Clinical Trial – Page 14 – American ME and CFS Society

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract:

Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing.

At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation.

PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01108731.

Source: Natelson BH, Vu D, Mao X, Weiduschat N, Togo F, Lange G, Blate M, Kang G, Coplan JD, Shungu DC. Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial. J Pain. 2015 Nov;16(11):1211-9. doi: 10.1016/j.jpain.2015.08.004. Epub 2015 Aug 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630071/ (Full article)

Multidisciplinary rehabilitation treatment versus cognitive behavioural therapy for patients with chronic fatigue syndrome: a randomized controlled trial

Abstract:

OBJECTIVES: The aim of this trial was to evaluate the difference in treatment effect, at 26 and 52 weeks after the start of treatment, between cognitive behavioural therapy (CBT) and multidisciplinary rehabilitation treatment (MRT) for patients with chronic fatigue syndrome (CFS).

DESIGN: Multicentre, randomized controlled trial of patients with CFS. Participants were randomly assigned to MRT or CBT.

SETTING: Four rehabilitation centres in the Netherlands.

SUBJECTS: A total of 122 patients participated in the trial.

MAIN OUTCOME MEASURES: Primary outcomes were fatigue measured by the fatigue subscale of the Checklist Individual Strength and health-related quality of life measured by the Short-Form 36. Outcomes were assessed prior to treatment and at 26 and 52 weeks after treatment initiation.

RESULTS: A total of 114 participants completed the assessment at 26 weeks, and 112 completed the assessment at 52 weeks. MRT was significantly more effective than CBT in reducing fatigue at 52 weeks. The estimated difference in fatigue between the two treatments was -3.02 [95% confidence interval (CI) -8.07 to 2.03; P = 0.24] at 26 weeks and -5.69 (95% CI -10.62 to -0.76; P = 0.02) at 52 weeks. Patients showed an improvement in quality of life over time, but between-group differences were not significant.

CONCLUSION: This study provides evidence that MRT is more effective in reducing long-term fatigue severity than CBT in patients with CFS. Although implementation in comparable populations can be recommended based on clinical effectiveness, it is advisable to analyse the cost-effectiveness and replicate these findings in another multicentre trial.

Source: Vos-Vromans DC, Smeets RJ, Huijnen IP, Köke AJ, Hitters WM, Rijnders LJ, Pont M, Winkens B, Knottnerus JA. Multidisciplinary rehabilitation treatment versus cognitive behavioural therapy for patients with chronic fatigue syndrome: a randomized controlled trial. J Intern Med. 2016 Mar;279(3):268-82. doi: 10.1111/joim.12402. Epub 2015 Aug 26. https://www.ncbi.nlm.nih.gov/pubmed/26306716

Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome – A randomized, controlled, double-blind trial

Abstract:

BACKGROUND & AIMS: Chronic Fatigue Syndrome (CFS) is a complex condition, characterized by severe disabling fatigue with no known cause, no established diagnostic tests, and no universally effective treatment. Several studies have proposed symptomatic treatment with coenzyme Q10 (CoQ10) and nicotinamide adenine dinucleotide (NADH) supplementation. The primary endpoint was to assess the effect of CoQ10 plus NADH supplementation on age-predicted maximum heart rate (max HR) during a cycle ergometer test. Secondary measures included fatigue, pain and sleep.

METHODS: A proof-of-concept, 8-week, randomized, controlled, double-blind trial was conducted in 80 CFS patients assigned to receive either CoQ10 plus NADH supplementation or matching placebo twice daily. Maximum HR was evaluated at baseline and at end of the run-in period using an exercise test. Fatigue, pain and sleep were evaluated at baseline, and then reassessed at 4- and 8-weeks through self-reported questionnaires.

RESULTS: The CoQ10 plus NADH group showed a significant reduction in max HR during a cycle ergometer test at week 8 versus baseline (P = 0.022). Perception of fatigue also showed a decrease through all follow-up visits in active group versus placebo (P = 0.03). However, pain and sleep did not improve in the active group. Coenzyme Q10 plus NADH was generally safe and well tolerated.

CONCLUSIONS: Our results suggest that CoQ10 plus NADH supplementation for 8 weeks is safe and potentially effective in reducing max HR during a cycle ergometer test and also on fatigue in CFS. Further additional larger controlled trials are needed to confirm these findings.

Clinical trial registration. This trial was registered at clinicaltrials.gov as NCT02063126.

Source: Castro-Marrero J, Sáez-Francàs N, Segundo MJ, Calvo N, Faro M, Aliste L, Fernández de Sevilla T, Alegre J. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome – A randomized, controlled, double-blind trial. Clin Nutr. 2016 Aug;35(4):826-34. doi: 10.1016/j.clnu.2015.07.010. Epub 2015 Jul 17. http://www.clinicalnutritionjournal.com/article/S0261-5614(15)00189-2/fulltext (Full article)

Acupuncture for chronic fatigue syndrome and idiopathic chronic fatigue: a multicenter, nonblinded, randomized controlled trial

Abstract:

BACKGROUND: The causes of chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF) are not clearly known, and there are no definitive treatments for them. Therefore, patients with CFS and ICF are interested in Oriental medicine or complementary and alternative medicine. For this reason, the effectiveness of complementary and alternative treatments should be verified. We investigated the effectiveness of two forms of acupuncture added to usual care for CFS and ICF compared to usual care alone.

METHODS: A three-arm parallel, non-blinded, randomized controlled trial was performed in four hospitals. We divided 150 participants into treatment and control groups at the same ratio. The treatment groups (Group A, body acupuncture; Group B, Sa-am acupuncture) received 10 sessions for 4 weeks. The control group (Group C) continued usual care alone. The primary outcome was the Fatigue Severity Scale (FSS) at 5 weeks after randomization. Secondary outcomes were the FSS at 13 weeks and a short form of the Stress Response Inventory (SRI), the Beck Depression Inventory (BDI), the Numeric Rating Scale (NRS), and the EuroQol-5 Dimension (EQ-5D) at 5 and 13 weeks.

RESULTS: Group A showed significantly lower FSS scores than Group C at 5 weeks (P = 0.023). SRI scores were significantly lower in the treatment groups than in the control group at 5 (Group A, P = 0.032; B, P <0.001) and 13 weeks (Group A, P = 0.037; B, P <0.001). Group B showed significantly lower BDI scores than Group C at 13 weeks (P = 0.007). NRS scores from the treatment groups were significantly reduced compared to control at 5 (Group A and B, P <0.001) and 13 weeks (Group A, P = 0.011; B, P = 0.002).

CONCLUSIONS: Body acupuncture for 4 weeks in addition to usual care may help improve fatigue in CFS and ICF patients.

TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0000508; Registered on 12 August 2012.

Source: Kim JE, Seo BK, Choi JB, Kim HJ, Kim TH, Lee MH, Kang KW, Kim JH, Shin KM, Lee S, Jung SY, Kim AR, Shin MS, Jung HJ, Park HJ, Kim SP, Baek YH, Hong KE, Choi SM. Acupuncture for chronic fatigue syndrome and idiopathic chronic fatigue: a multicenter, nonblinded, randomized controlled trial. Trials. 2015 Jul 26;16:314. doi: 10.1186/s13063-015-0857-0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515016/ (Full article)

The planning, implementation and publication of a complex intervention trial for chronic fatigue syndrome: the PACE trial

Abstract:

The PACE trial was a four-arm trial of specialist medical care, compared with specialist medical care with a supplementary therapy: adaptive pacing therapy, cognitive-behavioural therapy or graded exercise therapy, for patients with chronic fatigue syndrome. The trial found that both cognitive-behavioural and graded exercise therapies were more effective than either of the other two treatments in reducing fatigue and improving physical disability. This paper describes the design, conduct and main results of the trial, along with a description of the challenges that had to be overcome in order to produce clear answers to the clinically important questions the trial posed.

Source: White PD, Chalder T, Sharpe M. The planning, implementation and publication of a complex intervention trial for chronic fatigue syndrome: the PACE trial. BJPsych Bull. 2015 Feb;39(1):24-7. doi: 10.1192/pb.bp.113.045005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495840/ (Full article)

B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment

Abstract:

BACKGROUND: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.

METHODS: In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.

FINDINGS: Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.

CONCLUSION: In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01156909.

Source: Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898. doi: 10.1371/journal.pone.0129898. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488509/ (Full article)

A randomized, placebo-controlled, double-blinded trial of duloxetine in the treatment of general fatigue in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: To assess the efficacy and safety of duloxetine in patients with chronic fatigue syndrome.

METHODS: A 12-week, randomized, double-blind study was designed to compare duloxetine 60-120 mg/d (n = 30) with placebo (n = 30) for efficacy and safety in the treatment of patients with chronic fatigue syndrome. The primary outcome measure was the Multidimensional Fatigue Inventory general fatigue subscale (range: 4-20, with higher scores indicating greater fatigue). Secondary measures were the remaining Multidimensional Fatigue Inventory subscales, Brief Pain Inventory, Medical Outcomes Study Short Form-36, Hospital Anxiety and Depression Scale, Centers for Disease Control and Prevention Symptom Inventory, Patient Global Impression of Improvement, and Clinical Global Impression of Severity. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect.

RESULTS: The improvement in the Multidimensional Fatigue Inventory general fatigue scores for the duloxetine group was not significantly greater than for the placebo group (P = 0.23; estimated difference between groups at week 12 = -1.0 [95% CI: -2.8, 0.7]). The duloxetine group was significantly superior to the placebo group on the Multidimensional Fatigue Inventory mental fatigue score, Brief Pain Inventory average pain severity and interference scores, Short Form-36 bodily pain domain, and Clinical Global Impression of Severity score. Duloxetine was generally well tolerated.

CONCLUSION: The primary efficacy measure of general fatigue did not significantly improve with duloxetine when compared with placebo. Significant improvement in secondary measures of mental fatigue, pain, and global measure of severity suggests that duloxetine may be efficacious for some chronic fatigue syndrome symptom domains, but larger controlled trials are needed to confirm these results.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00375973.

Source: Arnold LM, Blom TJ, Welge JA, Mariutto E, Heller A. A randomized, placebo-controlled, double-blinded trial of duloxetine in the treatment of general fatigue in patients with chronic fatigue syndrome. Psychosomatics. 2015 May-Jun;56(3):242-53. doi: 10.1016/j.psym.2014.12.003. Epub 2014 Dec 16. https://www.ncbi.nlm.nih.gov/pubmed/25660434

Isometric yoga improves the fatigue and pain of patients with chronic fatigue syndrome who are resistant to conventional therapy: a randomized, controlled trial

Abstract:

BACKGROUND: Patients with chronic fatigue syndrome (CFS) often complain of persistent fatigue even after conventional therapies such as pharmacotherapy, cognitive behavioral therapy, or graded exercise therapy. The aim of this study was to investigate in a randomized, controlled trial the feasibility and efficacy of isometric yoga in patients with CFS who are resistant to conventional treatments.

METHODS: This trial enrolled 30 patients with CFS who did not have satisfactory improvement after receiving conventional therapy for at least six months. They were randomly divided into two groups and were treated with either conventional pharmacotherapy (control group, n = 15) or conventional therapy together with isometric yoga practice that consisted of biweekly, 20-minute sessions with a yoga instructor and daily in-home sessions (yoga group, n = 15) for approximately two months. The short-term effect of isometric yoga on fatigue was assessed by administration of the Profile of Mood Status (POMS) questionnaire immediately before and after the final 20-minute session with the instructor. The long-term effect of isometric yoga on fatigue was assessed by administration of the Chalder’s Fatigue Scale (FS) questionnaire to both groups before and after the intervention. Adverse events and changes in subjective symptoms were recorded for subjects in the yoga group.

RESULTS: All subjects completed the intervention. The mean POMS fatigue score decreased significantly (from 21.9 ± 7.7 to 13.8 ± 6.7, P < 0.001) after a yoga session. The Chalder’s FS score decreased significantly (from 25.9 ± 6.1 to 19.2 ± 7.5, P = 0.002) in the yoga group, but not in the control group. In addition to the improvement of fatigue, two patients with CFS and fibromyalgia syndrome in the yoga group also reported pain relief. Furthermore, many subjects reported that their bodies became warmer and lighter after practicing isometric yoga. Although there were no serious adverse events in the yoga group, two patients complained of tiredness and one of dizziness after the first yoga session with the instructor.

CONCLUSIONS: Isometric yoga as an add-on therapy is both feasible and successful at relieving the fatigue and pain of a subset of therapy-resistant patients with CFS.

TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN CTR) UMIN000009646.

Source: Oka T, Tanahashi T, Chijiwa T, Lkhagvasuren B, Sudo N, Oka K. Isometric yoga improves the fatigue and pain of patients with chronic fatigue syndrome who are resistant to conventional therapy: a randomized, controlled trial. Biopsychosoc Med. 2014 Dec 11;8(1):27. doi: 10.1186/s13030-014-0027-8. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269854/ (Full article)

Effect of intermittent vitamin D3 on vascular function and symptoms in chronic fatigue syndrome–a randomised controlled trial

Abstract:

BACKGROUND AND AIMS: Low 25-hydroxyvitamin D levels are common in patients with chronic fatigue syndrome; such patients also manifest impaired vascular health. We tested whether high-dose intermittent oral vitamin D therapy improved markers of vascular health and fatigue in patients with chronic fatigue syndrome.

METHODS AND RESULTS: Parallel-group, double-blind, randomised placebo-controlled trial. Patients with chronic fatigue syndrome according to the Fukuda (1994) and Canadian (2003) criteria were randomised to receive 100,000 units oral vitamin D3 or matching placebo every 2 months for 6 months. The primary outcome was arterial stiffness measured using carotid-femoral pulse wave velocity at 6 months. Secondary outcomes included flow-mediated dilatation of the brachial artery, blood pressure, cholesterol, insulin resistance, markers of inflammation and oxidative stress, and the Piper Fatigue scale. As many as 50 participants were randomised; mean age 49 (SD 13) years, mean baseline pulse wave velocity 7.8 m/s (SD 2.3), mean baseline office blood pressure 128/78 (18/12) mmHg and mean baseline 25-hydroxyvitamin D level 46 (18) nmol/L. 25-hydroxyvitamin D levels increased by 22 nmol/L at 6 months in the treatment group relative to placebo. There was no effect of treatment on pulse wave velocity at 6 months (adjusted treatment effect 0.0 m/s; 95% CI -0.6 to 0.6; p = 0.93). No improvement was seen in other vascular and metabolic outcomes, or in the Piper Fatigue scale at 6 months (adjusted treatment effect 0.2 points; 95% CI -0.8 to 1.2; p = 0.73).

CONCLUSION: High-dose oral vitamin D3 did not improve markers of vascular health or fatigue in patients with chronic fatigue syndrome.

TRIAL REGISTRATION: www.controlled-trials.com, ISRCTN59927814.

Source: Witham MD, Adams F, McSwiggan S, Kennedy G, Kabir G, Belch JJ, Khan F. Effect of intermittent vitamin D3 on vascular function and symptoms in chronic fatigue syndrome–a randomised controlled trial. Nutr Metab Cardiovasc Dis. 2015 Mar;25(3):287-94. doi: 10.1016/j.numecd.2014.10.007. Epub 2014 Oct 22. https://www.ncbi.nlm.nih.gov/pubmed/25455721

Robuvit® (Quercus robur extract) supplementation in subjects with chronic fatigue syndrome and increased oxidative stress. A pilot registry study.

Abstract:

AIM: The aim of this registry study was to evaluate the effects of supplementation with Robuvit® (French Quercus robur extract) capsules in subjects with Chronic Fatigue Syndrome (CFS) associated with an increased oxidative stress. Robuvit is a wood extract from Quercus robur (Horphag Research) used to improve liver dysfunction and chronic fatigue. After excluding any disease, subjects observed a defined management plan to improve CFS. Signs/symptoms had been present for more than 6 months in association with an increase in oxidative stress (measured as plasma free radicals). Blood tests were within normal values.

METHODS: The registry study included 38 CFS subjects and 42 comparable controls. There were no dropouts in the 4 weeks of follow-up; the subjects were evaluated for a further period of 6 months. The management plan included: improved/increased sleep; reduction/abolition in smoking and alcohol or any other agent that may have affected them; control of diet, increase in dietary proteins; good hydration; rest (1/2-1 h/day) and exercise (at least 30 min/day); planned relaxation time; increased time in open spaces. In the Robuvit® supplementation group 300 mg/day of Robuvit® was used.

RESULTS: Symptoms improved in both groups with a significantly more important improvement in the supplement group (P<0.05). The single items in the Multidimensional Assessment of Fatigue (MAF) questionnaire were statistically better improved (P<0.05) in the supplement group. A parallel improvement in oxidative stress was observed in the supplemented subjects. In the follow up, at 6 months no organic disease was discovered or disease markers found.

CONCLUSION: This preliminary registry indicates that supplementation with Robuvit® improves CFS in otherwise healthy subjects with no presence of clinical disease or risk conditions. The effects of Robuvit® in CFS may be partially mediated by a clear reduction of plasma free radicals and oxidative stress.

Source: Belcaro G, Cornelli U, Luzzi R, Ledda A, Cacchio M, Saggino A, Cesarone MR, Dugall M, Feragalli B, Hu S, Pellegrini L, Ippolito E. Robuvit® (Quercus robur extract) supplementation in subjects with chronic fatigue syndrome and increased oxidative stress. A pilot registry study. J Neurosurg Sci. 2015 Jun;59(2):105-17. Epub 2014 Nov 14. https://www.ncbi.nlm.nih.gov/pubmed/25394351