Bioequivalence Study of Two Formulations of Tablets Aceclofenac 100 mg in Healthy Volunteers Under Fasting Conditions

Open-label Randomized Crossover Two Period Single Dose Bioequivalence Study of Two Formulations Aceclofenac Tablets 100 mg (Pharmtechnology LLC, Republic of Belarus) and Airtal® Tablets 100 mg (Gedeon Richter- RUS", Russia / Gedeon Richter, Hungary; MA Holder: Almiral S.A., Spain) in Healthy Volunteers Under Fasting Conditions

This is an open-label, randomized, two period, single-center, crossover, comparative study, where each participant will be randomly assigned to the reference (Airtal ®, 100 mg film-coated tablets) or the test (Aceclofenac, 100 mg film-coated tablets) formulation in each period of study (sequences Test-Reference (TR) or Reference-Test (RT)), in order to evaluate if both formulations are bioequivalent.

This is an open-labeled, randomized, two period, crossover, a single-center, comparative, single-dose study, in which 36 healthy adult subjects will receive one of the study treatments during each study period.

The objective of this study is to determine the bioequivalence of two different formulations of aceclofenac after a single oral dose administration under fasting conditions.

Subject eligibility for this study will be determined at the screening visit and eligible subjects will be admitted to the clinical research unit at least 12 hours prior to drug administration for each study period.

Hospitalization in the first period of the study will last no more than 37 hours, after which, in the absence of indications for an extension of hospitalization, each subject will be released home; after that, the first period of the study will be completed.

The procedures of the second study period will be identical to the first period.

After completing all the procedures of the second study period, each subject will undergo a final examination, after which, in case of the absence of adverse events and indications for prolonging hospitalization, the study for the subjects will be considered completed.

The total duration of the study for the subject will be no more than 22 days.

Eligible subjects will be randomized to one of two treatment sequences. There will be two sequences in the study: TR and RT, where T = the test product, R = the reference product.

For each study period, subjects will receive a single 100 mg oral dose of aceclofenac (the test or the reference formulation). Study participants will be aware they will receive different formulations of the same drug, without being informed which product (Test or Reference) is being administered. For each subject, all scheduled postdose activities and assessments will be performed relative to the time of study drug administration.

Fasting will continue for at least 4 hours following drug administration, after which a standardized lunch will be served. Next meals will be provided for subjects in 6 hours, 9 hours and 12 hours after drug administration.

Water will be provided as needed until 1 hour predose. Water will be allowed beginning 2 hours after the administration of the drug.

A total of 20 blood samples will be collected (one tube of 6 mL each) in each study period for pharmacokinetic (PK) assessments. The first blood sample will be collected prior to drug administration while the others will be collected up to 24 hours after drug administration.

Aceclofenac plasma concentrations will be measured according to a validated bioanalytical method.

Statistical analysis of all PK parameters will be based on an ANOVA model. Two-sided 90% confidence interval of the ratio of geometric LSmeans obtained from the ln-transformed PK parameters will be calculated.

Statistical inference of aceclofenac will be based on a bioequivalence approach using the following standards: the ratio of geometric LSmeans with corresponding 90% confidence interval calculated from the exponential of the difference between the Test and the Reference for the ln-transformed parameters Cmax and AUC0-t should all be within the 80.00 to 125.00% bioequivalence range.

Inclusion Criteria:

1. Healthy european men or women aged between 18 to 45 years

2. The written consent of the volunteer to be included in the study

3. Verified diagnosis "healthy" according to the anamnesis data and the results of standard clinical, laboratory and instrumental examination methods, physical examination and anamnestic examination

4. The results of an X-ray or fluorographic examination of the chest organs within the normal range (the results of an examination carried out within 12 months before the start of the study may be provided)

5. Body mass index 18.5-30 kg/m² according to Quetelet's weight-height index

6. For female:

   • the results of the examination of the mammary glands (palpation or mammography) within the normal range according to the data obtained within 12 months before the start of the study;
   • non-breastfeeding women;
   • negative pregnancy test;
   • adherence to reliable methods of contraception for female of childbearing potential: sexual continence, or condom + spermicide, or diaphragm + spermicide, started at least 14 days before the first dose of the study drug; intrauterine contraception is also a reliable method of contraception, installed at least 4 weeks before taking the study drugs in the first period;
   • сonsent to use these methods of contraception within 30 days after taking the drug in the second period;
   • women who do not use acceptable methods of contraception, if they are considered incapable of childbearing, will also be able to participate in the study: women who have undergone a hysterectomy or tubal ligation, women with a clinical diagnosis of infertility, and women who are in menopause (at least a year without menstruation in the absence of alternative pathologies that may cause the cessation of menstruation);
   • in case of using contraceptives (injectable and oral hormonal contraceptives, subcutaneous hormonal implants or intrauterine hormonal therapeutic systems), the latter should be canceled at least 60 days before taking the drug in the first period;

7. For male: consent to use a double barrier method of contraception (condom + spermicide) or complete sexual abstinence, as well as consent not to participate in sperm donation during the entire study and 30 days after taking the drug in the second period.

8. Subjects are able to understand the requirements of the study, to sign a written informed consent, and also to accept all the restrictions imposed during the course of the study, and to agree to return for the required investigations.

Exclusion Criteria:

1. burdened allergic history, hypersensitivity to any ACE inhibitors, including aceclofenac or excipients that are part of any of the investigational drugs, or intolerance to these components;
2. bronchospasm, urticaria, rhinitis after taking acetylsalicylic acid or other NSAIDs in history (complete or incomplete acetylsalicylic acid intolerance syndrome - rhinosinusitis, urticaria, polyps of the nasal mucosa, bronchial asthma);
3. bleeding or perforation of the gastrointestinal tract associated with the use of NSAIDs in history;
4. acute bleeding or diseases accompanied by bleeding in the last 2 months;
5. clinically significant pathologies of the cardiovascular, bronchopulmonary, neuroendocrine systems, as well as diseases of the gastrointestinal tract, liver, kidneys and blood;
6. other diseases that, in the opinion of the researcher, may affect the absorption, distribution, metabolism or excretion of both drugs, or increase the risk of negative consequences for the volunteer;
7. the presence of mental disorders, including a history;
8. surgical interventions on the gastrointestinal tract, with the exception of appendectomy;
9. acute infectious diseases that ended less than 4 weeks before taking the drug in the first period;
10. dehydration due to diarrhea, vomiting or other reason within the last 24 hours before taking the drug in the first period of the study;
11. clinically significant abnormalities on the ECG, the level of systolic blood pressure (SBP) measured in the sitting position at the time of screening ≤ 100 mm Hg or ≥ 139 mm Hg and / or diastolic blood pressure (DBP) ≤ 70 mm Hg or ≥ 89 mm Hg;
12. heart rate less than 60 beats/min or more than 90 beats/min at the time of screening, respiratory rate less than 12 or more than 18 per minute at the time of screening, body temperature below 36.0 ° C or above 37.0 °C at the time of screening;
13. the use of injectable and oral hormonal contraceptives, subcutaneous hormonal implants or intrauterine hormonal therapeutic systems and other hormonal contraceptives for 60 days before taking the drug in the first period;
14. use of any drugs including herbs and food additives, vitamins that can have a significant effect on the PK of lisinopril or data on the effect of which on the pharmacokinetics of lisinopril are unknown, as well as question the characterization of the volunteer as healthy, less than 14 days before taking the drug in the first period;
15. taking known inhibitors or inducers of microsomal liver enzymes (barbiturates, omeprazole, cimetidine, etc.) or antiviral drugs less than 2 months before taking the drug in the first study period;
16. donation of plasma or blood (450 ml or more) less than 2 months before taking the drug in the first period;
17. adherence to any low-sodium diet within 2 weeks prior to taking the drug in the first study period, or adherence to a special diet (vegetarian, vegan, salt-restricted) or lifestyle (night work, extreme physical exercise);
18. consumption of caffeine and xanthine-containing drinks and products (tea, coffee, chocolate, cola, etc.), products containing poppy seeds, less than 48 hours before taking the drug in the first period;
19. consumption of alcohol and alcohol-containing foods and beverages less than 48 hours before taking the drug in the first period;
20. use of citrus fruits (including grapefruit and grapefruit juice) and cranberries (including juices, fruit drinks, etc.) less than 7 days before taking the drug in the first period;
21. intake of more than 10 units alcohol per week (1 unit of alcohol is equivalent to 500 ml of beer, 200 ml of dry wine or 50 ml of spirits ethyl 40%) or history of alcoholism, drug addiction, drug abuse;
22. inability to refrain from intensive physical activity and contact sports less than 24 hours before taking the drug in the first period;
23. smoking more than 10 cigarettes per day less than 24 hours before taking the drug in the first period;
24. participation in other clinical trials of drugs less than 3 months before taking the drug in the first period;
25. test positive for syphilis, hepatitis B, hepatitis C or HIV at the time of screening;
26. positive pregnancy test at screening;
27. breastfeeding;
28. positive test for alcohol in exhaled air at screening;
29. positive urinalysis for the content of narcotic and potent substances during screening (opiates, morphine, barbiturates, benzodiazepines, cannabinoids/marijuana);
30. the value of standard laboratory and instrumental parameters that go beyond the reference values;
31. lack of intention of volunteers to comply with the Protocol requirements throughout the course of the study and/or lack, in the opinion of the Investigator, of the volunteers' ability to understand and evaluate the information on this study as part of the informed consent form signing process, in particular regarding the expected risks and possible discomfort;
32. mental, physical and other reasons that do not allow the subject to adequately assess their behavior and correctly fulfill the conditions of the Research Protocol;
33. tattooing and piercing within 30 days prior to first drug administration;
34. difficulty swallowing tablets;
35. difficulty with taking blood;