# Abstract

 Most patients with fibromyalgia use complementary and alternative medicine (CAM). Properly designed controlled trials are necessary to assess the effectiveness of these practices. This study was a randomized, double-blind, placebo-controlled, early phase trial. Fifty patients seen at a fibromyalgia outpatient treatment program were randomly assigned to a daily soy or placebo (casein) shake. Outcome measures were scores of the Fibromyalgia Impact Questionnaire (FIQ) and the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and after 6 weeks of intervention. Analysis was with standard statistics based on the null hypothesis, and separation test for early phase CAM comparative trials. Twenty-eight patients completed the study. Use of standard statistics with intent-to-treat analysis showed that total FIQ scores decreased by 14% in the soy group (*P* = .02) and by 18% in the placebo group (*P* < .001). The difference in change in scores between the groups was not significant (*P* = .16). With the same analysis, CES-D scores decreased in the soy group by 16% (*P* = .004) and in the placebo group by 15% (*P* = .05). The change in scores was similar in the groups (*P* = .83). Results of statistical analysis using the separation test and intent-to-treat analysis revealed no benefit of soy compared with placebo. Shakes that contain soy and shakes that contain casein, when combined with a multidisciplinary fibromyalgia treatment program, provide a decrease in fibromyalgia symptoms. Separation between the effects of soy and casein (control) shakes did not favor the intervention. Therefore, large-sample studies using soy for patients with fibromyalgia are probably not indicated. # 3. Results 

## 3.1. Baseline Characteristics A total of 50 patients (49 women) were recruited for this trial. Median age was 47.7 years (range, 18--76 years). There was no significant difference in age (*P* = .99), FIQ scores (*P* = .36) or CES-D scores (*P* = .48) between the two groups. Twenty-eight patients (56%)---12 in the soy group and 16 in the placebo group (*P* = .39)---completed the 6-week trial. Reasons for not completing it are depicted in [Figure 1](#). Patients who did not finish the trial were significantly younger (median age, 39.8 years) than those who finished it (median age, 53.9 years) (*P* < .001). The median FIQ score was higher for patients who did not complete the trial (59.5) than for those who completed the study (54.8), but the difference was not statistically significant (*P* = .12). The median CES-D score also was higher for patients who did not complete the trial (26.5) than for patients who completed the trial (14.0), but this also was not a statistically significant difference (*P* = .14). 

## 3.2. Between-Group Comparisons With intent-to-treat analysis, the total FIQ scores determined at study entry and at study completion decreased 14% (±29) in the soy group and 18% (±25) in the placebo group (*P* = .16). With per-protocol analysis, the total FIQ scores decreased 29% (±36) in the soy group and 28% (±26) in the placebo group (*P* = .93) ([Figure 2](#)). No statistically significant decrease between the soy group and the placebo group was observed for any of the FIQ subclass scores. With intent-to-treat analysis, the CES-D scores improved 16% (±26) in the soy group and 15% (±41) in the placebo group (*P* = .83); with per-protocol analysis, the CES-D scores improved 33% (±30) in the soy group and 24% (±50) in the placebo group ([Figure 3](#)). However, the decrease between the groups was not statistically significant (*P* = .96). Using various cutoff points for depression (CES-D ≥ 16, CES-D ≥ 19 and CES-D ≥ 27) and intent-to-treat analysis, we found a depression rate of 52%, 48% and 28%, respectively, in the soy group and 52%, 48% and 32% in the control group at study entry. After 6 weeks, these percentages were 48%, 44% and 24% in the treatment group and 48%, 36% and 24% in the control group. There was no statistically significant difference between the groups (*P* = 1.00). Determined by using per-protocol analysis for these three different CES-D scores, the percentages of patients with depression at study entry in the treatment group were 42%, 33% and 8% and in the control group were 38%, 38% and 19%. After 6 weeks, 33% of the treatment group had CES-D scores of 16 or greater, 25% had scores of 19 or greater and 0% had scores of 27 or greater. The percentages for the control group were 31%, 19% and 6%, respectively. There was no statistically significant difference between the groups. The separation test using the difference from baseline to 6 weeks showed no benefit for soy, as determined by FIQ scores and CES-D scores for both intent-to-treat and per-protocol analyses. We did not have enough information to make any recommendation for or against the use of soy using the separation test per-protocol analysis based on total FIQ scores ([Table 1](#)). 

## 3.3. Within-Group Comparisons Significant, but modest, improvement in total FIQ scores (soy group, *P* = .02; placebo group, *P* < .001) ([Figure 2](#)) and CES-D scores (soy group, *P* = .004; placebo group, *P* = .05) ([Figure 3](#)) between study entry and study completion was seen in both groups. Using three different cutoff points for depression (CES-D ≥ 16, CES-D ≥ 19 and CES-D ≥ 27), we found no significant improvement using the McNemar test for the soy and control groups (*P* > .50). 

### 3.3.1. FIQ Subclass Scores The average score of answers to questions 1 through 11 showed no significant improvement from before treatment to after treatment in both groups, as did the average score of answers to questions 12 and 13. However, the average score of answers to questions 14 through 20 showed significant improvement from before treatment to after treatment in the soy group (*P* = .004) and the placebo group (*P* = .001). <figure> <p><img src="" /></p> <figcaption>Flow chart of patients in the placebo-controlled soy supplement trial.</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Total FIQ scores of patients in soy supplement trial, with intent-to-treat analysis (A–D) and per–protocol analysis (E–H). Score of patients randomly assigned to receive soy at study entry (A) and score of patients after 6 weeks of soy treatment (B). Score of patients randomly assigned to receive placebo at study entry (C) and score of patients after 6 weeks of placebo (D). Score of patients randomly assigned to receive soy at study entry (E) and score of patients after 6 weeks of soy treatment (F). Score of patients randomly assigned to receive placebo at study entry (G) and score of patients after 6 weeks of placebo (H).</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>CES-D scores of patients in soy supplement trial, with intent-to-treat analysis (A–D) and per-protocol analysis (E–H). Score of patients randomly assigned to receive soy at study entry (A) and score of patients after 6 weeks of soy treatment (B). Score of patients randomly assigned to receive placebo at study entry (C) and score of patients after 6 weeks of placebo (D). Score of patients randomly assigned to receive soy at study entry (E) and score of patients after 6 weeks of soy treatment (F). Score of patients randomly assigned to receive placebo at study entry (G) and score of patients after 6 weeks of placebo (H).</figcaption> </figure> ::::table-wrap

::: caption
Summary of data analysis with a separation test ^a^.
:::

Outcome Control (placebo) Treatment (soy) SDE Δ/2 ^b^ Mean difference (placebo/soy) Separation in favor of placebo or soy ^c^ Further research with soy indicated?

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```
                         Mean change in scores   95% CI            Mean change in scores   95% CI                                                                                                                                         
```

Intent-to-treat analysis\
F1-11^d^ −0.51 −3.55 to 2.54 −0.07 −1.93 to 1.79 0.18 0.15 −0.44 Placebo No
F12^d^ −2.06 −8.69 to 4.57 −1.26 −7.00 to 4.48 0.45 0.37 −0.80 Placebo No
F13^d^ −1.12 −7.01 to 4.77 −0.32 −5.08 to 4.44 0.39 0.32 −0.80 Placebo No
F14-20^d^ −8.84 −38.73 to 21.05 −6.56 −29.36 to 16.24 1.91 1.57 −2.28 Placebo No
Total FIQ scores −12.52 −53.34 to 28.29 −8.21 −39.39 to 22.97 2.61 2.15 −4.32 Placebo No
Total CES-D scores −5.12 −31.60 to 21.36 −1.92 −8.12 to 4.28 1.39 1.15 −3.20 Placebo No

Per-protocol analysis\
F1-11^d^ −0.79 −4.52 to 2.94 −0.15 −2.89 to 2.59 0.32 0.27 −0.64 Placebo No
F12^d^ −3.22 −10.63 to 4.20 −2.62 −10.16 to 4.92 0.71 0.58 −0.60 Placebo No
F13^d^ −1.75 −8.89 to 5.39 −0.67 −7.63 to 6.29 0.68 0.56 −1.08 Placebo No
F14-20^d^ −13.81 −47.69 to 20.07 −13.67 −40.64 to 13.30 2.95 2.42 −0.15 Neither ...^e^
Total FIQ scores −19.57 −65.40 to 26.26 −17.10 −55.62 to 21.42 4.06 3.34 −2.47 Neither ...
Total CES-D scores −8.00 −40.05 to 24.05 −4.00 −10.99 to 2.99 2.37 1.95 −4.00 Placebo No

^a^As described by Aickin \[[18](#), [19](#)\];  ^b^Δ/2 = 1.645∗SDE/2;
^c^If the mean difference exceeds Δ/2 (in the favorable direction,
positive for soy), further research is recommended;  ^d^F1-11, questions
1-11 of FIQ, which rate the ability to complete various activities and
are scored and summed to yield 1 physical impairment score (0, no
impairment; 10, maximum impairment); F12, question 12 of FIQ, which
inquires about the number of days out of the past 7 days when the
patient felt well (0, no impairment; 10, maximum impairment); F13,
question 13 of FIQ, which inquires about the number of days during the
past week when the patient missed work, including housework, because of
fibromyalgia (0, no impairment; 10, maximum impairment); F14-20,
questions 14-20 of FIQ, which are a series of visual analog scales for
rating the various symptoms characteristic of FMS (0, no impairment; 70,
maximum impairment);  ^e^Ellipses indicate not enough information to
make a recommendation. CI, confidence interval.::::


Extracted trial result:
Outcome: Fibromyalgia Impact Questionnaire scores (continuous)
Intervention: Soy shake
Comparator: Control
Intervention group size: 12
Intervention mean: -17.1
Intervention standard deviation: 68.08
Comparator group size: 16
Comparator mean: -19.57
Comparator standard deviation: 93.53
Notes: From per protocol