Category: Clinical Trial

The effect of counselling, graded exercise and usual care for people with chronic fatigue in primary care: a randomized trial

Abstract:

BACKGROUND: To evaluate the effectiveness of graded exercise therapy (GET), counselling (COUNS) and usual care plus a cognitive behaviour therapy (CBT) booklet (BUC) for people presenting with chronic fatigue in primary care.

METHOD: A randomized controlled trial in general practice. The main outcome measure was the change in the Chalder fatigue score between baseline and 6 months. Secondary outcomes included a measure of global outcome, including anxiety and depression, functional impairment and satisfaction.

RESULTS: The reduction in mean Chalder fatigue score at 6 months was 8.1 [95% confidence interval (CI) 6.6-10.4] for BUC, 10.1 (95% CI 7.5-12.6) for GET and 8.6 (95% CI 6.5-10.8) for COUNS. There were no significant differences in change scores between the three groups at the 6- or 12-month assessment. Dissatisfaction with care was high. In relation to the BUC group, the odds of dissatisfaction at the 12-month assessment were less for the GET [odds ratio (OR) 0.11, 95% CI 0.02-0.54, p=0.01] and COUNS groups (OR 0.13, 95% CI 0.03-0.53, p=0.004).

CONCLUSIONS: Our evidence suggests that fatigue presented to general practitioners (GPs) tends to remit over 6 months to a greater extent than found previously. Compared to BUC, those treated with graded exercise or counselling therapies were not significantly better with respect to the primary fatigue outcome, although they were less dissatisfied at 1 year. This evidence is generalizable nationally and internationally. We suggest that GPs ask patients to return at 6 months if their fatigue does not remit, when therapy options can be discussed further.

 

Source: Ridsdale L, Hurley M, King M, McCrone P, Donaldson N. The effect of counselling, graded exercise and usual care for people with chronic fatigue in primary care: a randomized trial. Psychol Med. 2012 Oct;42(10):2217-24. doi: 10.1017/S0033291712000256. Epub 2012 Feb 28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435871/ (Free article)

 

Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

METHODS AND FINDINGS: In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.

CONCLUSION: The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00848692.

 

Source: Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198463/ (Full article)

 

Serotonergic descending inhibition in chronic pain: design, preliminary results and early cessation of a randomized controlled trial

Abstract:

AIM: We examined whether activation of serotonergic descending pathways improves pain inhibition during exercise in patients with chronic fatigue syndrome (CFS) and comorbid fibromyalgia (FM) in comparison with rheumatoid arthritis (RA) and sedentary, healthy controls in a double-blind randomized controlled trial with cross-over design.

PATIENTS AND METHODS: Three female CFS/FM patients, one female RA patient and two healthy women were randomly allocated to the experimental group (2 ml of citalopram intravenously) or the placebo group (2 ml of 0.9% NaCl intravenously). Participants performed a submaximal exercise protocol, preceded and followed by an assessment of endogenous pain inhibition. Seven days later, groups were crossed over.

RESULTS: Significant side-effects were observed in all, but one participant immediately after intravenous administration of citalopram. One CFS/FM patient withdrew because of severe post-exertional malaise.

CONCLUSION: It was decided that proceeding with the study would be unethical. No conclusion could be made regarding pain inhibition during exercise in CFS/FM compared to RA and controls.

 

Source: Meeus M, Ickmans K, De Clerck LS, Moorkens G, Hans G, Grosemans S, Nijs J. Serotonergic descending inhibition in chronic pain: design, preliminary results and early cessation of a randomized controlled trial. In Vivo. 2011 Nov-Dec;25(6):1019-25. https://www.ncbi.nlm.nih.gov/pubmed/22021700

 

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

Abstract:

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.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Comment in:

 

Source: White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O’Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Collaborators (19). Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/ (Full article)

 

Fatigue In Teenagers on the interNET–the FITNET Trial. A randomized clinical trial of web-based cognitive behavioural therapy for adolescents with chronic fatigue syndrome: study protocol

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is increasingly recognized as a cause of disability and inactivity in adolescents in the Netherlands. CFS is characterized by unexplained fatigue lasting more than 6 months. Cognitive Behavioural Therapy (CBT) has proven to be effective. However, CBT availability for adolescents with CFS is limited and requires special therapeutic skills not always readily available. An alternative to the face-to-face CBT is FITNET, a web-based therapeutic program designed specifically for adolescents diagnosed with CFS, and their parents. This new CBT approach appeals to the modern youth, who grow up with internet as their main source of information. A web-based program offers the opportunity to lower thresholds for the acceptance and realization of healthcare. This treatment can be activated at any chosen time. The communication between patient and therapist can elapse asynchronously. If effective, this web-based program would greatly increase the therapeutic accessibility.

METHODS/DESIGN: A randomized clinical trial is currently conducted. One-hundred-forty adolescents aged 12-18 years diagnosed with CFS will be recruited and randomized to one of two groups: FITNET or usual care. After 6 months, the usual care group will have access to the FITNET program. Outcomes will be assessed at baseline, post intervention, and at 6 months follow-up. Primary outcome measures are school presence, fatigue severity, and physical functioning.

DISCUSSION: The FITNET study is the first randomized clinical trial which evaluates the effect of web-based CBT versus usual care in adolescents with CFS. The intervention is based on a theoretical existing model of CBT for patients with CFS. The results of this study will provide information about the possibility and efficacy of web-based CBT for adolescents with CFS and will reveal predictors of efficacy.

TRIAL REGISTRATION: ISRCTN: ISRCTN59878666 and ClinicalTrials.gov: NCT00893438.

 

Source: Nijhof SL, Bleijenberg G, Uiterwaal CS, Kimpen JL, van de Putte EM. Fatigue In Teenagers on the interNET–the FITNET Trial. A randomized clinical trial of web-based cognitive behavioural therapy for adolescents with chronic fatigue syndrome: study protocol. [ISRCTN59878666]. BMC Neurol. 2011 Feb 19;11:23. doi: 10.1186/1471-2377-11-23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049137/ (Full article)

 

Effect of Tuina on oxygen free radicals metabolism in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: To explore the mechanism of Tuina for treatment of chronic fatigue syndrome.

METHODS: A total of 90 patients were randomly divided into a Tuina group, a Taijiquan (take exercise) group and a Fluoxetine group, 30 cases in each group. They were treated with Tuina, Taijiquan and Fluoxetine, respectively. After a month, the therapeutic effects and the changes of malondialdehyde (MDA) content and the activity of serum superoxide dismutases (SOD) and serum glutathione peroxidase (GSH-Px) were observed.

RESULTS: The total effective rate of 93.3% (28/30) in the Tuina group was better than 80.0% (24/30) in the Taijiquan group and 73.3% (22/30) in the Fluoxetine group (both P < 0.05). After treatment, MDA contents in the three groups were all decreased (P < 0.01, P < 0.05), and the activity of SOD. GSH-Px in both the Tuina group and the Fluoxetine group were increased (P < 0.01, P < 0.05), and especially in the Tuina group with a significant difference as compared with the other two groups (P < 0.05, P < 0.01).

CONCLUSION: The therapeutic effect of the Tuina group is superior to that of the Taijiquan group and the Fluoxetine group. Tuina can regulate oxygen free radicals metabolism and clean superfluous oxygen free radicals to alleviate fatigue, which may be one of the mechanisms of Tuina in treating chronic fatigue syndrome.

 

Source: Liu CZ, Lei B. Effect of Tuina on oxygen free radicals metabolism in patients with chronic fatigue syndrome. Zhongguo Zhen Jiu. 2010 Nov;30(11):946-8. [Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/21246855

 

Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up

Abstract:

Chronic fatigue syndrome (CFS) produces physical and neurocognitive disability that significantly affects health-related quality of life (HRQL). Multidisciplinary treatment combining graded exercise therapy (GET) cognitive behavioural therapy (CBT) and pharmacological treatment has shown only short-term improvements.

Aim: To compare the effects on HRQL of (1) multidisciplinary treatment combining CBT, GET, and pharmacological treatment, and (2) usual treatment (exercise counselling and pharmacological treatment) at 12 months of follow-up.

Design: Prospective, randomized controlled trial with a follow-up of 12 months after the end of treatment.

Method: Patients consecutively diagnosed with CFS (Fukuda criteria) were randomly assigned to intervention (n = 60) or usual treatment (n = 60) groups. HRQL was assessed at baseline and 12 months by the Medical Outcomes Study Short-Form questionnaire (SF-36). Secondary outcomes included functional capacity for activities of daily living measured by the Stanford Health Assessment Questionnaire (HAQ) and comorbidities.

Results: At baseline, the two groups were similar, except for lower SF-36 emotional role scores in the intervention group. At 12 months, the intervention did not improve HRQL scores, with worse SF-36 physical function and bodily pain scores in the intervention group.

Conclusion: Multidisciplinary treatment was not superior to usual treatment at 12 months in terms of HRQL. The possible benefits of GET as part of multidisciplinary treatment for CFS should be assessed on an individual patient basis.

 

Source: Núñez M, Fernández-Solà J, Nuñez E, Fernández-Huerta JM, Godás-Sieso T, Gomez-Gil E. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011 Mar;30(3):381-9. doi: 10.1007/s10067-010-1677-y. Epub 2011 Jan 15. https://www.ncbi.nlm.nih.gov/pubmed/21234629

For a list of references see: http://link.springer.com/article/10.1007/s10067-010-1677-y

 

Amisulpride vs. fluoxetine treatment of chronic fatigue syndrome: a pilot study

Abstract:

Different pharmacologic agents have been evaluated in the treatment of Chronic Fatigue Syndrome (CFS), albeit with moderate efficacy. Among the compounds thought to present with potential to be efficacious in CFS patients stands out low-dose amisulpride, a substituted benzamide that has been shown to be an useful treatment for conditions which exhibit some overlap with CFS such as dysthymia and somatoform disorders.

We thus recruited forty non-depressed CFS patients that were randomized to receive either amisulpride 25mg bid, or fluoxetine 20mg uid; all subjects were un-blinded to the treatment regimen. At the time of enrollment in the study and after twelve weeks of treatment, enrolled subjects completed the Krupp Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and a visual analog scale focused on pain and bodily discomfort. Moreover, all subjects were evaluated by a clinician, blinded to the treatment regimen, using the Clinical Global Impression Severity Scale.

Our data revealed a significant improvement both in self-report, and observer-based measures for the amisulpride-treated, but not for the fluoxetine-treated patients. Amisulpride-treated subjects also presented with a significant reduction of somatic complaints, while the amisulpride effect on anxiety and mood levels was not significant. Both drugs were equally well tolerated.

Summing up, we showed a positive symptomatic effect of amisulpride, compared to SSRI treatment, in a group of non-depressed CSF patients on self-report and on observer-based measures of fatigue and somatic complaints. If confirmed by larger, blinded studies, amisulpride thus could represent an effective approach to this difficult-to-treat condition.

Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.

 

Source: Pardini M, Guida S, Primavera A, Krueger F, Cocito L, Gialloreti LE. Amisulpride vs. fluoxetine treatment of chronic fatigue syndrome: a pilot study. Eur Neuropsychopharmacol. 2011 Mar;21(3):282-6. doi: 10.1016/j.euroneuro.2010.10.008. Epub 2010 Nov 26. https://www.ncbi.nlm.nih.gov/pubmed/21112746

 

Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Nicotinamide adenine dinucleotide (NADH) may be depleted in chronic fatigue syndrome (SFC). The purpose of the study was to evaluate the efficacy of supplementation with NADH in these patients.

MATERIAL AND METHODS: A double blind, placebo controlled, 3 month long clinical trial was conducted. The patients were randomized to oral NADH oral 20mg or placebo during the first two months. The intensity of the fatigue, functional performance, mood state, functional impact of the fatigue, quality of life, sleep quality, exercise capacity and functional reserve as well as the investigator’s and patient’s opinion on the efficacy of the intervention prior to and at 30, 60 and 90 days of the onset of the treatment were evaluated. A stress test was performed in the baseline visit and at 60 days (last day of the double blind treatment).

RESULTS: A total of 86 patients, 77 of whom completed the study (mean age, 47 years, 72 women) were enrolled. No significant differences were found in most of the variable studied at the end of the study. Administration of NADH was associated to a decrease in anxiety condition of -1.0 points (p<0.05) and of -0.2 points (p=NS) in the placebo assigned group. Maximum heart rate after the stress test decreased a mean of -8.1l/min (p<0.05) in the NADH group and increased by +1.7l/min in the placebo group (p=0.73). No differences were found in the perception of efficacy with NADH and placebo, by the investigator and patients.

CONCLUSIONS: Administration of oral NADH was associated to a decrease in anxiety and maximum heart rate, after a stress test in patients with CFS. On the contrary, this treatment did not modify other clinical variables and the global functional performance.

 

Source: Alegre J, Rosés JM, Javierre C, Ruiz-Baqués A, Segundo MJ, de Sevilla TF. Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome. Rev Clin Esp. 2010 Jun;210(6):284-8. doi: 10.1016/j.rce.2009.09.015. Epub 2010 May 5. [Article in Spanish] https://www.ncbi.nlm.nih.gov/pubmed/20447621

 

Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial

Abstract:

OBJECTIVE: To evaluate the effectiveness of home delivered pragmatic rehabilitation-a programme of gradually increasing activity designed collaboratively by the patient and the therapist-and supportive listening-an approach based on non-directive counselling-for patients in primary care with chronic fatigue syndrome/myalgic encephalomyelitis or encephalitis (CFS/ME).

DESIGN: Single blind, randomised, controlled trial.

SETTING: 186 general practices across the north west of England between February 2005 and May 2007.

PARTICIPANTS: 296 patients aged 18 or over with CFS/ME (median illness duration seven years) diagnosed using the Oxford criteria.

INTERVENTIONS: Participants were randomly allocated to pragmatic rehabilitation, supportive listening, or general practitioner treatment as usual. Both therapies were delivered at home in 10 sessions over 18 weeks by one of three adult specialty general nurses who had received four months’ training, including supervised practice, in each of the interventions. GP treatment as usual was unconstrained except that patients were not to be referred for systematic psychological therapies during the treatment period. Main outcome measures The primary clinical outcomes were fatigue and physical functioning at the end of treatment (20 weeks) and 70 weeks from recruitment compared with GP treatment as usual. Lower fatigue scores and higher physical functioning scores denote better outcomes.

RESULTS: A total of 257 (87%) of the 296 patients who entered the trial were assessed at 70 weeks, the primary outcome point. Analysis was on an intention to treat basis, with robust treatment effects estimated after adjustment for missing data using probability weights. Immediately after treatment (at 20 weeks), patients allocated to pragmatic rehabilitation (n=95) had significantly improved fatigue (effect estimate -1.18, 95% confidence interval -2.18 to -0.18; P=0.021) but not physical functioning (-0.18, 95% CI -5.88 to +5.52; P=0.950) compared with patients allocated to treatment as usual (n=100). At one year after finishing treatment (70 weeks), there were no statistically significant differences in fatigue or physical functioning between patients allocated to pragmatic rehabilitation and those on treatment as usual (-1.00, 95% CI -2.10 to +0.11; P=0.076 and +2.57, 95% CI 3.90 to +9.03; P=0.435). At 20 weeks, patients allocated to supportive listening (n=101) had poorer physical functioning than those allocated to treatment as usual (-7.54, 95% CI -12.76 to -2.33; P=0.005) and no difference in fatigue. At 70 weeks, patients allocated to supportive listening did not differ significantly from those allocated to treatment as usual on either primary outcome.

CONCLUSIONS: For patients with CFS/ME in primary care, pragmatic rehabilitation delivered by trained nurse therapists improves fatigue in the short term compared with unconstrained GP treatment as usual, but the effect is small and not statistically significant at one year follow-up. Supportive listening delivered by trained nurse therapists is not an effective treatment for CFS/ME.

Trial registration International Standard Randomised Controlled Trial Number IRCTN74156610.

Comment in:

Pragmatic rehabilitation for chronic fatigue syndrome. [BMJ. 2010]

Nurse-delivered, home-based pragmatic rehabilitation has a short-term effect on improving fatigue in people with chronic fatigue syndrome compared with usual GP care, but effects were not sustained at 1 year. [Evid Based Nurs. 2010]

 

Source: Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, Riste L, Richardson G, Lovell K, Dunn G; Fatigue Intervention by Nurses Evaluation (FINE) trial writing group and the FINE trial group and 23 Collaborators. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ. 2010 Apr 23;340:c1777. doi: 10.1136/bmj.c1777. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859122/ (Full article)