Clinical Trial – Page 10 – American ME and CFS Society

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME

Abstract:

Introduction: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases.

Methods: 10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry.

Results: IgG levels dropped to median 0.73 g/l (normal 7–16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6–12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.

Conclusions: IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

Source: Carmen Scheibenbogen, Madlen Loebel, Helma Freitag, Anne Krueger, Sandra Bauer, Michaela Antelmann, Wolfram Doehner, Nadja Scherbakov, Harald Heidecke, Petra Reinke, Hans-Dieter Volk, Patricia Grabowski. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLOS ONE. Published: March 15, 2018 https://doi.org/10.1371/journal.pone.0193672 (Full article)

Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial

Abstract:

BACKGROUND: Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and disabling condition. The National Institute for Health and Clinical Excellence (NICE) recommends Cognitive Behavioural Therapy (CBT) as a treatment option for paediatric CFS/ME because there is good evidence that it is effective. Despite this, most young people in the UK are unable to access local specialist CBT for CFS/ME. A randomised controlled trial (RCT) showed FITNET was effective in the Netherlands but we do not know if it is effective in the National Health Service (NHS) or if it is cost-effective. This trial will investigate whether FITNET-NHS is clinically effective and cost-effective in the NHS.

METHODS: Seven hundred and thirty-four paediatric patients (aged 11-17 years) with CFS/ ME will be randomised (1:1) to receive either FITNET-NHS (online CBT) or Activity Management (delivered via video call). The internal pilot study will use integrated qualitative methods to examine the feasibility of recruitment and the acceptability of treatment. The full trial will assess whether FITNET-NHS is clinically effective and cost-effective. The primary outcome is disability at 6 months, measured using the SF-36-PFS (Physical Function Scale) questionnaire. Cost-effectiveness is measured via cost-utility analysis from an NHS perspective. Secondary subgroup analysis will investigate the effectiveness of FITNET-NHS in those with co-morbid mood disorders.

DISCUSSION: If FITNET-NHS is found to be feasible and acceptable (internal pilot) and effective and cost-effective (full trial), its provision by the NHS has the potential to deliver substantial health gains for the large number of young people suffering from CFS/ME but unable to access treatment because there is no local specialist service. This trial will provide further evidence evaluating the delivery of online CBT to young people with chronic conditions.

TRIAL REGISTRATION: ISRCTN registry, registration number: ISRCTN18020851 . Registered on 4 August 2016.

Source: Baos S, Brigden A, Anderson E, Hollingworth W, Price S, Mills N, Beasant L, Gaunt D, Garfield K, Metcalfe C, Parslow R, Downing H, Kessler D, Macleod J, Stallard P, Knoop H, Van de Putte E, Nijhof S, Bleijenberg G, Crawley E. Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial. Trials. 2018 Feb 22;19(1):136. doi: 10.1186/s13063-018-2500-3. https://www.ncbi.nlm.nih.gov/pubmed/29471861

Note: Update published December 19, 2019. https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3895-1

Time to Reject the PACE Study

Abstract:

The PACE trial investigated the efficacy of graded exercise therapy and cognitive behavioral therapy for ME/CFS. The design and the implementation of the study were flawed, and the conclusions are contradicted by the data. It is time to reject the study.

https://www.researchgate.net/publication/320101462_Time_to_Reject_the_PACE_Study [Full article].

This is a translation of an article that was published in slightly shortened form in Läkartidningen, Stockholm, Sweden, on 28 September 2017. http://www.lakartidningen.se/

Link to the shortened article in Swedish: http://www.lakartidningen.se/Opinion/De-batt/2017/09/Dags-att-forkasta-PACE-studien/

Source: Helmfrid S, Edsberg J. Dags att förkasta PACE-studien. Lakartid-ningen. 2017;114:ETLE.

Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons

Abstract:

BACKGROUND: Preliminary evidence suggests that the enteric microbiota may play a role in the expression of neurological symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overlapping symptoms with the acute presentation of D-lactic acidosis has prompted the use of antibiotic treatment to target the overgrowth of species within the Streptococcus genus found in commensal enteric microbiota as a possible treatment for neurological symptoms in ME/CFS.

METHODS: An open-label, repeated measures design was used to examine treatment efficacy and enable sex comparisons. Participants included 44 adult ME/CFS patients (27 females) from one specialist medical clinic with Streptococcus viable counts above 3.00 × 105 cfu/g (wet weight of faeces) and with a count greater than 5% of the total count of aerobic microorganisms. The 4-week treatment protocol included alternate weeks of Erythromycin (400 mg of erythromycin as ethyl succinate salt) twice daily and probiotic (D-lactate free multistrain probiotic, 5 × 1010 cfu twice daily). 2 × 2 repeated measures ANOVAs were used to assess sex-time interactions and effects across pre- and post-intervention for microbial, lactate and clinical outcomes. Ancillary non-parametric correlations were conducted to examine interactions between change in microbiota and clinical outcomes.

RESULTS: Large treatment effects were observed for the intention-to-treat sample with a reduction in Streptococcus viable count and improvement on several clinical outcomes including total symptoms, some sleep (less awakenings, greater efficiency and quality) and cognitive symptoms (attention, processing speed, cognitive flexibility, story memory and verbal fluency). Mood, fatigue and urine D:L lactate ratio remained similar across time. Ancillary results infer that shifts in microbiota were associated with more of the variance in clinical changes for males compared with females.

CONCLUSIONS: Results support the notion that specific microorganisms interact with some ME/CFS symptoms and offer promise for the therapeutic potential of targeting gut dysbiosis in this population. Streptococcus spp. are not the primary or sole producers of D-lactate. Further investigation of lactate concentrations are needed to elucidate any role of D-lactate in this population. Concurrent microbial shifts that may be associated with clinical improvement (i.e., increased Bacteroides and Bifidobacterium or decreased Clostridium in males) invite enquiry into alternative strategies for individualised treatment.

Trial Registration Australian and New Zealand Clinical Trial Registry (ACTRN12614001077651) 9th October 2014. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366933&isReview=true.

Source: Wallis A, Ball M, Butt H, Lewis DP, McKechnie S, Paull P, Jaa-Kwee A, Bruck D. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. J Transl Med. 2018 Feb 6;16(1):24. doi: 10.1186/s12967-018-1392-z. https://www.ncbi.nlm.nih.gov/pubmed/29409505

Chronic fatigue syndrome treated with transcutaneous electrical acupoint stimulation: a randomized controlled trial

Abstract:

OBJECTIVE: To evaluate the clinical therapeutic effects and safety of chronic fatigue syndrome treated with transcutaneous electrical acupoint stimulation (TEAS) on the conception vessel and the governor vessel.

METHODS: Eighty-nine patients of chronic fatigue syndrome were randomized into an observation group (46 cases) and a control group (43 cases). In the observation group, TEAS was applied at Dazhui (GV 14) and Mingmen (GV 4), Shenque (CV 8) and Guanyuan (CV 4) [the current intensity: (14±2) mA]. In the control group, the simulated TEAS was applied at the same acupoints as the observation group (the current intensity: 1 mA). The treatment was given for 30 min, once a day, 5 times a week and the treatment of 4 weeks was as 1 session in the two groups. One session of treatment was required. Before treatment and at the end of 1 session of treatment, the fatigue severity scale (FSS) was adopted to evaluate the fatigue symptoms and the somatic and psychological health report (SPHERE) was adopted to evaluate the potential symptoms and observe the safety of TEAS therapy.

RESULTS: At the end of treatment, FSS score and SPHERE score in the control group were not different significantly as compared with those before treatment (both P>0.05). FSS score and SPHERE score in the observation group were reduced significantly as compared with those before treatment (both P<0.01). FSS score and SPHERE score in the observation group were reduced apparently as compared with those in the control group (both P<0.001). In the entire process of treatment with TEAS, no any adverse reaction occurred.

CONCLUSION: TEAS on the conception vessel and the governor vessel relieves fatigue symptoms and the potential symptoms in the patients of chronic fatigue syndrome. It is a safe therapy.

Source: Li J, Xie J, Pan Z, Guo X, Li Y, Fu R. Chronic fatigue syndrome treated with transcutaneous electrical acupoint stimulation: a randomized controlled trial. Zhongguo Zhen Jiu. 2017 Dec 12;37(12):1276-9. doi: 10.13703/j.0255-2930.2017.12.006. [Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/29354991

Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment

Abstract:

BACKGROUND: Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades.

METHODS: Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a ‘proximity extension assay’ (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA.

RESULTS: In CFS/ME patients, the ‘normalized protein expression’ value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls.

CONCLUSIONS: In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra.

TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014.

Source: Roerink ME, Knoop H, Bronkhorst EM, Mouthaan HA, Hawinkels LJAC, Joosten LAB, van der Meer JWM. Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment. J Transl Med. 2017 Dec 29;15(1):267. doi: 10.1186/s12967-017-1371-9. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1371-9 (Full article)

A randomised controlled trial of the monoaminergic stabiliser (-)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

OBJECTIVE: The monoaminergic stabiliser (-)-OSU6162 has in previous studies shown promising effects on mental fatigue after stroke and traumatic brain injury. This study investigated the safety and effectiveness of (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome.

METHODS: A total of 62 patients were randomly assigned to placebo or (-)-OSU6162. Primary outcomes were assessment on the mental fatigue scale (MFS) and the clinical global impression of change (CGI-C) scale. Secondary outcomes were results on the FibroFatigue scale (FF), the Beck Depression Inventory (BDI), the pain visual analogue scale and neuropsychological tests. Assessments were performed at baseline, after 1 and 2 weeks of treatment and at follow-up after 6 weeks.

RESULTS: MFS and CGI-C showed significant improvements for both treatment groups after treatment but not at follow-up; a similar pattern was seen for FF and BDI. However, significant differences between groups could not be demonstrated. On the other hand, correlation analyses showed a significant correlation between (-)-OSU6162 concentration and change in MFS, FF, and BDI score within the concentration interval 0.1-0.7 µM. Exploratory subgroup analyses showed a larger treatment effect with (-)-OSU6162 in improving MFS and FF symptoms in patients on antidepressant therapy compared to those without antidepressant treatment.

CONCLUSION: (-)-OSU6162 was found to be safe and well tolerated. When analysing the entire material (-)-OSU6162 was not found to differ significantly from placebo in alleviating fatigue in ME patients but was superior to placebo in counteracting fatigue in a subgroup of ME patients who received concomitant pharmacological treatment for depression.

Source: Nilsson MKL, Zachrisson O, Gottfries CG, Matousek M, Peilot B, Forsmark S, Schuit RC, Carlsson ML, Kloberg A, Carlsson A. A randomised controlled trial of the monoaminergic stabiliser (-)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome. Acta Neuropsychiatr. 2017 Dec 7:1-10. doi: 10.1017/neu.2017.35. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29212562

The Young ME Sufferers Trust: No Reported Harassment at Bristol University (Information Obtained Under FOI)

There has been no reported harassment of staff at Bristol University. Yes, you read that correctly.

We have all become accustomed to the increasingly shrill ‘harassment’ accusations against ME patients
and ‘activists’, both via the media and in lectures. This campaign appears to have originated at that now
infamous meeting of the Science Media Centre, revealed by our original 2014 Freedom of Information
Report, now updated under the title Shining a Light on the CMRC Setup (http://www.tymestrust.org/pdfs/ shiningalight.pdf). Members of the UK Research Collaborative have continued to spread these allegations ever since its launch.

In Shining a Light we stated: In the records of the meeting where ‘harassment’ of researchers was discussed, no mention was made of personal threats such as have been reported in the media. Freedom of Information (FOI) requests were listed as the most damaging type of ‘harassment’. The 2016 tribunal appeal Judgement ordering QMUL to release the PACE trial data highlights that Professor Trudie Chalder accepts that “no threats have been made either to researchers or participants”.

And yet the accusations persist and have even escalated. Tymes Trust has found this constant narrative so abhorrent that we have sought some answers. We have, once again, sought evidence.

You can read the rest of this report here: http://www.tymestrust.org/pdfs/noharassmentbristol.pdf

Clinical and cost-effectiveness of the Lightning Process in addition to specialist medical care for paediatric chronic fatigue syndrome: randomised controlled trial

Editor’s Comment: Numerous critiques of the Lightning Process have been made by physicians, medical practitioners, and patient organizations. There are cases in which LP has resulted in long-lasting physical harm. (You can read about these cases here and here.) Dr. Charles Shepherd, an ME/CFS specialist, does not recommend LP for any ME/CFS patients.

Abstract:

OBJECTIVE: Investigate the effectiveness and cost-effectiveness of the Lightning Process (LP) in addition to specialist medical care (SMC) compared with SMC alone, for children with chronic fatigue syndrome (CFS)/myalgic encephalitis (ME).

DESIGN: Pragmatic randomised controlled open trial. Participants were randomly assigned to SMC or SMC+LP. Randomisation was minimised by age and gender.

SETTING: Specialist paediatric CFS/ME service.

PATIENTS: 12-18 year olds with mild/moderate CFS/ME.

MAIN OUTCOME MEASURES: The primary outcome was the the 36-Item Short-Form Health Survey Physical Function Subscale (SF-36-PFS) at 6 months. Secondary outcomes included pain, anxiety, depression, school attendance and cost-effectiveness from a health service perspective at 3, 6 and 12 months.

RESULTS: We recruited 100 participants, of whom 51 were randomised to SMC+LP. Data from 81 participants were analysed at 6 months. Physical function (SF-36-PFS) was better in those allocated SMC+LP (adjusted difference in means 12.5(95% CI 4.5 to 20.5), p=0.003) and this improved further at 12 months (15.1 (5.8 to 24.4), p=0.002). At 6 months, fatigue and anxiety were reduced, and at 12 months, fatigue, anxiety, depression and school attendance had improved in the SMC+LP arm. Results were similar following multiple imputation. SMC+LP was probably more cost-effective in the multiple imputation dataset (difference in means in net monetary benefit at 12 months £1474(95% CI £111 to £2836), p=0.034) but not for complete cases.

CONCLUSION: The LP is effective and is probably cost-effective when provided in addition to SMC for mild/moderately affected adolescents with CFS/ME.

TRIAL REGISTRATION NUMBER: ISRCTN81456207.

Source: Crawley EM, Gaunt DM, Garfield K, Hollingworth W, Sterne JAC, Beasant L, Collin SM, Mills N, Montgomery AA. Clinical and cost-effectiveness of the Lightning Process in addition to specialist medical care for paediatric chronic fatigue syndrome: randomised controlled trial. Arch Dis Child. 2017 Sep 20. pii: archdischild-2017-313375. doi: 10.1136/archdischild-2017-313375. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28931531

How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting in tensions between patients and professionals providing them with care. A major constraint limiting progress has been the lack of a ‘gold standard’ for diagnosis; with a number of imperfect clinical and research criteria used, each defining different, though overlapping, groups of people with myalgic encephalomyelitis or chronic fatigue syndrome. We review basic epidemiological concepts to illustrate how the use of more specific and restrictive case definitions could improve research validity and drive progress in the field by reducing selection bias caused by diagnostic misclassification.

Source: Nacul L, Lacerda EM, Kingdon CC, Curran H, Bowman EW. How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? J Health Psychol. 2017 Mar 1:1359105317695803. doi: 10.1177/1359105317695803. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28810428