Category: Clinical Trial

Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue

Abstract:

BACKGROUND:Twelve patients with long-standing symptoms of central nervous system (CNS) dysfunction were found to have elevated antibody titres to human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV). All patients had four or more of the following neurocognitive symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression.

OBJECTIVES: We sought to determine whether elevated antibodies to EBV and HHV-6 indicated chronic viral activation in patients with CNS dysfunction and if their symptoms could be improved by suppressing viral activity with oral valganciclovir.

STUDY DESIGN: Patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1-8 years) were treated with 6 months of valganciclovir in an open label study.

RESULTS: Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activites. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (p = 0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (p = 0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients.

CONCLUSION: These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.

 

Source: Kogelnik AM, Loomis K, Hoegh-Petersen M, Rosso F, Hischier C, Montoya JG. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006 Dec;37 Suppl 1:S33-8. https://www.ncbi.nlm.nih.gov/pubmed/17276366

 

Chronic fatigue syndrome

I have just read the review of treatments for chronic fatigue syndrome (CFS) in the October issue of the JRSM. It included my study, but some of the details were inaccurate and the overall judgement was unfair and potentially misleading.

In the original ‘York’ review of the various treatments for CFS, my study received a validity score of two. However, after clarification regarding the statistical analysis, this was changed to three (Kleijnen, personal communication). Chambers et al. were clearly not aware of the ‘correction’ and published the original score. It’s a minor issue, but it wasn’t the only one.

Another example relates to the assessment of the results. According to the table (p. 511), the programme had no overall effect—but as the authors noted in their recent review for NICE (http://www.nice.org.uk/page.aspx?o=368933, appendix 1, p. 423), there were ‘significant differences between groups for fatigue… and somatic symptoms’. They would also have been aware that 82% of the patients rated themselves as ‘better’ or ‘much better’ and that 23% had improved to such a degree that they were discharged.

To summarize, patients reported less fatigue, fewer somatic symptoms, less anxiety and depression after six months compared to the controls, and the improvements were maintained at follow-up. Yet the authors judged the treatment had ‘no overall effect’.

My study is one of the few which has assessed an alternative to the CBT-based programmes. It’s also one of the few controlled trials to include pacing, a strategy which many patients regard as a particularly helpful way of managing their limited energy. In my opinion, it deserved an accurate evaluation and a fair summary of the outcome. It didn’t get that.

You can read the rest of this comment here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1761664/

Comment on: Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. [J R Soc Med. 2006]

 

Source: Goudsmit EM. Chronic fatigue syndrome. J R Soc Med. 2007 Jan;100(1):7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1761664/ (Full article)

 

A placebo-controlled, double-blind, randomized controlled trial of a natural killer cell stimulant (BioBran MGN-3) in chronic fatigue syndrome

Abstract:

BACKGROUND: Previous research has suggested that natural killer (NK) cell activity may be reduced in patients with chronic fatigue syndrome (CFS).

AIM: To evaluate the effectiveness of a putative NK cell stimulant, BioBran MGN-3, in reducing fatigue in CFS patients.

DESIGN: Randomized, double-blind, placebo-controlled trial.

METHODS: We recruited 71 patients with CFS (according to the Centers for Disease Control 1994 criteria) attending an out-patient specialist CFS service. Participants were given oral BioBran MGN-3 for 8 weeks (2 g three times per day) or placebo equivalent. The primary outcome measure was the Chalder physical fatigue score. Self-reported fatigue measures, self-assessment of improvement, change in key symptoms, quality of life, anxiety and depression measures were also included.

RESULTS: Data were complete in 64/71 patients. Both groups showed marked improvement over the study duration, but without significant differences. Mean improvement in the Chalder fatigue score (physical scale) was 0.3 (95%CI -2.6 to 3.2) lower in the BioBran group.

DISCUSSION: The findings do not support a specific therapeutic effect for BioBran in CFS. The improvement showed by both groups over time highlights the importance of placebo controls when evaluating interventions in CFS.

 

Source: McDermott C, Richards SC, Thomas PW, Montgomery J, Lewith G. A placebo-controlled, double-blind, randomized controlled trial of a natural killer cell stimulant (BioBran MGN-3) in chronic fatigue syndrome. QJM. 2006 Jul;99(7):461-8. Epub 2006 Jun 29. http://qjmed.oxfordjournals.org/content/99/7/461.long (Full article)

 

Fatigue Intervention by Nurses Evaluation–the FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol.[ISRCTN74156610]

Abstract:

BACKGROUND: Chronic fatigue syndrome, also known as ME (CFS/ME), is a condition characterised primarily by severe, disabling fatigue, of unknown origin, which has a poor prognosis and serious personal and economic consequences. Evidence for the effectiveness of any treatment for CFS/ME in primary care, where most patients are seen, is sparse. Recently, a brief, pragmatic treatment for CFS/ME, based on a physiological dysregulation model of the condition, was shown to be successful in improving fatigue and physical functioning in patients in secondary care. The treatment involves providing patients with a readily understandable explanation of their symptoms, from which flows the rationale for a graded rehabilitative plan, developed collaboratively with the therapist. The present trial will test the effectiveness and cost-effectiveness of pragmatic rehabilitation when delivered by specially trained general nurses in primary care. We selected a client-centred counselling intervention, called supportive listening, as a comparison treatment. Counselling has been shown to be as effective as cognitive behaviour therapy for treating fatigue in primary care, is more readily available, and controls for supportive therapist contact time. Our control condition is treatment as usual by the general practitioner (GP).

METHODS AND DESIGN: This study protocol describes the design of an ongoing, single-blind, pragmatic randomized controlled trial of a brief (18 week) self-help treatment, pragmatic rehabilitation, delivered by specially trained nurse-therapists in patients’ homes, compared with nurse-therapist delivered supportive listening and treatment as usual by the GP. An economic evaluation, taking a societal viewpoint, is being carried out alongside the clinical trial. Three adult general nurses were trained over a six month period to deliver the two interventions. Patients aged over 18 and fulfilling the Oxford criteria for CFS are assessed at baseline, after the intervention, and again one year later. Primary outcomes are self-reported physical functioning and fatigue at one year, and will be analysed on an intention-to-treat basis. A qualitative study will examine the interventions’ mechanisms of change, and also GPs’ drivers and barriers towards referral.

 

Source: Wearden AJ, Riste L, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, Dunn G, Richardson G, Lovell K, Powell P. Fatigue Intervention by Nurses Evaluation–the FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. [ISRCTN74156610]. BMC Med. 2006 Apr 7;4:9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456982/ (Full article)

 

Does methylphenidate reduce the symptoms of chronic fatigue syndrome?

Abstract:

PURPOSE: Chronic fatigue syndrome is a clinical entity consisting of prolonged and debilitating fatigue in which concentration disturbances are very frequent. Until now, no medical treatment has shown any efficacy. The objectives of this study were to investigate the short-term effects of methylphenidate, an amphetamine derivative, on fatigue, concentration disturbances, and quality of life.

SUBJECTS AND METHODS: A double-blind randomized placebo-controlled crossover study was conducted in 60 patients who fulfilled the 1994 Centers for Disease Control criteria for chronic fatigue syndrome and had concentration difficulties. Patients were enrolled between March 2003 and March 2004 at the outpatient department of a university hospital referral center for chronic fatigue syndrome patients. Random assignment to 4 weeks treatment with methylphenidate 2 x 10 mg/day, followed by 4 weeks of placebo treatment, or 4 weeks of placebo treatment, followed by methylphenidate treatment. Fatigue and concentration were measured with a Checklist Individual Strength (CIS) and a Visual Analogue Scale (VAS).

RESULTS: Fatigue scores fell significantly during methylphenidate intake in comparison with baseline (mean difference: -0.7, P = .010 for VAS; mean difference: -11.8, P <.0001 for CIS) and in comparison with placebo (mean difference: -1.0, P = .001 for VAS; mean difference: -9.7, P <.0001 for CIS). Concentration disturbances, measured with a VAS improved significantly under methylphenidate treatment compared with baseline (mean difference: -1.3, P <.0001) and compared with placebo (mean difference: -1.1, P <.0001). A clinical significant effect (> or =33% improvement or CIS < or =76) on fatigue was achieved in 17% of patients, who were considered responders; on concentration in 22% of patients.

CONCLUSIONS: Methylphenidate at a dose of 2 x 10 mg/day is significantly better than placebo in relieving fatigue and concentration disturbances in a minority of chronic fatigue syndrome patients. Further studies are needed to investigate the long-term effects of this treatment.

 

Source: Blockmans D, Persoons P, Van Houdenhove B, Bobbaers H. Does methylphenidate reduce the symptoms of chronic fatigue syndrome? Am J Med. 2006 Feb;119(2):167.e23-30. https://www.ncbi.nlm.nih.gov/pubmed/16443425

 

Effect of physical factors on bioelectric properties of cell nuclei of buccal epithelium in students with chronic fatigue syndrome

Abstract:

60 students with the syndrome of chronic fatigue have been observed in a sanatorium. 35 patients of the main (first) group underwent hydrokinesotherapy. The patients of the second group attended physical exercises as follows: girls attended shaping classes and contrast douche, boys exercised on different training apparatus and took too contrast douche. An estimation of efficiency of the carried out treatment was conducted with the help of clinical and paraclinical methods of the study.

Electrokinetic properties of cellular nuclei of buccalium epithelium were tested to reveal a general nonspecific resistance of the human body. The data of assessment of an electrical potential (Z-potential) showed that clinical improvement coincided with the increase in electrokinetic mobility of cell nucleus of buccalium epithelium (P<0.01). Physical factors proved to have positive influence on homeostas of patients of the main group. This index was not reliable in patients of the second group (P>0.5).

 

Source: Samoĭlovych VA, Hutarieva NV, Tondiĭ LD. Effect of physical factors on bioelectric properties of cell nuclei of buccal epithelium in students with chronic fatigue syndrome. Lik Sprava. 2005 Jul-Sep;(5-6):60-4. [Article in Ukrainian] http://www.ncbi.nlm.nih.gov/pubmed/16396296

 

Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome

Abstract:

OBJECTIVE: To compare effectiveness of oral therapy with reduced nicotinamide adenine dinucleotide (NADH) to conventional modalities of treatment in patients with chronic fatigue syndrome (CFS).

BACKGROUND: CFS is a potentially disabling condition of unknown etiology. Although its clinical presentation is associated to a myriad of symptoms, fatigue is a universal and essential finding for its diagnosis. No therapeutic regimen has proven effective for this condition.

METHODS: A total of 31 patients fulfilling the Centers for Disease Control criteria for CFS, were randomly assigned to either NADH or nutritional supplements and psychological therapy for 24 months. A thorough medical history, physical examination and completion of a questionnaire on the severity of fatigue and other symptoms were performed each trimester of therapy. In addition, all of them underwent evaluation in terms of immunological parameters and viral antibody titers. Statistical analysis was applied to the demographic data, as well as to symptoms scores at baseline and at each trimester of therapy.

RESULTS: The twelve patients who received NADH had a dramatic and statistically significant reduction of the mean symptom score in the first trimester (p < 0.001). However, symptom scores in the subsequent trimesters of therapy were similar in both treatment groups. Elevated IgG and Ig E antibody levels were found in a significant number of patients.

CONCLUSIONS: Observed effectiveness of NADH over conventional treatment in the first trimester of the trial and the trend of improvement of that modality in the subsequent trimesters should be further assessed in a larger patient sample.

 

Source: Santaella ML, Font I, Disdier OM. Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. P R Health Sci J. 2004 Jun;23(2):89-93. http://www.ncbi.nlm.nih.gov/pubmed/15377055

 

Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial

Abstract:

CONTEXT: There is no established pharmacological treatment for the core symptoms of chronic fatigue syndrome (CFS). Galantamine hydrobromide, an acetyl cholesterone inhibitor, has pharmacological properties that might benefit patients with CFS.

OBJECTIVE: To compare the efficacy and tolerability of galantamine hydrobromide in patients with CFS.

DESIGN, SETTING, AND PATIENTS: Randomized, double-blind trial conducted June 1997 through July 1999 at 35 outpatient centers in the United Kingdom (n = 17), United States (n = 14), the Netherlands (n = 2), Sweden (n = 1), and Belgium (n = 1) involving 434 patients with a clinical diagnosis of CFS (modified US Centers for Disease Control and Prevention criteria).

INTERVENTIONS: A total of 89 patients were randomly assigned to receive 2.5 mg of galantamine hydrobromide; 86 patients, 5.0 mg; 91 patients, 7.5 mg; and 86 patients, 10 mg (these patients received medicine in the tablet form 3 times per day); a total of 82 patients received matching placebo tablets 3 times per day.

MAIN OUTCOME MEASURES: The primary efficacy variable was the global change on the Clinician Global Impression Scale after 4, 8, 12, and 16 weeks of treatment. Secondary outcomes were changes in core symptoms of CFS on the Chalder Fatigue Rating Scale, the Fibromyalgia Impact Questionnaire, and the Pittsburgh Sleep Quality Index; changes in quality of life on the Nottingham Health Profile; and assessment of plasma-free cortisol levels and cognitive performance on a computer-based battery of tests.

RESULTS: After 16 weeks, there were no statistically significant differences between any of the galantamine or placebo groups in clinical condition on the Clinician Global Impression Scale, or for any of the secondary end points. Exploratory regression analysis failed to detect any consistent prognostic factor that might have influenced the primary or any secondary outcome measures.

CONCLUSION: This trial did not demonstrate any benefit of galantamine over placebo in the treatment of patients with CFS.

Comment in:

Pharmacotherapy of chronic fatigue syndrome: another gallant attempt. [JAMA. 2004]

Chronic fatigue syndrome and the cholinergic hypothesis. [JAMA. 2004]

 

Source: Blacker CV, Greenwood DT, Wesnes KA, Wilson R, Woodward C, Howe I, Ali T. Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial. JAMA. 2004 Sep 8;292(10):1195-204. http://www.ncbi.nlm.nih.gov/pubmed/15353532

 

Randomised controlled trial of graded exercise in chronic fatigue syndrome

Abstract:

OBJECTIVE: To investigate whether 12 weeks of graded exercise with pacing would improve specific physiological, psychological and cognitive functions in people with chronic fatigue syndrome (CFS).

DESIGN: Randomised controlled trial.

SETTING: Human performance laboratory at the University of Western Australia.

PARTICIPANTS: 61 patients aged between 16 and 74 years diagnosed with CFS.

INTERVENTIONS: Either graded exercise with pacing (32 patients) or relaxation/flexibility therapy (29 patients) performed twice a day over 12 weeks.

MAIN OUTCOME MEASURES: Changes in any of the physiological, psychological or cognitive variables assessed.

RESULTS: Following the graded exercise intervention, scores were improved for resting systolic blood pressure (P = 0.018), work capacity (W.kg(-1)) (P = 0.019), net blood lactate production (P = 0.036), depression (P = 0.027) and performance on a modified Stroop Colour Word test (P = 0.029). Rating of perceived exertion scores, associated with an exercise test, was lower after graded exercise (P = 0.013). No such changes were observed in the relaxation/flexibility condition, which served as an attention-placebo control.

CONCLUSIONS: Graded exercise was associated with improvements in physical work capacity, as well as in specific psychological and cognitive variables. Improvements may be associated with the abandonment of avoidance behaviours.

Comment in:

To exercise or not to exercise in chronic fatigue syndrome? No longer a question. [Med J Aust. 2004]

To exercise or not to exercise in chronic fatigue syndrome? [Med J Aust. 2004]

 

Source: Wallman KE1, Morton AR, Goodman C, Grove R, Guilfoyle AM. Randomised controlled trial of graded exercise in chronic fatigue syndrome. Med J Aust. 2004 May 3;180(9):444-8. http://www.ncbi.nlm.nih.gov/pubmed/15115421

 

Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome

Abstract:

OBJECTIVES: We compared the effects of acetylcarnitine, propionylcarnitine and both compounds on the symptoms of chronic fatigue syndrome(CFS).

METHODS: In an open, randomized fashion we compared 2 g/d acetyl-L-carnitine, 2 g/d propionyl-L-carnitine, and its combination in 3 groups of 30 CFS patients during 24 weeks. Effects were rated by clinical global impression of change. Secondary endpoints were the Multidimensional Fatigue Inventory, McGill Pain Questionnaire, and the Stroop attention concentration test. Scores were assessed 8 weeks before treatment; at randomization; after 8, 16, and 24 weeks of treatment; and 2 weeks later.

RESULTS: Clinical global impression of change after treatment showed considerable improvement in 59% of the patients in the acetylcarnitine group and 63% in the propionylcarnitine group, but less in the acetylcarnitine plus propionylcarnitine group (37%). Acetylcarnitine significantly improved mental fatigue (p =.015) and propionylcarnitine improved general fatigue (p =.004). Attention concentration improved in all groups, whereas pain complaints did not decrease in any group. Two weeks after treatment, worsening of fatigue was experienced by 52%, 50%, and 37% in the acetylcarnitine, propionylcarnitine, and combined group, respectively. In the acetylcarnitine group, but not in the other groups, the changes in plasma carnitine levels correlated with clinical improvement.

CONCLUSIONS: Acetylcarnitine and propionylcarnitine showed beneficial effect on fatigue and attention concentration. Less improvement was found by the combined treatment. Acetylcarnitine had main effect on mental fatigue and propionylcarnitine on general fatigue.

 

Source: Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004 Mar-Apr;66(2):276-82. http://www.ncbi.nlm.nih.gov/pubmed/15039515