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.

A Single-centre, Parallel-cohort, Randomized, Open-label, Two-period, Cross-over, Bioequivalence Study of the Fixed Dose Combination of Dapagliflozin/Metformin XR Relative to Co-administration of the Individual Components in Two Cohorts of Healthy Chinese Subjects in the Fed State.

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

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: Dapagliflozin/metformin XR FDC 5/500 mg; Drug: Dapagliflozin 5 mg + Metformin 500 mg XR; Drug: Dapagliflozin/metformin XR FDC 10/1000 mg; Drug: Dapagliflozin 10 mg + Metformin 1000 mg XR

Detailed Description

A Single-centre, Parallel-cohort, Randomized, Open-label, Two-period, Cross-over, Bioequivalence Study of the Fixed Dose Combination of Dapagliflozin/Metformin XR Relative to Co-administration of the Individual Components in Two Cohorts of Healthy Chinese Subjects in the Fed State.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Suzhou, China, 215006
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.
2. 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.
3. Male or female, ages 18 to 55 years, inclusive, at the time of signing the informed consent
4. 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.
5. Female participants: Women of childbearing potential must use one highly effective form of birth control.
6. Must be able to communicate with the investigator, understand and comply with all study requirements.

Exclusion Criteria:

1. Any significant acute or chronic medical illness.
2. 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.
3. Any major surgery, as determined by the investigator, within 4 weeks prior to study drug administration.
4. Donation of blood within 3 months prior to study drug administration.
5. Blood transfusion within 4 weeks prior to study drug administration.
6. Inability to tolerate oral medication.
7. Inability to tolerate venous access.
8. 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.
9. Regularly drink more than 3 cups of coffee or other caffeine-containing products a day, or 5 cups of tea a day.
10. 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 .
11. Any other sound medical, psychiatric and/or social reason as determined by the investigator.

12. Any of the following on ECG prior to study drug administration:

    1. PR≥210ms
    2. QRS≥120ms
    3. QT≥500ms
    4. QTcF≥450ms(male) or QTcF≥470ms(female)
13. Positive urine screen for drugs of abuse.
14. Any clinically significant abnormal findings in urinalysis (may repeat once) at screening, as judged by the investigator.
15. Glucosuria at screening.
16. Abnormal liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or total bilirubin > 10% above upper limit of normal [ULN]).
17. Elevated serum creatinine (> ULN).
18. Positive blood screen for HIV antibody , Syphilis antibody, hepatitis C antibody , or Hepatitis B surface antigen (HbsAg) or only Hepatitis B core antibody (anti-HBc) in Hepatitis B serologic test.
19. History of allergy to SGLT2 inhibitor drug class or related compounds.
20. History of allergy or intolerance to metformin or other similar acting agents.
21. History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
22. Prior exposure to metformin or dapagliflozin within 3 months of study drug administration.
23. Exposure to any investigational product or placebo within 4 weeks prior to study drug administration.
24. Use of any prescription drugs or over-the counter (OTC), traditional Chinese medicine and herbal preparations within 4 weeks prior to study drug administration.
25. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff or staff at the study site).
26. Previous enrolled or randomized in the present study.
27. For women only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
28. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
29. Has clinical signs and symptoms consistent with COVID-19 infection (eg fever, dry cough, dyspnea, sore throat, fatigue.. etc) as judged by investigator or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission.
30. History of COVID-19.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin 5mg + Metformin 500mg XR; 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; 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.; Other Names: Xigduo XR
Experimental: Dapagliflozin/metformin XR FDC 5/500 mg; single FDC tablet consisting of 5mg dapagliflozin and 500mg metformin XR subject	Drug: Dapagliflozin 5 mg + Metformin 500 mg XR; 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.; Other Names: Forxiga + Glucophage XR
Experimental: Dapagliflozin 10mg + Metformin 1000mg XR; 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; 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.; Other Names: Xigduo XR
Experimental: Dapagliflozin/metformin XR FDC 10/1000 mg; ingle FDC tablet consisting of 10mg dapagliflozin and 1000mg metformin XR	Drug: Dapagliflozin 10 mg + Metformin 1000 mg XR; 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.; Other Names: Forxiga + Glucophage XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to maximum observed plasma concentration (tmax) 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.
Terminal elimination rate constant (λz) 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.
Half-life associated with terminal slope of a semi-logarithmic concentration-time curve(t½λz) 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.
Apparent total body clearance of drug from plasma after extravascular administration (CL/F) 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.
Apparent volume of distribution following extravascular administration (Vz/F) 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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Haematology and clinical chemistry laboratory variables over time - SI unit - Change from baseline	To further assess the safety and tolerability of dapagliflozin/metformin XR FDC and coadministration of the individual components in healthy Chinese subjects in the fed state.	Day 2 and Day 4 in Treatment period 1 and 2, respectively.
Vital signs over time - Change from baseline	To further assess the safety and tolerability of dapagliflozin/metformin XR FDC and coadministration of the individual components in healthy Chinese subjects in the fed state.	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	To further assess the safety and tolerability of dapagliflozin/metformin XR FDC and coadministration of the individual components in healthy Chinese subjects in the fed state.	Day 1, 4 hours and 8 hours after dosing and Day 4 in Treatment period 1 and 2, respectively.
Urinalysis data over time	To further assess the safety and tolerability of dapagliflozin/metformin XR FDC and coadministration of the individual components in healthy Chinese subjects in the fed state.	Day 2 and Day 4 in Treatment period 1 and 2, respectively.
Incidence of adverse events	To further assess the safety and tolerability of dapagliflozin/metformin XR FDC and coadministration of the individual components in healthy Chinese subjects in the fed state.	From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Liyan Miao, MD, The First Affiliated Hospital Of Soochow University

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2021
• Primary Completion (Actual): June 14, 2021
• Study Completion (Actual): June 14, 2021

Study Registration Dates

• First Submitted: April 9, 2021
• First Submitted That Met QC Criteria: April 20, 2021
• First Posted (Actual): April 22, 2021

Study Record Updates

• Last Update Posted (Actual): April 29, 2022
• Last Update Submitted That Met QC Criteria: April 25, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Dapagliflozin; Bioequivalence; Forxiga; Cross-over; Metformin XR; Glucophage XR; Xigduo XR
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin; Metformin
• Other Study ID Numbers: D1691C00011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No