Fever, Pain
Conditions
Brief summary
This study aims to evaluate the bioequivalence of new formulated orodispersible tablet (ODT) containing 500 milligram (mg) paracetamol in comparison to the European marketed Alvedon (paracetamol) 500 mg film-coated tablets and the Australian marketed Panadol (paracetamol) 500 mg film-coated tablets as reference products.
Detailed description
This will be a single center, open-label, randomized (order of treatments), balanced, 3-period, 3-sequence, single dose, change-over trial with oral administration under fasting conditions separated by a washout period of at least 72 hours. Fifty-four healthy participants of both sexes (27 male, 27 female) are intended to be randomized to obtain 42 evaluable participants. The investigational products will be administered in fasted state as single oral doses of 500 mg paracetamol tablet. 1 tablet of test and 1 film-coated tablet of reference 1 and 1 film-coated tablet of reference 2 will be administered in a cross-over manner. Blood sampling will be performed over 24-hour post dose in order to characterize pharmacokinetic parameters.
Interventions
DRUGParacetamol ODT
Experimental Paracetamol 500 mg ODT
DRUGAlvedon film-coated tablet
Marketed Paracetamol 500 mg film-coated tablet
DRUGPanadol film-coated Tablet
Marketed Paracetamol 500 mg film-coated tablet
Sponsors
HALEON
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the participants participating in the clinical trial. * Sex: male/female. * Age: 18 to 55 years (including) * Body-mass index (BMI): more than or equal to (\>=)18.5 kilogram per meter square (kg/m\^2) and less than or equal to (\<=) 30.0 kg/m\^2. * Body weight: \>= 50.0 kg for males and \>= 45.0 kg for females. * Good state of health. * Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. * Female participant of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 7 days after the last dose of assigned treatment. * Non-smoker or ex-smoker for at least 3 months (including non-nicotine vapers, nicotine chewing gum or pouches or nicotine replacement therapy).
Exclusion criteria
* Safety Concerns 1. Existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient. 2. Existing renal diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient. 3. Current evidence of ongoing hepatic disease or impaired hepatic function at screening. A participant will be excluded if more than one of the following lab value deviations are found: 1) Aspartate aminotransferase (AST) (\>= 1.2 upper limit of normal \[ULN\]), Alanine transaminase (ALT) (\>= 1.2 ULN), 2) Gamma-glutamyl transferase (GGT) (\>= 1.2 ULN), Alkaline phosphatase (ALP) (\>= 1.2 ULN), 3) total bilirubin (greater than \[\>\] 2.00 milligrams per deciliter (mg/dL), except in case of existing Morbus Gilbert-Meulengracht deduced from anamnesis/medical history) or creatine kinase (\>= 3 ULN), and creatinine \> 0.1 mg/dL ULN (limit of \> 0.1 mg/dL correspondents to of \> 9 micromole per liter \[μmol/l\] ULN). A single deviation from the above values is acceptable and will not exclude the candidate, unless specifically advised by the investigator. 4. Existing gastrointestinal diseases or pathological findings, which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient. 5. History of relevant central nervous system (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders. 6. History or clinical evidence at screening of pancreatic injury or pancreatitis. 7. History of inflammatory bowel disease or gastrointestinal bleeding including peptic ulcers. 8. Diagnosis of systemic lupus erythematosus, thyroid diseases, secondary Raynaud's syndrome; known hyperkalemia. 9. Evidence of urinary obstruction (example, due to benign prostate hyperplasia) or difficulty in voiding at screening. 10. Status of glutathione depletion (eating disorder, cystic fibrosis, human immunodeficiency virus \[HIV\] infection, starvation, cachexia) due to metabolic deficiencies. 11. Oral surgery within 4 weeks of dosing, dental work or extractions within 2 weeks of dosing, or presence of any clinically significant (as determined by the principal investigator or designee) oral pathology including lesions, sores or inflammation. 12. History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling or gastric banding (note: this is not applicable for minor abdominal surgery without significant tissue resection, example, appendectomy and herniorrhaphy). 13. Participants, who report a frequent occurrence of migraine attacks. 14. Acute or chronic diseases which may interfere with the pharmacokinetics of the investigational medicinal product (IMP). 15. Clinically relevant chronic or acute infectious illnesses or febrile infections within two weeks prior to start of the study. 16. History or current evidence of renal disease or impaired renal function at screening as indicated by abnormal levels of serum creatinine (\> 1.43 mg/dL) or blood urea nitrogen (BUN) (\>= 35 mg/dL) or the presence of clinically significant abnormal urinary constituents (example, albuminuria). 17. Systolic blood pressure less than (\<) 90 or \> 139 millimeter of mercury (mmHg). 18. Diastolic blood pressure \< 50 or \> 89 mmHg. 19. Heart rate \< 50 beats per minute (bpm) or \> 90 bpm. 20. Corrected QT interval (QTc) interval \> 450 milliseconds (ms) for men and \> 470 ms for women. 21. Hemoglobin value \< 12.0 grams per deciliter (g/dL) for males and \< 11.5 g/dL for females. 22. Evidence or history of medication overuse headache, or allergic disease to medication within the last 5 years that may increase the risk associated with study participation. 23. Laboratory values out of normal range unless the deviation from normal is judged as not relevant for the clinical trial by the investigator. 24. Positive anti-HIV-test (if positive to be verified by western blot), hepatitis B surface antigen (HBs-AG) test and anti-hepatitis B core immunoglobulin M (HBc IgM) or anti-hepatitis C virus (HCV) test. 25. Known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations. 26. Any history of asthma, urticaria, or other significant allergic diathesis or allergic reaction to any other pain reliever/fever reducer. Participant with uncomplicated seasonal allergic rhinitis can be accepted if expected allergy season is clearly outside enrollment/treatment period. 27. History of severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator. * Lack of suitability for the clinical trial 1. History of illegal or legal drug abuse within 1 year prior to screening or recreational use of soft drugs (such as marijuana, codeine) within 1 month or hard drugs (such as cocaine, phencyclidine \[PCP\], crack, any opioid derivatives such as heroin or fentanyl, and amphetamine derivatives) within 3 months prior to screening. 2. Positive alcohol, cotinine or drug test at screening examination. 3. History of alcohol abuse in the last 5 years or regular intake of alcoholic food or beverages of \>= 24 gram (g) pure ethanol for men or \>= 12 g pure ethanol for women per day. 4. Participants who are on a diet which could affect the pharmacokinetics of the active ingredient. 5. Regular intake of beverages or food containing xanthine derivatives or xanthine-related compounds (example, coffee, tea, caffeine-containing sodas and chocolate), equivalent to \>= 500 milligram (mg) xanthine per day. 6. Performance of strenuous physical exercise (body building, high performance sports) from 2 weeks prior to admission and throughout the entire study. 7. Participant reports consumption of any drug metabolizing enzyme (example, Cytochrome P450 3A4 (CYP3A4) or other cytochrome P450 enzymes) inducing or inhibiting aliments, beverages or food supplements (example, broccoli, Brussels sprouts, grapefruit, grapefruit juice, star fruit, St. John's Wort and so on) within 2 weeks prior to admission to the unit. 8. Use of any systemic or topical medication (including over the counter \[OTC\] medications, herbal remedies, cannabidiol cosmetics and any anticholinergic medicines or other medicines that may cause dry mouth) within 2 weeks or within less than 10 times the elimination half-life of the respective drug (whichever is longer) before first scheduled study drug administration, or is anticipated to require any concomitant medication during that period or at any time throughout the study. 9. Any history of long-term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes. 10. Any vaccination, including Coronavirus disease (COVID)-19 vaccine, within 14 days prior to the first dose. 11. Donation of plasma within 7 days prior to dosing or donation or loss of 500 milliliter (mL) or more of whole blood within 8 weeks prior to dosing. 12. Participation in a clinical trial in which they have tried an IMP, a medical device or a marketed medicinal product during the last 6 months prior to individual enrolment of the participant. 13. Simultaneous participation in another clinical trial with active ingredients, medical devices or marketed medicinal products. * For female participants with childbearing potential only 1. Positive pregnancy test at screening examination. 2. Pregnant or lactating women. 3. Female participants who do not agree to apply highly effective contraceptive methods. * Administrative reasons 1. Close affiliation with the sponsor or the investigational site; example, a close relative of the investigator, dependent person (example, employee of or student at the investigational site), employee of the sponsor or affiliates. 2. Participants who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tlast for Paracetamol ODT (Test) vs. Paracetamol (Panadol Film-coated Tablet) (Reference 2) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUC0-tlast was defined as area under the concentration vs. time curve from dosing time to the last measurement time point with a concentration value above the lower limit of quantitation, calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations. Blood samples were collected at indicated timepoints for the analysis of AUC0-tlast). PK parameters were determined by non-compartmental analysis. |
| Tmax for Paracetamol ODT (Test) vs. Paracetamol (Panadol Film-coated Tablet) (Reference 2) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | Blood samples were collected at indicated timepoints for the analysis of tmax. PK parameters were determined by non-compartmental analysis. |
| Cmax for Paracetamol ODT (Test) vs. Paracetamol (Panadol Film-coated Tablet) (Reference 2) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | Cmax was defined as maximum observed post-dose plasma concentration for paracetamol. Blood samples were collected at indicated timepoints for the analysis of Cmax. PK parameters were determined by non-compartmental analysis. |
| Maximum Observed Concentration (Cmax) for Paracetamol ODT (Test) Versus (vs.) Paracetamol (Alvedon Film-coated Tablet) (Reference 1) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | Cmax was defined as maximum observed post-dose plasma concentration for paracetamol. Blood samples were collected at indicated timepoints for the analysis of Cmax. Pharmacokinetic (PK) parameters were determined by non-compartmental analysis. |
| Area Under the Concentration vs. Time Curve From Dosing Time to the Last Measurement Time Point (AUC0-tlast) for Paracetamol ODT (Test) vs. Paracetamol (Alvedon Film-coated Tablet) (Reference 1) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUC0-tlast was defined as area under the concentration vs. time curve from dosing time to the last measurement time point with a concentration value above the lower limit of quantitation, calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations). Blood samples were collected at indicated timepoints for the analysis of AUC0-tlast. PK parameters were determined by non-compartmental analysis. |
| Time to Reach Maximum Concentration (Tmax) for Paracetamol ODT (Test) vs. Paracetamol (Alvedon Film-coated Tablet) (Reference 1) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | Blood samples were collected at indicated timepoints for the analysis of tmax. PK parameters were determined by non-compartmental analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-inf) for Paracetamol (Panadol Film-coated Tablet) (Reference 2) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUC (0-inf)= AUC0-tlast + AUCexpol, where AUCexpol = Clast/Lz, where Clast was observed concentration at the last time point with a concentration value above the lower limit of quantitation, directly taken from measured concentration values and Lz was apparent terminal elimination rate constant determined by log-linear regression; the regression generally involved at least 3 consecutive measurable concentrations that decreased over time. Blood samples were collected at indicated timepoints for the analysis of AUC (0-inf). PK parameters were determined by non-compartmental analysis. |
| AUCexpol% for Paracetamol ODT (Test) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUCexpol%= AUCexpol multiplied by (\*)100/AUC0-inf, where AUCexpol = Clast/Lz. Blood samples were collected at indicated timepoints for the analysis of AUCexpol%. PK parameters were determined by non-compartmental analysis. |
| AUCexpol% for Paracetamol (Alvedon Film-coated Tablet) (Reference 1) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUCexpol%= AUCexpol\*100/AUC0-inf, where AUCexpol = Clast/Lz. Blood samples were collected at indicated timepoints for the analysis of AUCexpol%. PK parameters were determined by non-compartmental analysis. |
| AUCexpol% for Paracetamol (Panadol Film-coated Tablet) (Reference 2) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUCexpol%= AUCexpol\*100/AUC0-inf, where AUCexpol = Clast/Lz. Blood samples were collected at indicated timepoints for the analysis of AUCexpol%. PK parameters were determined by non-compartmental analysis. |
| Lz for Paracetamol ODT (Test) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | Lz was an apparent terminal elimination rate constant determined by log-linear regression; the regression generally involved at least 3 consecutive measurable concentrations that decreased over time. Blood samples were collected at indicated timepoints for the analysis of Lz. PK parameters were determined by non-compartmental analysis. |
| Lz for Paracetamol (Alvedon Film-coated Tablet) (Reference 1) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | Lz was an apparent terminal elimination rate constant determined by log-linear regression; the regression generally involved at least 3 consecutive measurable concentrations that decreased over time. Blood samples were collected at indicated timepoints for the analysis of Lz. PK parameters were determined by non-compartmental analysis. |
| Lz for Paracetamol (Panadol Film-coated Tablet) (Reference 2) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | Lz was an apparent terminal elimination rate constant determined by log-linear regression; the regression generally involved at least 3 consecutive measurable concentrations that decreased over time. Blood samples were collected at indicated timepoints for the analysis of Lz. PK parameters were determined by non-compartmental analysis. |
| Apparent Terminal Elimination Half-life (t1/2) for Paracetamol ODT (Test) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | t1/2 = ln(2) / Lz. Blood samples were collected at indicated timepoints for the analysis of t1/2. PK parameters were determined by non-compartmental analysis. |
| t1/2 for Paracetamol (Alvedon Film-coated Tablet) (Reference 1) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | t1/2 = ln(2) / Lz. Blood samples were collected at indicated timepoints for the analysis of t1/2. PK parameters were determined by non-compartmental analysis. |
| t1/2 for Paracetamol (Panadol Film-coated Tablet) (Reference 2) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | t1/2 = ln(2) / Lz. Blood samples were collected at indicated timepoints for the analysis of t1/2. PK parameters were determined by non-compartmental analysis. |
| Area Under the Plasma Concentration vs. Time Curve Calculated From Time Zero to Infinity [AUC (0-inf)] for Paracetamol ODT (Test) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUC (0-inf) equal to(=) AUC0-tlast addition(+) AUCexpol, where AUCexpol = Clast/Lz, where Clast was observed concentration at the last time point with a concentration value above the lower limit of quantitation, directly taken from measured concentration values and Lz was apparent terminal elimination rate constant determined by log-linear regression(Lz); the regression generally involved at least 3 consecutive measurable concentrations that decreased over time. Blood samples were collected at indicated timepoints for the analysis of AUC (0-inf). PK parameters were determined by non-compartmental analysis. |
| AUC (0-inf) for Paracetamol (Alvedon Film-coated Tablet) (Reference 1) | Within one hour prior to dosing, at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 90, 120, 150, 180 minutes and at 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours following dosing in each treatment period | AUC (0-inf)= AUC0-tlast + AUCexpol, where AUCexpol = Clast/Lz, where Clast was observed concentration at the last time point with a concentration value above the lower limit of quantitation, directly taken from measured concentration values and Lz was apparent terminal elimination rate constant determined by log-linear regression; the regression generally involved at least 3 consecutive measurable concentrations that decreased over time. Blood samples were collected at indicated timepoints for the analysis of AUC (0-inf). PK parameters were determined by non-compartmental analysis. |
Countries
Germany
Participant flow
Recruitment details
This study was conducted at a single center in Germany.
Pre-assignment details
A total of 54 participants were enrolled and randomized to treatment groups. A total of 52 randomized participants subsequently completed the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 53 | 0 / 53 |
| other Total, other adverse events | 12 / 53 | 16 / 53 | 9 / 53 |
| serious Total, serious adverse events | 0 / 53 | 0 / 53 | 0 / 53 |
Outcome results
None listed