Two-way Crossover, Single Dose Randomized, Two-stage Bioequivalence of Ketoprofen Lysine Salt Immediate Release vs Granules Oral Solution

Study Overview
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Brief Summary
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The present bioequivalence phase I study is needed to compare the bioavailability and the concentration-time profile of the new immediate release formulation of KLS 40 mg with the reference compound OKi®, ketoprofen lysine salt 80 mg granules for oral solution (bipartite sachets). The objective of the study is to investigate the bioequivalence between two formulations containing ketoprofen lysine salt (KLS) when administered as single oral dose in two consecutive study periods to healthy male and female volunteers under fasting conditions.

Detailed Description
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As a part of the Dompé extension line program, Dompé develops a new immediate release tablets formulation of ketoprofen lysine salt 40 mg. The new immediate release tablets formulation of KLS 40 mg (corresponding to 25 mg of ketoprofen free acid) is expected to be essentially similar to the formulations of ketoprofen 25 mg for oral administration, that are already available in the European Community with the same indications: pain such as episodic tension-type headache, dental pain, neuralgia, dysmenorrhoea, postpartum pain, muscular and osteoarticular pain. The objective of the study is to investigate the bioequivalence (Cmax and extent of absorption of ketoprofen after single dose administration)between two formulations containing ketoprofen lysine salt (KLS) when administered as single oral dose in two consecutive study periods to healthy male and female volunteers under fasting conditions. Furthermore, to collect safety and tolerability data after single dose administration of test and reference. Due to the lack of information about the PK profile of the new formulation it was not possible to calculate the sample size properly. For this reason it was decided to use a two stage bioequivalence study design. The sample size of 30 subjects is regarded as sufficient to satisfy the primary objective for the first stage of the study. After the end of study stage 1, PK parameters will be calculated and an ad interim bioequivalence test will be performed on the calculated PK parameters Cmax, AUC0-t and AUC0-∞. To safeguard the overall type I error, the Pocock spending function will be used to determine the α level of the bioequivalence test. Should bioequivalence be proven with the results of the subjects of the first stage and with an a posteriori calculated power of at least 80%, the primary objective of the study would then be satisfied and the second study stage will not take place. Should bioequivalence not be proven with the results of the subjects of the first stage or should it be proven with an a posteriori calculated power lower than 80%, the overall sample size for the study (stage 1 plus 2) will be calculated on the basis of the ad interim bioequivalence results. The Sponsor will decide whether the study has to continue or not. In the first case, the additional subjects will be enrolled into the second study stage. After completion of stage 2, the PK analysis and the bioequivalence test will be performed on the pooled subjects of the two study stages. The second stage will be performed after notification of the sample size to the local Ethics Committee and to the central Swiss authority (Swissmedic). An open design was chosen as it was considered adequate to evaluate objective measures such as pharmacokinetic parameters. All the personnel involved in the analytical determinations of the ketoprofen in the plasma samples withdrawn from the volunteers will be maintained in blinding. The sequence of treatments in the two study periods will be assigned to each randomised subject according to a computer generated randomisation list. A wash-out period of at least 4 days between the two administrations is justified by the elimination half-life of the ketoprofen (1-2 h).

Official Title
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Two-way Crossover, Randomised, Single Dose and Two-stage Bioequivalence Phase I Study of Ketoprofen Lysine Salt as Immediate Release Tablets Formulation (40 mg) Versus Ketoprofen Lysine Salt as Granules for Oral Solution (80 mg Bipartite Sachet, Half Sachet) After Oral Administration to Healthy Volunteers of Both Sexes

Conditions
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Pain Disorders

Intervention / Treatment
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* Drug: KSL 40 mg
* Drug: OKi® 80 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be enrolled in this study, subjects must fulfil all these criteria: Informed consent: signed written informed consent before inclusion in the study Sex and Age: males/females, 18-55 years old inclusive Body Mass Index (BMI): 18.5-30 kg/m2 inclusive Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, pulse rate (PR) 50-90 bpm and body temperature (BT) ≤ 37.5° C, measured after 5 min of rest in the sitting position; Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study Contraception and fertility (females only): females of child-bearing potential and with an active sexual life must be using at least one of the following reliable methods of contraception: Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit A male sexual partner who agrees to use a male condom with spermicide A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects, pregnancy test result must be negative at screening. Exclusion Criteria: Subjects meeting any of these criteria will not be enrolled in the study: Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness Allergy: ascertained or presumptive hypersensitivity to the active principles (ketoprofen) and/or formulations' ingredients; history of hypersensitivity to drugs (in particular to NSAIDs) or allergic reactions in general, which the Investigator considers may affect the outcome of the study Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory (including asthma), skin, haematological, endocrine or neurological and autoimmune diseases that may interfere with the aim of the study Medications: medications, including over the counter (OTC) drugs [in particular ketoprofen and acetylsalicylic acid (ASA) and NSAIDs in general], herbal remedies and food supplements taken 2 weeks before the start of the study. Hormonal contraceptives for females will be allowed Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study (date of the informed consent signature) Blood donation: blood donations for 3 months before this study Drug, alcohol, caffeine, tobacco: history of drug, alcohol [> 1 drink/day for females and > 2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010 (6)], caffeine (> 5 cups coffee/tea/day) or tobacco abuse (≥ 6 cigarettes/day) Drug test: positive result at the drug test at screening Alcohol test: positive alcohol breath test at day -1 Diet: abnormal diets (< 1600 or > 3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KSL 40 mg<br>Ketoprofen lysine salt (KLS) immediate release tablets 40 mg, corresponding to 25 mg of ketoprofen free acid | Drug: KSL 40 mg<br>* Ketoprofen lysine salt oral immediate release tablets 40 mg<br>|
| Active Comparator: OKi® 80 mg<br>OKi® 80 mg granules for oral solution (bipartite sachets: each half sachet containing 40 mg of KLS corresponding to 25 mg of ketoprofen free acid) | Drug: OKi® 80 mg<br>* Ketoprofen lysine salt granules for oral solution 40 mg (half of a bipartite sachet)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Cmax (0-8 hours)of ketoprofen calculated from plasma concentrations after single oral dose of test and reference | 8 hours | 
| AUC0-t | AUC0-t (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-∞ | AUC0-∞ (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference | 8 hours | 
| Tmax | Tmax (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference | 8 hours | 
| T1/2 | T1/2 (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference | 8 hours | 
| TEAES | Screening (From Day -14 to Day -2) - Treatment Emergent Adverse Events | Visit 1(From Day -14 to Day -2) | 
| TEAES | First Treatment period (Day -1) - Treatment Emergent Adverse Events | Visit 2(Day -1) | 
| TEAES | First Treatment period (Day 1) - Treatment Emergent Adverse Events | Visit 3 (Day 1) | 
| TEAES | Second Treatment period (Day -1) - Treatment Emergent Adverse Events | Visit 4 (Day -1) | 
| TEAES | Second Treatment period (Day 1) - Treatment Emergent Adverse Events | Visit 5 (Day 1) | 
| TEAES | Within 24 hours from Visit 5 - Treatment Emergent Adverse Events | Visit 6 9 (Within 24 hours from Visit 5) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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headache, dental pain, neuralgia, dysmenorrhoea, muscular and osteoarticular pain