Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.

BACKGROUND: Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments. METHODS: In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094. FINDINGS: We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p = 0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p = 0·0003), but did not differ for APT (0·7 [-0·9 to 2·3] points lower; p = 0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p = 0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p = 0·0005), but did not differ for APT (3·4 [-1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p = 0·0027; GET p = 0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group. INTERPRETATION: CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition. FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.

Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

OBJECTIVES: To test the hypothesis that group cognitive behavioural therapy (CBT) will produce an effective and cost-effective management strategy for patients in primary care with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME). DESIGN: A double-blind, randomised controlled trial was adopted with three arms. Outcomes were assessed at baseline and 6 and 12 months after first assessment and results were analysed on an intention-to-treat basis. SETTING: A health psychology department for the management of chronic illness in a general hospital in Bristol, UK. PARTICIPANTS: Adults with a diagnosis of CFS/ME referred by their GP. INTERVENTIONS: The three interventions were group CBT incorporating graded activity scheduling, education and support group (EAS) and standard medical care (SMC). OUTCOME MEASURES: The primary outcome measure was the Short Form with 36 Items (SF-36) physical and mental health summary scales. Other outcome measures included the Chalder fatigue scale, Hospital Anxiety and Depression Scale, General Health Questionnaire, physical function (shuttles walked, walking speed and perceived fatigue), health utilities index and cognitive function (mood, recall and reaction times). RESULTS: A total of 153 patients were recruited to the trial and 52 were randomised to receive CBT, 50 to EAS and 51 to SMC. Twelve patients failed to attend for the 12-month follow-up and 19 patients attended one follow-up, but not both. The sample was found to be representative of the patient group and the characteristics of the three groups were similar at baseline. Three outcome measures, SF-36 mental health score, Chalder fatigue scale and walking speed, showed statistically significant differences between the groups. Patients in the CBT group had significantly higher mental health scores [difference +4.35, 95% confidence interval (CI) +0.72 to +7.97, p = 0.019], less fatigue (difference -2.61, 95% CI -4.92 to -0.30, p = 0.027) and were able to walk faster (difference +2.83 shuttles, 95% CI +1.12 to +5.53, p = 0.0013) than patients in the SMC group. CBT patients also walked faster and were less fatigued than those randomised to EAS (walking speed: difference +1.77, 95% CI +0.025 to +3.51, p = 0.047; fatigue: difference -3.16, 95% CI -5.59 to -0.74, p = 0.011). Overall, no other statistically significant difference across the groups was found, although for many measures a trend towards an improved outcome with CBT was seen. Except for walking speed, which, on average, increased by +0.87 shuttles (95% CI +0.09 to +1.65, p = 0.029) between the 6- and 12-month follow-ups, the scores were similar at 6 and 12 months. At baseline, 30% of patients had an SF-36 physical score within the normal range and 52% had an SF-36 mental health score in the normal range. At 12 months, the physical score was in the normal range for 46% of the CBT group, 26% of the EAS group and 44% of SMC patients. For mental health score the percentages were CBT 74%, EAS 67% and SMC 70%. Of the CBT group, 32% showed at least a 15% increase in physical function and 64% achieved a similar improvement in their mental health. For the EAS and SMC groups, this improvement in physical and mental health was achieved for 40 and 60% (EAS) and 49 and 53% (SMC), respectively. The cost-effectiveness of the intervention proved very difficult to assess and did not yield reliable conclusions. CONCLUSIONS: Group CBT did not achieve the expected change in the primary outcome measure as a significant number did not achieve scores within the normal range post-intervention. The treatment did not return a significant number of subjects to within the normal range on this domain; however, significant improvements were evident in some areas. Group CBT was effective in treating symptoms of fatigue, mood and physical fitness in CFS/ME. It was found to be as effective as trials using individual therapy in these domains. However, it did not bring about improvement in cognitive function or quality of life. There was also evidence of improvement in the EAS group, which indicates that there is limited value in the non-specific effects of therapy. Further research is needed to develop better outcome measures, assessments of the broader costs of the illness and a clearer picture of the characteristics best fitted to this type of intervention.

Antimalarial sulfide, sulfone, and sulfonamide trioxanes.

A series of trioxanes featuring sulfide, sulfone, and sulfonamide substituents in diverse positions has been prepared. Structure-activity relationship (SAR) generalizations highlight two major factors controlling the antimalarial potency of these new chemical entities: (1) the proximity of the sulfur-containing substituent to the crucial peroxide bond and (2) the oxidation state of the sulfur-containing substituent. Generally, sulfones are more antimalarially potent than the corresponding sulfides.

Antimalarial, antiproliferative, and antitumor activities of artemisinin-derived, chemically robust, trioxane dimers.

Nine C-10 non-acetal derivatives of the natural trioxane artemisinin (1) were prepared as dimers using some novel chemistry. As designed, each dimer was stable chemically. C-10 Olefinic dimers 7 and C-10 saturated dimers 8-13 all showed good to excellent antimalarial and antiproliferative activities in vitro. Dimers 8, 10, and 12 were especially potent and selective at inhibiting growth of some human cancer cell lines in the NCI in vitro 60-cell line assay.

Antimalarial cyclic peroxy ketals.

Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with readily available aryl methyl ketones. Structure-activity correlations using in vitro antimalarial data as a guide for optimization of potency have led to the design and synthesis of seven new peroxides that have IC50 values of 31-85 nM (artemisinin IC50 = 8.4 nM). Some SAR generalizations are discussed.