Clinical Study Synopsis for Public Disclosure

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1 abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis - which is part of the clinical study report - had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non-approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of. V1.0/2014

2 Title of study: Randomized, double blind, comparative trial of the efficacy and tolerability of i.v. vs. Placebo i.v. in the prevention of postoperative pain in children of 6 and 11 years old undergoing minor surgery Investigator: Study centers: Multicentre study (cf. section 6 and Appendix ) Publication (reference): Clinical phase: Objectives: Data of this study has not been published IV Primary: To assess the analgesic efficacy in the prevention of postoperative pain in children undergoing minor surgery (herniorraphy, tonsillectomy). Secondary: To assess the tolerability of in this group of patients. Methodology: Randomized, double blind, placebo-controlled, parallel groups No. of subjects: planned: entered: 132 actual: enrolled: 127 Treatment : entered: 61 treated: 57 analysed (for primary endpoint): Treatment Placebo: entered: 61 treated: 61 analysed (for primary endpoint): Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Duration of treatment: Postoperative pain in children of 6 to 11 years old undergoing minor surgery (inguinal hernia repair, tonsillectomy) 30 mg/ Kg i.v. R171 Single dose

3 Reference therapy: Placebo dose: - mode of admin.: batch no.: Criteria for evaluation: Efficacy: Safety: Statistical methods: i.v. B The percentage of children who required rescue medication during the four hours after trial drug administration; time until rescue medication was given; the percentage of children who required rescue medication during the first two hours after the administration of the medication; evaluation of the pain intensity by the patient by means of a Visual Analogue Scale (VAS); evaluation of the pain intensity by the patient by means of a Verbal Rating Scale (VRS); assessment of the state of the patient by the guardian by means of the CHEOPS test (an scale to evaluate the intensity of the port-surgical pain observing in the child: crying, facial verbal expressions, movements or position of torso, the attitude towards the wound and the leg movement); assessment of the partial efficacy in every visit by means of a 4 points VRS; assessment of the total efficacy by means of a VRS in the final visit. Post-surgical level of sedation was evaluated by means of the Ramsay scale. The patient had to reach the score 2 (eyes opened, collaborative, orientated, calm) within 90 minutes after the trial drug administration in order to he/she could continue in the trial. Incidence and intensity of the Adverse Events (AEs); withdrawals due to AEs; assessment of the total tolerability by means of a four point VRS in the final visit. Primary analysis: Cochran-Mantel-Haenszel method (percentage of patients needing rescue medication during the four hours after trial drug administration). Secondary analysis: Kaplan-Meier estimates, log rank, Wilcoxon tests (time until rescue medication administration), Cochran-Mantel-Haenszel method (percentage of patients needing rescue medication during the first two hours after trial drug administration). Generalized Linear Model (pain VRS measures, global efficacy evaluation, tolerability, patients with Ramsay=2), random coefficient model, ANCOVA model (CHEOPS). The significance level was 0.05.

4 SUMMARY CONCLUSIONS: Efficacy results: A total of 127 patients were enrolled in this trial and signed the informed consent. Five patients were not randomised. Therefore, 122 patients were randomised/treated: 61 in the arm and 61 in the placebo arm. Fifty seven (57) (44.9 %) patients completed the trial according to protocol: 29 (47.5 %) in the arm and 28 (45.9 %) in the placebo arm. No difference between treatment arms was found regarding demographic and baseline characteristics. This homogeneity was also observed when post-surgical level of sedation was evaluated by the Ramsay scale. The curves of the VAS mean values throughout the trial for both treatments revealed more pronounced decrease in the arm. The primary endpoint, the number of children requiring rescue medication during the first four hours after drug administration, showed no significant difference between treatments, though a higher number of patients in the placebo arm requested rescue medication: 29 (50.9%) patients in the arm versus 37 (60.7%) patients in the placebo arm. In time from trial drug administration till rescue medication a median difference marginally significant appeared, possibly meaning that patients in the arm needed rescue medication later than those who received placebo. Differences between treatments appeared lately, though the log rank test did not detect them. No covariates showed effect on the time to rescue medication. The time from end of surgery till rescue medication showed similar median values in both treatments even though the median value in the arm was higher than in the placebo. The differences between treatments also appeared lately, although the log rank test did not detect them again. Age showed a marginal effect on the time to rescue medication, meaning that the hazard of requiring rescue diminished when age increased. The time from first awake till rescue medication showed a big difference in median values (240 min in the arm versus 120 min in the placebo), though it was not statistically significant. The differences between treatments appeared very early and the median value was reached later in the arm. The log rank test detected marginal differences. Age and duration of the surgery also showed a marginal effect on the time to rescue medication, what means that the hazard of requiring rescue medication diminished when age increased, and this hazard increased when the duration of the surgery increased.

5 Efficacy results (cont.): CHEOPS showed a better effect in the arm, and also the rate of change (slope) was more pronounced in this treatment. Regarding efficacy evaluation by the investigator over the study in the arm, the lower category ( Good ) was almost 2 times that of the odds in the Placebo arm, what means that patients treated with reported a more effective treatment. However, the final global efficacy by the investigator showed no treatment differences. Safety results: In the safety analysis performed in all treated population, no important differences were observed between the two treatment groups. The intensity of AEs was evaluated by the investigator according to: mild, moderate and severe. A total of 49 patients (40.2%) experienced one or more AEs: 29 patients (47.5%) in the group and 19 patients (31.1%) in the placebo group. However, this difference only corresponded to the number of mild AEs (haematemesis, nausea and vomiting) observed between the two treatments arms. Haematemesis is quite frequent in patients undergoing tonsillectomy. The proportion of patients experiencing any severe AE was the same in the two arms (1.6 % in both and placebo). In both treatment arms, the most frequently observed AEs were (according to SOCs): gastrointestinal system disorders (45.9 % of patients in the arm versus 27.9 % in the placebo). The number of patients with serious adverse events was slightly higher in the placebo arm (6.5 % in the arm versus 9.8 % in the placebo). During the study one patient receiving experienced one AE that was considered by the investigator to be related to study medication: Patient no. 131 had vomiting of mild intensity. None of the appeared SAE was considered to have a reasonable causal relationship with the study drug as assessed by the investigator. No patient died during the study. In relation to the systolic and diastolic blood pressure and heart rate, considering all treated population, both treatments were safe, since no significant changes were observed due to the study drugs.

6 Conclusions: In this trial in children and due to the chosen strict primary endpoint, no significant effect was seen in the arm regarding the number of patients requiring rescue medication. However, a trend in favour of can be observed, as patients in this arm needed rescue medication later that those in the placebo arm; and that age and duration of surgery marginally affected the time to rescue medication. Patients in the arm experienced a higher pain release and reported a better condition. Regarding safety, both and placebo treatments were safe and well tolerated.