Clinical Trial – Page 17 – American ME and CFS Society

Recovery from chronic fatigue syndrome after treatments given in the PACE trial

Abstract:

BACKGROUND: A multi-centre, four-arm trial (the PACE trial) found that rehabilitative cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective treatments for chronic fatigue syndrome (CFS) than specialist medical care (SMC) alone, when each was added to SMC, and more effective than adaptive pacing therapy (APT) when added to SMC. In this study we compared how many participants recovered after each treatment.

METHOD: We defined recovery operationally using multiple criteria, and compared the proportions of participants meeting each individual criterion along with two composite criteria, defined as (a) recovery in the context of the trial and (b) clinical recovery from the current episode of the illness, however defined, 52 weeks after randomization. We used logistic regression modelling to compare treatments.

RESULTS: The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, 8% (12/149) after APT and 7% (11/150) after SMC. Similar proportions met criteria for clinical recovery. The odds ratio (OR) for trial recovery after CBT was 3.36 [95% confidence interval (CI) 1.64–6.88] and for GET 3.38 (95% CI 1.65–6.93), when compared to APT, and after CBT 3.69 (95% CI 1.77–7.69) and GET 3.71 (95% CI 1.78–7.74), when compared to SMC (p values < or =0.001 for all comparisons). There was no significant difference between APT and SMC. Similar proportions recovered in trial subgroups meeting different definitions of the illness.

CONCLUSIONS: This study confirms that recovery from CFS is possible, and that CBT and GET are the therapies most likely to lead to recovery.

Comment in: Reports of recovery in chronic fatigue syndrome may present less than meets the eye. [Evid Based Ment Health. 2014]

Source: White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35. doi: 10.1017/S0033291713000020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285/ (Full study)

Cost-effectiveness of supported self-management for CFS/ME patients in primary care

Abstract:

BACKGROUND: Nurse led self-help treatments for people with chronic fatigue syndrome/myalgic encephalitis (CFS/ME) have been shown to be effective in reducing fatigue but their cost-effectiveness is unknown.

METHODS: Cost-effectiveness analysis conducted alongside a single blind randomised controlled trial comparing pragmatic rehabilitation (PR) and supportive listening (SL) delivered by primary care nurses, and treatment as usual (TAU) delivered by the general practitioner (GP) in North West England. A within trial analysis was conducted comparing the costs and quality adjusted life years (QALYs) measured within the time frame of the trial. 296 patients aged 18 and over with CFS/ME diagnosed using the Oxford criteria were included in the cost-effectiveness analysis.

RESULTS: Treatment as usual is less expensive and leads to better patient outcomes compared with Supportive Listening. Treatment as usual is also less expensive than Pragmatic Rehabilitation. PR was effective at reducing fatigue in the short term, but the impact of the intervention on QALYs was uncertain. However, based on the results of this trial, PR is unlikely to be cost-effective in this patient population.

CONCLUSIONS: This analysis does not support the introduction of SL. Any benefits generated by PR are unlikely to be of sufficient magnitude to warrant recommending PR for this patient group on cost-effectiveness grounds alone. However, dissatisfaction with current treatment options means simply continuing with ‘treatment as usual’ in primary care is unlikely to be acceptable to patients and practitioners.

TRIAL REGISTRATION: The trial registration number is IRCTN74156610.

Source: Richardson G, Epstein D, Chew-Graham C, Dowrick C, Bentall RP, Morriss RK, Peters S, Riste L, Lovell K, Dunn G, Wearden AJ; FINE Trial Writing group on behalf of the FINE Trial group. Collaborators (23). Cost-effectiveness of supported self-management for CFS/ME patients in primary care. BMC Fam Pract. 2013 Jan 18;14:12. doi: 10.1186/1471-2296-14-12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556109/ (Full article)

Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers

Abstract:

Valganciclovir has been reported to improve physical and cognitive symptoms in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) IgG antibody titers. This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients.

An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG ≥ 1:320, EBV viral capsid antigen (VCA) IgG ≥ 1:640, and EBV early antigen (EA) IgG ≥ 1:160. Patients self-rated physical and cognitive functioning as a percentage of their functioning prior to illness. Patients were categorized as responders if they experienced at least 30% improvement in physical and/or cognitive functioning. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. Baseline antibody titers showed no significant association with response.

After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001). Longer treatment was associated with improved response (P = 0.0002). No significant difference was found between responders and non-responders among other variables analyzed. Valganciclovir treatment, independent of the baseline antibody titers, was associated with self-rated improvement in physical and cognitive functioning for CFS patients who had positive HHV-6 and/or EBV serologies. Longer valganciclovir treatment correlated with an improved response.

Source: Watt T, Oberfoell S, Balise R, Lunn MR, Kar AK, Merrihew L, Bhangoo MS, Montoya JG. Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J Med Virol. 2012 Dec;84(12):1967-74. doi: 10.1002/jmv.23411. https://www.ncbi.nlm.nih.gov/pubmed/23080504

Use of lisdexamfetamine dimesylate in treatment of executive functioning deficits and chronic fatigue syndrome: a double blind, placebo-controlled study

Abstract:

The purpose of this study was to assess the efficacy of lisdexamfetamine dimesylate (LDX) for the treatment of executive functioning deficits in adults (ages 18-60) with chronic fatigue syndrome (CFS). The study’s primary outcome measure was the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A). Secondary outcome measures were standardized assessments of fatigue, pain and global functioning.

Twenty-six adults who met criteria for CFS and had clinically significant executive functioning deficits were randomly assigned to a flexible morning dose (30, 50, 70 mg/day) of either placebo or LDX for a 6-week trial. The data were analyzed with standard analysis of variance (ANOVA) procedures. Participants in the LDX group showed significantly more positive change in BRIEF-A scores (Mchange=21.38, SD=15.85) than those in the placebo group (Mchange=3.36, SD=7.26).

Participants in the active group also reported significantly less fatigue and generalized pain relative to the placebo group. Although future studies with LDX should examine whether these benefits generalize to larger, more diverse samples of patients, these results suggest that LDX could be a safe and efficacious treatment for the executive functioning deficits often associated with CFS. The possibility that dopaminergic medications could play an important role addressing the symptoms of CFS is also discussed.

Source: Young JL. Use of lisdexamfetamine dimesylate in treatment of executive functioning deficits and chronic fatigue syndrome: a double blind, placebo-controlled study. Psychiatry Res. 2013 May 15;207(1-2):127-33. doi: 10.1016/j.psychres.2012.09.007. Epub 2012 Oct 9. https://www.ncbi.nlm.nih.gov/pubmed/23062791

Cost-effectiveness of counselling, graded-exercise and usual care for chronic fatigue: evidence from a randomised trial in primary care

Abstract:

BACKGROUND: Fatigue is common and has been shown to result in high economic costs to society. The aim of this study is to compare the cost-effectiveness of two active therapies, graded-exercise (GET) and counselling (COUN) with usual care plus a self-help booklet (BUC) for people presenting with chronic fatigue.

METHODS: A randomised controlled trial was conducted with participants consulting for fatigue of over three months’ duration recruited from 31 general practices in South East England and allocated to one of three arms. Outcomes and use of services were assessed at 6-month follow-up. The main outcome measure used in the economic evaluation was clinically significant improvements in fatigue, measured using the Chalder fatigue scale. Cost-effectiveness was assessed using the net-benefit approach and cost-effectiveness acceptability curves.

RESULTS: Full economic and outcome data at six months were available for 163 participants; GET = 51, COUN = 58 and BUC = 54. Those receiving the active therapies (GET and COUN) had more contacts with care professionals and therefore higher costs, these differences being statistically significant. COUN was more expensive and less effective than the other two therapies. The incremental cost-effectiveness ratio of GET compared to BUC was equal to £987 per unit of clinically significant improvement. However, there was much uncertainty around this result.

CONCLUSION: This study does not provide a clear recommendation about which therapeutic option to adopt, based on efficiency, for patients with chronic fatigue. It suggests that COUN is not cost-effective, but it is unclear whether GET represents value for money compared to BUC.

Clinical Trial Registration number at ISRCTN register: 72136156.

Source: Sabes-Figuera R, McCrone P, Hurley M, King M, Donaldson AN, Ridsdale L. Cost-effectiveness of counselling, graded-exercise and usual care for chronic fatigue: evidence from a randomised trial in primary care. BMC Health Serv Res. 2012 Aug 20;12:264. doi: 10.1186/1472-6963-12-264. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480915/ (Full article)

Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial

Abstract:

BACKGROUND: This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.

FINDINGS: Five adolescent CFS patients (14-19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.

CONCLUSION: Clonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).

Source: Fagermoen E, Sulheim D, Winger A, Andersen AM, Vethe NT, Saul JP, Thaulow E, Wyller VB. Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial. BMC Res Notes. 2012 Aug 7;5:418. doi: 10.1186/1756-0500-5-418. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461473/ (Full article)

Cognitive behavioural therapy versus multidisciplinary rehabilitation treatment for patients with chronic fatigue syndrome: study protocol for a randomised controlled trial (FatiGo)

Abstract:

BACKGROUND: Patients with chronic fatigue syndrome experience extreme fatigue, which often leads to substantial limitations of occupational, educational, social and personal activities. Currently, there is no consensus regarding the treatment. Patients try many different therapies to overcome their fatigue. Although there is no consensus, cognitive behavioural therapy is seen as one of the most effective treatments. Little is known about multidisciplinary rehabilitation treatment, a combination of cognitive behavioural therapy with principles of mindfulness, gradual increase of activities, body awareness therapy and pacing. The difference in effectiveness and cost-effectiveness between multidisciplinary rehabilitation treatment and cognitive behavioural therapy is as yet unknown. The FatiGo (Fatigue-Go) trial aims to compare the effects of both treatment approaches in outpatient rehabilitation on fatigue severity and quality of life in patients with chronic fatigue syndrome.

METHODS: One hundred twenty patients who meet the criteria of chronic fatigue syndrome, fulfill the inclusion criteria and sign the informed consent form will be recruited. Both treatments take 6 months to complete. The outcome will be assessed at 6 and 12 months after the start of treatment. Two weeks after the start of treatment, expectancy and credibility will be measured, and patients will be asked to write down their personal goals and score their current performance on these goals on a visual analogue scale. At 6 and 14 weeks after the start of treatment, the primary outcome and three potential mediators-self-efficacy, causal attributions and present-centred attention-awareness-will be measured. Primary outcomes are fatigue severity and quality of life. Secondary outcomes are physical activity, psychological symptoms, self-efficacy, causal attributions, impact of disease on emotional and physical functioning, present-centred attention-awareness, life satisfaction, patient personal goals, self-rated improvement and economic costs. The primary analysis will be based on intention to treat, and longitudinal analysis of covariance will be used to compare treatments.

DISCUSSION: The results of the trial will provide information on the effects of cognitive behavioural therapy and multidisciplinary rehabilitation treatment at 6 and 12 months follow-up, mediators of the outcome, cost-effectiveness, cost-utility, and the influence of treatment expectancy and credibility on the effectiveness of both treatments in patients with chronic fatigue syndrome.

TRIAL REGISTRATION: Current Controlled Trials ISRCTN77567702.

Source: Vos-Vromans DC, Smeets RJ, Rijnders LJ, Gorrissen RR, Pont M, Köke AJ, Hitters MW, Evers SM, Knottnerus AJ. Cognitive behavioural therapy versus multidisciplinary rehabilitation treatment for patients with chronic fatigue syndrome: study protocol for a randomised controlled trial (FatiGo). Trials. 2012 May 30;13:71. doi: 10.1186/1745-6215-13-71. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781576/ (Full article)

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C(12)U), in patients with debilitating CFS/ME.

METHODS AND FINDINGS: A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.

CONCLUSIONS/SIGNIFICANCE: Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00215800.

Source: Strayer DR, Carter WA, Stouch BC, Stevens SR, Bateman L, Cimoch PJ, Lapp CW, Peterson DL; Chronic Fatigue Syndrome AMP-516 Study Group, Mitchell WM.Collaborators (12). A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. doi: 10.1371/journal.pone.0031334. Epub 2012 Mar 14.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/ (Full article)

Protocol for the “four steps to control your fatigue (4-STEPS)” randomised controlled trial: a self-regulation based physical activity intervention for patients with unexplained chronic fatigue

Abstract:

BACKGROUND: Unexplained Chronic Fatigue is a medical condition characterized by the presence of persistent, severe and debilitating medically unexplained fatigue, leading to impaired functioning and lower quality of life. Research suggests that physical activity can contribute to the reduction of fatigue and other somatic symptoms and can thus significantly improve physical functioning and quality of life in these patients. Based on the self-regulation (SR) theory of behaviour change, we developed a brief physical activity program for patients suffering from unexplained chronic fatigue which focuses on the training of self-regulation skills, the “4-STEPS to control your fatigue” program.

METHODS/DESIGN: This is a multi-centre, randomised controlled trial (RCT) that will be carried out in local primary care centres and at the Portuguese Fibromyalgia and Chronic Fatigue Syndrome Patients Association. Patients aged between 18 and 65 and fulfilling operationalized criteria for Idiopathic Chronic Fatigue (ICF) and Chronic Fatigue Syndrome (CFS) will be recruited and randomly allocated to standard care (SC) or standard care plus a self-regulation based physical activity program (4-STEPS). Patients will be assessed at baseline, after the intervention (3 months) and at 12 months follow-up. The primary outcome is fatigue severity.

DISCUSSION: The results of the RCT will provide information about the effectiveness of a brief self-regulation intervention for promoting physical activity in patients with unexplained chronic fatigue. If the program proves to be effective, it may be considered as an adjunctive treatment for these patients.

TRIAL REGISTRATION: ISRCTN: ISRCTN70763996.

Source: Marques M, De Gucht V, Maes S, Leal I. Protocol for the “four steps to control your fatigue (4-STEPS)” randomised controlled trial: a self-regulation based physical activity intervention for patients with unexplained chronic fatigue. BMC Public Health. 2012 Mar 19;12:202. doi: 10.1186/1471-2458-12-202. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359226/ (Full article)

Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial

Abstract:

BACKGROUND: Chronic fatigue syndrome is characterised by persistent fatigue and severe disability. Cognitive behavioural therapy seems to be a promising treatment, but its availability is restricted. We developed Fatigue In Teenagers on the interNET (FITNET), the first dedicated internet-based therapeutic program for adolescents with this disorder, and compared its effectiveness with that of usual care.

METHODS: Adolescents aged 12-18 years with chronic fatigue syndrome were assigned to FITNET or usual care in a 1:1 ratio at one tertiary treatment centre in the Netherlands by use of a computer-generated blocked randomisation allocation schedule. The study was open label. Primary outcomes were school attendance, fatigue severity, and physical functioning, and were assessed at 6 months with computerised questionnaires. Analysis was by intention to treat. Thereafter, all patients were offered FITNET if needed. This trial is registered, number ISRCTN59878666.

FINDINGS: 68 of 135 adolescents were assigned to FITNET and 67 to usual care, and 67 and 64, respectively, were analysed. FITNET was significantly more effective than was usual care for all dichotomised primary outcomes at 6 months-full school attendance (50 [75%] vs 10 [16%], relative risk 4·8, 95% CI 2·7-8·9; p<0·0001), absence of severe fatigue (57 [85%] vs 17 [27%], 3·2, 2·1-4·9; p<0·0001), and normal physical functioning (52 [78%] vs 13 [20%], 3·8, 2·3-6·3; p<0·0001). No serious adverse events were reported.

INTERPRETATION: FITNET offers a readily accessible and highly effective treatment for adolescents with chronic fatigue syndrome. The results of this study justify implementation on a broader scale.

FUNDING: Netherlands Organisation for Health Research and Development.

Source: Nijhof SL, Bleijenberg G, Uiterwaal CS, Kimpen JL, van de Putte EM. Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial. Lancet. 2012 Apr 14;379(9824):1412-8. doi: 10.1016/S0140-6736(12)60025-7. Epub 2012 Mar 3. https://www.ncbi.nlm.nih.gov/pubmed/22385683