A Phase 1 interventional study of Diclofenac sodium and Diclofenac sodium and safinamide in Healthy, sponsored by Zambon SpA. Completed at 1 site in Switzerland. Open to participants aged 22 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2016-04-15.
Sponsored by Zambon SpA · Phase 1 and Interventional
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.
Zambon SpA is the lead sponsor of 23 studies on the registry; none are open to participants now.
Of its 5 completed or terminated interventional studies of FDA-regulated products, 4 (80%) have results posted.
Counted across the registry records on this site, refreshed daily.
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:
Diclofenac sodium 50 mg oral tablets, single dose
Drug: Diclofenac sodium
Diclofenac sodium 50 mg oral tablets, single dose, and safinamide 200 mg oral tablets, single dose
Drug: Diclofenac sodium and safinamide
Diclofenac sodium 50 mg single dose
Also known as: Voltaren
Diclofenac 50 mg single dose and safinamide 200 mg single dose
Also known as: Voltaren and Xadago
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.
Time frame: 24 hours
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.
Time frame: 24 hours
Tmax and T1/2
Time frame: 24 hours
Lamda z
Time frame: 24 hours
Relative Bioavailability (Frel)
calculated as ratio between AUC0-t (test) / AUC0-t (reference)
Time frame: 24 hours
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
| Milestone | Diclofenac Sodium First, Safinamide + Diclofenac Sodium Second | Safinamide + Diclofenac Sodium First, Diclofenac Sodium Second |
|---|---|---|
| Started | 13 | 10 |
| Completed | 13 | 10 |
| Not completed | 0 | 0 |
| Milestone | Diclofenac Sodium First, Safinamide + Diclofenac Sodium Second | Safinamide + Diclofenac Sodium First, Diclofenac Sodium Second |
|---|---|---|
| Started | 12 | 10 |
| Completed | 12 | 10 |
| Not completed | 0 | 0 |
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.
| h X ng per mL | Diclofenac Sodium | Diclofenac Sodium and Safinamide |
|---|---|---|
| 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. | 1323.28 ± 390.53 | 1381.32 ± 393.77 |
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.
| ng/mL | Diclofenac Sodium | Diclofenac Sodium and Safinamide |
|---|---|---|
| Evaluate Diclofenac Rate of Absorption Reported as Plasma Cmax After Single Administration of 50 mg Diclofenac With and Without 200 mg of Safinamide. | 766.59 ± 390.01 | 833.50 ± 443.34 |
| hours | Diclofenac Sodium | Diclofenac Sodium and Safinamide |
|---|---|---|
| Tmax | 0.88 ± 0.41 | 1.0 ± 0.43 |
| T1/2 | 1.24 ± 0.43 | 1.19 ± 0.40 |
| 1/hours | Diclofenac Sodium | Diclofenac Sodium and Safinamide |
|---|---|---|
| Lamda z | 0.63 ± 0.22 | 0.63 ± 0.16 |
calculated as ratio between AUC0-t (test) / AUC0-t (reference)
| ratio | Diclofenac Sodium | Diclofenac Sodium and Safinamide |
|---|---|---|
| Relative Bioavailability (Frel) | 107.67 ± 28.84 | 109.61 ± 32.14 |
Collected over 1 month. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Diclofenac Sodium | — | 0/23 (0%) | 0/23 (0%) |
| Diclofenac Sodium and Safinamide | — | 0/23 (0%) | 0/23 (0%) |
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
| Age, Categorical(Participants) | Intervention |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 23 |
| >=65 years | 0 |
| Age, Continuous(years) | Intervention |
|---|---|
| Mean | 41.6 ± 9.1 |
| Sex: Female, Male(Participants) | Intervention |
|---|---|
| Female | 12 |
| Male | 11 |
| Race (NIH/OMB)(Participants) | Intervention |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 23 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Intervention |
|---|---|
| Switzerland | 23 |
Plan to share: No — Bioequivalence data are to be considered as a whole in all subjects (90%CI).
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Zambon SpA