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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: EFB0026 (metformin immediate-release); Drug: EFB0027 (metformin delayed release)

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85283
      • Celerion, Inc.
  • Nebraska
    • Lincoln, Nebraska, United States, 68502
      • Celerion, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Is 19 to 70 (inclusive) years old at Visit 1 (Screening).

2. 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.
3. 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].
4. Has a body mass index (BMI) of 25.0 to 40.0 kg/m^2 (inclusive) at Screening.

5. 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
6. Has a physical examination with no clinically significant abnormalities as judged by the investigator.
7. Ability to understand and willingness to adhere to protocol requirements.
8. 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:

1. 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
2. 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).
3. 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).
4. Has had major surgery of any kind within 6 months of Visit 1 (Screening).
5. Has received a blood transfusion within 6 months of Visit 1 (Screening).
6. Has a history of >5 kg weight change within 3 months of Visit 1 (Screening).
7. 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).
8. Has physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study.
9. 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.
10. Has donated blood within 2 months of Visit 1 (Screening) or is planning to donate blood during the study.
11. Has used insulin within 3 months of Visit 1 (Screening).
12. Has received GLP-1 receptor agonists and/or thiazolidinedione treatment within 6 months of Visit 1 (Screening).
13. Has known intolerance to metformin.
14. Has received any investigational drug within 1 month (or five half-lives of the investigational drug, whichever is greater) of Visit 1 (Screening).
15. Has known allergies or hypersensitivity to any component of study treatment.
16. Is employed by Elcelyx Therapeutics, Inc (that is an employee, temporary contract worker, or designee of the company).
17. Smokes more than 10 cigarettes per day, 2 cigars per day, or uses more than 1 can of smokeless tobacco per week.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Elcelyx Therapeutics, Inc.

Publications and helpful links

General Publications

• DeFronzo RA, Buse JB, Kim T, Burns C, Skare S, Baron A, Fineman M. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia. 2016 Aug;59(8):1645-54. doi: 10.1007/s00125-016-3992-6. Epub 2016 May 23.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: August 23, 2012
• First Submitted That Met QC Criteria: August 29, 2012
• First Posted (Estimate): September 3, 2012

Study Record Updates

• Last Update Posted (Estimate): September 20, 2016
• Last Update Submitted That Met QC Criteria: August 12, 2016
• Last Verified: August 1, 2016

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; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: LCPOC10