Category: Clinical Trial

The protocol for a randomised controlled trial comparing intermittent and graded exercise to usual care for chronic fatigue syndrome patients

Abstract:

BACKGROUND: Chronic Fatigue Syndrome is a debilitating disorder with an unknown aetiology but suspected multifactorial origins. Common “triggers” include severe viral infections and emotional stress. Recent studies have also found evidence of immune dysfunction and elevated inflammatory cytokines in CFS patients, but there has been considerable variation in the outcome measures and magnitude of these studies. Currently, there is no cure for CFS but treatments include rest, specialist medical care, cognitive behavioural therapy, and graded (self-paced) exercise. To date, several studies have examined the efficacy of graded exercise with or without Cognitive Behavioural Therapy, with some success for patients. However, improvements in functional capacity have not necessarily correlated with improvements in immune function, fatigue or other symptoms. This 12-week pilot trial compares graded and intermittent exercise to normal care, measuring physiological outcomes, fatigue levels, immune function and wellness.

METHODS/DESIGN: 90 patients aged between 16 to 60 years, who meet the diagnostic criteria for CFS and have been diagnosed by their medical practitioner, will be randomly recruited into groups consisting of Intermittent exercise, Graded exercise and usual care (Control). The outcomes will be measured pre-study (Week 0) and post-study (Week 13). Primary outcomes are VO2peak, anaerobic threshold, peak power, levels of fatigue, immune cell (CD3+CD4+, CD3+CD8+, CD19+, CD 16+CD56+) concentrations and activation. Secondary outcomes include onset of secondary CFS symptoms (e.g. fever, swollen lymph nodes), wellness, mood and sleep patterns. Primary analysis will be based on intention to treat using logistic regression models to compare treatments. Quantitative data will be analysed using repeated measures ANOVA with a linear model, and Cohen’s effect size. Qualitative data such as participants’ responses (e.g. changes in mood and other reactions) following the exercise modalities will be read and sections demarcated. A code will be applied to each segment. A prevalence of codes will be considered thematically.

DISCUSSION: The results of the trial will provide information about the efficacy of intermittent and graded exercise compared to usual care (rest and lifestyle recommendations), contributing to the evidence for best-practice CFS management.

TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12612001241820.

 

Source: Broadbent S, Coutts R. The protocol for a randomised controlled trial comparing intermittent and graded exercise to usual care for chronic fatigue syndrome patients. BMC Sports Sci Med Rehabil. 2013 Aug 30;5(1):16. doi: 10.1186/2052-1847-5-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848853/ (Full article)

 

Acupuncture for chronic fatigue syndrome: a randomized, sham-controlled trial with single-blinded design

Abstract:

CONTEXT: Given that the etiology of chronic fatigue syndrome (CFS) is believed to be multidimensional, interventions generally have been nonspecific and typically produce only mild to moderate effects. In medical practice, treatment for CFS remains largely symptomatic. Preliminary evidence of the efficacy of acupuncture for CFS is available, but the field has lacked high-quality trials.

OBJECTIVE: The research team conducted the study to determine the efficacy of acupuncture for CFS.

DESIGN: A two-arm, randomized, controlled, singleblinded design was adopted.

SETTING: The study took place in a teaching laboratory at the School of Chinese Medicine at the University of Hong Kong, Hong Kong, China.

PARTICIPANTS: Recruited through press publicity in Hong Kong, 127 individuals–40 men and 87 women–participated in the study. Intervention Through careful implementation of sham acupuncture in the control group (CG), the study blinded all participants with regard to their experimental or control status. The treatment regime was 2 sessions/wk for 4 consecutive wk.

OUTCOME MEASURES: Measures of fatigue (Chalder’s Fatigue Scale), health-related quality of life (SF-12), and general mental health (GH Q-12) were taken at baseline and upon completion of treatment.

RESULTS: Ninety-nine participants completed the interventions, with 50 and 49 participants in the experimental group (EG) and CG respectively. Repeated measures ANOVA revealed a significant decrease in physical (F(1,93) = 4.327; P = .040) and mental fatigue (F(1,96) = 10.451; P = .002) and improvement in the physical component score of SF-12 (F(1,93) = 4.774; P = .031). Considerable effects with Cohen’s d were observed in the sham-control group: 0.92, 0.78, and 0.38 for the three scores, respectively. These positive effects could have included some therapeutic effects due to pressure on the acupuncture points from the sham needles in addition to normal placebo effects. The EG showed moderate net effect sizes with Cohen’s d: 0.52, 0.63, and 0.54 for the three outcome measures, respectively.

CONCLUSION: Despite considerable positive effects for the CG, the EG demonstrated significant net-effect sizes at a moderate magnitude in physical and mental fatigue and in the physical component of health-related quality of life. The impacts on general mental health outcomes appeared to be smaller.

 

Source: Ng SM, Yiu YM. Acupuncture for chronic fatigue syndrome: a randomized, sham-controlled trial with single-blinded design. Altern Ther Health Med. 2013 Jul-Aug;19(4):21-6. https://www.ncbi.nlm.nih.gov/pubmed/23981369

 

Response to Derek Enlander

Sir,

Derek Enlander’s comments refer to Table 4 in our paper1 which describes the association of baseline characteristics with change in physical function at follow-up. It does not describe the outcome which can be found in Table 2. This shows an improvement in fatigue (−6.8; 95% CI −7.4 to −6.2; P < 0.001), physical function (4.4, 95% CI 3.0 to 5.8; P < 0.001), anxiety, depression and pain at follow-up.

In addition, as we state in the methods, the scores from the different inventories were re-scaled, so that a regression coefficient of 1 represents a 10% change in the score. Hence, the coefficient of −0.47 (95% CI −0.58 to −0.36) for the mean change in (re-scaled) SF-36 physical function per unit (re-scaled) Chalder Fatigue score at baseline, indicates that each 10% increment in baseline Chalder Fatigue (i.e. 3.3 points on the original 0 to 33 scale) is associated with a mean change of −4.7 points (95% CI −5.8 to −3.6 points) on the original 0 to 100 SF-36 scale at follow-up. Similarly, the coefficient of 0.81 (95% CI 0.75 to 0.87) for the mean change in (re-scaled) SF-36 physical function per unit (re-scaled) SF-36 score at baseline, indicates that each 10% increment in baseline physical function (i.e. 10 points on the original 0 to 100 SF-36 scale) is associated with a mean change of 8.1 points (95% CI 7.5 to 8.7 points) on the original 0 to 100 SF-36 scale at follow-up.

In summary, our paper shows that patients showed improvements in fatigue, physical disability, anxiety, depression and pain. Table 4 referred to by Derek Enlander show that worse fatigue and disability at assessment predict a worse outcome for disability at follow-up.

You can read the rest of this comment here: https://academic.oup.com/qjmed/article/107/3/247/1569245/Response-to-Derek-Enlander

Comment on

 

Source: Crawley E. Response to Derek Enlander. QJM. 2014 Mar;107(3):247. doi: 10.1093/qjmed/hct171. Epub 2013 Aug 22. https://academic.oup.com/qjmed/article/107/3/247/1569245/Response-to-Derek-Enlander (Full article)

 

 

RE: ‘Treatment outcome in adults with chronic fatigue syndrome: a prospective study

Sir,

In a very impressive paper1 embracing a large cohort (834) of ME CFS (myalgic encephalomyelitis, Chronic fatigue syndrome) patients selected by the Fukuda criteria, we can see in Table 4 the associations and changes of baseline characteristics with physical function at follow-up in the Chalder Fatigue scale −0.47 (−0.58 to −0.36) and in the SF-36 (physical function phase) 0.81 (0.75 to 0.87). This perhaps represents approximately an 8% change after the PACE recommended GET/CBT therapy after a variable number of months of therapy. This shows a relatively insignificant improvement. Do we presume that the authors therefore are not emphatically encouraging the PACE recommendation of GET/CBT as a means of primary treatment of ME CFS?

Comment in

Comment on

Source: Enlander D. RE: ‘Treatment outcome in adults with chronic fatigue syndrome: a prospective study. QJM. 2014 Jan;107(1):87. doi: 10.1093/qjmed/hct169. Epub 2013 Aug 22. https://academic.oup.com/qjmed/article/107/1/87/1513843/RE-Treatment-outcome-in-adults-with-chronic

 

Pain in chronic fatigue syndrome: response to rehabilitative treatments in the PACE trial

Abstract:

BACKGROUND: Pain is a common symptom of chronic fatigue syndrome (CFS). We investigated the effects of the treatments used in the PACE trial [cognitive behavioural therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy (APT) and specialist medical care (SMC)] on pain in CFS.

METHOD: We compared pain outcomes including individual painful symptoms, taken from the CDC criteria for CFS and co-morbid fibromyalgia. We modelled outcomes adjusting for baseline variables with multiple linear regression.

RESULTS: Significantly less frequent muscle pain was reported by patients following treatment with CBT compared to SMC (mean difference = 0.38 unit change in frequency, p = 0.02), GET versus SMC (0.42, p = 0.01) and GET versus APT (0.37, p = 0.01). Significantly less joint pain was reported following CBT versus APT (0.35, p = 0.02) and GET versus APT (0.36, p = 0.02). Co-morbid fibromyalgia was less frequent following GET versus SMC (0.03, p = 0.03). The effect sizes of these differences varied between 0.25 and 0.31 for muscle pain and 0.24 and 0.26 for joint pain. Treatment effects on pain were independent of ‘change in fatigue’.

CONCLUSIONS: CBT and GET were more effective in reducing the frequency of both muscle and joint pain than APT and SMC. When compared to SMC, GET also reduced the frequency of co-morbid fibromyalgia; the size of this effect on pain was small.

 

Source: Bourke JH, Johnson AL, Sharpe M, Chalder T, White PD. Pain in chronic fatigue syndrome: response to rehabilitative treatments in the PACE trial. Psychol Med. 2014 May;44(7):1545-52. doi: 10.1017/S0033291713002201. Epub 2013 Aug 23. https://www.ncbi.nlm.nih.gov/pubmed/23967878

 

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome

Abstract:

There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have been proposed as infectious triggers.

Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI-20) and Fatigue Severity Scale (FSS) scores, self-reported cognitive function, and physician-determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels.

VGCV patients experienced a greater improvement by MFI-20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders (P = 0.029). In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1-profile (P < 0.001). Viral IgG antibody titers did not differ between arms.

VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00478465.

© 2013 Wiley Periodicals, Inc.

 

Source: Montoya JG, Kogelnik AM, Bhangoo M, Lunn MR, Flamand L, Merrihew LE, Watt T, Kubo JT, Paik J, Desai M. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013 Dec;85(12):2101-9. doi: 10.1002/jmv.23713. Epub 2013 Aug 19. https://www.ncbi.nlm.nih.gov/pubmed/23959519

 

Chronic fatigue self-management in primary care: a randomized trial

Abstract:

OBJECTIVE: To assess the efficacy of brief fatigue self-management (FSM) for medically unexplained chronic fatigue (UCF) and chronic fatigue syndrome (CFS) in primary care.

METHODS: A randomized controlled design was used wherein 111 patients with UCF or CFS were randomly assigned to two sessions of FSM, two sessions of symptom monitoring support (attention control; AC), or a usual care control condition (UC). Participants were assessed at baseline and at 3 and 12 months after treatment. The primary outcome, the Fatigue Severity Scale, measured fatigue impact on functioning. Analysis was by intention to treat (multiple imputation) and also by per protocol.

RESULTS: A group × time interaction across the 15-month trial showed significantly greater reductions in fatigue impact in the FSM group in comparison with the AC group (p < .023) and the UC group (p < .013). Medium effect sizes for reduced fatigue impact in the FSM group were found in comparison with the AC group (d = 0.46) and the UC group (d = 0.40). The per-protocol analysis revealed large effect sizes for the same comparisons. Clinically significant decreases in fatigue impact were found for 53% of participants in the FSM condition, 14% in the AC condition, and 17% in the UC condition. Dropout rates at the 12-month follow-up were high (42%-53%), perhaps attributable to the burden of monthly telephone calls to assess health care use.

CONCLUSION: A brief self-management intervention for patients with UCF or CFS seemed to be clinically effective for reducing the impact of fatigue on functioning.

Trial Registration clinicaltrials.gov Identifier: NCT00997451.

 

Source: Friedberg F, Napoli A, Coronel J, Adamowicz J, Seva V, Caikauskaite I, Ngan MC, Chang J, Meng H. Chronic fatigue self-management in primary care: a randomized trial. Psychosom Med. 2013 Sep;75(7):650-7. doi: 10.1097/PSY.0b013e31829dbed4. Epub 2013 Aug 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785003/ (Full article)

 

Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut

Abstract:

Certain therapeutic microbes, including Bifidobacteria infantis (B. infantis) 35624 exert beneficial immunoregulatory effects by mimicking commensal-immune interactions; however, the value of these effects in patients with non-gastrointestinal inflammatory conditions remains unclear.

In this study, we assessed the impact of oral administration of B. infantis 35624, for 6‒8 weeks on inflammatory biomarker and plasma cytokine levels in patients with ulcerative colitis (UC) (n = 22), chronic fatigue syndrome (CFS) (n = 48) and psoriasis (n = 26) in three separate randomized, double-blind, placebo-controlled interventions. Additionally, the effect of B. infantis 35624 on immunological biomarkers in healthy subjects (n = 22) was assessed.

At baseline, both gastrointestinal (UC) and non-gastrointestinal (CFS and psoriasis) patients had significantly increased plasma levels of C-reactive protein (CRP) and the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) compared with healthy volunteers. B. infantis 35624 feeding resulted in reduced plasma CRP levels in all three inflammatory disorders compared with placebo.

Interestingly, plasma TNF-α was reduced in CFS and psoriasis while IL-6 was reduced in UC and CFS. Furthermore, in healthy subjects, LPS-stimulated TNF-α and IL-6 secretion by peripheral blood mononuclear cells (PBMCs) was significantly reduced in the B. infantis 35624-treated groups compared with placebo following eight weeks of feeding.

These results demonstrate the ability of this microbe to reduce systemic pro-inflammatory biomarkers in both gastrointestinal and non-gastrointestinal conditions. In conclusion, these data show that the immunomodulatory effects of the microbiota in humans are not limited to the mucosal immune system but extend to the systemic immune system.

 

Source: Groeger D, O’Mahony L, Murphy EF, Bourke JF, Dinan TG, Kiely B, Shanahan F, Quigley EM. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013 Jul-Aug;4(4):325-39. doi: 10.4161/gmic.25487. Epub 2013 Jun 21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744517/ (Full article)

 

An open-label study of effects of acupuncture on chronic fatigue syndrome and idiopathic chronic fatigue: study protocol for a randomized controlled trial

Abstract:

BACKGROUND: Even though chronic fatigue syndrome and idiopathic chronic fatigue are quite common, there are no clearly known causes. Most treatments are therefore symptomatic in nature, and chronic fatigue syndrome and idiopathic chronic fatigue patients are highly interested in using oriental medicine or complementary and alternative medicine treatment. Acupuncture, one of the major treatments used in oriental medicine, is effective in treating various diseases. This study will attempt to analyze the effectiveness and safety of acupuncture in the treatment of chronic fatigue by comparing the two treatment groups (body acupuncture, Sa-am acupuncture) and the control group (usual care).

METHODS/DESIGN: This study consists of a four-center, three-arm, randomized, controlled, and open-label trial. One hundred and fifty participants are randomly divided into treatment groups A and B and a control group. The treatment groups will receive acupuncture treatments either two or three times per week for a total of 10 sessions over a period of 4 weeks. The control group will not receive acupuncture treatments and will continue their usual care during this period. The primary outcome variable is the Fatigue Severity Scale, which will be utilized 5 weeks after randomization. Secondary outcome variables are the Fatigue Severity Scale at 13 weeks, a short form of the Stress Response Inventory, the Beck Depression Inventory, the Numeric Rating Scale, and the EuroQol-5 Dimension at 5 and 13 weeks after randomization.

DISCUSSION: This study will provide evidence with high external validity on the effectiveness and safety of acupuncture as a treatment for chronic fatigue syndrome and idiopathic chronic fatigue.

TRIAL REGISTRATION: Clinical Research Information Service KCT0000508.

 

Source: Kim JE, Hong KE, Kim HJ, Choi JB, Baek YH, Seo BK, Lee S, Kang KW, Lee MH, Kim JH, Lee S, Jung SY, Jung HJ, Shin MS, Choi SM. An open-label study of effects of acupuncture on chronic fatigue syndrome and idiopathic chronic fatigue: study protocol for a randomized controlled trial. Trials. 2013 May 21;14:147. doi: 10.1186/1745-6215-14-147. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663812/ (Full article)

 

Apology

Dear Sir,

In our commentary [1] on paper by Broderick et al. regarding diagnostic criteria for CFS [2], Professor van Der Meer and I inadvertently cited a letter by Stouten et al. in a section of our correspondence suggesting that their response to the publication of the PACE [3] trial for patients with CFS was unscientific and included personal attacks on the authors of that study, as it was interspersed with a series of letters that met those descriptors. However, it is clear that the letter by Stouten et al. raised valid scientific concerns about the trial. We wish to note that this letter should not have been included as an example in our correspondence and apologize to the authors for any distress caused.

Comment on: A controversial consensus–comment on article by Broderick et al. [J Intern Med. 2012]

 

Source: Lloyd AR. Apology. J Intern Med. 2013 Jun;273(6):628. doi: 10.1111/joim.12074. Epub 2013 May 6. http://onlinelibrary.wiley.com/doi/10.1111/joim.12074/full (Full article)