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).

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Met DR; Drug: Met XR; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 600 mg DR; 600 mg delayed-release metformin once daily in the morning	Drug: Met DR; metformin delayed-release tablets
Experimental: 800 mg DR; 800 mg delayed-release metformin once daily in the morning	Drug: Met DR; metformin delayed-release tablets
Experimental: 1000 mg DR; 1000 mg delayed-release metformin once daily in the morning	Drug: Met DR; metformin delayed-release tablets
Active Comparator: 1000 mg XR; 1000 mg extended-release metformin once daily in the evening	Drug: Met XR; metformin extended-release tablets
Active Comparator: 2000 mg XR; 2000 mg extended-release metformin once daily in the evening	Drug: Met XR; metformin extended-release tablets
Placebo Comparator: Placebo; Placebo once daily in the morning	Drug: Placebo; placebo delayed-release tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Fasting Plasma Glucose (mg/dL) at 4 Weeks	Baseline and 4 weeks after the first dose of study medication

Secondary Outcome Measures

Outcome Measure	Time Frame
AUC4-12wk of Change in Fasting Plasma Glucose (mg/dL*Week) Concentrations From Baseline to 12 Weeks	Baseline and 4 to 12 weeks after the first dose of study medication
Change in HbA1c (%) at 12 Weeks	Baseline and 12 weeks after the first dose of study medication

Collaborators and Investigators

• Sponsor: Elcelyx Therapeutics, Inc.
• Investigators: Principal Investigator: Andrew Lewin, National Research Institute - Wilshire; Principal Investigator: Rubin Saavedra, Alliance Against Diabetes / AAD Clinical Research; Principal Investigator: Robert Lipetz, Encompass Clinical Research; Principal Investigator: Audrey Lacour, Juno Research, LLC - Houston; Principal Investigator: Donald Hurley, Medical Research South, LLC; Principal Investigator: Eli M Roth, Sterling Research Group, Ltd. - Auburn; Principal Investigator: Robert Strzinek, Protenium Clinical Research, LLC; Principal Investigator: Richard Marple, Castlerock Clinical Research Consultants, Llc; Principal Investigator: Farah Sultan, Achieve Clinical Research, LLC; Principal Investigator: Thomas Moretto, American Health Network - Indianapolis; Principal Investigator: Azazuddin A Ahmed, Apex Medical Research - Illinois; Principal Investigator: Cynthia Strout, Coastal Carolina Research Center; Principal Investigator: John Pullman, Big Sky Clinical Research; Principal Investigator: Gregory Collins, Charlotte Clinical Research; Principal Investigator: David Hassman, Comprehensive Clinical Research; Principal Investigator: Leonard Zemel, Creekside Endocrine Associates; Principal Investigator: Diane Smith, CSRA Partners in Health, Inc.; Principal Investigator: Julio Rosenstock, Dallas Diabetes and Endocrine Center; Principal Investigator: David Johnson, Searcy Medical Center; Principal Investigator: Stephen Ong, MD Medical Research; Principal Investigator: Cynthia Huffman, Meridien Research - Tampa; Principal Investigator: Ramon Vargas, New Orleans Center for Clinical Research; Principal Investigator: Almena Free, Pinnacle Research Group; Principal Investigator: Douglas Short, PMG Research of Raleigh, LLC; Principal Investigator: Jonathan Wilson, PMG Research of Winston-Salem, LLC; Principal Investigator: Alexander White, Progressive Medical Research; Principal Investigator: Ronald Brazg, Rainier Clinical Research Center; Principal Investigator: Matthew Davis, Rochester Clinical Research, Inc.; Principal Investigator: Charles Fogarty, Spartanburg Medical Research; Principal Investigator: Ralph DeFronzo, The University of Texas Health Science Center at San Antonio; Principal Investigator: Craig S Thompson, Craig S Thompson MD LLC; Principal Investigator: Subodh Bhuchar, Pioneer Research Solutions Inc.; Principal Investigator: Susan Greco, Jacksonville Center for Clinical Research; Principal Investigator: Harold Bays, Louisville Metabolic and Atherosclerosis Research Center; Principal Investigator: Barry Lubin, National Clinical Research - Norfolk, Inc.; Principal Investigator: Mark Christiansen, Diablo Clinical Research, Inc.; Principal Investigator: Andrea Lawless, Biofortis, Inc.; Principal Investigator: Kathryn J Lucas, Diabetes and Endocrinology Consultants, P.C.; Principal Investigator: Hugo Toro, Juno Research, LLC - Katy; Principal Investigator: Eva M Heurich, Compass Research, LLC; Principal Investigator: Chander Arora, RAS Health LTD; Principal Investigator: Patricia Buchanan, Willamette Valley Clinical Studies; Principal Investigator: Thomas Blevins, Texas Diabetes & Endocrinology, P.A. - Austin; Principal Investigator: Anna Chang, John Muir Physician Network Clinical Research Center; Principal Investigator: John Hoekstra, National Clinical Research - Richmond, Inc.; Principal Investigator: Lyle Myers, Kentucky Diabetes Endocrinology Center; Principal Investigator: Stephanie Shaw, Texas Diabetes and Endocrinology, P.A. - Round Rock; Principal Investigator: Purvi Mehra, eStudySite; Principal Investigator: Traci Turner, Metabolic and Atherosclerosis Research Center

Publications and helpful links

General Publications

• Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M. The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies. Diabetes Care. 2016 Feb;39(2):198-205. doi: 10.2337/dc15-0488. Epub 2015 Aug 18.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: March 19, 2013
• First Submitted That Met QC Criteria: March 22, 2013
• First Posted (Estimate): March 27, 2013

Study Record Updates

• Last Update Posted (Actual): March 15, 2017
• Last Update Submitted That Met QC Criteria: February 6, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: LCRM105