Assessing the PK and Effect on Glucose and GI Hormone Concentrations of Metformin Delayed-Release in Subjects With T2DM

Study Overview
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Brief Summary
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This study will evaluate how EFB0027 and EFB0026 behave in subjects with type 2 diabetes mellitus. In addition, this study will compare the effects of EFB0027 and EFB0026 on circulating concentrations of glucose and gastrointestinal hormones in subjects with type 2 diabetes mellitus.

Official Title
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A Randomized, Crossover Study Assessing the Effects of pH 6.5 Enteric Coating of Metformin HCl Tablets on Pharmacokinetics and Changes in Circulating Glucose and Gastrointestinal Hormone Concentrations in Subjects With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: EFB0027 (metformin delayed release)
* Drug: EFB0026 (metformin immediate-release)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is 19 to 70 (inclusive) years old at Visit 1 (Screening). Is diagnosed with Type 2 Diabetes Mellitus with HbA1c between 6.0 to 9.5% (inclusive) for subjects managing their diabetes with: i. Diet and exercise alone, or ii. A stable regimen (minimum of 2 months at Visit 1) of metformin alone, or iii. A stable regimen (minimum of 2 months at Visit 1) of DPP-4 inhibitor alone, OR HbA1c between 6.0 to 8.5% (inclusive) for subjects managing their diabetes with a stable (minimum of 2 months at Visit 1) combination regimen of metformin and DPP-4 inhibitors. Has serum creatinine below the upper limit of normal at Visit 1 and an estimated creatinine clearance above 80 using the Crockroft and Gault equation (CrCl = [(140 - age) x body weight in kg] / (serum creatinine x 72) x (0.85 for females) [ref. 3]. Has a body mass index (BMI) of 25.0 to 40.0 kg/m^2 (inclusive) at Screening. Is male, or is female and meets all of the following criteria: Not breastfeeding Negative pregnancy test result (human chorionic gonadotropin, beta subunit) at Visit 1 (Screening) (not applicable to hysterectomized females) 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 Has a physical examination with no clinically significant abnormalities as judged by the investigator. Ability to understand and willingness to adhere to protocol requirements. If on chronic thyroid pharmacologic therapy, the dose must be stable for at least 3 months prior to Visit 1 (Screening), and must have thyroid-stimulating hormone (TSH) test result in normal range at Visit 1 (Screening). Exclusion Criteria: Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being, as judged by the investigator, including but not limited to the following conditions: Hepatic disease Renal disease Gastrointestinal disease Endocrine disorder except diabetes Cardiovascular disease Seizure disorder Organ transplantation Chronic infection Has any chronic disease requiring medication that has been adjusted in the past 90 days (subjects may take acute intermittent over-the-counter medications such as Tylenol, if needed). Has any drug treatment that affects gastric pH (prescription or over-the-counter), including any antacids or medications such as Rolaids or Pepcid within 2 days of Visit 1 (Screening). Has had major surgery of any kind within 6 months of Visit 1 (Screening). Has received a blood transfusion within 6 months of Visit 1 (Screening). Has a history of >5 kg weight change within 3 months of Visit 1 (Screening). Has clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities other than those expected in subjects with diabetes and judged by the investigator to be clinically significant at Visit 1 (Screening). Has physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study. 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. Has donated blood within 2 months of Visit 1 (Screening) or is planning to donate blood during the study. Has used insulin within 3 months of Visit 1 (Screening). Has received GLP-1 receptor agonists and/or thiazolidinedione treatment within 6 months of Visit 1 (Screening). Has known intolerance to metformin. Has received any investigational drug within 1 month (or five half-lives of the investigational drug, whichever is greater) of Visit 1 (Screening). Has known allergies or hypersensitivity to any component of study treatment. Is employed by Elcelyx Therapeutics, Inc (that is an employee, temporary contract worker, or designee of the company). Smokes more than 10 cigarettes per day, 2 cigars per day, or uses more than 1 can of smokeless tobacco per week.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1000 mg EFB0026 (metformin immediate-release)<br>BID | Drug: EFB0026 (metformin immediate-release)<br>* Active comparator<br>* Other names: Glucophage;|
| Experimental: 1000 mg EFB0027 (metformin delayed-release)<br>BID | Drug: EFB0027 (metformin delayed release)<br>* Comparison of enteric-coating to assess effect on PK<br>* Other names: Met DR;|
| Experimental: 500 mg EFB0027 (metformin delayed-release)<br>BID | Drug: EFB0027 (metformin delayed release)<br>* Comparison of enteric-coating to assess effect on PK<br>* Other names: Met DR;|
| Experimental: 500 mg EFB0026 + 1000 mg EFB0027<br>BID | Drug: EFB0027 (metformin delayed release)<br>* Comparison of enteric-coating to assess effect on PK<br>* Other names: Met DR;Drug: EFB0026 (metformin immediate-release)<br>* Active comparator<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (0-t) of Plasma Metformin | Measures from the time of dosing (0 h) to the time of the last quantifiable concentration following dose administration. The dose of study medication was administered at t = -1 min relative to the start time of the standardized breakfast. | Time points at which data were collected to create the area under the curve (0-t) for plasma metformin were: t = -0.08, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 11 h relative to the start time of the standardized breakfast. | 
| Change in Fasting Plasma Glucose | LS mean difference from Baseline (Day 1) to Day 5 | Change from Baseline (Day 1) to Day 5 | 
| Within Treatment Comparison Based on Ratios of AUCs of GLP-1 |  | Ratio of Day 5 to Baseline | 
| Within Treatment Comparison Based on Ratios of AUCs of PYY |  | Ratio of Day 5 to Baseline |