A Study to Assess the Bioequivalence of Fixed Dose Combination of Dapagliflozin/Metformin XR Relative to Co-administration of the Individual Components in Healthy Chinese Subjects.

NCT04856007 | Completed Phase 1

• 1 other identifier: D1691C00011
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

To assess the bioequivalence between dapagliflozin/metformin XR FDC tablet and co-administration of dapagliflozin and metformin XR tablets.

Conditions

Healthy Volunteer

Keywords

Dapagliflozin; Forxiga; Metformin XR; Glucophage XR; Xigduo XR; Bioequivalence; Cross-over

Outcome Measures

Primary Outcomes (3)

• Area under the plasma concentration-time curve from zero to the last quantifiable concentration(AUClast) of dapagliflozin and metformin.

  For period 1 and 2, PK samples will be collected pre-dose and 0.5,1,2,3,4,6,8,10,12,24(Day2),36,48(Day3), and 72(Day4) hours post dose.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

• Area under the plasma concentration-time curve from zero to infinity (AUCinf) of dapagliflozin and metformin.

  For period 1 and 2, PK samples will be collected pre-dose and 0.5,1,2,3,4,6,8,10,12,24(Day2),36,48(Day3), and 72(Day4) hours post dose.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

• Maximum observed plasma concentration (Cmax) of dapagliflozin and metformin.

  For period 1 and 2, PK samples will be collected pre-dose and 0.5,1,2,3,4,6,8,10,12,24(Day2),36,48(Day3), and 72(Day4) hours post dose.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

Secondary Outcomes (5)

• Time to maximum observed plasma concentration (tmax) of dapagliflozin and metformin.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

• Terminal elimination rate constant (λz) of dapagliflozin and metformin.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

• Half-life associated with terminal slope of a semi-logarithmic concentration-time curve(t½λz) of dapagliflozin and metformin.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

• Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of dapagliflozin and metformin.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

• Apparent volume of distribution following extravascular administration (Vz/F) of dapagliflozin and metformin.

  From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

Other Outcomes (5)

• Haematology and clinical chemistry laboratory variables over time - SI unit - Change from baseline

  Day 2 and Day 4 in Treatment period 1 and 2, respectively.

• Vital signs over time - Change from baseline

  From Day 2 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

• ECG variables over time - Change from baseline

  Day 1, 4 hours and 8 hours after dosing and Day 4 in Treatment period 1 and 2, respectively.

Study Arms (4)

Dapagliflozin 5mg + Metformin 500mg XR

EXPERIMENTAL

co-administration of a single oral dose of a 5mg dapagliflozin (Forxiga® 5mg) tablet and a 500mg metformin XR (Glucophage XR®) tablet

Drug: Dapagliflozin/metformin XR FDC 5/500 mg

Dapagliflozin/metformin XR FDC 5/500 mg

EXPERIMENTAL

single FDC tablet consisting of 5mg dapagliflozin and 500mg metformin XR subject

Drug: Dapagliflozin 5 mg + Metformin 500 mg XR

Dapagliflozin 10mg + Metformin 1000mg XR

EXPERIMENTAL

co-administration of a single oral dose of a 10mg dapagliflozin (Forxiga® 10mg) tablet and two 500mg metformin XR (Glucophage XR®) tablets

Drug: Dapagliflozin/metformin XR FDC 10/1000 mg

Dapagliflozin/metformin XR FDC 10/1000 mg

EXPERIMENTAL

ingle FDC tablet consisting of 10mg dapagliflozin and 1000mg metformin XR

Drug: Dapagliflozin 10 mg + Metformin 1000 mg XR

Interventions

Dapagliflozin/metformin XR FDC 5/500 mg DRUG

In cohort 1, subjects will be randomized to receive co-administration of a single oral dose of a 5mg dapagliflozin tablet and a 500mg metformin XR tablets (Treatment A) followed by 7 to 14 days washout and then receive single FDC tablet consisting of 5mg dapagliflozin and 500mg metformin XR (Treatment B) on Day 1 in one treatment sequence. Or subjects will be randomized to be administered the Treatment B followed by 7 to 14 days washout and then received Treatment A on Day1 in the other treatment sequence.

Also known as: Xigduo XR

Dapagliflozin 5mg + Metformin 500mg XR

Dapagliflozin/metformin XR FDC 10/1000 mg DRUG

In cohort 2, subjects will be randomized to receive co-administration of a single oral dose of a 10mg dapagliflozin tablet and two 500mg metformin XR tablets (Treatment C) followed by 7 to 14 days washout and then receive single FDC tablet consisting of 10mg dapagliflozin and 1000mg metformin XR (Treatment D) on Day 1 in one treatment sequence. Or subjects will be randomized to be administered the Treatment D followed by 7 to 14 days washout and then received Treatment C on Day1 in the other treatment sequence.

Also known as: Xigduo XR

Dapagliflozin 10mg + Metformin 1000mg XR

Dapagliflozin 5 mg + Metformin 500 mg XR DRUG

In cohort 1, subjects will be randomized to receive co-administration of a single oral dose of a 5mg dapagliflozin tablet and a 500mg metformin XR tablets (Treatment A) followed by 7 to 14 days washout and then receive single FDC tablet consisting of 5mg dapagliflozin and 500mg metformin XR (Treatment B) on Day 1 in one treatment sequence. Or subjects will be randomized to be administered the Treatment B followed by 7 to 14 days washout and then received Treatment A on Day1 in the other treatment sequence.

Also known as: Forxiga + Glucophage XR

Dapagliflozin/metformin XR FDC 5/500 mg

Dapagliflozin 10 mg + Metformin 1000 mg XR DRUG

In cohort 2, subjects will be randomized to receive co-administration of a single oral dose of a 10mg dapagliflozin tablet and two 500mg metformin XR tablets (Treatment C) followed by 7 to 14 days washout and then receive single FDC tablet consisting of 10mg dapagliflozin and 1000mg metformin XR (Treatment D) on Day 1 in one treatment sequence. Or subjects will be randomized to be administered the Treatment D followed by 7 to 14 days washout and then received Treatment C on Day1 in the other treatment sequence.

Also known as: Forxiga + Glucophage XR

Dapagliflozin/metformin XR FDC 10/1000 mg

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of informed consent prior to any study specific procedures.
• Healthy Chinese subjects as determined by no clinically significant deviation from normal in medical history, vital signs, physical examination, 12-lead ECG, and clinical laboratory evaluations.
• Male or female, ages 18 to 55 years, inclusive, at the time of signing the informed consent
• Weigh at least 50 kg (for male) and 45 kg (for female), respectively, and have a body mass index (BMI) ≥ 19 and \<26 kg/m2. BMI = weight (kg)/\[height (m)\]2.
• Female participants: Women of childbearing potential must use one highly effective form of birth control.
• Must be able to communicate with the investigator, understand and comply with all study requirements.

You may not qualify if:

• Any significant acute or chronic medical illness.
• Current or recent (within 3 months prior to study drug administration) gastrointestinal disease that may impact drug absorption and affect PK of the study drugs. Additionally, any gastrointestinal surgery (eg, partial gastrectomy, pyloroplasty) that could impact the absorption of study drug.
• Any major surgery, as determined by the investigator, within 4 weeks prior to study drug administration.
• Donation of blood within 3 months prior to study drug administration.
• Blood transfusion within 4 weeks prior to study drug administration.
• Inability to tolerate oral medication.
• Inability to tolerate venous access.
• Drug or alcohol abuse within 6 months prior to study drug administration. Alcohol abuse is defined as a history of regular alcohol consumption exceeding 14 drinks per week, or a positive breath alcohol test at screening and/or check-in. 1 drink equals to 5 ounces (150ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of hard liquor.
• Regularly drink more than 3 cups of coffee or other caffeine-containing products a day, or 5 cups of tea a day.
• Regular smoker (the subject should be able to abstain from smoking for the duration of the study without having abstinence, therefore they should not be regular smokers, regular smokers are defined as people who smoke everyday), use of tobacco-containing or nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 4 weeks prior to study drug administration .
• Any other sound medical, psychiatric and/or social reason as determined by the investigator.
• Any of the following on ECG prior to study drug administration:
• PR≥210ms
• QRS≥120ms
• QT≥500ms

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Suzhou, 215006, China

Location

Related Publications (1)

• Zhao X, Ning R, Hui A, Boulton DW, Tang W. Pharmacokinetic Variables of Dapagliflozin/Metformin Extended-release Fixed-dose Combination in Healthy Chinese Volunteers and Regional Comparison. Clin Ther. 2023 Aug;45(8):762-769. doi: 10.1016/j.clinthera.2023.06.012. Epub 2023 Jul 11.

  PMID: 37442656 DERIVED

MeSH Terms

Interventions

dapagliflozin; Metformin

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Liyan Miao, MD

  The First Affiliated Hospital of Soochow University

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: There will be two independent cohorts of subjects who will each receive two treatments in a randomized order, and each treatment will be followed by 72 hours of blood sampling for pharmacokinetic assessments, with safety and tolerability. In each cohort approximately 40 healthy subjects will be randomized to receive treatment with IP in order to complete at least 36 evaluable subjects.

Study Record Dates

• First Submitted: April 9, 2021
• First Posted: April 22, 2021
• Study Start: April 12, 2021
• Primary Completion: June 14, 2021
• Study Completion: June 14, 2021
• Last Updated: April 29, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

CN (1)