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| Name | Class |
|---|---|
| Cross Research S.A. | INDUSTRY |
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To evaluate if a single dose of safinamide 200 mg has an effect on the pharmacokinetics of diclofenamic acid, concomitantly administered as a single 50 mg diclofenac sodium dose, with respect to 50 mg diclofenac sodium administered alone.
According to Xadago™ SmPC, safinamide may transiently inhibit BCRP, therefore a time interval of 5 h should be kept between dosing of safinamide and medicinal products that are BCRP substrates with a Tmax ≤2 h (e.g. diclofenac, pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan or glyburide).
Following a specific request of EMA CHMP, the present interaction study in healthy male and female volunteers was conducted to determine if co-administration of safinamide with a BCRP substrate alters plasma exposure of the BCRP substrate in vivo.
Diclofenac was chosen among the other BCRP substrates considering its large use in the general population. Diclofenac in fact is an important analgesic and anti-inflammatory drug, widely used for the treatment of postoperative pain, rheumatoid arthritis, and chronic pain. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur.
Voltaren®, 50 mg soluble tablets, was selected among other possible diclofenac products because with this formulation peak concentration of diclofenamic acid is achieved at approximately 1 h, i.e. in less than 2 h.
The present interaction study was designed in agreement with the FDA Guideline on Drug Interaction studies, taking also in consideration the EMA guideline on the Investigation of drug interactions.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Diclofenac sodium | Experimental | Diclofenac sodium 50 mg oral tablets, single dose |
|
| Diclofenac sodium and safinamide | Active Comparator | Diclofenac sodium 50 mg oral tablets, single dose, and safinamide 200 mg oral tablets, single dose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Diclofenac sodium | Drug | Diclofenac sodium 50 mg single dose |
|
| Measure | Description | Time Frame |
|---|---|---|
| To Evaluate Plasma Diclofenamic Acid Extent of Exposure Reported as Plasma AUC After Single Administration of 50 mg Diclofenac Sodium, With and Without Co-administration of a Single 200 mg Dose of Safinamide. | Plasma diclofenamic acid AUC0-t after T2 single dose, with and without T1 co-administration. To measure AUC plasma samples were taken by the participants at different time points, and the concentrations of diclofenac and safinamide were measured. AUC0-t is the area under the concentration-time curve from administration to the last observed concentration time t; PK parameters AUC0-t were analysed using analysis of variance (ANOVA). Before analysis, the data were transformed using a neperian logarithmic transformation. ANOVA was performed taking into account treatment, period, sequence and subject (sequence) as fixed effects with a variance components structure of the covariance matrix. | 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide. | Cmax, of plasma diclofenamic acid after T2 single dose, with and without T1 co-administration. The parametric point estimators (PE) for the ratios of T2 treatment with T1 co-administration / T2 treatment without T1 co-administration for the PK parameters under consideration, and the two-sided 90% confidence interval (CI), were calculated using the adjusted least squares means (LSMEANS) from the ANOVA. LSmeans differences obtained in the log scale for Cmax were back-transformed to obtain the PE (i.e. geometric mean ratio) and the two-sided 90% CI as percentages. |
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Inclusion Criteria:
A non-hormonal intrauterine device 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 agreed 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 were admitted.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Milko Radicioni, MD | Cross Research SA | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cross Research SA, Phase I Unit | Arzo | Canton Ticino | 6864 | Switzerland |
Bioequivalence data are to be considered as a whole in all subjects (90%CI).
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Twenty-four (24) subjects were randomised in the study. One of the 24 subjects discontinued the study before study treatment. Twenty-two (22) subjects completed the study per protocol.
The recruitment started and finished on May 2015 and the study was performed in Switzerland at CROSS Research S.A., Phase I Unit, Via F.A. Giorgioli 14 CH-6864 Arzo, Switzerland
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| ID | Title | Description |
|---|---|---|
| FG000 | Diclofenac Sodium First, Safinamide + Diclofenac Sodium Second | Diclofenac sodium 50 mg oral tablets, single dose, and safinamide 200 mg oral tablets, single dose |
| FG001 | Safinamide + Diclofenac Sodium First, Diclofenac Sodium Second | Diclofenac sodium 50 mg oral tablets, single dose Safinamide 200 mg oral tablets, single dose |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
| |||||||||||||
| Second Intervention |
|
males and females healthy volunteers, age 22-55 inclusive. This is a cross-over study, so 23 subjects were enrolled in total and participated in both groups
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| ID | Title | Description |
|---|---|---|
| BG000 | Intervention | Diclofenac sodium 50 mg oral tablets, single dose Diclofenac sodium 50 mg oral tablets, single dose and safinamide 200 mg oral tablets, single dose |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | healthy volunteers, both sexes, 22-55 years old inclusive |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | To Evaluate Plasma Diclofenamic Acid Extent of Exposure Reported as Plasma AUC After Single Administration of 50 mg Diclofenac Sodium, With and Without Co-administration of a Single 200 mg Dose of Safinamide. | Plasma diclofenamic acid AUC0-t after T2 single dose, with and without T1 co-administration. To measure AUC plasma samples were taken by the participants at different time points, and the concentrations of diclofenac and safinamide were measured. AUC0-t is the area under the concentration-time curve from administration to the last observed concentration time t; PK parameters AUC0-t were analysed using analysis of variance (ANOVA). Before analysis, the data were transformed using a neperian logarithmic transformation. ANOVA was performed taking into account treatment, period, sequence and subject (sequence) as fixed effects with a variance components structure of the covariance matrix. | healthy volunteers | Posted | Mean | Standard Deviation | h X ng per mL | 24 hours |
|
1 month
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Diclofenac Sodium | Diclofenac sodium 50 mg oral tablets, single dose |
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no limitations
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Milko Radicioni | CROSS REsearch SA | +41.91.63.00 | 510 | clinic@croalliance.com |
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| ID | Term |
|---|---|
| D004008 | Diclofenac |
| C092797 | safinamide |
| ID | Term |
|---|---|
| D010648 | Phenylacetates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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| Diclofenac sodium and safinamide | Drug | Diclofenac 50 mg single dose and safinamide 200 mg single dose |
|
|
| 24 hours |
| Tmax and T1/2 | 24 hours |
| Lamda z | 24 hours |
| Relative Bioavailability (Frel) | calculated as ratio between AUC0-t (test) / AUC0-t (reference) | 24 hours |
| NOT COMPLETED |
|
| Count of Participants |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Diclofenac sodium 50 mg oral tablets, single dose Diclofenac sodium: Diclofenac sodium 50 mg single dose |
| OG001 | Diclofenac Sodium and Safinamide | Diclofenac sodium 50 mg oral tablets, single dose, and safinamide 200 mg oral tablets, single dose Diclofenac sodium and safinamide: Diclofenac 50 mg single dose and safinamide 200 mg single dose |
|
|
|
| Secondary | Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide. | Cmax, of plasma diclofenamic acid after T2 single dose, with and without T1 co-administration. The parametric point estimators (PE) for the ratios of T2 treatment with T1 co-administration / T2 treatment without T1 co-administration for the PK parameters under consideration, and the two-sided 90% confidence interval (CI), were calculated using the adjusted least squares means (LSMEANS) from the ANOVA. LSmeans differences obtained in the log scale for Cmax were back-transformed to obtain the PE (i.e. geometric mean ratio) and the two-sided 90% CI as percentages. | Posted | Least Squares Mean | Standard Deviation | ng/mL | 24 hours |
|
|
|
|
| Secondary | Tmax and T1/2 | Posted | Least Squares Mean | Standard Deviation | hours | 24 hours |
|
|
|
| Secondary | Lamda z | Posted | Mean | Standard Deviation | 1/hours | 24 hours |
|
|
|
| Secondary | Relative Bioavailability (Frel) | calculated as ratio between AUC0-t (test) / AUC0-t (reference) | Posted | Mean | Standard Deviation | ratio | 24 hours |
|
|
|
| 0 |
| 23 |
| 0 |
| 23 |
| EG001 | Diclofenac Sodium and Safinamide | Diclofenac sodium 50 mg oral tablets, single dose, and safinamide 200 mg oral tablets, single dose | 0 | 23 | 0 | 23 |
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