Title: Dexketoprofen/tramadol 25mg/75mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy

Transcription

1 Author s response to reviews Title: Dexketoprofen/tramadol 25mg/75mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy Authors: R Andrew Moore (andrew.moore@ndcn.ox.ac.uk) Henry J McQuay (henrymcquay@gmail.com) Janusz Tomaszewski (klinika.jtomaszewski@wp.pl) Grzegorz Raba (g.raba@plusnet.pl) Daniel Tutunaru (daniel.tutunaru@yahoo.com) Nellija Lietuviete (nellija.lietuviete@aslimnica.lv) Jan Galad (galad@gynpor.sk) Laszlo Hagymasy (lhagymasy@mail.fmkorhaz.hu) Dace Melka (dace.melka@inbox.lv) Jan Kotarski (j.kotarski@am.lublin.pl) Tomasz Rechberger (rechbergt@yahoo.com) Bela Fülesdi (fulesdi@med.unideb.hu) Andrea Nizzardo (ANizzardo@menarini-ricerche.it) Cristina Guerrero-Bayón(cguerrero@menarini.es) Susanna Cuadripani (scuadripani@menarini.es) Bartomeu Pizà-Vallespir (bvallespir@menarini.es) Monica Bertolotti (MBertolotti@menarini-ricerche.it) Version: 1 Date: 26 Oct 2015

2 Author s response to reviews: REVIEWER #2 GENERAL COMMENTS In this multicentre randomised double-blind trial the authors investigate the analgesic effect of dexketoprofen/tramadol as a single formulation with fixed doses 25/75 mg respectively compared to the single components in patients undergoing abdominal hysterectomy. 1. -Was a significant non-homogeneity in the results obtained from the different study centres and the different countries? Post-hoc ANCOVA analyses were performed for the primary endpoint including country or site as additional covariates. A significant (p<0.0001) effect, probably related to some low recruiting sites and countries, was detected in both cases (Table 1; see cover letter). However, the differences between treatment arms remained significant (p<0.01).for all comparisons (Table 2; see cover letter). The results of these analyses have been included in the discussion (tables have not been included) 2. The authors use the word efficacy throughout the text. Efficacy and effectiveness are not identical concepts: Effectiveness is defined as the extent to which a treatment achieves its intended effect in the usual clinical setting (real life). Efficacy has been defined as the extent to which a treatment has the ability to achieve its intended effect under ideal circumstances. Since the IIT analysis was implemented to analyze the results "efficacy" must be replaced by "effectiveness" throughout the text. We would keep the word efficacy throughout the text taking into account that article describes an explanatory clinical trial seeking to determine the effect of an intervention under controlled conditions which included defined eligibility criteria, study procedures and efficacy and safety assessments. Patients were duly informed in advance and agreed to participate into an explanatory clinical trial which encompassed procedures that differ considerably from usual clinical practice, including the administration of study drugs subject to strict dosing schedules and monitoring, the use of placebo, performing frequent assessments during the study period, additional safety tests (e.g. blood laboratory tests), etc. In this sense, the study cannot be considered a pragmatic study in real life contitions. Intention-to-treat analysis was used according to ICH guideline E9, Statistical Principles for Clinical Trials, which sets the effect of a treatment can be best assessed by an evaluation based on the intention to treat a subject (i.e. the planned treatment regimen) rather than the actual treatment given. 3. Too many not recognized abbreviations and acronyms. The reader has to learn several "new words", very inconvenient. Please replace RM (could be Raphe Magnus), PI (could

3 be primary investigator), PAR, PGE (it reminds prostaglandins) BOCF, LOCF, WOCF, SPID (it reminds a misspelled word "speed"), TOTPAR and so on with the full words throughout the text! Explain also in tables the PBO abbreviation. The abbreviations RM, PI, PAR, BOCF, LOCF and WOCF have been replaced by the corresponding full words name all through the text. However we would rather keep SPID, TOTPAR and PGE, if possible, as they are well-recognised acronyms used in published literature on analgesic trials. The PBO abbreviation in Additional file 4 (former Additional file 3) has been replaced by the full word placebo. SPECIFIC COMMENTS Introduction Page 6 4. Lines 10-14: Give evidence and relevant references for the optimum combination of the 25/75 mg dose. In a previous dose-finding trial evaluating four different dose-combinations of dexketoprofen and tramadol, the particular combination of dexketoprofen 25mg plus tramadol 75mg demonstrated a consistently superior efficacy in all parameters of analgesia tested [9], and it was therefore selected as the optimum combination of doses for further analysis. (Added to the Background; reference also included) 5. Add the study hypothesis It was hypothesised that dexketoprofen/tramadol 25mg/75mg would provide a level of analgesia above that achievable by each component alone, without compromising the safety profile. (Added to the Background) Methods Page Why during the single-dose phase VAS scores were measured only at rest and not on movement as well? Please add reasons to the Discussion. During single-dose phase VAS scores were measured only at rest and not on movement as well to avoid unnecessary interferences with pain at rest measurements provided that SPID8 at rest was the primary endpoint of the study. This has been included in the discussion. Page 11

4 7. Line 53:" of treatment-emergent adverse events": please name them. As per ICH guideline E9, Statistical Principles for Clinical Trials, definition treatmentemergent adverse events refer to all adverse events experienced by patient starting from the first study drug administration (a clarification has been added to this sentence in safety evaluation section); therefore all the adverse events spontaneously reported by the patient were considered for the analysis. No checklist of specific adverse events was not provided in advance to investigator or patient. The summary of all related treatment-emergent adverse events (ADRs) recorded during the study is provided on Table 5 (safety results section). 8. It is not clear to me why a placebo group was required. Both tramadol and dexketoprofen have been validated as analgesics by their own effect. What seems important is the superiority of the combined formulation versus each single analgesic. Even so the NNT of placebo versus active comparators would be simpler approach. Due to the high and variable placebo response rate, placebo-controlled designs with appropriate use of rescue medication are strongly recommended by the EMA guideline Note for Guidance on Clinical Investigation of Medicinal Products for Treatment of Nociceptive Pain (CPMP/EWP/612/00). Comparisons of active comparators to placebo are intended to prove the internal sensitivity of the study. The approach selected was to validate the sensitivity in all variables considered to evaluate the efficacy of the combination during the single dose phase, and not only by demonstrating superiority of single agents over placebo in a selected endpoint. Results 9. Page 13 - Lines 14-19: Efficacy analyses were performed on the "intention to treat population " Please change to effectiveness analyses. Change throughout the text. (See comment number 2 above) Page Line 3: Delete "and female". Only females can have hysterectomy! It has been deleted. 11. Lines 21 and 29: For reasons explained above please replace efficacy by effectiveness. (See comment number 2 above)

5 12. Lines 35-43: No reason to repeat the results shown in figure 2. You may rephrase as follows: The results of the primary analysis (SPID8) showed the superiority of dexketoprofen/tramadol over dexketoprofen and tramadol alone (p < and p < respectively) and are shown in figure 2. Modified. Page Lines 22-30: Please show the P<0.05 for the mean SPID at rest 2, 4, 6, 24 and 48 hours in the relevant figures. Similarly add the P<0.001 in the relevant figure for the mean SPID scores on movement and mention in the figure legend the groups that differ significantly (in SPID on movement). Statistical significant mentioned in the legend in the corresponding variables in Additional files 1 and 2 when applicable; the detailed p values are included in Additional files 3 and 4 respectively; the same modification has been made for TOTPAR relevant files (Additional file 7). In addition, a new figure (Figure 5) referent to the time course of mean SPID at rest during the single-dose phase has been included. Also, text referred to model sensitivity for the secondary endpoints has been deleted from the text, as all corresponding p values are detailed in the accompanying tables. 14. Lines 34-39: The higher mean SPID scores on movement differed statistically between the the DKP/TRAM and DKP groups but not between the DKP/TRAM and TRAM groups? According to the Additional file 4 the p SPID24 and SPID48 values for the DKP/TRAM vs TRAM groups (on movement) are and respectively. Change the sentence "There was evidence of higher on both single components to "There was evidence of higher on DKP alone) since for the same time points the statistically significant difference was found only for the DKP/TRAM vs DKP group. Corrected as requested. Page Lines 1-7: the mean % max SPID on movement over 24 and 48 hours for the DKP/TRAM group differs significantly from both single treatments (p < for DKP and p < 0.05 for tramadol). Which of these outcomes (mean SPID or the mean % max SPID on movement) is the most clinically applicable and significant? Please comment in the Discussion. Both outcomes, SPID and % max SPID, are calculated upon time-specific pain intensity differences. The most appropriate is to consider both together as they are not independent but complementary outcomes. SPID represents the area under the pain intensity difference-time curve and its value depends on the pain intensity scale used, on the duration of the period considered, and

6 importantly, on the baseline pain intensity. It provides a measure of the cumulative analgesic response useful to perform comparisons between different interventions. % max SPID is calculated taking into account the maximum theoretical SPID score for each patient, which heavily depends on patients pain intensity baseline. This represents as a percentage how much of the potential maximum analgesic response is achieved by patients. Low % max SPID indicate that there is still a lot of unmet pain, conversely, high % max SPID indicate that most of the initial pain intensity is resolved. Most efficacious analgesics would have both high SPID scores and high % max SPID. In terms of clinical application, analgesic efficacy should be consistently shown in different outcomes, demonstrated across several clinical trials. 16. Lines 27-29: Rephrase: "During the multiple dose-phase at 48 hours the percentage of pain intensity obtained at rest was highest with DKP/TRAM.etc. Please clarify that the 93%, 83% etc are referred AT REST. Modified: During the multiple-dose phase, the highest percentage of responders at rest over 48 hours was achieved with dexketoprofen/tramadol (94% for dexketoprofen/tramadol vs. 83% for dexketoprofen [p<0.001] and 89% for tramadol [p=0.048]). Similar results were seen for the response to treatment on movement over 48 hours (80% for dexketoprofen/tramadol vs. 67% for dexketoprofen [p=0.003] and 71% for tramadol [p=0.024]) Discussion 17. Start Discussion with a sentence summarizing the main study results: for example "The results of the present study show the superiority of the dextoketoprofen/tramadol combination in a single formulation of fixed doses" or something like that. The study results confirmed that dexketoprofen/tramadol 25mg/75mg can provide a level of analgesia above that achievable by each component alone and with an extended duration of effect. Efficacy results were consistent during single and multiple-dose phases, thus supporting the selection of the doses and the regimen proposed. (Moved to the first paragraph in the Discussion) 18. Give evidence and discuss why you selected the 25/75 mg dose. It is explained in the Background (see comment number 4). 19. Which of the outcomes mean SPID or the mean % max SPID on movement is the most clinically applicable and significant? Please comment. See related comment above (comment number 15) 20. Describe the limitations of the study. Added to the Discussion:

7 Figures Figure quality must be improved. Improved. 21. Figure 2: Replace the present figure presentation by two dimension columns and add the SDs in the figure. Also indicate with symbols the statistically significant differences wherever appropriate. Corrected as requested. 22. Figure 3: Better presentation should be in columns showing the SDs and the p values wherever significant or add symbols wherever appropriate indicating the statistically significant differences. We have tried to present the data in columns but we realised it is clearer to keep the graph as it was originally. Symbols indicating statistically significance have been added. It is not possible to add all SDs in the figure as they would overlap. 23. Figures 4 and 5: Vertical axis in each figure should be labelled same as in figure 3, thus PI (VAS) at rest and PI (VAS) on movement. Indicate with symbols the statistically significant differences. Corrected as requested.