Summary. Introduction. F.M. BROUWERS 1, S. VAN DER WERF 2,G.BLEIJENBERG 2, L. VAN DER ZEE 3 and J.W.M. VAN DER MEER 1

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1 Q J Med 2002; 95: The effect of a polynutrient supplement on fatigue and physical activity of patients with chronic fatigue syndrome: a double-blind randomized controlled trial F.M. BROUWERS 1, S. VAN DER WERF 2,G.BLEIJENBERG 2, L. VAN DER ZEE 3 and J.W.M. VAN DER MEER 1 From the Departments of 1 General Internal Medicine and 2 Medical Psychology, University Medical Center Nijmegen, The Netherlands, and 3 Numico Research, Wageningen, The Netherlands Received 29 August 2001 and in revised form 28 May 2002 Summary Background: The efficacy of dietary supplements in chronic fatigue syndrome (CFS) is uncertain, with conflicting evidence. Aim: To assess the effect of a polynutrient supplement on fatigue and physical activity of patients with CFS. Design: Prospective randomized placebo-controlled, double-blind trial. Methods: Fifty-three patients (16 males, 37 females) fulfilling the CDC criteria of CFS. The entry criteria were a score on the Checklist Individual Strength subscale fatigue severity (CIS fatigue) 040 and a weighted sum score of 0750 for the eight subscales of the Sickness Impact Profile (SIP8) and no use of nutritional supplements in the 4 weeks prior to entry. The exclusion criteria were pregnancy and lactose intolerance. The intervention a polynutrient supplement containing several vitamins, minerals and (co)enzymes, or placebo, twice daily for 10 weeks was preceded by 2 weeks of baseline measurements. Outcome measurements took place in week 9 and 10 of the intervention. Five participants dropped out (4 supplement, 1 placebo). The main outcome measures were CIS fatigue score, number of CDC symptoms and SIP8 score. Efficacy analyses were performed on an intention-to-treat basis. Results: No significant differences were found between the placebo and the treated group on any of the outcome measures: CIS fatigue q2.16 (95%CI 4.3 to q4.39, p = 0.984); CDC symptoms q0.42 (95%CI 0.61 to q1.46, p = 0.417); SIP8 q182 (95%CI 165 to q529, p = 0.297). No patient reported full recovery. Discussion: The findings do not support the use of a broad-spectrum nutritional supplement in treating CFS-related symptoms. Introduction Chronic Fatigue Syndrome (CFS) is a clinically defined condition characterized by long-lasting (at least 6 months) severe disabling fatigue and associated symptoms such as memory and concentration difficulties, muscle aches, sleep disturbances, and headache. The symptoms are not caused by another medical condition. 2 According to the literature, 3 and in our own clinical experience, many CFS patients use dietary supplements during their illness. Grant et al. found that 89% of 28 consecutive female patients reported daily use of % of the Recommended Daily Allowance (RDA) for vitamin and mineral supplements. in contrast to 40% of Address correspondence to Dr J.W.M. van der Meer, University Medical Center Nijmegen, Department of General Internal Medicine (541), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. J.vanderMeer@aig.azn.nl ß Association of Physicians 2002

2 678 F.M. Brouwers et al. 10 controls. 3 Similarly, in another study only 17 (16%) of 101 CFS patients reported not to have taken any vitamin preparation during the course of their illness. 4 A number of studies have investigated whether nutritional deficiencies might be involved in the pathophysiology of CFS. Some studies found CFS patients to be deficient in magnesium, 5 phosphate, 6 B-vitamins 4 or (acyl)carnitine. 7,8 However, these findings have been disputed in other studies, on the basis of methodological limitations or conflicting results. 3,4,9 12 It has been hypothesized that a reduced cellular energy status, caused by an increase in oxidative stress resulting in cellular damage, could be a contributing factor to the fatigue in CFS, 13,14 which would suggest that CFS patients might benefit from antioxidant supplements. Consequently, several studies have evaluated the effects of dietary supplements, such as vitamins, minerals and enzymes, upon the general well-being and functional status of CFS patients. 5,9,11,15 20 Most of these clinical trials evaluated single components, and again their results varied considerably. The inconsistencies between the studies could be explained by differences in the selection of the patients, the design (e.g. randomization, blind assessment of outcome) and the methods used for assessing outcome (lack of validated test-scores). In a recent review, it was concluded that the efficacy of dietary supplements in CFS is still unknown. 1 Taking into account the frequent use of supplements by CFS patients and the lack of controlled studies, the aim of the present study was to assess the effect of a polynutrient dietary supplement in a well-defined CFS population using validated outcome measures and a randomized double-blind placebo controlled design. Methods The study was approved by the medical ethical committee of the University Medical Center Nijmegen. Written informed consent was obtained from all patients prior to enrollment. All procedures were in accordance with institutional and international guidelines. Patients All patients were recruited from a database of the department of General Internal Medicine of the University Medical Center Nijmegen in the Netherlands. The database consisted of clinically diagnosed CFS patients who at the time of diagnosis indicate that they were interested in participating in research projects. Patients had to fulfill the 1994 CDC criteria for chronic fatigue syndrome. 2 Fatigue severity and disability were rated with the subscale subjective fatigue of the Checklist Individual Strength (CIS-fatigue) and the summed scores of eight subscales of the Sickness Impact Profile (SIP8) Patients were included in this study when they had both high fatigue severity scores (CIS-fatigue 040) and high disability scores (SIP8-total 0750). Similar inclusion criteria have been used in previous studies of our research group. 25 The minimum age for participation was 18 years. Pregnant or lactating women and patients with intolerance for lactose were excluded, as were patients who used experimental medication. During the trial, patients were not allowed to take vitamins and minerals (other than the trial supplements) and the use of vitamins and other supplements had to be discontinued 4 weeks prior to entry into the study. Trial design and randomization procedure This study was designed as a randomized, doubleblind, placebo-controlled study with a total duration per participant of 12 weeks. Following the measurement of baseline parameters in the first two weeks (weeks 1 and 2), patients were randomly allocated to receive the nutritional supplement or placebo in a 50:50 ratio. All patients were required to take the nutritional supplement or placebo twice a day for 10 weeks (weeks 3 12). In the last two weeks (weeks 11 and 12), baseline measurements were repeated. To maintain balance over time, the randomization was in blocks of two. All patients enrolled in Randomization and allocation to treatment or placebo group was based on a patient s study number. At entry, a patient received the lowest study number available (1 53). The investigators were blind to the treatment condition, as the randomization list that correlated the study number with treatment group was held by an independent organization in charge of the distribution of the trial product. Nutritional supplement and placebo The nutritional supplement, provided by Numico Research BV, contained several vitamins, minerals and (co)enzymes and was specifically developed to

3 Dietary supplements for CFS 679 Table 1 Composition of the nutritional supplement (per 100 ml) Category Component Amount Category Component Amount Protein Casein 3.0 g Minerals Na 43 mg Whey 3.0 g K 300 mg Cysteine 0.1g Cl 81 mg Carbohydrates Sugars 6.7 g Ca 126 mg Lactose 0.61 g P 73 mg Sacharose 6.1 g Mg 8 mg Organic acids 0.3 g Vitamins Vitamin A 267 mgre Other 0.1 g Vitamin D 2.0 mg Fat Saturates 0.5 g Vitamin E 215 mg a-te Monounsaturates 1.8 g Thiamin 10 mg Polyunsaturates 0.8 g Riboflavin 1.2 mg Linoleic acid 0.69 g Niacin 8.0 mg NE Linolenic acid 0.15 g Pantothenate 1.6 mg Trace elements Fe 0.40 mg Vitamin B6 2.4 mg Zn 6.0 mg Folate 240 mg Cu 0.60 mg Vitamin B mg Mn 1.2 mg Biotin 40 mg F 0.40 mg Vitamin C 100 mg Mo 20 mg Other Carnitine 1200 mg Se 20 mg Choline 40 mg Cr 13 mg Creatine 1200 mg I 40mg Taurine 1200 mg Fe 0.40 mg Coenzyme Q10 60 mg have a high antioxidative capacity. The composition is shown in Table 1. Placebo and supplement were identical in appearance (125 ml packages). Primary outcome measures Fatigue severity The subscale fatigue severity of the Checklist Individual Strength was used (CIS-fatigue). The score on this eight-item scale ranges from 8 (no fatigue at all) to 56 (maximally fatigued). 23 CDC checklist The patient was asked to indicate which of the following symptoms were present in the previous 6 months: impaired memory or concentration, sore throat, tender cervical or axillary nodes, muscle pain, multi-joint pain, new headaches, unrefreshing sleep, and post-exertion malaise. Thus the number of CDC symptoms varied between 0 and 8. 2 Functional impairment Eight subscales of the Sickness Impact Scale (SIP8) were used to rate both physical and psychosocial disability. The physical subscales included were: mobility, walking, home-making and recreation and pastimes. The psychosocial subscales were social interactions, concentration difficulties, and sleep/rest problems. Secondary outcome measures Physical activity levels Physical activity levels were measured using actigraphic assessment. A motion sensing device (actometer) was worn around the ankle day and night for a two-week period. The actometer continuously sampled accelerations every second and stored data at 5-min intervals. Consequently, the maximum number of movements (activity) reached per 5-min interval was 300 (accelerations). A procedure, described in detail elsewhere, was used to distinguish active (day) and inactive (night) periods. Subsequently, the average scores over the 12 day periods were computed. 24 Daily fatigue levels Patients rated the intensity of their fatigue during a two-week period in a complaint diary. They rated the Daily Observed Fatigue (DOF) four times a day on a scale of 0 (no fatigue) to 4 (severely fatigued). The DOF score thus ranged between 0 and The mean of 12 consecutive DOF scores was used.

4 680 F.M. Brouwers et al. Figure 1. Patient recruitment flow chart Self-reported improvement at follow up Patients were also asked to indicate whether any changes had occurred in the severity of their complaints since the start of the trial. There were four response categories: recovered, improved, unchanged and worse. Statistical analysis All statistical analyses used the Statistical Package for Social Sciences (SPSS 9.0). Prior to the start of the study, a power analysis to estimate the number of patients minimally required to detect a difference of at least 1 SD on any of the primary outcome measures indicated that to detect such a difference with 90% certainty, using a double-sided significance level of 5%, a sample size of 48 subjects was required. Anticipating a drop-out rate of 10% at least 53 patients had to be approached. All analyses were performed on an intention to treat basis. Follow-up data were also collected from patients who discontinued treatment. Whenever this was not possible, the missing data at follow-up assessment were substituted by available baseline data. Independent-sample t-tests were done, with the difference between baseline and end of treatment outcome measures as dependent variables, and group membership (i.e. placebo vs. supplement) as the independent variable. Differences between both groups on the categorical secondary outcome measures were tested by Fisher-Z or x 2 tests. Results A total of 53 patients entered the study. Figure 1 illustrates the participant flow. Forty-eight patients completed the study and five dropped out. Of these five patients, three stopped because they did not tolerate the study treatment (nausea, all three in supplement group). The remaining two patients gave personal problems and the time burden of participation as reasons. Follow-up data were collected for three of these five patients; in the remaining two, missing values at follow-up assessment were replaced by baseline measures. Demographics and illness duration of the groups Table 2 shows baseline characteristics for the placebo and treatments groups. The groups did not differ significantly with respect to gender, age, illness duration and educational levels.

5 Dietary supplements for CFS 681 Table 2 Sociodemographic data and drop out rate of the total sample Total (n = 53) Supplement (n = 27) Placebo (n = 26) Significance Mean (SD) Age (years) 39.3 (10.3) 40.0 (9.9) 38.9 (10.9) t = 0.51, p = 0.61 a Female (%) x 2 = 0.15, p = 0.70 b Mean (SD) education rating 4.3 (1.5) 4.3 (1.4) 4.4 (1.6) t = 0.31, p = 0.76 a Dropped out n = 5 (9.2%) n = 4 (14.8%) n = 1 (3.8%) x 2 = 1.86, p = 0.35 b Median (IRQ) illness duration (years) 5.0 (2 12) 8.0 (2 15) 4.5 (2 10) Z = 1.33, p = 0.19 c a t-test; b x 2 -test; c Mann-Whitney. IRQ, interquartile range. Table 3 Baseline and follow up scores of the primary and secondary outcome measures Supplement (n = 27) Placebo (n = 26) CIS fatigue score at 51.4" "3.6 baseline CIS fatigue score at 48.6" "7.6 follow-up CIS fatigue -40 at 15% 16% follow-up (%) Number of CDC 6.7" "2.0 symptoms baseline Number of CDC 6.7" "1.5 symptoms follow-up Functional impairment 1911" "683 (SIP8) score at baseline Functional impairment 1650" "644 (SIP8) score at follow-up SIP8-750 at follow-up (%) 4% 12% Actometer baseline score* 62.9" "19.4 Actometer follow-up score* 57.2" "22.4 Daily fatigue baseline score 8.1" "2.7 Daily fatigue follow-up score 7.7" "2.3 Self-reported improvement at follow-up Completely recovered (%) 0% 0% Improved (%) 20% 16% Similar (%) 76% 68% Worse (%) 4% 1% *Higher actoscores reflect higher levels of physical activity. All data are means"sd, unless otherwise stated. Outcome Table 3 shows baseline measurements and followup data for the primary and secondary outcome measures. The results of the independent sample t-tests on baseline-follow-up change scores are reported in Table 4. None of the primary outcome measures and none of the secondary outcome measures showed significant differences between supplement and placebo. The majority of patients in both groups reported that there had been no change in complaints, and no patient reported complete recovery at follow-up assessment (x 2 = 2.0, df(1,2), p = 0.36). Discussion This study is one of the first to evaluate the effects of a polynutritional dietary supplement in a welldefined CFS population with the design of a randomized controlled trial. No significant treatment effects were found on either self-report measures or a behavioural measure. The polynutritional supplement used in this study resembled the multivitamin use reported by CFS patients and was compatible with the advice regarding supplement use in CFS found on CFS information pages on the Internet. Two previous studies also assessed the effect of a polynutritional supplement on fatigue. 19,20 In the Table 4 Estimated differences (ED) between supplement and placebo groups: for changes from baseline scores ED SE p df 95%CI CIS fatigue to q4.39 Number of CDC symptoms to q1.46 Impairment (SIP8) to q529 Actoscore to q13.72 Daily Observed Fatigue to q0.95 Except for the actoscore, positive ED values reflect more improvement for the supplement group. SE, standard error; df, degrees of freedom.

6 682 F.M. Brouwers et al. first, which used a placebo-controlled double-blind cross-over design, the drop out was high, with only 19/42 enrolled patients completing the 6-month trial. 19 This study reported similar findings to our results. The other, sponsored by Pharmaton Capsules, reported beneficial effects of supplementation on the complaints of patients with functional fatigue for over 15 years on a self-report questionnaire. 20 This study also used a randomized double-blind design. Many different measurement methods have been used in other trials to assess the effects of supplement use. It is probable that this methodological diversity accounted for some of the conflicting results in these studies. 5,11,15 20 Since our study not only used validated measures but also assessed various dimensions of fatigue, the lack of significant differences on any of these measures strengthens our overall finding. We did not assess the nutritional status of the patients in details prior to treatment, especially with respect to possible nutritional deficiencies. No overt signs of malnutrition were encountered. Since a strict randomization procedure was used, it is unlikely that both groups would differ in the proportion of patients suffering certain subtle deficiencies. One could hypothesize that some components of the polynutrient mixture might have opposing effects, and that one should study a single component at a time rather than assessing a polynutrient preparation. However, such effects are not described in the literature, and it seems also unlikely that the combination would render all individual components ineffective. In the supplement sample, the median illness duration showed a trend to be longer. One could theorize that a longer duration of illness might be associated with a further decrease in anti-oxidative capacity. To check whether a patient s response to therapy was perhaps influenced by illness duration, post hoc analyses of variance were done, with illness duration as a covariate. These analyses again showed no significant differences between both groups on any of the outcome measures. In most trials that reported beneficial effects of treatment with a nutritional supplement (vitamin, mineral or enzyme), the effect was seen within 4 to 6 weeks after initiation of the therapy. 5,17,18,20 In the present study, patients received the supplement for a total duration of 10 weeks. It thus seems unlikely that the lack of effect in our study is attributable to inadequate duration of treatment. Although nutritional supplements have been widely used by CFS patients, and are claimed to be beneficial for alleviating CFS complaints by many of them, this could not be substantiated in the present study. Such effects might be due to the expectations patients have about controlling their symptoms. 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