Clinical trial NCT01658514: Assessing the Behavior of Met DR in Subjects With Kidney Dysfunction
Official title: A Randomized, Crossover Study Assessing the Single Dose Pharmacokinetics of Delayed-Release Metformin in Subjects With Renal Dysfunction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Renal Insufficiency
Lead sponsor: Elcelyx Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2012-08-07
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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)

Primary outcomes:
measure: AUC (0-t) of Plasma Metformin
timeFrame: from the time of dosing (0 h) to 72 hours postdose
measure: Cmax of Plasma Metformin
timeFrame: from the time of dosing (0 h) to 72 hours postdose
measure: Correlation of Placebo-adjusted Change From Pre-dose Value in Lactate Versus Metformin Concentration
timeFrame: from the time of dosing (0 h) to 24 hours postdose
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Prism Research
name: George Canas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Pharmacology of Miami, Inc
name: Kenneth Lasseter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Progressive Medical Research
name: Alexander White, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Louisville Metabolic and Atherosclerosis Research Center
name: Harold Bays, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Compass Research
name: Craig Curtis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cincinnati Veterans Affairs Medical Center Department of Internal Medicine
name: Prabir Roy-Chaudhury
role: PRINCIPAL_INVESTIGATOR
affiliation: San Diego Veterans Healthcare System
name: Sunder Mudaliar
role: PRINCIPAL_INVESTIGATOR
affiliation: Northeast Clinical Research Center
name: Nelson Kopyt
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.