Assessing the Behavior of Met DR in Subjects With Kidney Dysfunction

A Randomized, Crossover Study Assessing the Single Dose Pharmacokinetics of Delayed-Release Metformin in Subjects With Renal Dysfunction

This study evaluated how a single dose of delayed-release metformin (Met DR) behaves in subjects with normal kidney function, mild kidney dysfunction, moderate kidney dysfunction, or severe kidney dysfunction. The safety and tolerability of Met DR was also examined. In addition, this study compared the behavior of a single dose of Met DR with that of extended-release metformin (Met XR) and placebo in subjects with the varying levels of kidney function described above.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency
• Intervention / Treatment: Drug: Placebo; Drug: Met DR; Drug: Met XR

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 to 80 (inclusive) years old at Visit 1 (Screening)

2. Male, or female and met all of the following criteria:

   • Not breastfeeding
   • Negative pregnancy test result at Visit 1 (Screening) (not applicable to postmenopausal or surgically sterile 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
   • Body weight of ≥45 kg
3. Body mass index (BMI) of 18.0 to 40.0 kg/m² (inclusive) at Visit 1 (Screening)
4. Had type 2 diabetes mellitus and an HbA1c ≤10.0%
5. Had a physical examination with no clinically significant abnormalities as judged by the investigator
6. Estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m² based on the Modification of Diet in Renal Disease (MDRD) equation
7. Ability to understand and willingness to adhere to protocol requirements

Exclusion Criteria:

1. Had End Stage Renal Disease requiring dialysis or severe renal dysfunction with eGFR <15 mL/min/1.73 m²
2. Was on dialysis or had been on dialysis within 12 months of Visit 1 (Screening)
3. Had received or planned to receive any iodinated contrast dye within 1 week prior to Visit 1 (Screening) or after study medication administration
4. Was taking or had taken within 1 week of Visit 1 cationic drugs that are eliminated by renal tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin)

5. 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
   • Gastrointestinal disease
   • Endocrine disorder (type 2 diabetes mellitus was allowed)
   • 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
6. Had any chronic disease requiring medication that had been adjusted in the past 14 days (subjects could take acute intermittent over-the-counter medications such as Tylenol, if needed)
7. Had major surgery of any kind within 6 months of Visit 1 (Screening)
8. Had a clinically significant finding of an electrocardiogram (ECG) as assessed by the investigator at Visit 1 (Screening)
9. Had clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities, other than those related to diabetes or renal disease and other stable diseases, judged by the investigator to be clinically significant at Visit 1 (Screening)
10. Had a hemoglobin result <8 g/dL or a level indicating severe anemia of renal origin
11. Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study
12. Had received Byetta® or short-acting insulin within 3 days of Visit 1 (Screening)
13. Had received metformin within 4 weeks of Visit 1 (Screening)
14. Had any drug treatment that affects gastrointestinal motility or gastric pH (prescription or over-the-counter), including any antacids or medications such as Rolaids or Pepcid, within 2 days of Visit 2
15. 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
16. Smoked more than 10 cigarettes, 3 cigars, or 3 pipes per day
17. Had donated blood within 2 months of Visit 1 (Screening) or was planning to donate blood during the study
18. Had received any investigational drug within one month (or seven half-lives of the investigational drug, whichever was greater) of Visit 1 (Screening)
19. Had known allergies or hypersensitivity to any component of study treatment
20. Was employed by Elcelyx Therapeutics, Inc (that is an employee, temporary contract worker, or designee of the company)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Met DR; One dose of 1000 mg metformin delayed-release	Drug: Met DR; metformin delayed-release tablets
Active Comparator: Met XR; One dose of 1000 mg metformin extended-release	Drug: Met XR; metformin extended-release tablets
Placebo Comparator: Placebo; One dose of Placebo	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC (0-t) of Plasma Metformin	AUC (0-t) = Area under the curve from the time of dosing (0 h) to the time of the last quantifiable concentration following dose administration	from the time of dosing (0 h) to 72 hours postdose
Cmax of Plasma Metformin	Cmax = Maximum concentration from the time of dosing (0 h) to the time of the last quantifiable metformin concentration following dose administration	from the time of dosing (0 h) to 72 hours postdose
Correlation of Placebo-adjusted Change From Pre-dose Value in Lactate Versus Metformin Concentration	To determine the exposure-response relationship of metformin and plasma lactate concentrations	from the time of dosing (0 h) to 24 hours postdose

Collaborators and Investigators

• Sponsor: Elcelyx Therapeutics, Inc.
• Investigators: Principal Investigator: Craig Curtis, MD, Compass Research; Principal Investigator: George Canas, MD, Prism Research; Principal Investigator: Kenneth Lasseter, MD, Clinical Pharmacology of Miami, Inc; Principal Investigator: Alexander White, MD, Progressive Medical Research; Principal Investigator: Harold Bays, MD, Louisville Metabolic and Atherosclerosis Research Center; Principal Investigator: Prabir Roy-Chaudhury, Cincinnati Veterans Affairs Medical Center Department of Internal Medicine; Principal Investigator: Sunder Mudaliar, San Diego Veterans Healthcare System; Principal Investigator: Nelson Kopyt, Northeast Clinical Research Center

Publications and helpful links

General Publications

• Bakris GL, Mudaliar, S, Kim T, Burns C, Skare S, Baron A, Fineman M. Effects of New Metformin Formulation in Stage 3 and 4 CKD: A Pilot Study. J Am Soc Nephrol. 2014; 25:549A.
• DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016 Feb;65(2):20-9. doi: 10.1016/j.metabol.2015.10.014. Epub 2015 Oct 9.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: August 1, 2012
• First Submitted That Met QC Criteria: August 2, 2012
• First Posted (Estimate): August 7, 2012

Study Record Updates

• Last Update Posted (Estimate): December 30, 2015
• Last Update Submitted That Met QC Criteria: November 25, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency
• Other Study ID Numbers: LCRM101