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

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

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).

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 to 70 (inclusive) years old at Visit 1 (Screening)

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

5. 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
6. Had 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 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:

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:

   • 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
2. 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)
3. 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)
4. Had major surgery of any kind within 6 months of Visit 1 (Screening)
5. Had received a blood transfusion within 6 months of Visit 1 (Screening)
6. Had a history of >5 kg weight change within 3 months of Visit 1 (Screening)
7. 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)
8. Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study
9. 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
10. 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
11. Used insulin within 3 months of Visit 1 (Screening)
12. Had received GLP-1 receptor agonists and/or thiazolidinedione treatment within 6 months of Visit 1 (Screening)
13. Had known intolerance to metformin
14. Had received any investigational drug within 2 months (or five half-lives of the investigational drug, whichever was greater) of Visit 1 (Screening)
15. Had known allergies or hypersensitivity to any component of study treatment
16. Was employed by Elcelyx Therapeutics, Inc. (that is an employee, temporary contract worker, or designee of the company)
17. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Elcelyx Therapeutics, Inc.

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.
• 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: December 1, 2012
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: March 4, 2013
• First Submitted That Met QC Criteria: March 4, 2013
• First Posted (Estimate): March 5, 2013

Study Record Updates

• Last Update Posted (Estimate): October 21, 2016
• Last Update Submitted That Met QC Criteria: October 19, 2016
• Last Verified: October 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
• Other Study ID Numbers: LCRM104