Deflazacort for the treatment of Duchenne Dystrophy: A systematic review

Duchenne Dystrophy (DD) is a chronic degenerative muscle disorder that becomes evident in mid-childhood. Several therapies have been examined with the aim of slowing the progression of muscle weakness in children with DD. Corticosteroids have been the drug of main interest with prednisone demonstrating evidence of improvement in some patients and a lack of deterioration in others [1]. Multiple randomized trials have found improved function and strength in children treated with prednisone [2–5]. Unfortunately, in these studies prednisone had a great deal of side effects which may temper its usefulness. A methyloxazoline derivative of prednisolone, deflazacort (DFZ), has shown some promise in providing similar effects to prednisone with a less concerning side effect profile [6, 7]. If both drugs are similarly effective in improving strength, and if weight gain is less evident with DFZ then improvements in functional strength may exceed those seen with prednisone. A recent call has been noted for a systematic examination of the evidence for the effectiveness and safety of DFZ in the DD population [8].

Thus, the clinical questions that arise are whether DFZ is an effective therapy for improving strength in children with DD?; is DFZ more effective than other therapies?; and, does DFZ have fewer side effects than other steroid agents used in the treatment of DD? This systematic review attempted to answer these queries by identifying randomized controlled trials of DFZ in the DD population with the goal of completing a meta-analysis of the treatment effects and safety profile.

The review was conducted adhering to the principles of the QUORUM statement [9]. The techniques for identifying relevant studies included several different procedures. First, electronic database sources were searched using Ovid without restriction on language or publication status. The original search strategy is given in Appendix A [see Additional file 1]. At first, the search included specifics to identify randomized trials but, the search was broadened to find any articles with the population terms "Duchenne muscular dystrophy", "muscular dystrophy" or "myopathy" and the treatment terms "deflazacort", "21-deacetyl deflazacort" or "steroid". The databases search included: MEDLINE (1966-Week 4 2002), EMBASE (1974–2002, week 19), Current Contents (1993-Week 14 2002), Dissertation Abstracts (1861-Feb 2001), Health Star (1987-Jan 2002), PsychINFO (1887–2002). The Cochrane Controlled Trials Register (issue 2, 2002) was searched and served as a surrogate hand search. Because of few identified studies during each search the abstracts were accessed and reviewed for relevancy at the time of the search.

Second, reference lists from the selected trials were reviewed as well as reference sections from textbooks and review articles. Third, four content experts were contacted to try to identify unpublished trials. Finally, the company that is manufacturing DFZ for use in Canada, Aventis, was contacted to identify trials that were conducted internally.

Searching article and textbook reference lists identified two additional references, however neither resulted in studies meeting eligibility criteria. Two of four content experts responded to our correspondence, with one identifying a study not previously identified via other methods. Aventis did not know of any trials, conducted or sponsored, that were not already in the literature.

A total of 291 patients were randomized, however, because two trials did not specify the size of the groups it is not clear how many received treatment compared to control. One trial made up 73% (n = 196) of the total participant number. Four of the trials included appeared to arise from one group of investigators and these appeared to be financially supported by the same agency.

The Jadad scale score and allocation concealment status is given in Table 3. Quality assessment was consistent between authors with identical scores on four of five studies. The disagreement came on the description of dropouts in study B with one author assigning no point and the other one point. Following review of the article the consensus was that an adequate account had been given in the text regarding dropouts and the study was given one point for this criterion. Two studies received a score of 3 on the Jadad scale. None of the studies made any comment on allocation concealment techniques. Attempts to clarify methodological information from the authors of the two studies found only in abstract form were unsuccessful.

The dose of DFZ was relatively uniform over the four trials ranging between the equivalent of 0.9 and 1.2 mg/kg each day. In only one trial was any mention made of co-interventions and in this case it was dietary advice to help control weight gain. Three trials compared DFZ to prednisone. Of these, two trials reported follow-up data to 12 months and one until three months. Three trials compared DFZ to placebo. One had 24 months follow-up, however, marked drop out occurred in the second year so reliable data was only available until the 12 month time period. The second trial comparing placebo to DFZ was the four-arm trial (Study N) but because of substantial differences found in strength which was in favor of steroids the placebo arm was discontinued at three months time.

This review included five randomized controlled trials comparing DFZ treatment to a control group. One further RCT was identified (study D, L, H, O and likely J) but was not included because the outcomes have never been published. These six studies have included 391 participants in at least three different countries. Unfortunately, the two largest trials, including 196 [12] and 100 [13] patients have never been published in journal article format for peer review. The first of these two trials (Study N) was published in abstract form but, as was demonstrated in Table 5 and 6, the reporting of the trial in this format did not allow the reader to gain insight into the efficacy of DFZ. The second large trial (Study D, H, L, O, and likely J), a multi-centre study, was last reported on in 1998 and compared prenisolone with DFZ. At the time of the meeting proceeding the randomization code had been broken, however, the proceeding gave no numeric indication of the results and suggested that "both steroids slowed the degradation equally well"[13]. The investigator of this study confirmed that the results remain unpublished and that data is not currently available for use in meta-analysis.

The fact that data remains unpublished from these two trials is an unfortunate situation from both a clinical and a research ethics perspective. As this review has demonstrated, there is no convincing body of evidence to support the superiority or, on the other hand, the equivalence of prednisone and DFZ for improving or maintaining strength or function in children with DD. This issue would certainly be clarified by publication of this data. Access to DFZ is difficult in Canada and the United States as there is currently very little information to support its use. From an ethical perspective, participants in research studies deserve that the results of their outcomes in trials will be used to improve care for others in similar circumstance. In this scenario the participants have not been well served for the risks they incurred by entry into the studies. From a methodologic perspective, the findings of this review support the belief that unpublished data should be sought and included in systematic reviews and meta-analyses [14].

Of the studies eligible under the criteria and mandate of this review, only one study provided evidence of the efficacy of DFZ (Study B). This study had a placebo control and used 11 different methods of measuring efficacy. The sample size was relatively small, 28 patients total, but was able to demonstrate significant differences between placebo and DFZ on seven of 11 strength measures. The other four tests all showed point estimates favoring DFZ. The second study demonstrating efficacy of DFZ over placebo (study N) followed the placebo group for only three months and the third study in this groupclaimed an improvement in strength. Unfortunately, given the minimal information in these latter two studies the results could not be synthesized by meta-analysis. The evidence from these three randomized trials suggests a clinically and statistically significant benefit on measures of strength with the use of DFZ compared to no treatment (placebo).

The other eligible studies (study A, F, and N) all compared DFZ to prednisone, and as demonstrated in Table 5 and discussed in the result section, no reasonable conclusions can be drawn from these studies. None of the studies described what was considered a minimal clinically important difference or the power of the study to detect it. All the authors concluded that there was no substantial difference between DFZ and prednisone with one author (study A) stating that the two therapies were equally effective.

Weight gain was the side effect which received the most focus in the studies examined. Two studies (study A and N) provided numerical comparisons with statistical tests comparing the mean weight gain as a percentage of baseline weight. These two studies both found an approximately ten percent difference in weight gain favoring DFZ over prednisone. No age by treatment or severity by treatment effects are reported to determine who is at the greatest risk for weight related problems. Thus, the evidence from these two trials show that weight gain is less of a problem on DFZ and this should be considered in therapeutic decisions. Unfortunately the incidence of side effects was infrequent and not often reported by treatment group making conclusions difficult. A body of anecdotal and observational literature exists regarding side effects but at the current time conclusions can not be drawn from randomized trial sources or meta-analysis.

Quality assessment of randomized controlled trials for the purpose of systematic review and meta-analysis is difficult with numerous scales available [15]. In this case the Jadad scale was chosen as it is a well validated scale [10]. An indication of allocation concealment was also used as is suggested in the Cochrane guidelines [16]. The studies identified for this review were generally of low quality with an average Jadad score of 1.8 and none commenting on allocation concealment. This may be primarily due to the fact that three of the studies, with scores of 2 (Study N), 1 (Study F) and 0 (Study G) were available only in abstract form, which is not what the Jadad scale was ideally intended for. Furthermore, the trials were largely published prior to the widespread use of CONSORT guidelines. The quality of reporting of summary statistics was poor, perhaps even more so than expected from the Jadad scores. The data presentation and lack of summary statistics in most cases did not allow the reader a thorough exploration of the outcomes, and certainly provided no ability to carry out a meta-analysis. The clinical conclusions from the individual studies included in this review must be interpreted with the knowledge that some evidence exists to suggest that studies obtaining lower quality scores may be associated with increased estimate of benefit [17].

As in any systematic review, the limitations in drawing conclusions are directly dependent on the thoroughness of reporting in identified studies. Despite an intention to synthesize the data using meta-analytic techniques this could not be accomplished due to the inability to obtain and extract data. In this respect the review is certainly limited, and any strong conclusions or changes in clinical practice should be tempered by the realization that the reporting of trial results was such that summary statistics were not available or consistently presented. This review does not use the flow diagram format suggested in the QUORUM statement as it was felt that with such a small number of relevant studies using a tabular format would be more informative. The approach to the reporting of the review otherwise adheres to the QUORUM statement [9].

Clearly, the most important component needed to determine the efficacy and safety of DFZ is the publication of the two large trials identified in this review. If these studies do not provide a meaningful answer to the efficacy and safety issues then calls for a further randomized trial would be necessary. A systematic review of observational studies, despite being practically and methodologically more challenging, may help to clarify the situation. Although randomized controlled trials are considered the highest quality of study, high quality observational studies may not over estimate treatment effects to a point of concern [18].