment. A history of gastrointestinal intolerance to metformin is not exclusionary. 12. Is employed by Elcelyx Therapeutics, Inc. (that is an employee, contract worker, or designee of the company). 13. Has a fasting plasma glucose value \>270 mg/dL at Visit 1 (Screening), Visit 2 (Week -2), and an unscheduled visit to be completed within 1 week following Visit 2. The unscheduled visit is to be completed only for subjects with a fasting plasma glucose value \>270 mg/dL at Visit 1 and Visit 2.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in HbA1c (%) at 16 Weeks | Baseline and 16 weeks after the first dose of study medication |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 600 mg Met DR qAM 600 mg metformin delayed-release once daily in the morning
Met DR: metformin delayed-release tablets | 94 |
| 900 mg Met DR qAM 900 mg metformin delayed-release once daily in the morning
Met DR: metformin delayed-release tablets | 95 |
| 1200 mg Met DR qAM 1200 mg metformin delayed-release once daily in the morning
Met DR: metformin delayed-release tablets | 96 |
| 1500 mg Met DR qAM 1500 mg metformin delayed-release once daily in the morning
Met DR: metformin delayed-release tablets | 96 |
| Placebo placebo match for 600 and 1200 mg Met DR qAM treatment groups (Placebo 1) and placebo match for 900 and 1500 mg Met DR qAM treatment groups (Placebo 2)
Placebo | 96 |
| 2000 mg Met IR 1000 mg metformin immediate-release twice daily
Met IR: metformin immediate-release tablets | 94 |
| Total | 571 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 | 4 | 2 | 6 | 8 |
| Overall Study | Loss of Glucose Control | 0 | 0 | 3 | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 3 | 8 | 1 | 2 | 5 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 3 | 1 | 5 | 3 | 4 | 3 |
| Overall Study | Sponsor Decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 6 | 1 | 9 | 5 |
Baseline characteristics
| Characteristic | Total | 900 mg Met DR qAM | 1200 mg Met DR qAM | 1500 mg Met DR qAM | Placebo | 600 mg Met DR qAM | 2000 mg Met IR |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 10.5 | 55 years STANDARD_DEVIATION 10.5 | 55 years STANDARD_DEVIATION 11.1 | 55 years STANDARD_DEVIATION 8.9 | 57 years STANDARD_DEVIATION 11 | 56 years STANDARD_DEVIATION 10.2 | 57 years STANDARD_DEVIATION 11.1 |
| Body Mass Index | 32 kg/m² STANDARD_DEVIATION 5.5 | 32 kg/m² STANDARD_DEVIATION 5.5 | 32 kg/m² STANDARD_DEVIATION 5.9 | 33 kg/m² STANDARD_DEVIATION 5.8 | 31 kg/m² STANDARD_DEVIATION 5.1 | 33 kg/m² STANDARD_DEVIATION 5.1 | 32 kg/m² STANDARD_DEVIATION 5.4 |
| Body Weight | 91 kg STANDARD_DEVIATION 20.2 | 89 kg STANDARD_DEVIATION 18.5 | 93 kg STANDARD_DEVIATION 20.9 | 95 kg STANDARD_DEVIATION 22.2 | 86 kg STANDARD_DEVIATION 17.1 | 94 kg STANDARD_DEVIATION 19.9 | 89 kg STANDARD_DEVIATION 21.3 |
| Diabetes Duration | 7.9 years STANDARD_DEVIATION 6.67 | 8.8 years STANDARD_DEVIATION 8.01 | 7.3 years STANDARD_DEVIATION 6.25 | 7.6 years STANDARD_DEVIATION 5.99 | 8.3 years STANDARD_DEVIATION 6.99 | 6.6 years STANDARD_DEVIATION 5.2 | 8.6 years STANDARD_DEVIATION 7.13 |
| Estimated Glomerular Filtration Rate | 95.6 mL/min/1.73m² STANDARD_DEVIATION 23.22 | 94.5 mL/min/1.73m² STANDARD_DEVIATION 22.83 | 96.2 mL/min/1.73m² STANDARD_DEVIATION 24.48 | 95.9 mL/min/1.73m² STANDARD_DEVIATION 22.77 | 96.4 mL/min/1.73m² STANDARD_DEVIATION 27.42 | 94.4 mL/min/1.73m² STANDARD_DEVIATION 19.05 | 96.2 mL/min/1.73m² STANDARD_DEVIATION 22.42 |
| Estimated Glomerular Filtration Rate Subgroup <90 mL/min/1.73m² | 251 Participants | 46 Participants | 36 Participants | 42 Participants | 42 Participants | 42 Participants | 43 Participants |
| Estimated Glomerular Filtration Rate Subgroup ≥90 mL/min/1.73m² | 320 Participants | 49 Participants | 60 Participants | 54 Participants | 54 Participants | 52 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 245 Participants | 44 Participants | 41 Participants | 42 Participants | 37 Participants | 36 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 326 Participants | 51 Participants | 55 Participants | 54 Participants | 59 Participants | 58 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting Plasma Glucose | 205 mg/dL STANDARD_DEVIATION 54 | 202 mg/dL STANDARD_DEVIATION 45.3 | 205 mg/dL STANDARD_DEVIATION 59 | 212 mg/dL STANDARD_DEVIATION 53.5 | 204 mg/dL STANDARD_DEVIATION 57.3 | 204 mg/dL STANDARD_DEVIATION 58.1 | 200 mg/dL STANDARD_DEVIATION 50.3 |
| HbA1c | 8.6 % STANDARD_DEVIATION 0.88 | 8.7 % STANDARD_DEVIATION 0.82 | 8.7 % STANDARD_DEVIATION 0.9 | 8.6 % STANDARD_DEVIATION 0.94 | 8.6 % STANDARD_DEVIATION 0.87 | 8.6 % STANDARD_DEVIATION 0.85 | 8.6 % STANDARD_DEVIATION 0.92 |
| HbA1c stratum <8.5% | 272 Participants | 45 Participants | 46 Participants | 46 Participants | 45 Participants | 45 Participants | 45 Participants |
| HbA1c stratum ≥8.5% | 299 Participants | 50 Participants | 50 Participants | 50 Participants | 51 Participants | 49 Participants | 49 Participants |
| Prior Metformin Use | 277 Participants | 47 Participants | 40 Participants | 49 Participants | 54 Participants | 40 Participants | 47 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 22 Participants | 6 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 88 Participants | 7 Participants | 23 Participants | 19 Participants | 17 Participants | 14 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 454 Participants | 82 Participants | 70 Participants | 73 Participants | 72 Participants | 75 Participants | 82 Participants |
| Sex: Female, Male Female | 269 Participants | 38 Participants | 45 Participants | 42 Participants | 53 Participants | 46 Participants | 45 Participants |
| Sex: Female, Male Male | 302 Participants | 57 Participants | 51 Participants | 54 Participants | 43 Participants | 48 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 94 | 0 / 95 | 0 / 96 | 0 / 96 | 1 / 96 | 0 / 94 |
| other Total, other adverse events | 19 / 94 | 24 / 95 | 19 / 96 | 20 / 96 | 17 / 96 | 23 / 94 |
| serious Total, serious adverse events | 1 / 94 | 0 / 95 | 4 / 96 | 1 / 96 | 4 / 96 | 1 / 94 |
Outcome results
Primary
Change in HbA1c (%) at 16 Weeks
Time frame: Baseline and 16 weeks after the first dose of study medication
Population: Modified Intent-to-Treat: Subjects who took ≥1 dose of randomized study medication and had ≥1 post-Baseline value for HbA1c collected ≤1 week after discontinuing study medication and prior to administration of any new anti-diabetic medication with timing and/or dosage that may have reasonably influenced any subsequent glycemic data collected.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 600 mg Met DR qAM | Change in HbA1c (%) at 16 Weeks | -0.33 % glycated haemoglobin | Standard Error 0.129 |
| 900 mg Met DR qAM | Change in HbA1c (%) at 16 Weeks | -0.40 % glycated haemoglobin | Standard Error 0.123 |
| 1200 mg Met DR qAM | Change in HbA1c (%) at 16 Weeks | -0.49 % glycated haemoglobin | Standard Error 0.129 |
| 1500 mg Met DR qAM | Change in HbA1c (%) at 16 Weeks | -0.62 % glycated haemoglobin | Standard Error 0.124 |
| Placebo | Change in HbA1c (%) at 16 Weeks | -0.06 % glycated haemoglobin | Standard Error 0.131 |
| 2000 mg Met IR | Change in HbA1c (%) at 16 Weeks | -1.10 % glycated haemoglobin | Standard Error 0.129 |
p-value: 0.144995% CI: [-0.63, 0.09]Mixed Models Analysis
p-value: 0.064395% CI: [-0.69, 0.02]Mixed Models Analysis
p-value: 0.021495% CI: [-0.79, -0.06]Mixed Models Analysis
p-value: 0.002295% CI: [-0.91, -0.2]Mixed Models Analysis
p-value: <0.000195% CI: [-1.39, -0.67]Mixed Models Analysis