عوارض جانبی و زوال شده گزارش شده توسط شرکت کنندگان در آزمایش سرعت جهت درمان سندرم خستگی مزمن

Objective Adverse events (AEs) are health related events, reported by participants in clinical trials. We describe AEs in the PACE trial of treatments for chronic fatigue syndrome (CFS) and baseline characteristics associated with them. Methods AEs were recorded on three occasions over one year in 641 participants. We compared the numbers and nature of AEs between treatment arms of specialist medical care (SMC) alone, or SMC supplemented by adaptive pacing therapy (APT), cognitive behaviour therapy (CBT) or graded exercise therapy (GET). We examined associations with baseline measures by binary logistic regression analyses, and compared the proportions of participants who deteriorated by clinically important amounts. Results Serious adverse events and reactions were infrequent. Non-serious adverse events were common; the median (quartiles) number was 4 (2, 8) per participant, with no significant differences between treatments (P = .47). A greater number of NSAEs were associated with recruitment centre, and baseline physical symptom count, body mass index, and depressive disorder. Physical function deteriorated in 39 (25%) participants after APT, 15 (9%) after CBT, 18 (11%) after GET, and 28 (18%) after SMC (P < .001), with no significant differences in worsening fatigue. Conclusions The numbers of adverse events did not differ significantly between trial treatments, but physical deterioration occurred most often after APT. The reporting of non-serious adverse events may reflect the nature of the illness rather than the effect of treatments. Differences between centres suggest that both standardisation of ascertainment methods and training are important when collecting adverse event data.

Clinical trials frequently attribute health problems that arise during a trial to the intervention. But, when health problems typically remit and relapse, the attribution of all new health problems to the intervention may be misleading. This study aims to explore this issue in patients with chronic fatigue syndrome (CFS) who participated in a treatment trial. Adverse events reported by participants in clinical trials of treatments may be considered to be clinically serious or not, and to be reactions to trial treatments or not. Few studies have examined the associations and predictions of adverse events in trials. Several trials have suggested a relationship between the reporting of adverse events and negative affect; anxiety [1], depression [2] and neuroticism [3]. Females and introverted participants of phase 1 medical trials are more likely to report adverse events than males and extroverts [4]. Physical symptoms at baseline predicted having a treatment related adverse reaction in an antidepressant controlled trial [5]. As well as this small literature regarding adverse events in trials, there are well established associations between reporting physical symptoms, outside of trials, and both mood disorders [6], [7], [8], [9] and [10] and symptom burden [11]. Chronic fatigue syndrome (CFS) is characterised by long-standing disabling fatigue and other symptoms that have no alternative medical or psychiatric explanation [12]. Its nosological status and aetiology are uncertain [13]. CFS is associated with functional somatic syndromes such as irritable bowel syndrome and fibromyalgia [14]. Treatments recommended by the National Institute of Healthcare and Clinical Excellence (NICE) include cognitive behaviour therapy (CBT) and graded exercise therapy (GET) [15], but patient organisations have expressed concern about their efficacy and safety [16]. The PACE trial was a four arm randomised trial, which was designed to compare three therapies each added to specialist medical care (SMC) against SMC alone to determine both efficacy and safety [17]. The trial found that two therapies, CBT and GET, were more effective than adaptive pacing therapy (APT), when any of these therapies were added to SMC, and were more effective than SMC alone [17]. Whilst CBT and GET were designed to be rehabilitative, the goal of APT was to optimise adaptation to the illness by planning and pacing activities to avoid or reduce fatigue [17]. The trial measures of safety included systematic assessments of adverse events (AEs), which occur uncommonly in trials of behavioural interventions [18]. We have already reported that there were few serious adverse events (SAEs) and even fewer serious adverse reactions (SARs), the numbers of which did not differ significantly across treatment arms [17]. We have also reported various measures of deterioration, but not whether there are any differences across treatment arms in the proportions of participants who deteriorated in the two primary outcomes by a clinically important amount [17]. This paper reports the more commonly reported non-serious adverse events (NSAEs), compares their frequency between treatment arms, and also identifies baseline factors associated with reporting larger numbers of NSAEs [17] and [19]. On the basis of the previous literature, we hypothesised that NSAEs would be associated with female sex, a larger number of physical symptoms at baseline, and both depressive and anxiety disorders present at baseline. To our knowledge there has been no previous study examining associations of NSAEs in a trial of treatments for CFS or functional somatic syndromes.

We found that there were no important differences in any of the adverse events between treatment arms, and no excess associated with either CBT or GET. Clinically important deterioration occurred least often after CBT and GET; APT may be associated with more frequent deterioration in physical functioning. We also noted that the reporting of non-serious adverse events in a clinical trial of treatment for CFS varied by recruitment centre, perhaps related to the method of ascertainment. This important finding has implications for the design of future trials. Research assessors need clear manualised guidance on the various definitions of adverse events, and specific training and supervision in order to implement them. We also found that baseline symptom count, having a depressive disorder and BMI were significantly associated with a greater number of NSAEs, independently of the treatment arms. This has both research and clinical implications for clinicians running trials, particularly those including patients with CFS. Adverse events in trials may more accurately reflect fluctuations in a condition, rather than reactions to interventions.