Clinical trial NCT01804842: Assessing the Effect of Met DR on Plasma Glucose and PK in Subjects With T2DM
Official title: A Randomized, Crossover Study Assessing the Effect of EFB0027 on Plasma Glucose and Pharmacokinetics in Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Elcelyx Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2013-03-05
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: AUC (0-24) of Plasma Metformin
timeFrame: 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.
measure: Cmax of Plasma Metformin
timeFrame: 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.
measure: AUC (0-24) of Plasma Glucose
timeFrame: 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.
measure: Rmax (0-24) of Plasma Glucose
timeFrame: 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.
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Celerion
name: Danielle Armas, MD
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.
citation: 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.