Clinical trial NCT01819272: Assessing the Efficacy, Safety, and Tolerability of Met DR in Subjects With T2DM Over 12 Weeks
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Elcelyx Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2013-03-27
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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)

Primary outcomes:
measure: Change in Fasting Plasma Glucose (mg/dL) at 4 Weeks
timeFrame: Baseline and 4 weeks after the first dose of study medication
Secondary outcomes:
measure: AUC4-12wk of Change in Fasting Plasma Glucose (mg/dL*Week) Concentrations From Baseline to 12 Weeks
timeFrame: Baseline and 4 to 12 weeks after the first dose of study medication
measure: Change in HbA1c (%) at 12 Weeks
timeFrame: Baseline and 12 weeks after the first dose of study medication
Other outcomes:
Locations:
Study officials:
affiliation: National Research Institute - Wilshire
name: Andrew Lewin
role: PRINCIPAL_INVESTIGATOR
affiliation: Alliance Against Diabetes / AAD Clinical Research
name: Rubin Saavedra
role: PRINCIPAL_INVESTIGATOR
affiliation: Axis Clinical Trials
name: Lydie Hazan
role: PRINCIPAL_INVESTIGATOR
affiliation: Encompass Clinical Research
name: Robert Lipetz
role: PRINCIPAL_INVESTIGATOR
affiliation: Juno Research, LLC - Houston
name: Audrey Lacour
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Research South, LLC
name: Donald Hurley
role: PRINCIPAL_INVESTIGATOR
affiliation: Sterling Research Group, Ltd. - Auburn
name: Eli M Roth
role: PRINCIPAL_INVESTIGATOR
affiliation: Protenium Clinical Research, LLC
name: Robert Strzinek
role: PRINCIPAL_INVESTIGATOR
affiliation: Castlerock Clinical Research Consultants, LLC
name: Richard Marple
role: PRINCIPAL_INVESTIGATOR
affiliation: Achieve Clinical Research, LLC
name: Farah Sultan
role: PRINCIPAL_INVESTIGATOR
affiliation: American Health Network - Indianapolis
name: Thomas Moretto
role: PRINCIPAL_INVESTIGATOR
affiliation: Apex Medical Research - Illinois
name: Azazuddin A Ahmed
role: PRINCIPAL_INVESTIGATOR
affiliation: Coastal Carolina Research Center
name: Cynthia Strout
role: PRINCIPAL_INVESTIGATOR
affiliation: Big Sky Clinical Research
name: John Pullman
role: PRINCIPAL_INVESTIGATOR
affiliation: Charlotte Clinical Research
name: Gregory Collins
role: PRINCIPAL_INVESTIGATOR
affiliation: Comprehensive Clinical Research
name: David Hassman
role: PRINCIPAL_INVESTIGATOR
affiliation: Creekside Endocrine Associates
name: Leonard Zemel
role: PRINCIPAL_INVESTIGATOR
affiliation: CSRA Partners in Health, Inc.
name: Diane Smith
role: PRINCIPAL_INVESTIGATOR
affiliation: Dallas Diabetes and Endocrine Center
name: Julio Rosenstock
role: PRINCIPAL_INVESTIGATOR
affiliation: Searcy Medical Center
name: David Johnson
role: PRINCIPAL_INVESTIGATOR
affiliation: MD Medical Research
name: Stephen Ong
role: PRINCIPAL_INVESTIGATOR
affiliation: Meridien Research - Tampa
name: Cynthia Huffman
role: PRINCIPAL_INVESTIGATOR
affiliation: New Orleans Center for Clinical Research
name: Ramon Vargas
role: PRINCIPAL_INVESTIGATOR
affiliation: Pinnacle Research Group
name: Almena Free
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Research of Raleigh, LLC
name: Douglas Short
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Research of Winston-Salem, LLC
name: Jonathan Wilson
role: PRINCIPAL_INVESTIGATOR
affiliation: Progressive Medical Research
name: Alexander White
role: PRINCIPAL_INVESTIGATOR
affiliation: Rainier Clinical Research Center
name: Ronald Brazg
role: PRINCIPAL_INVESTIGATOR
affiliation: Rochester Clinical Research
name: Matthew Davis
role: PRINCIPAL_INVESTIGATOR
affiliation: Spartanburg Medical Research
name: Charles Fogarty
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center at San Antonio
name: Ralph DeFronzo
role: PRINCIPAL_INVESTIGATOR
affiliation: Craig S Thompson MD LLC
name: Craig S Thompson
role: PRINCIPAL_INVESTIGATOR
affiliation: Pioneer Research Solutions Inc.
name: Subodh Bhuchar
role: PRINCIPAL_INVESTIGATOR
affiliation: Jacksonville Center For Clinical Research
name: Susan Greco
role: PRINCIPAL_INVESTIGATOR
affiliation: Louisville Metabolic and Atherosclerosis Research Center
name: Harold Bays
role: PRINCIPAL_INVESTIGATOR
affiliation: National Clinical Research - Norfolk, Inc.
name: Barry Lubin
role: PRINCIPAL_INVESTIGATOR
affiliation: Diablo Clinical Research, Inc.
name: Mark Christiansen
role: PRINCIPAL_INVESTIGATOR
affiliation: Biofortis, Inc.
name: Andrea Lawless
role: PRINCIPAL_INVESTIGATOR
affiliation: Diabetes and Endocrinology Consultants, P.C.
name: Kathryn J Lucas
role: PRINCIPAL_INVESTIGATOR
affiliation: Juno Research, LLC - Katy
name: Hugo Toro
role: PRINCIPAL_INVESTIGATOR
affiliation: Compass Research, LLC
name: Eva M Heurich
role: PRINCIPAL_INVESTIGATOR
affiliation: RAS Health Ltd
name: Chander Arora
role: PRINCIPAL_INVESTIGATOR
affiliation: Willamette Valley Clinical Studies
name: Patricia Buchanan
role: PRINCIPAL_INVESTIGATOR
affiliation: Texas Diabetes & Endocrinology, P.A. - Austin
name: Thomas Blevins
role: PRINCIPAL_INVESTIGATOR
affiliation: John Muir Physician Network Clinical Research Center
name: Anna Chang
role: PRINCIPAL_INVESTIGATOR
affiliation: National Clinical Research - Richmond, Inc.
name: John Hoekstra
role: PRINCIPAL_INVESTIGATOR
affiliation: Kentucky Diabetes Endocrinology Center
name: Lyle Myers
role: PRINCIPAL_INVESTIGATOR
affiliation: Texas Diabetes and Endocrinology, P.A. - Round Rock
name: Stephanie Shaw
role: PRINCIPAL_INVESTIGATOR
affiliation: eStudySite
name: Purvi Mehra
role: PRINCIPAL_INVESTIGATOR
affiliation: Metabolic and Atherosclerosis Research Center
name: Traci Turner
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.