To Assess the Bioavailability of TK-254RX in Comparison with Oral Flurbiprofen Tablets and the Adhesion of TK-254RX in Healthy Subjects

Characterization of Relative Bioavailability of a Newly Developed Esflurbiprofen Topical System (EFTS) in Comparison with a Marketed Oral Flurbiprofen-containing Tablet Formulation After Multiple-dose Administration Including EFTS Adhesion Assessment - a Phase I, Open-label, Randomized, 2-period, Cross-over Study in Healthy Subjects

This study is a single-center, open-label, multiple-dose trial performed in a 2-period, 2- sequence-cross-over design in healthy volunteers. The primary purpose of this study is to assess non-superiority of the bioavailability of TK-254RX compared with that of a marketed oral flurbiprofen-containing tablet formulation in healthy volunteers in a 2-period, 2- sequence-cross-over design and evaluate adhesion of TK-254RX. Secondary purpose is to assess safety of TK-254RX and residual amount of the patch.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Esflurbiprofen Topical System; Drug: Flurbiprofen tablet

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Erfurt
    • Mainzerhofplatz 14, Erfurt, Germany, 99084
      • SocraTec R&D GmbH Clinical Pharmacology Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• age: 18 years to 64 years (inclusive)
• body-mass index (BMI): ≥18.5 kg/m² and ≤ 30.0 kg/m²
• good state of health
• non-smoker or ex-smoker for at least 3 months
• 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 subjects participating in the clinical triall

Exclusion Criteria:

• existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient
• existing or history of hypertension and/or heart failure
• existing hepatic and/or renal diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient
• existing gastrointestinal diseases or pathological findings, which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient
• history of gastrointestinal bleeding or perforation related to previous NSAID therapy
• active, or history of ulcerative colitis, Crohn's disease, peptic ulceration or gastrointestinal haemorrhage
• existing metabolic, endocrine and/or immunologic diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient
• diabetes mellitus
• hyperlipidaemia (LDL > 4.16 mmol/l, HDL < 0.91 mmol/l, triglycerides > 2.28 mmol/l, cholesterol > 6.24 mmol/l)
• history of relevant CNS and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders
• presence or history of acute or chronic diseases of the skin (e.g., atopic dermatitis (eczema), neurodermatitis, contact allergy, psoriasis, vitiligo, melanoma, squamous cell carcinoma), any dermatological condition or skin sensitivity which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient
• existing or history of bronchial asthma
• known allergic reactions (e.g., bronchospasm, rhinitis, angioedema, or urticaria) to the active ingredients used, to acetylsalicylic acid or other NSAIDs, or to constituents of the pharmaceutical preparations
• history of severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
• fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency
• galactose intolerance or Lapp lactase deficiency
• systolic blood pressure < 90 or > 139 mmHg
• diastolic blood pressure < 60 or > 89 mmHg
• heart rate < 50 bpm or > 90 bpm
• QTc interval > 450 ms for men and > 470 ms for women
• laboratory values out of normal range unless the deviation from normal is judged as not relevant for the clinical trial by the investigator
• ASAT > 20% ULN, ALAT > 10% ULN, bilirubin > 20% ULN (except in case of existing Morbus Gilbert-Meulengracht deduced from anamnesis/medical history) and creatinine > 0.1 mg/dL ULN (limit of > 0.1 mg/dL correspondents to > 9 µmol/l ULN)
• positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test or anti-HCV-test
• vaccination against COVID-19 within the last 4 weeks prior to individual intended IMP administration
• skin abnormality (e.g., tattoo (including tattoo that was removed), scar, sunburn, or obvious difference in skin colour), open sores, or excessive hair at the application sites
• acute or chronic diseases which may interfere with the pharmacokinetics of the IMP
• history of or current drug or alcohol dependence
• positive alcohol or drug test at screening examination
• regular intake of alcoholic food or beverages of ≥ 24 g pure ethanol for male or ≥ 12 g pure ethanol for female per day
• subjects who are on a diet which could affect the pharmacokinetics of the active ingredient
• regular intake of caffeine containing food or beverages of ≥ 500 mg caffeine per day
• blood donation or other blood loss of more than 400 ml within the last 2 months prior to individual enrolment of the subject
• participation in a clinical trial with administration of any investigational medicinal product during the last 2 months prior to individual enrolment of the subject
• simultaneous participation in another clinical trial with active ingredients
• regular treatment with any systemically available medication (except sexual and thyroid hormones)
• subjects, who report a frequent occurrence of migraine attacks
• positive pregnancy test at screening examination
• pregnant or lactating women
• female subjects who do not agree to apply highly effective contraceptive methods (highly effective contraceptive methods)
• subject is vulnerable such as detained or committed to an institution by a court of law or by legal authorities or close affiliation with the sponsor or the investigational site (e.g., a close relative of the investigator, dependent person (e.g., employee of or student at the investigational site), employee of the sponsor or affiliates)
• subject suspected or known not to follow instructions
• subjects 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TK-254RX; TK-254RX will be applied to left and right lower leg above ankle once daily over 5 consecutive days i.e. 10 patches will be applied totally.	Drug: Esflurbiprofen Topical System; The total of two TK-254RX per day for 5 days (one patch applied to left and right lower leg above ankle)
Experimental: Tablet (reference product); Tablets containing 100mg flurbiprofen will be administered three times daily (every 8 h) over 4 consecutive days i.e. 12 tablets will be administered totally.	Drug: Flurbiprofen tablet; 3 tablets per day for 4 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration versus time curve over 24 hours of S-flurbiprofen for TK-254RX and tablet under steady-state conditions		Day 5 to Day 6
Peak Plasma Concentration of S-flurbiprofen for TK-254RX and tablet under steady-state conditions		Day 5 to Day 6
Characterization of patch adhesion	Measuring patch adhesion area by percentage of visually by site staff with remaining patch adhered	Day 1 to Day 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration versus time curve over 24 hours of S-flurbiprofen for TK-254RX on Day 1		Day 1 to Day 2
Peak Plasma Concentration of S-flurbiprofen for TK-254RX on Day 1		Day 1 to Day 2
Time to reach Peak Plasma Concentration of TK-254RX after the first two patches application on Day 1		Day 1
Time before first concentration value above the lower limit of quantitation of TK-254RX after the first two patches application on Day 1		Day 1
Trough concentration of TK-254RX	minimum concentration at the end of each dosing	24 hours, 48 hours, 72 hours, 96 hours, 120 hours after first TK-254RX application
Trough concentration of tablet	minimum concentration at the end of each dosing	24 hours, 48 hours, 72 hours, 96 hours after first tablet application
Area under the plasma concentration versus time curve of R- flurbiprofen and metabolites from the last two TK-254RX application to the time point of 24 hours under steady condition		Day 5
Peak Plasma Concentration of R-flurbiprofen and metabolites under steady condition		Day 5
Minimum plasma concentration of TK-254RX under steady condition		Day 5
Time to reach Peak Plasma Concentration of TK-254RX under steady condition		Day 5
Percentage of peak trough fluction of TK-254RX under steady condition		Day 5
Average concentration at time points on Day 5 under steady condition		Day 5
Area under the plasma concentration versus time curve from the last two TK-254RX application to last measurement time point with a concentration value above lower limit of quantitation		Day 5 to Day 8
Percentage of area under the plasma concentration versus time curve extrapolated to infinity to area under the plasma concentration versus time curve from 0 hour to infinity of the last TK-254RX application		Day 5 to Day 8
Area under the plasma concentration versus time curve from 0 hour to infinity of the last TK-254RX application		Day 5 to Day 8
Concentration at the last time point with concentration value above the lower limit of quantitation of the last TK-254RX application		Day 5 to Day 8
Last time point with concentration value above the lower limit of quantitation of the last TK-254RX application		Day 5 to Day 8
Apparent terminal elimination half-life of TK-254RX		Day 5 to Day 8
Apparent terminal elimination rate constant determined by log-linear regression of TK-254RX		Day 5 to Day 8
Area under the plasma concentration versus time curve of R-flurbiprofen and metabolites over 24 hours under steady condition		Day 4 to Day 7
Peak plasma concentration of R-flurbiprofen and metabolites of tablet under steady condition		Day 4 to Day 7
Minimum plasma concentration of tablet under steady condition		Day 4 to Day 7
Time to reach Peak Plasma Concentration of tablet under steady condition		Day 4 to Day 7
Percentage of peak trough fluction of tablet under steady condition		Day 4 to Day 7
Average concentration at time points of tablet under steady condition		Day 4 to Day 7
Area under the plasma concentration versus time curve from the first tablet administration on day 4 to last measurement time point with a concentration value above lower limit of quantitation		Day 4 to Day 7
Area under the plasma concentration versus time curve from 0 hour to infinity of tablet of administration on 4th day		Day 4 to Day 7
Percentage of area under the plasma concentration versus time curve extrapolated to infinity to area under the plasma concentration versus time curve from 0 hour to infinity of tablet of administration on 4th day		Day 4 to Day 7
Concentration at the last time point with concentration value above the lower limit of quantitation of tablet of administration on 4th day		Day 4 to Day 7
Last time point with concentration value above the lower limit of quantitation of tablet of administration on 4th day		Day 4 to Day 7
Apparent terminal elimination half-life of tablet		Day 4 to Day 7
Apparent terminal elimination rate constant determined by log-linear regression of tablet		Day 4 to Day 7
Local tolerability	Assessing the local tolerability by using the 8-point dermal response and other effects score according to FDA recommendation	within 5 min after removal of each patch as well as 12 h, 24 h, and 36 h after removal of the last 2 patches on study Day 6
Residual amount of S-flurbiprofen	residual amount of S-flurbiprofen in used patch applied on Day 5	Day 5 to Day 6

Collaborators and Investigators

• Sponsor: Teikoku Seiyaku Co., Ltd.
• Collaborators: SocraTec R&D GmbH; SocraMetrics GmbH; HWI pharma services GmbH
• Investigators: Study Chair: Kenichi Nishiyama, Teikoku Seiyaku Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2025
• Primary Completion (Actual): February 12, 2025
• Study Completion (Actual): February 24, 2025

Study Registration Dates

• First Submitted: January 19, 2025
• First Submitted That Met QC Criteria: February 6, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 6, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cicatrix; Fibrosis; Tissue Adhesions; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Flurbiprofen
• Other Study ID Numbers: TK-254RX-0102; 2024-513058-31-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No