Category: Clinical Trial

Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a disorder of unknown etiology, consisting of prolonged, debilitating fatigue, and a multitude of symptoms including neurocognitive dysfunction, flu-like symptoms, myalgia, weakness, arthralgia, low-grade fever, sore throat, headache, sleep disturbances, and swelling and tenderness of lymph nodes. No effective treatment for CFS is known.

OBJECTIVE: The purpose of the study was to evaluate the efficacy of the reduced form of nicotinamide adenine dinucleotide (NADH) i.e., ENADA the stabilized oral absorbable form, in a randomized, double-blind, placebo-controlled crossover study in patients with CFS. Nicotinamide adenine dinucleotide is known to trigger energy production through ATP generation which may form the basis of its potential effects.

METHODS: Twenty-six eligible patients who fulfilled the Center for Disease Control and Prevention criteria for CFS completed the study. Medical history, physical examination, laboratory studies, and questionnaire were obtained at baseline, 4, 8, and 12 weeks. Subjects were randomly assigned to receive either 10 mg of NADH or placebo for a 4-week period. Following a 4-week washout period, subjects were crossed to the alternate regimen for a final 4-week period.

RESULTS: No severe adverse effects were observed related to the study drug. Within this cohort of 26 patients, 8 of 26 (31%) responded favorably to NADH in contrast to 2 of 26 (8%) to placebo. Based upon these encouraging results we have decided to conduct an open-label study in a larger cohort of patients.

CONCLUSION: Collectively, the results of this pilot study indicate that NADH may be a valuable adjunctive therapy in the management of the chronic fatigue syndrome and suggest that further clinical trials be performed to establish its efficacy in this clinically perplexing disorder.

Comment in: Is NADH effective in the treatment of chronic fatigue syndrome? [Ann Allergy Asthma Immunol. 2000]

 

Source: Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr, Birkmayer GD, Bellanti JA. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1999 Feb;82(2):185-91. http://www.ncbi.nlm.nih.gov/pubmed/10071523

 

The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA

Abstract:

OBJECTIVE: To replicate the treatment study by Behan et al. (1990) using current research criteria for Chronic Fatigue Syndrome (CFS).

METHOD: Fifty patients who fulfilled the Oxford Criteria for CFS were randomly allocated to treatment with either Efamol Marine or placebo for 3 months. They were seen monthly and completed a physical symptoms checklist and the Beck Inventory for Depression and reported if they were the same, better or worse at the end of the study.

RESULTS: Symptoms generally improved with time but not significantly and there were no significant differences between the treatment and placebo groups. Pretreatment red-cell membrane (RBC) lipids of patients compared with age-and sex-matched normal controls showed no significant differences.

DISCUSSION: The results of this study contrast sharply with the previous study where 85% of patients had a clinically significant improvement of symptoms with Efamol Marine over a 3-month treatment period.

 

Source: Warren G, McKendrick M, Peet M. The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand. 1999 Feb;99(2):112-6. http://www.ncbi.nlm.nih.gov/pubmed/10071170

 

Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial

Abstract:

BACKGROUND: Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment.

METHODS: In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat.

FINDINGS: None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher’s exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo.

INTERPRETATION: In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

Comment in:

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

Chronic fatigue syndrome and functional hypoadrenia–fighting vainly the old ennui. [Lancet. 1999]

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

Hydrocortisone and chronic fatigue syndrome. [Lancet. 1999]

 

Source: Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999 Feb 6;353(9151):455-8. http://www.ncbi.nlm.nih.gov/pubmed/9989716

 

Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome

Erratum in: Br J Psychiatry 1998 Jul;173:89.

 

Abstract:

BACKGROUND: The Joint Working Group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners (1996) recommended graded exercise and antidepressants for patients with chronic fatigue syndrome. We assessed efficacy and acceptability of these treatments.

METHOD: Six-month prospective randomised placebo and therapist contact time controlled trial with allocation to one of four treatment cells: exercise and 20 mg fluoxetine, exercise and placebo drug, appointments only and 20 mg fluoxetine, appointments and placebo drug. Drug treatment was double blind and patients were blind to assignment to exercise or appointments.

RESULTS: Ninety-six (71%) of 136 patients completed the trial. Patients were more likely to drop out of exercise than non-exercise treatment (P = 0.05). In an intention to treat analysis, exercise resulted in fewer patients with case level fatigue than appointments only at 26 weeks (12 (18%) v. 4 (6%) respectively P = 0.025) and improvement in functional work capacity at 12 (P = 0.005) and 26 weeks (P = 0.03). Fluoxetine had a significant effect on depression at week 12 only (P = 0.04). Exercise significantly improved health perception (P = 0.012) and fatigue (P = 0.028) at 28 weeks.

CONCLUSIONS: Graded exercise produced improvements in functional work capacity and fatigue, while fluoxetine improved depression only.

Comment in:

Commentary on: randomised, double-blind, placebo-controlled trial of fluoxetine and graded exercise for chronic fatigue syndrome. [Br J Psychiatry. 1998]

Analysis of drop-out data in treatment trials. [Br J Psychiatry. 1998]

Fluoxetine and graded exercise in chronic fatigue syndrome. [Br J Psychiatry. 1998]

 

Source: Wearden AJ, Morriss RK, Mullis R, Strickland PL, Pearson DJ, Appleby L, Campbell IT, Morris JA. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome. Br J Psychiatry. 1998 Jun;172:485-90. http://www.ncbi.nlm.nih.gov/pubmed/9828987

 

Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial

Abstract:

CONTEXT: Chronic fatigue syndrome (CFS) is associated with a dysregulated hypothalamic-pituitary adrenal axis and hypocortisolemia.

OBJECTIVE: To evaluate the efficacy and safety of low-dose oral hydrocortisone as a treatment for CFS.

DESIGN: A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996.

SETTING: A single-center study in a tertiary care research institution.

PATIENTS: A total of 56 women and 14 men aged 18 to 55 years who met the 1988 Centers for Disease Control and Prevention case criteria for CFS and who withheld concomitant treatment with other medications.

INTERVENTION: Oral hydrocortisone, 13 mg/m2 of body surface area every morning and 3 mg/m2 every afternoon, or placebo, for approximately 12 weeks.

MAIN OUTCOME MEASURES: A global Wellness scale and other self-rating instruments were completed repeatedly before and during treatment. Resting and cosyntropin-stimulated cortisol levels were obtained before and at the end of treatment. Patients recorded adverse effects on a checklist.

RESULTS: The number of patients showing improvement on the Wellness scale was 19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients (P =.31). Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points; P=.06), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo recipients (P<.001). Statistical evidence of improvement was not seen with other self-rating scales. Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group (P<.001).

CONCLUSIONS: Although hydrocortisone treatment was associated with some improvement in symptoms of CFS, the degree of adrenal suppression precludes its practical use for CFS.

 

Source: McKenzie R, O’Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, Garcia-Borreguero D, Blackwelder W, Straus SE. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998 Sep 23-30;280(12):1061-6. http://www.ncbi.nlm.nih.gov/pubmed/9757853

 

Illness beliefs and treatment outcome in chronic fatigue syndrome

Abstract:

Longitudinal studies have shown that physical illness attributions are associated with poor prognosis in chronic fatigue syndrome (CFS). Speculation exists over whether such attributions influence treatment outcome. This study reports the effect of illness beliefs on outcome in a randomized controlled trial of cognitive-behavior therapy versus relaxation.

Causal attributions and beliefs about exercise, activity, and rest were recorded before and after treatment in 60 CFS patients recruited to the trial. Physical illness attributions were widespread, did not change with treatment, and were not associated with poor outcome in either the cognitive-behavior therapy group or the control group.

Beliefs about avoidance of exercise and activity changed in the cognitive behavior therapy group, but not in the control group. This change was associated with improved outcome. These findings suggest that physical illness attributions are less important in determining outcome (at least in treatment studies) than has been previously thought. In this study, good outcome is associated with change in avoidance behavior, and related beliefs, rather than causal attributions.

 

Source: Deale A, Chalder T, Wessely S. Illness beliefs and treatment outcome in chronic fatigue syndrome. J Psychosom Res. 1998 Jul;45(1):77-83. http://www.ncbi.nlm.nih.gov/pubmed/9720857

 

Single-blind, placebo phase-in trial of two escalating doses of selegiline in the chronic fatigue syndrome

Abstract:

AIM: To perform a clinical trial of selegiline in 25 patients with chronic fatigue syndrome (CFS) where patients were told they would receive placebo or active agent at different times during the 6-week trial. We chose selegiline, a specific monoamine oxidase (MAO) B receptor inhibitor, because a prior trial of lowdose phenelzine, a nonspecific MAO inhibitor, showed a small but significant therapeutic effect.

METHODS: Questionnaires comprised of 19 tests of mood, fatigue, functional status and symptom severity were collected at the start and end of the trial as well as 2 weeks after its start. The trial was done in three 2-week blocks: in the first, 2 placebo pills were given per day; in the next, one 5-mg tablet of agent and one placebo were given per day, and in the last, a 5-mg tablet of agent was given twice a day. The plan was to compare the changes in the 19 tests during the placebo phase to those found in the active treatment phase in 19 patients completing the trial.

FINDINGS: Significant improvement in 3 variables-tension/anxiety, vigor and sexual relations-was found. A significant pattern of improvement compared to worsening was found for the 19 self-report vehicles during active treatment as compared with placebo treatment. Evidence for an antidepressant effect of the drug was not found.

CONCLUSIONS: Selegiline has a small but significant therapeutic effect in CFS which appears independent of an antidepressant effect.

 

Source: Natelson BH, Cheu J, Hill N, Bergen M, Korn L, Denny T, Dahl K. Single-blind, placebo phase-in trial of two escalating doses of selegiline in the chronic fatigue syndrome. Neuropsychobiology. 1998;37(3):150-4. http://www.ncbi.nlm.nih.gov/pubmed/9597672

 

A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome

Abstract:

OBJECTIVE: To provide a preliminary assessment of the efficacy and safety of fludrocortisone acetate treatment of chronic fatigue syndrome.

DESIGN: A placebo-controlled, double-blind, random-allocation crossover trial of 6 weeks of fludrocortisone.

SETTING: An outpatient clinical trials unit.

PATIENTS: Twenty-five participants with chronic fatigue syndrome (mean age, 40 years; 19 [76%] women; mean duration of illness, 7.0 years) were recruited from a research and clinic registry. Five patients withdrew from the trial.

INTERVENTIONS: All participants were scheduled to receive fludrocortisone acetate (0.1-0.2 mg) or a placebo for 6 weeks in each treatment.

MAIN OUTCOME MEASURES: Self-administered questionnaires were completed at the beginning and end of each treatment arm that asked patients to rate the severity of their symptoms on a visual analogue scale. The Medical Outcomes Study 36-Item Short-Form Health Survey, a reaction time test, and a treadmill exercise test were used to assess functional status. Blood pressure, heart rate, and plasma norepinephrine levels were obtained at baseline. Blood pressure and heart rate were recorded at the end of the exercise test and monitored at all subsequent visits.

RESULTS: At baseline, the study participants reported symptom severity greater than 5 for most symptoms, and all had evidence of marked functional impairments. No improvement was observed in the severity of any symptom or in any test of function for the 20 participants who completed both arms of the trial. Blood pressure and heart rate readings were unaffected by treatment, and plasma norepinephrine levels did not differ from those of a healthy control group. The incidence of adverse experiences was similar in the fludrocortisone and placebo arms of the trial.

CONCLUSION: Low-dose fludrocortisone does not provide sufficient benefit to be evident in a preliminary blinded trial of unselected patients with chronic fatigue syndrome.

Comment in: Treatment for chronic fatigue syndrome. [Arch Intern Med. 1998]

 

Source: Peterson PK, Pheley A, Schroeppel J, Schenck C, Marshall P, Kind A, Haugland JM, Lambrecht LJ, Swan S, Goldsmith S. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med. 1998 Apr 27;158(8):908-14. http://www.ncbi.nlm.nih.gov/pubmed/9570178

Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome

Abstract:

PURPOSE: To determine whether the reported therapeutic benefit of intravenous immunoglobulin in patients with chronic fatigue syndrome (CFS) is dose dependent.

PATIENTS AND METHODS: Ninety-nine adult patients, who fulfilled diagnostic criteria for CFS, participated in this double-blind, randomized, and placebo-controlled trial. Patients received intravenous infusions with either a placebo solution (1% albumin) or one of three doses of immunoglobulin (0.5, 1, or 2 g/kg) on a monthly basis for 3 months, followed by a treatment-free follow-up period of 3 months. Outcome was assessed by changes in a series of self-reported measures (quality-of-life visual analog scales, standardized diaries of daily activities, the profile of mood states questionnaire) and the Karnofsky performance scale. Cell-mediated immunity was evaluated by T-cell subset analysis and delayed-type hypersensitivity (DTH) skin testing.

RESULTS: No dose of intravenous immunoglobulin was associated with a specific therapeutic benefit. Adverse reactions, typically constitutional symptoms, were reported by 70% to 80% of patients, with no relationship to immunoglobulin treatment.

CONCLUSIONS: Intravenous immunoglobulin cannot be recommended as a therapy for the treatment of CFS. A better understanding of the pathophysiology of this disorder is needed before effective treatment can be developed.

 

Source: Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, Tymms K, Wakefield D, Dwyer J, Lloyd A. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med. 1997 Jul;103(1):38-43. http://www.ncbi.nlm.nih.gov/pubmed/9236484

 

Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome

Abstract:

OBJECTIVE: To test the efficacy of a graded aerobic exercise programme in the chronic fatigue syndrome.

DESIGN: Randomised controlled trial with control treatment crossover after the first follow up examination.

SETTING: Chronic fatigue clinic in a general hospital department of psychiatry.

SUBJECTS: 66 patients with the chronic fatigue syndrome who had neither a psychiatric disorder nor appreciable sleep disturbance.

INTERVENTIONS: Random allocation to 12 weeks of either graded aerobic exercise or flexibility exercises and relaxation therapy. Patients who completed the flexibility programme were invited to cross over to the exercise programme afterwards.

MAIN OUTCOME MEASURE: The self rated clinical global impression change score, “very much better” or “much better” being considered as clinically important.

RESULTS: Four patients receiving exercise and three receiving flexibility treatment dropped out before completion. 15 of 29 patients rated themselves as better after completing exercise treatment compared with eight of 30 patients who completed flexibility treatment. Analysis by intention to treat gave similar results (17/33 v 9/33 patients better). Fatigue, functional capacity, and fitness were significantly better after exercise than after flexibility treatment. 12 of 22 patients who crossed over to exercise after flexibility treatment rated themselves as better after completing exercise treatment 32 of 47 patients rated themselves as better three months after completing supervised exercise treatment 35 of 47 patients rated themselves as better one year after completing supervised exercise treatment.

CONCLUSION: These findings support the use of appropriately prescribed graded aerobic exercise in the management of patients with the chronic fatigue syndrome.

Comment in:

Graded exercise in chronic fatigue syndrome. Including patients who rated themselves as a little better would have altered results. [BMJ. 1997]

Managing chronic fatigue syndrome in children. [BMJ. 1997]

Graded exercise in chronic fatigue syndrome. Chronic fatigue syndrome is heterogeneous condition. [BMJ. 1997]

Graded exercise in chronic fatigue syndrome. Patients should have initial period of rest before gradual increase in activity. [BMJ. 1997]

Graded exercise in chronic fatigue syndrome. Patients were selected group. [BMJ. 1997]

 

Source: Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ. 1997 Jun 7;314(7095):1647-52. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2126868/ (Full article)