Clinical trial NCT05498233: Pharmacokinetics and Bioequivalence of Doxylamine + Pyridoxine, Film-coated, Enteric-soluble Tablets, and Diclectin, Delayed Release Tablets, in Healthy Volunteers
Official title: Open Randomized Cross-over Two-period Study on Comparative Pharmacokinetics and Bioequivalence of Doxylamine + Pyridoxine, Enteric-soluble Film-coated Tablets, 10 mg + 10 mg (Valenta Farm, Russia) in Healthy Volunteers in Fasted Conditions
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pregnancy Related
Nausea
Lead sponsor: Valenta Pharm JSC
Sponsor class: INDUSTRY
First posted: 2022-08-12
Enrollment: 28
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: The study aimed for:

1. Comparative assessment of pharmacokinetic parameters and bioequivalence of the drug Doxylamine + Pyridoxine, enteric-soluble film-coated tablets, 10 mg + 10 mg (Valenta Pharm JSC, Russia), and Diclectin, delayed-release tablets, 10 mg + 10 mg (registrant: Tzamal Bio-Pharma, Israel, manufacturer: Duchesnay Inc, Canada), in healthy volunteers in fasted conditions.
2. Comparative evaluation of the safety of the drug Doxylamine + Pyridoxine, enteric-soluble film-coated tablets, 10 mg + 10 mg (Valenta Pharm JSK, Russia), and Diclectin, delayed-release tablets, 10 mg + 10 mg (registrant: Tzamal Bio-Pharma, Israel, manufacturer: Duchesnay Inc, Canada), based on the analysis of adverse events (AEs).


Eligibility criteria: Inclusion Criteria:

1. Voluntary and handwritten informed consent form signed by a healthy volunteer to participate in the study before any of the study procedures.
2. Women of reproductive age (18 to 49 years inclusive, according to World Health Organization criteria).
3. Verified diagnosis "healthy" (absence of abnormalities according to clinical, laboratory, instrumental methods of examination stipulated by the protocol).
4. Blood pressure (BP) level: systolic blood pressure (SBP) from 100 to 139 mmHg, diastolic blood pressure (DBP) from 60 to 89 mmHg (inclusive).
5. Heart rate (HR) from 60 to 90 bpm (inclusive).
6. Respiratory rate (HR) from 12 to 18 bpm (inclusive).
7. Body temperature of 36 to 36.9°C (inclusive).
8. Body mass index (BMI) is 18.5 ≤ BMI ≤ 30 kg/m2, and the body weight must be ≥ 45 kg.
9. Consent to use adequate methods of contraception throughout the study and for 30 days after completion, negative pregnancy test.
10. Volunteers must behave adequately, coherent speech must be observed.

Exclusion Criteria:

1. A history of allergic reactions.
2. Drug intolerance of active and/or excipients included in the study drugs in the anamnesis.
3. Chronic diseases of the cardiovascular, lymphatic, respiratory, nervous, endocrine, digestive, musculoskeletal, covering, immune systems, as well as of the urogenital system and hematopoietic organs.
4. Values of standard laboratory and instrumental indices beyond the limits of local laboratory norms.
5. History of gastrointestinal surgery (except appendectomy at least 1 year before screening).
6. Diseases/conditions that the investigator believes may affect the absorption, distribution, metabolism, or excretion of the study medication.
7. Acute infectious disease less than 4 weeks prior to screening.
8. Taking drugs that have a significant effect on hemodynamics and drugs that affect liver function (barbiturates, benzodiazepines, omeprazole, cimetidine, etc.) for less than one month before screening.
9. Regular intake of drugs less than 2 weeks before screening and one-time intake of drugs less than 7 days before screening.
10. Donating blood or plasma less than 3 months before the screening visit.
11. Use of hormonal contraceptives less than 2 months before the screening visit.
12. Using depot injections of any medications less than 3 months prior to the screening visit.
13. Pregnancy or lactation, positive pregnancy test.
14. Participation in another clinical trial less than 3 months before screening or concurrently with this study.
15. Taking more than 10 units of alcohol (1 unit of alcohol is equivalent to 330 ml of beer, 150 ml of wine, or 40 ml of spirits) in the week in the last month before inclusion in the study or anamnestic evidence of alcoholism, drug abuse, or medicine abuse.
16. Smoking.
17. Positive blood tests for antibodies to human immunodeficiency virus (HIV) type 1 and 2, antibodies to Treponema pallidum antigens, hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus antigens, laboratory examination of biomaterial (nasopharyngeal swab) for SARS-Cov-2 RNA (COVID-19).
18. Clinically significant abnormalities on electrocardiogram (ECG).
19. Positive urinalysis for narcotics and powerful drugs.
20. Positive breath alcohol vapor test.
21. Scheduling an inpatient stay during the study period, for any reason other than hospitalization required by this protocol.
22. Failure or inability to comply with protocol requirements, perform protocol-prescribed procedures, diet, and activity regimen.
23. Observance of a religious fast or special diet (e.g., vegetarian, vegan).
24. Other conditions that, in the opinion of the Investigator, preclude a volunteer from enrolling in the study or may result in early withdrawal from the study, including special lifestyles (night work, extreme physical activity).

Withdrawal criteria:

1. The volunteer's refusal to further participate in the study.
2. Failure of the volunteer to comply with the rules of participation in the study (skipping study procedures, independent use of drugs prohibited in the study, violation of dietary and lifestyle restrictions, etc.).
3. Occurrence of causes/occurrence during the study of situations that threaten the safety of the volunteer (e.g., hypersensitivity reactions, etc.).
4. Volunteers included in the study in violation of the inclusion/inclusion criteria.
5. Development of a severe and/or serious adverse event (AE) in a volunteer during the study.
6. Missing 2 or more consecutive blood samples or 3 or more blood samples during one Period of the pharmacokinetic portion of the study.
7. Occurrence of vomiting/diarrhea within 24 h of study drug administration (the choice of time interval is based on the tmax parameter value for doxylamine and pyridoxal-5-phosphate not exceeding 7.2 ± 1.9 and 11.7 ± 5.3 h, respectively, according to the manufacturer of the reference drug).
8. Positive urine test for narcotic substances and potent drugs.
9. Positive breath alcohol vapor test.
10. A positive pregnancy test.
11. Positive test for SARS-Cov-2 RNA (COVID-19);
12. Other causes occurring in the course of the study that prevent the study from being conducted according to the protocol.

Primary outcomes:
measure: Pharmacokinetics - Cmax (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - Cmax (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - tmax (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - tmax (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - AUC0-t (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - AUC0-t (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - AUC0-inf (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - AUC0-inf (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - AUCextr (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - AUCextr (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - t1/2 (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - t1/2 (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - kel (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - kel (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - MRT (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Pharmacokinetics - MRT (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Bioequivalence - ratio of Cmax (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Bioequivalence - ratio of Cmax (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Bioequivalence - ratio of AUC0-t (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Bioequivalence - ratio of AUC0-t (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Bioequivalence - ratio of AUC0-inf (Doxylamine)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
measure: Bioequivalence - ratio of AUC0-inf (Pyridoxal-5-phosphate)
timeFrame: From 0 to 72 hours (Day 1-4 and Day 22-25)
Secondary outcomes:
measure: Safety and Tolerability: adverse event (AE) number and frequency
timeFrame: From the screening (and signing informed consent form) to Day 29 of the study or to an early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: serious adverse event (SAE) number and frequency
timeFrame: From the screening (and signing informed consent form) to Day 29 of the study or to an early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: vital signs - systolic blood pressure (SBP)
timeFrame: Screening, from Day 0 to Day 4, from Day 21 to Day 25, and/or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: vital signs - diastolic blood pressure (DBP)
timeFrame: Screening, from Day 0 to Day 4, from Day 21 to Day 25, and/or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: vital signs - respiratory rate (RR)
timeFrame: Screening, from Day 0 to Day 4, from Day 21 to Day 25, and/or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: vital signs - heart rate (HR)
timeFrame: Screening, from Day 0 to Day 4, from Day 21 to Day 25, and/or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: vital signs - body temperature
timeFrame: Screening, from Day 0 to Day 4, from Day 21 to Day 25, and/or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: physical examination results
timeFrame: Screening, from Day 0 to Day 4, from Day 21 to Day 25, and/or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: 12-lead electrocardiogram (ECG) - heart rate
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: 12-lead electrocardiogram (ECG) - PQ interval
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: 12-lead electrocardiogram (ECG) - QRS complex
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: 12-lead electrocardiogram (ECG) - corrected QT interval (QTc)
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis - color
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis - transparency
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis - pH
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis - specific gravity
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis - protein
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis - glucose
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis (microscopy) - red blood cells
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis (microscopy) - white blood cells
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis (microscopy) - epithelial cells
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis (microscopy) - cylinders
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis (microscopy) - mucus
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: urinalysis (microscopy) - bacteria
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - hemoglobin
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - red blood cells
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - hematocrit
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - platelets
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - white blood cells
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - erythrocyte sedimentation rate
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - neutrophils
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - lymphocytes
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - eosinophils
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - monocytes
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: complete blood count - basophils
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - total protein
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - creatinine
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - glucose
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - total bilirubin
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - total cholesterol
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - alanine transaminase (ALT)
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - aspartate transaminase (AST)
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
measure: Safety and Tolerability: blood test results - alkaline phosphatase (ALP)
timeFrame: Screening, Day 4, Day 25 or on early termination visit within the time frame of the study (from Day 0 to Day 29)
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: Llc "Certa Clinic"
Study officials:
References: