Safety and efficacy of pregabalin in adolescents with fibromyalgia: a randomized, double-blind, placebo-controlled trial and a 6-month open-label extension study
In this randomized, double blind, parallel-group, placebo-controlled trial in adolescents (aged 12–17 years) with FM, pregabalin did not significantly improve the primary outcome of mean change in pain score at endpoint. Certain secondary and exploratory outcomes measuring pain and impression of change were significantly improved with pregabalin. Other secondary outcomes, including FIQ-C and most sleep quality assessments, demonstrated greater improvements with pregabalin compared with placebo, but these were not statistically significant. The safety results in the double-blind and open-label studies were similar to the established safety profile in adults with FM.
While the treatment difference in the primary outcome in the double-blind study was not significant, the treatment effect on pain with pregabalin (?0.66) was within the range of those seen in prior clinical trials of pregabalin in adults with FM that had demonstrated a statistically significant treatment effect [21–23, 28]. In those trials the treatment effect (at approved doses) ranged from ?0.44 [28] to ?0.98 [21]. At the same time, the overall placebo response in this study was not meaningfully different from that in previous trials. The change in mean pain score at endpoint with placebo was ?0.94 in this study compared with a range of ?1.03 [28] to ?1.40 [22] in prior trials.
In studies of pregabalin in adults with FM, patients were treated with a minimum of 300 mg/day (with the exception of the first study, which included the 150 mg/day dose level) [22], and pregabalin is approved in adults at doses of 300 or 450 mg/day [17]. In this double-blind study, almost half (44.2 %) of the subjects were treated with a maintenance dose of pregabalin that was 300 mg/day.
Post hoc analyses of the double-blind study revealed significant differences in response between subjects from the United States and those from other countries. For example, the median dose of pregabalin in non-US subjects was 75 mg/day, indicating that the majority of non-US subjects received a much lower dose than has been shown to be efficacious in adults. As these subjects had a notably smaller treatment effect with pregabalin, this might have initially suggested that utilizing a fixed, higher dose of pregabalin could have changed the outcome of this study. However, the placebo response in non-US subjects was notably large; the change in pain score at endpoint with placebo was ?2.55, compared with ?0.52 in US subjects. At the same time, 71.4 % of non-US subjects treated with placebo indicated that their condition was very much improved or much improved at endpoint, compared with 10.0 % of placebo-treated US subjects. This notably large placebo response suggests that a higher dose of pregabalin alone would have been unlikely to have resulted in a significant treatment difference in these subjects.
It is not clear why the placebo response was particularly high in non-US subjects. It has been suggested that the increased support and frequency of direct interaction with healthcare providers in a clinical trial can improve patients’ sense of well-being and satisfaction and contribute to a greater placebo response [29]. This may be particularly true for a condition such as FM which can benefit from a higher degree of interaction with healthcare professionals [30] and in which the lack of validation of FM as a disease has been shown to negatively affect FM patients’ sense of well-being [31]. However, it is not clear why this effect should be significantly more pronounced in the non-US subjects included in this study.
The adolescent FM population is not as well characterized as the adult FM population, and this double-blind study included a number of newer exploratory outcomes. Responses on the exploratory outcome of parent GIC were shown to be consistent with the more established method of PGIC, suggesting the parent GIC could be an effective measure in future trials in this population. While the change in FIQ-C total score with pregabalin compared with placebo in the double-blind study (?2.46) was not statistically significant, it was within the range of FIQ scores that were seen in prior studies of pregabalin in adults with FM [21, 23, 28] in which the treatment difference ranged from ?2.05 [23] to ?5.24 [21]. This similarity in change in FIQ-C total score between studies was despite the fact that baseline FIQ-C scores in this study (~47) were less severe than the baseline FIQ scores in prior studies (~60) [21, 23, 27]. The FIQ-C may be useful as an outcome measure in future trials in this adolescent population, although further validation is required.
The incidence and nature of AEs with pregabalin in this trial were similar to that in trials of pregabalin conducted in adults with FM [21–23, 28]. There were, however, some exceptions. The incidence of nausea in the double-blind study (22.2 %) was higher than in previous trials in adult patients in which it was ~8 %, typically less than the incidence with placebo in those trials [21, 23, 27]. The incidence of fatigue was also higher in the double-blind study than in prior trials in adults (14.8 % vs ~7.5 %). The incidence of somnolence in the double-blind study was lower than in prior trials in adults (9.3 % vs ~20 %). The reasons for these differences are not clear. FM in adolescents is commonly associated with symptoms of fatigue [7], which may make adolescent patients more prone to this AE with pregabalin. In the open-label study, there was typically a lower incidence of each common AE. The incidence of nausea was 7.9 %, similar to that seen with placebo in the double-blind trial and with pregabalin in prior trials in adults.
It was challenging to recruit patients into this trial; it required 4.5 years to enroll 107 subjects. Given the trend toward improvement in the primary efficacy outcome, it may be that the outcome could have been different if there was a larger sample size. A recent planned randomized withdrawal trial in adolescents with FM also found it challenging to recruit sufficient numbers of patients and was terminated prior to completion [20]. Clinical trials in pediatric populations are an ongoing challenge [32] and in the terminated trial, as in this one, recruitment efforts were likely limited by the underrecognition of FM in adolescents [7, 20]. Greater recognition of FM in adolescents and reassurance of patients, and their parents, that the condition can be managed, even in the absence of a definitive medical cause, may encourage families to engage with treatment recommendations [7] and to consider enrolling in clinical trials.