An Open-label, Randomized, Crossover Study of Comparative Pharmacokinetics and Bioequivalence of Dapagliflozin + Metformin, 10 mg + 1000 mg Versus the Combined Use of Forxiga™, 10 mg and Two Glucophage® Long, ER Tablets, 500 mg Co-administered to Healthy Volunteers Under Standard Fed Conditions

NCT02722239 | Completed Phase 1 Results

• 1 other identifier: D1691C00012
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this study is to demonstrate bioequivalence of fixed dose combination Dapagliflozin + Metformin modified -release, film-coated tablets, 10 mg + 1000 mg, (AstraZeneca AB, Sweden) versus Forxiga™ (Dapagliflozin), film-coated tablets, 10 mg (Bristol Myers Squibb Company, USA) and Glucophage® long (Metformin), ER tablets, 1000 mg (2 x 500 mg) (Merck Santé S.A.S., France) which are already registered in the Russian Federation.

Conditions

Diabetes Mellitus, Type 2

Keywords

Xigduo;; bioequivalence;; crossover;; Russia

Outcome Measures

Primary Outcomes (5)

• Maximum Concentration (Cmax).

  Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product.

• Area Under the "Concentration - Time" Curve (AUC0-t)

  Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product.

• Area Under the "Concentration - Time" Curve (AUC0-∞)

  Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product.

• Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios

  The drugs are considered bioequivalent if the 90% confidence intervals for the Test : Reference products geometric least squares mean ratios of AUC, Cmax и Cmax/AUC parameters are in the range of 80% - 125%.

  Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product.

• Adverse Events

  Adverse events data for Dapagliflozin + Metformin, modified-release film-coated tablets, 10 mg + 1000 mg (AstraZeneca AB, Sweden) and for co-administered Forxiga™ (Dapagliflozin), film-coated tablets, 10 mg, (Bristol Myers Squibb Company, USA) and Glucophage® long (Metformin), XR tablets, 500 mg/2 tablets (Merck Santé S.A.S, France)

  AE information will be collected from the time of the first dosing to the last study procedure made in the hospital, approximately 1 month

Study Arms (2)

T/R

EXPERIMENTAL

Test product (T): a single oral dose of modified release fixed dose combination film-coated tablet consisting of 10 mg dapagliflozin IR and 1000 mg metformin hydrochloride extended release. Volunteers enrolled to group 1, on the first study period will take the study test product (Т), and on the second study period after wash out period of 7 days the volunteers will be given the Reference product (R)

Drug: Xigduo XR; Drug: Metformin ER (Glucophage® long); Drug: Dapagliflozin (Forxiga)

R/T

EXPERIMENTAL

Reference product (R): co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long). Volunteers from group 2 will be administered with the study drug in reverse order. It means that group 1 will take the study products in sequence T-R and group 2 in the sequence R-T.

Drug: Xigduo XR; Drug: Metformin ER (Glucophage® long); Drug: Dapagliflozin (Forxiga)

Interventions

Xigduo XR DRUG

a single oral dose of modified release fixed dose combination film-coated tablet consisting of 10 mg dapagliflozin IR and 1000 mg metformin hydrochloride extended release

R/T; T/R

Metformin ER (Glucophage® long) DRUG

co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long).

R/T; T/R

Dapagliflozin (Forxiga) DRUG

co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long).

R/T; T/R

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• The volunteer is able to understand the requirements of the study, to sign the informed consent form, and agrees with all the restrictions imposed in the course of the study;
• Male and female subjects aged 18-45, inclusive;
• Caucasian race;
• Body-mass index (BMI) within the range dated 18.5 to 30 kg/m2;
• Verified diagnosis "healthy" as confirmed by the results of standard clinical, laboratory, and instrumental evaluations;
• A negative pregnancy test at the Screening Visit for female subjects of childbearing potential.
• Postmenopausal (no menses for at least 1 year) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) females are exempted from the requirement. In case of using hormonal contraceptives, these should be withdrawn at least 2 months before the study;
• Volunteers' with preserved reproductive potential agree to use adequate contraception throughout the study and for 30 days thereafter

You may not qualify if:

• Known hypersensitivity or intolerance to dapagliflozin or metformin or any other excipient of the study drugs;
• History of allergy to Na+ glucose co-transport inhibitor;
• Complicated allergic history including food intolerance;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Chronic diseases of the cardiovascular, bronchopulmonary, nervous, endocrine, or musculoskeletal systems, as well as diseases of the gastrointestinal tract, liver, kidneys, blood, immune system, mental disorders;
• Deviations from the normal parameters in clinical blood count analysis, biochemical blood analysis, urinalysis; vital signs;
• Mental, physical and other reasons that do not allow the subjects according to investigator's opinion to assess their behavior adequately, to follow correctly the requirements of the clinical study protocol and to assess the expected risks and possible discomfort;
• Organic brain damage, history of increased seizure activity;
• Changes on ECG (clinically significant);
• Systolic blood pressure (AD) measured in a sitting position, less than 100 mmHg or above 130 mmHg and / or diastolic blood pressure below 70 mm Hg or above 90 mmHg at screening or any time during the study;
• Heart rate less than 60 or more than 80 beats per minute at screening or prior to administration of the drug in each period of the study;
• Scheduled radioisotope or radiological examinations using iodinated contrast agents during \< 2 days before dosing;
• Rare hereditary diseases manifestating with fructose or sorbitol intolerance;
• Gastrointestinal tract surgery (except appendectomy);
• Acute infectious diseases less than 4 weeks before the start of the study;

Sponsors & Collaborators

• AstraZeneca: lead
• Biocard: collaborator

Study Sites (1)

Research Site

Moscow, 123423, Russia

Location

Related Publications (1)

• Khomitskaya Y, Tikhonova N, Gudkov K, Erofeeva S, Holmes V, Dayton B, Davies N, Boulton DW, Tang W. Bioequivalence of Dapagliflozin/Metformin Extended-release Fixed-combination Drug Product and Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Russian Subjects. Clin Ther. 2018 Apr;40(4):550-561.e3. doi: 10.1016/j.clinthera.2018.02.006. Epub 2018 Mar 14.

  PMID: 29548719 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Metformin; dapagliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Nadiya Rizvanova
• Organization: Biocard Research LLC

n.rizvanova@biocard.com

+74993088278

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 15, 2016
• First Posted: March 29, 2016
• Study Start: March 30, 2016
• Primary Completion: May 5, 2016
• Study Completion: May 5, 2016
• Last Updated: February 19, 2018
• Results First Posted: February 19, 2018

Record last verified: 2017-08

Locations

RU (1)