Assessing the Efficacy, Safety, and Tolerability of Met DR in Subjects With T2DM Over 12 Weeks

A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Delayed-Release Metformin in Subjects With Type 2 Diabetes Mellitus

This study compared the effect of delayed-release metformin (Met DR) to placebo and extended release metformin (Met XR) on glycemic control (fasting plasma glucose and HbA1c) and body weight, and assessed the safety and tolerability of a range of doses of Met DR when administered in subjects with type 2 diabetes mellitus (T2DM).

Inclusion Criteria:

1. Male or female with T2DM who was ≥18 and ≤65 years of age at Visit 1

2. Had a body mass index (BMI) of 25.0 kg/m² to 45.0 kg/m², inclusive, at Visit 1

3. Screening HbA1c 7.0 to 9.5% (inclusive) at Visit 1 if treated with diet and exercise alone, or 6.0 to 9.5% (inclusive) if on a stable dose of either metformin or DPP-4 inhibitor monotherapy for a minimum of 2 months at Visit 1, or a combination of these 2 agents only on a stable regimen for a minimum of 2 months at Visit 1

4. Had serum creatinine concentration of <1.5 mg/dL (male) or <1.4 mg/dL (female) and an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m² based on the Modification of Diet in Renal Disease (MDRD) equation

5. Had a fasting glucose concentration of <280 mg/dL at Visit 1

6. Had a stable body weight, i.e., not varying by >5% for at least 6 months prior to Visit 1 as documented by the investigator

7. Was male, or if female and met all of the following criteria:

   1. Not breastfeeding
   2. Negative pregnancy test result (human chorionic gonadotropin, beta subunit [βhCG]) at Visit 1 (not applicable to hysterectomized females)
   3. If of child bearing potential (including perimenopausal women who have had a menstrual period within 1 year), must have practiced and be willing to continue to practice appropriate birth control during the entire duration of the study

8. Had a physical examination and ECG with no clinically significant abnormalities as judged by the investigator at Visit 1

9. Had no clinically significant laboratory test values (clinical chemistry, hematology, urinalysis) other than those expected in subjects with diabetes as judged by the investigator at Visit 1

10. Either was not treated with or had been on a stable treatment regimen with any of the following medications for a minimum of 2 months prior to Visit 1:

    1. Hormone replacement therapy (female subjects)
    2. Oral contraceptives (female subjects)
    3. Antihypertensive agents
    4. Lipid-lowering agents
    5. Thyroid replacement therapy
    6. Antidepressant agents
    7. Testosterone therapy (male subjects)

11. If on chronic thyroid pharmacologic therapy, had a serum thyroid-stimulating hormone test result within the normal range at Visit 1

12. Was willing and able to follow study procedures

13. Was able to read, understand, and sign the Informed Consent Form and an Authorization to Use and Disclose Protected Health Information form, answer the study questions, communicate with the investigator, and understand and comply with protocol requirements

Exclusion Criteria:

1. 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:

   1. Hepatic disease
   2. Renal disease
   3. Gastrointestinal disease
   4. Endocrine disorder except T2DM
   5. Cardiovascular disease
   6. Central nervous system diseases
   7. Psychiatric or neurological disorders
   8. Organ transplantation
   9. Chronic or acute infection (e.g., tuberculosis, human immunodeficiency virus, hepatitis B virus, or hepatitis C virus)
   10. Orthostatic hypotension, fainting spells or blackouts
   11. Allergy or hypersensitivity

2. Clinically significant malignant disease (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 1

3. Had known hypersensitivity, intolerability, or allergies to metformin HCl or any component of study treatment

4. Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study

5. Current drugs or alcohol abuse or had a history of abuse that in the investigator's opinion would cause the individual to be noncompliant with study procedures

6. Had major surgery or a blood transfusion within 2 months of Visit 1 or was planning to donate blood during the study, or had a significant blood loss within 2 months prior to Visit 1

7. Had been treated, was being treated, or was expected to require or undergo treatment with any of the following excluded medications:

   1. Insulin or sulphonylurea treatment within 3 months of Visit 1
   2. GLP-1 receptor agonists and/or thiazolidinedione treatment within 6 months of Visit 1
   3. Nifedipine within 3 months of Visit 1
   4. Systemic corticosteroids by oral, intravenous, intra-articular, or intra-muscular route within 30 days of screening or for more than 1 week within 3 months of Visit 1
   5. Prescription weight loss medications within 3 months of Visit 1
   6. Chronic or frequent use, in the judgment of the investigator, of any drug treatment that affects gastric pH (prescription or over-the-counter), including proton pump inhibitors or any antacids or medications such as Rolaids or Pepcid within 1 month of Visit 1
   7. Had received or planned to receive any iodinated contrast dye within 1 week prior to Visit 1 (Screening)

8. Had a surgical gastrointestinal procedure that may impact the gut hormonal response to study medication

9. History or presence of inflammatory bowel disease or other severe gastrointestinal disease, particularly those which may impact gastric emptying, such as gastroparesis, pyloric stenosis, gastric bypass surgery or gastric banding surgery

10. Had received any investigational drug within 30 days (or five half-lives of the investigational drug, whichever was greater) of Visit 1

11. Was an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the clinical study site, or was directly affiliated with the study at the clinical study site

12. Was employed by Elcelyx Therapeutics, Inc. (that is an employee, temporary contract worker, or designee responsible for the conduct of the study)