Assessing the Effect of Met DR on Plasma Glucose and PK in Subjects With T2DM

Study Overview
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Brief Summary
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This study compared the effects of delayed-release metformin (Met DR, EFB0027) administered once daily in the morning (qAM), administered once daily in the evening (qPM), and administered twice daily (BID) on circulating glucose concentrations and metformin pharmacokinetics (PK) in subjects with type 2 diabetes mellitus (T2DM).

Official Title
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A Randomized, Crossover Study Assessing the Effect of EFB0027 on Plasma Glucose and Pharmacokinetics in Subjects With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Met DR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 70 (inclusive) years old at Visit 1 (Screening) Was 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 Had normal renal function with an estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m^2 based on the Modification of Diet in Renal Disease (MDRD) equation Body mass index (BMI) of 25.0 to 40.0 kg/m^2 (inclusive) at Screening Male, or if female and met 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, practiced and was willing to continue to practice appropriate birth control during the entire duration of the study Had 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 have been 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: Had 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 Central nervous system diseases Psychiatric or neurological disorders Organ transplantation Chronic or acute infection Orthostatic hypotension, fainting spells or blackouts Allergy or hypersensitivity Had any chronic disease requiring medication that was adjusted in the past 90 days (subjects could take acute intermittent over-the-counter medications such as Tylenol, if needed) Had 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) Had major surgery of any kind within 6 months of Visit 1 (Screening) Had received a blood transfusion within 6 months of Visit 1 (Screening) Had a history of >5 kg weight change within 3 months of Visit 1 (Screening) Had clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities other than those expected in subjects with type 2 diabetes and judged by the investigator to be clinically significant at Visit 1 (Screening) Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study Abused drugs or alcohol or had a history of abuse that in the investigator's opinion would cause the individual to be noncompliant with study procedures Had donated blood within 3 months of the date of the first dose of randomized study medication, or was planning to donate blood during the study Used insulin within 3 months of Visit 1 (Screening) Had received GLP-1 receptor agonists and/or thiazolidinedione treatment within 6 months of Visit 1 (Screening) Had known intolerance to metformin Had received any investigational drug within 2 months (or five half-lives of the investigational drug, whichever was greater) of Visit 1 (Screening) Had known allergies or hypersensitivity to any component of study treatment Was employed by Elcelyx Therapeutics, Inc. (that is an employee, temporary contract worker, or designee of the company) Smoked more than 10 cigarettes per day, 3 cigars per day, 3 pipes per day, used more than 1 can of smokeless tobacco per week, or used a combination of tobacco products that approximate nicotine doses equivalent to 10 cigarettes per day

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 500 mg Met DR BID<br>Two doses of 500 mg metformin delayed-release | Drug: Met DR<br>* metformin delayed-release tablets<br>* Other names: EFB0027;|
| Experimental: 1000 mg Met DR qAM<br>One dose of 1000 mg metformin delayed-release in the morning | Drug: Met DR<br>* metformin delayed-release tablets<br>* Other names: EFB0027;|
| Experimental: 1000 mg Met DR qPM<br>One dose of 1000 mg metformin delayed-release in the evening | Drug: Met DR<br>* metformin delayed-release tablets<br>* Other names: EFB0027;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC (0-24) of Plasma Metformin | AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. | Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. | 
| Cmax of Plasma Metformin | Cmax = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. | Times points to determine Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. | 
| AUC (0-24) of Plasma Glucose | AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. | Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the time of the standardized dinner. | 
| Rmax (0-24) of Plasma Glucose | Rmax (0-24) = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. | Times points to determine Rmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. |