Clinical trial NCT04856007: 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.
Official title: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer
Keywords: Dapagliflozin
Forxiga
Metformin XR
Glucophage XR
Xigduo XR
Bioequivalence
Cross-over
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-04-22
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: OTHER

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Area under the plasma concentration-time curve from zero to the last quantifiable concentration(AUClast) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
measure: Area under the plasma concentration-time curve from zero to infinity (AUCinf) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
measure: Maximum observed plasma concentration (Cmax) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
Secondary outcomes:
measure: Time to maximum observed plasma concentration (tmax) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
measure: Terminal elimination rate constant (λz) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
measure: Half-life associated with terminal slope of a semi-logarithmic concentration-time curve(t½λz) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
measure: Apparent volume of distribution following extravascular administration (Vz/F) of dapagliflozin and metformin.
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
Other outcomes:
measure: Haematology and clinical chemistry laboratory variables over time - SI unit - Change from baseline
timeFrame: Day 2 and Day 4 in Treatment period 1 and 2, respectively.
measure: Vital signs over time - Change from baseline
timeFrame: From Day 2 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
measure: ECG variables over time - Change from baseline
timeFrame: Day 1, 4 hours and 8 hours after dosing and Day 4 in Treatment period 1 and 2, respectively.
measure: Urinalysis data over time
timeFrame: Day 2 and Day 4 in Treatment period 1 and 2, respectively.
measure: Incidence of adverse events
timeFrame: From Day 1 to Day 4, in Treatment period 1 and 2, respectively. An average of 11 to 18 days.
Locations:
city: Suzhou
country: China
facility: Research Site
Study officials:
affiliation: The First Affiliated Hospital of Soochow University
name: Liyan Miao, MD
role: PRINCIPAL_INVESTIGATOR
References: