A Phase 1 interventional study of KSL 40 mg and OKi® 80 mg in Pain Disorders, sponsored by Dompé Farmaceutici S.p.A. Completed at 1 site in Switzerland. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-04-19.
Sponsored by Dompé Farmaceutici S.p.A · Phase 1, Interventional, and Basic science
Objectives:
The objective of the study was to investigate the bioequivalence between two formulations containing ketoprofen lysine salt (KLS) when administered as single oral doses in two consecutive study periods to healthy male and female volunteers under fasting conditions.
Primary end-point: to evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of ketoprofen after single dose administration of test and reference products.
Secondary end-points:
This was a single centre, single dose, open, randomised, two-way cross-over, two-stage bioequivalence study. According to the two-stage design of the study, an initial group of subjects was treated in study stage 1 and data were analysed. Since bioequivalence was demonstrated, according to the protocol the study was terminated after stage 1, and stage 2 was not performed.
The study was conducted as planned and consisted of a screening visit, a treatment phase of 2 study periods separated by a wash-out interval of at least 4 days and a final visit / early termination visit (ETV).
Considering the lack of information about the PK profile of the new formulation, it was decided to use a "two stage" bioequivalence study design, that allows a re-calculation of the sample size in case the number of subjects initially enrolled in the study is not large enough to provide a reliable answer to the questions addressed, due to a possible underestimation of the variability or misleading estimation of the point estimate for the test/reference ratio of the geometric means.
The sequence of treatments in the two study periods was 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).
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To be enrolled in this study, subjects must fulfil all these criteria:
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:
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:
In this arm, a single dose of the test product (1 tablet; 40 mg KLS) was orally administered, under fasting conditions, in the first study period (day 1, 08:00±1h), and, after a wash-out period of at least 4 days, a single dose of the reference product OKi® 80 mg (half a sachet, 40 mg KLS) was orally administered, under fasting conditions, in the second study period (day 1, Visit 5, 08:00 ±1h).
Drug: KSL 40 mg · Drug: OKi® 80 mg
In this arm, a single dose of the reference product OKi® 80 mg (half a sachet, 40 mg KLS) was orally administered, under fasting conditions, in the first study period (day 1, Visit 3, 08:00 ±1h) and, after a wash-out period of at least 4 days, a single dose of the test product (1 tablet; 40 mg KLS) was orally administered, under fasting conditions, in the second study period (day 1, Visit 5, 08:00±1h).
Drug: KSL 40 mg · Drug: OKi® 80 mg
Ketoprofen lysine salt (KLS) immediate release oral tablets 40 mg, corresponding to 25 mg of ketoprofen free acid. Ketoprofen lysine salt was administered according to the randomisation list and the cross-over design. One (1) tablet of test formulation was administered to the subjects in the morning with 240 mL of still mineral water. Afterwards, no fluid intake was permitted for 2 h. All subjects were under fasting conditions from the evening before investigational product administration (i.e. for at least 10 h, overnight).
Also known as: Ketoprofen lysine salt
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). Ketoprofen lysine salt was administered according to the randomisation list and the cross-over design. The content of half sachet of the reference formulation was dissolved in 190 mL of still mineral water. The subject drank the entire solution immediately. Then the glass was rinsed with 50 mL of still mineral water and the subject drank the rinse immediately. Afterwards, no fluid intake was permitted for 2 h. All subjects were under fasting conditions from the evening before investigational product administration (i.e. for at least 10 h, overnight).
Also known as: Ketoprofen lysine salt
Ketoprofen Plasma PK Parameters: Cmax
Cmax = maximum plasma concentration. Cmax a of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder.
Time frame: 0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose
Ketoprofen Plasma PK Parameters: AUC0-t
AUC0-t = Area under the concentration-time curve from administration to the last observed concentration time t, calculated with the linear trapezoidal method. AUC0-t of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder specified. Please note that AUC0-t was considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0-∞ equalled or exceeded a factor of 0.8, i.e. if %AUCextra was \< 20%. Arithmetic means + standard deviation are reported hereunder.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Ketoprofen Plasma PK Parameters: AUC0-∞
AUC0-∞ = Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. AUC0-∞ of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose
Ketoprofen Plasma PK Parameters: Tmax
Tmax = Time to achieve Cmax. Tmax (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Ketoprofen Plasma PK Parameters: T1/2
T1/2 = Half-life, calculated, if feasible, as ln2/λz. T1/2 (0-8 hours) of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Ketoprofen Plasma PK Parameters: Frel
Frel = Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
Time frame: 0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose
Number of TEAEs
TEAE = Treatment Emergent Adverse Events. TEAEs were assessed throughout the study, from informed consent up to the final visit / early termination visit (ETV), which takes place after visit 5 on day 1 of period 2, more precisely after the 8 h blood sampling and vital signs check.
Time frame: From Day -14 to Day 1 of period 2 (Final visit/ETV), approximately 1 month
30 healthy volunteers were randomized, receiving a single dose of Test and Reference treatment. Based on the cross-over design, a single dose of product was given orally in one of the two possible sequences: in the "test-reference" arm, subjects received Ketoprofen lysine salt (KLS) firstly and then the reference product OKI. In the "Reference-Test" arm, subjects received reference product OKi first, then Ketoprofen lysine salt (KLS)"). A wash-out interval separated the 2 treatment periods.
| Milestone | Sequence "Test - Reference" | Sequence "Reference - Test" |
|---|---|---|
| Started | 15 | 15 |
| Completed | 15 | 15 |
| Not completed | 0 | 0 |
| Milestone | Sequence "Test - Reference" | Sequence "Reference - Test" |
|---|---|---|
| Started | 15 | 15 |
| Completed | 15 | 15 |
| Not completed | 0 | 0 |
| Milestone | Sequence "Test - Reference" | Sequence "Reference - Test" |
|---|---|---|
| Started | 15 | 15 |
| Completed | 15 | 15 |
| Not completed | 0 | 0 |
Cmax = maximum plasma concentration. Cmax a of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder.
| μg/mL | KSL 40 mg (Test Product) | OKi® 80 mg (Reference Product) |
|---|---|---|
| Ketoprofen Plasma PK Parameters: Cmax | 3.61 ± 1.17 | 3.40 ± 1.38 |
AUC0-t = Area under the concentration-time curve from administration to the last observed concentration time t, calculated with the linear trapezoidal method. AUC0-t of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder specified. Please note that AUC0-t was considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0-∞ equalled or exceeded a factor of 0.8, i.e. if %AUCextra was \< 20%. Arithmetic means + standard deviation are reported hereunder.
| h*μg/mL | KSL 40 mg | OKi® 80 mg |
|---|---|---|
| Ketoprofen Plasma PK Parameters: AUC0-t | 4.53 ± 1.35 | 4.12 ± 1.35 |
AUC0-∞ = Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. AUC0-∞ of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder.
| h*μg/mL | KSL 40 mg | OKi® 80 mg |
|---|---|---|
| Ketoprofen Plasma PK Parameters: AUC0-∞ | 4.64 ± 1.40 | 4.22 ± 1.39 |
Tmax = Time to achieve Cmax. Tmax (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
| h | KSL 40 mg | OKi® 80 mg |
|---|---|---|
| Ketoprofen Plasma PK Parameters: Tmax | 0.39 ± 0.19 | 0.30 ± 0.10 |
T1/2 = Half-life, calculated, if feasible, as ln2/λz. T1/2 (0-8 hours) of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
| h | KSL 40 mg | OKi® 80 mg |
|---|---|---|
| Ketoprofen Plasma PK Parameters: T1/2 | 1.64 ± 0.17 | 1.64 ± 0.17 |
Frel = Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
| % of bioavailability | All Participants |
|---|---|
| Ketoprofen Plasma PK Parameters: Frel | 112.07 ± 18.70 |
TEAE = Treatment Emergent Adverse Events. TEAEs were assessed throughout the study, from informed consent up to the final visit / early termination visit (ETV), which takes place after visit 5 on day 1 of period 2, more precisely after the 8 h blood sampling and vital signs check.
| number of events | KSL 40 mg (Test Product) | OKi® 80 mg (Reference Product) |
|---|---|---|
| TEAE related to treatment | 1 | 2 |
| TEAE not related to treatment | 0 | 0 |
| mild | 1 | 2 |
| moderate | 0 | 0 |
| severe | 0 | 0 |
| TEAE leading to discontinuation | 0 | 0 |
| serious TEAE | 0 | 0 |
Collected over TEAEs were assessed throughout the study, from informed consent up to the final visit / early termination visit (ETV), which takes place after visit 5 on day 1 of period 2, more precisely after the 8 h blood sampling and vital signs check. From Day -14 to Day 1 of period 2 (Final visit/ETV), approximately 1 month.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| KSL 40 mg | 0/30 (0%) | 0/30 (0%) | 1/30 (3.3%) |
| OKi® 80 mg | 0/30 (0%) | 0/30 (0%) | 2/30 (6.7%) |
| Event | KSL 40 mg | OKi® 80 mg |
|---|---|---|
| DizzinessNervous system disorders | 1/30 | 1/30 |
| HeadacheNervous system disorders | 0/30 | 1/30 |
The 30 randomised subjects completed the study per protocol and were included in the PK and Safety sets.
| Age, Categorical(Participants) | All Study Participants |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 30 |
| >=65 years | 0 |
| Age, Continuous(years) | All Study Participants |
|---|---|
| Mean | 38.7 ± 8.2 |
| Sex: Female, Male(Participants) | All Study Participants |
|---|---|
| Female | 15 |
| Male | 15 |
| Race (NIH/OMB)(Participants) | All Study Participants |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 30 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | All Study Participants |
|---|---|
| Switzerland | 30 |
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Dompé Farmaceutici S.p.A