




































Regular paper


Page 1 of 11 

 

Start intake

(4 weeks) (8 weeks) (12 weeks)

ENROLLMENT: ●

Informed consent ●

Allocation ●

INTERVENTION:

Placebo

Test sample

ASSESSMENTS:

X-ray CT ● ● ● ●

Physical examination ● ● ● ●

Urinalysis ● ● ● ●

Hematological analysis ● ● ● ●

Subjective symptoms ● ● ● ●

Dietary survey
1 ● ● ● ●

Medical questionnaire ● ● ● ●

Daily record
2

Closed circles (●): executed timing.

1
 Dietary survey was conducted for 3 days before each test day.

2
 Daily record included the record of fructose intake.

Appendix 1. Schedule of enrollment, intervention, and assessments.

4 weeks after

intake

8 weeks after

intake

12 weeks after

intake
Enrollment

Before intake

(Baseline)

Intervention period

Allocation



Page 2 of 11 

 

 

Appendix 2. The supplemental data of VFA.

Mean SE EMM
1 95%

CI−

95%

CI+
Mean SE EMM

1 95%

CI−

95%

CI+
Difference

95%

CI−

95%

CI+

VFA (cm
2
) Baseline

2 99.3 3.7 − − − 99.6 4.0 − − − 　 0.4 −10.4 11.2

4 weeks
3 98.3 3.8 98.5 95.4 101.5 95.9 3.8 95.8 92.7 98.8 　 −2.7 −7.0 1.7

8 weeks
3 98.1 3.7 98.2 95.2 101.3 94.0 3.9 93.8 90.7 96.9 　 −4.4 −8.8 −0.1

12 weeks
3 98.5 4.0 98.6 95.6 101.7 93.2 4.0 93.0 89.9 96.1 　 −5.6 −10.0 −1.3

ΔVFA (cm
2
) 4 weeks

3 −1.0 1.6 −1.0 −4.1 2.1 −3.7 1.8 −3.7 −6.8 −0.6 　 −2.7 −7.0 1.7

8 weeks
3 −1.2 1.4 −1.2 −4.3 1.8 −5.7 1.6 −5.7 −8.8 −2.6 　 −4.4 −8.8 −0.1

12 weeks
3 −0.8 1.4 −0.8 −3.9 2.2 −6.5 1.8 −6.4 −9.5 −3.4 　 −5.6 −10.0 −1.3

1
 EMM of the difference was obtained by subtracting the value of the placebo group from that of the intervention group.

2
 Data are presented as the mean ± SE.

3 Data are presented as the mean ± SE, EMM, and the 95%CI (95%CI−, 95%CI+).

Parameter

(Unit)

Intervention

period

Placebo group (n = 95) Intervention group (n = 94)
Difference between

the two groups



Page 3 of 11 

 

 

EMM
1 95%

CI−

95%

CI+
EMM

1 95%

CI−

95%

CI+

VFA (cm
2
) Baseline 99.3 91.7 106.8 99.6 91.9 107.4

4 weeks 98.3 90.8 105.8 95.9 88.2 103.7

8 weeks 98.1 90.5 105.6 94.0 86.2 101.7

12 weeks 98.5 90.9 106.0 93.2 85.4 101.0

SFA (cm
2
) Baseline 223.9 209.5 238.2 225.8 211.4 240.2

4 weeks 224.1 209.7 238.5 225.1 210.7 239.5

8 weeks 224.3 210.0 238.7 228.1 213.7 242.5

12 weeks 225.3 210.9 239.7 228.7 214.3 243.1

TFA (cm
2
) Baseline 323.1 307.0 339.3 325.4 308.9 342.0

4 weeks 322.4 306.2 338.5 321.0 304.5 337.5

8 weeks 322.4 306.2 338.6 322.1 305.6 338.6

12 weeks 323.8 307.6 340.0 321.9 305.4 338.4

1
 EMM of the difference was obtained by subtracting the value of the baseline from the reading at the time.

Intervention group (n = 94)

Intervention

period

Placebo group (n = 95)

Parameter (Unit)

Appendix 3. The EMM and the 95%CI of physical examination parameters for analysis of intragroup analysis.



Page 4 of 11 

 

 

Mean SE EMM
1 95%

CI−

95%

CI+
Mean SE EMM

1 95%

CI−

95%

CI+
Difference

95%

CI−

95%

CI+
P  value

SFA (cm
2
) Baseline

2 223.9 7.0 − − − 　 225.8 7.3 − − − 　 1.9 −18.0 21.9 0.848

4 weeks
3 224.1 7.2 225.0 220.9 229.2 　 225.1 7.3 224.2 220.0 228.3 　 −0.9 −6.7 5.0 0.774

8 weeks
3 224.3 7.4 225.3 221.1 229.4 　 228.1 7.1 227.2 223.0 231.3 　 1.9 −4.0 7.7 0.528

12 weeks
3 225.3 7.4 226.3 222.1 230.4 　 228.7 7.4 227.7 223.6 231.9 　 1.4 −4.4 7.3 0.628

ΔSFA (cm
2
) 4 weeks

3 0.2 2.0 0.2 −3.9 4.3 　 −0.7 1.9 −0.7 −4.8 3.5 　 −0.9 −6.7 5.0 0.774

8 weeks
3 0.5 2.3 0.5 −3.7 4.6 　 2.3 1.8 2.3 −1.8 6.5 　 1.9 −4.0 7.7 0.528

12 weeks
3 1.5 2.3 1.4 −2.7 5.6 　 2.9 2.1 2.9 −1.3 7.0 　 1.4 −4.4 7.3 0.628

TFA (cm
2
) Baseline

2 323.1 7.8 − − − 　 325.4 8.3 − − − 　 2.3 −20.2 24.8 0.840

4 weeks
3 322.4 8.1 323.5 318.0 329.0 　 321.0 8.2 319.9 314.4 325.5 　 −3.5 −11.4 4.3 0.374

8 weeks
3 322.4 8.3 323.5 318.0 329.0 　 322.1 8.1 321.0 315.4 326.5 　 −2.6 −10.4 5.3 0.521

12 weeks
3 323.8 8.4 324.9 319.4 330.4 　 321.9 8.6 320.7 315.2 326.3 　 −4.2 −12.0 3.6 0.292

ΔTFA (cm
2
) 4 weeks

3 −0.8 2.8 −0.8 −6.3 4.7 　 −4.4 2.7 −4.3 −9.9 1.2 　 −3.5 −11.4 4.3 0.374

8 weeks
3 −0.7 2.9 −0.8 −6.3 4.7 　 −3.4 2.7 −3.3 −8.9 2.2 　 −2.6 −10.4 5.3 0.521

12 weeks
3 0.6 2.8 0.6 −4.9 6.2 　 −3.6 2.9 −3.6 −9.1 2.0 　 −4.2 −12.0 3.6 0.292

Appendix 4. Intergroup comparisons of SFA and TFA between the two groups.

Parameter (Unit)
Intervention

period

Placebo group (n = 95) Intervention group (n = 94) Difference between the two groups

1
 EMM of the difference was obtained by subtracting the value of the placebo group from that of the intervention group.

2
 Data are presented as the mean ± SE and were compared between the two groups using the Student's t-test.

3 Data are presented as the mean ± SE, EMM, and the 95%CI (95%CI−, 95%CI+). The data for each timepoint and the changes from baseline were compared between groups in

linear mixed models with baseline values as covariates, time, group, in-teraction between time and group, interaction between baseline values and time, and study participants as

factors.



Page 5 of 11 

 

 

Mean SE Mean SE Mean SE EMM 
3 95%

CI−

95%

CI+
Mean SE EMM 

3 95%

CI−

95%

CI+
Mean SE EMM 

3 95%

CI−

95%

CI+
Mean SE EMM 

3 95%

CI−

95%

CI+
Mean SE EMM 

3 95%

CI−

95%

CI+
Mean SE EMM 

3 95%

CI−

95%

CI+

Body weight (kg) 69.6 1.0 　 69.6 0.9 　 69.4 0.9 69.4 69.0 69.9 　 69.3 0.9 69.3 68.8 69.7 　 69.3 1.0 69.3 68.9 69.8 　 69.0 0.9 69.0 68.6 69.5 　 69.0 1.0 69.0 68.6 69.5 　 68.3 1.0 68.3 67.8 68.7

ΔBody weight (kg) − − 　 − − 　 −0.2 0.2 −0.2 −0.7 0.3 　 −0.4 0.2 −0.4 −0.8 0.1 　 −0.3 0.2 −0.3 −0.8 0.2 　 −0.6 0.2 −0.6 −1.1 −0.2 　 −0.6 0.2 −0.6 −1.0 −0.1 　 −1.3 0.4 −1.3 −1.8 −0.9

BMI (kg/m
2
) 25.6 0.2 　 25.7 0.2 　 25.6 0.2 25.6 25.4 25.8 　 25.5 0.2 25.5 25.3 25.7 　 25.5 0.2 25.5 25.4 25.7 　 25.4 0.2 25.4 25.2 25.6 　 25.4 0.2 25.4 25.3 25.6 　 25.2 0.2 25.1 25.0 25.3

ΔBMI (kg/m
2
) − − 　 − − 　 −0.1 0.1 −0.1 −0.2 0.1 　 −0.1 0.1 −0.1 −0.3 0.0 　 −0.1 0.1 −0.1 −0.3 0.1 　 −0.2 0.1 −0.2 −0.4 −0.1 　 −0.2 0.1 −0.2 −0.4 0.0 　 −0.5 0.2 −0.5 −0.7 −0.3

Abdominal circumference
4
 (cm) 92.1 0.6 　 92.0 0.7 　 91.7 0.6 91.7 90.9 92.5 　 91.6 0.7 91.6 90.8 92.3 　 92.0 0.7 91.9 91.2 92.7 　 91.5 0.7 91.5 90.7 92.3 　 91.4 0.7 91.4 90.6 92.2 　 91.3 0.7 91.3 90.5 92.0

ΔAbdominal circumference
4
 (cm) − − 　 − − 　 −0.4 0.4 −0.4 −1.1 0.4 　 −0.5 0.4 −0.5 −1.2 0.3 　 −0.1 0.4 −0.1 −0.9 0.7 　 −0.6 0.4 −0.6 −1.3 0.2 　 −0.6 0.4 −0.7 −1.4 0.1 　 −0.8 0.4 −0.8 −1.6 0.0

Waist circumference
5
 (cm) 84.0 0.6 　 84.7 0.7 　 84.5 0.7 84.7 84.0 85.4 　 84.7 0.7 84.4 83.7 85.1 　 84.7 0.6 84.9 84.2 85.7 　 84.1 0.7 83.8 83.1 84.5 　 84.0 0.6 84.3 83.6 85.0 　 84.1 0.7 83.8 83.1 84.5

ΔWaist circumference
5
 (cm) − − 　 − − 　 0.4 0.3 0.4 −0.3 1.1 　 0.0 0.4 0.0 −0.7 0.7 　 0.6 0.3 0.6 −0.1 1.3 　 −0.6 0.4 −0.6 −1.3 0.1 　 0.0 0.3 −0.1 −0.8 0.6 　 −0.6 0.4 −0.5 −1.3 0.2

Body fat ratio (%) 30.9 0.8 　 31.4 0.7 　 30.3 0.8 30.5 30.1 30.9 　 30.4 0.8 30.2 29.8 30.6 　 29.8 0.8 30.0 29.6 30.4 　 30.5 0.7 30.3 29.9 30.7 　 29.6 0.8 29.8 29.4 30.2 　 30.1 0.7 29.9 29.5 30.3

ΔBody fat ratio (%) − − 　 − − 　 −0.6 0.2 −0.7 −1.0 −0.3 　 −1.0 0.2 −1.0 −1.4 −0.6 　 −1.1 0.2 −1.1 −1.5 −0.7 　 −0.9 0.2 −0.9 −1.3 −0.5 　 −1.3 0.2 −1.3 −1.7 −0.9 　 −1.3 0.2 −1.3 −1.7 −0.9

Fat mass (kg) 21.3 0.5 　 21.6 0.5 　 20.8 0.5 21.0 20.6 21.3 　 20.9 0.5 20.7 20.3 21.0 　 20.4 0.5 20.6 20.2 20.9 　 20.8 0.5 20.6 20.3 21.0 　 20.2 0.5 20.4 20.1 20.8 　 20.7 0.5 20.5 20.1 20.8

ΔFat mass (kg) − − 　 − − 　 −0.5 0.1 −0.5 −0.9 −0.2 　 −0.8 0.2 −0.8 −1.1 −0.4 　 −0.9 0.2 −0.9 −1.2 −0.5 　 −0.8 0.2 −0.8 −1.2 −0.5 　 −1.0 0.2 −1.0 −1.4 −0.7 　 −1.0 0.2 −1.0 −1.3 −0.6

Lean mass (kg) 48.3 1.0 　 48.0 0.9 　 48.6 1.0 48.5 48.1 48.8 　 48.7 1.0 48.9 48.6 49.3 　 48.9 1.0 48.7 48.3 49.1 　 48.2 0.9 48.4 48.1 48.8 　 48.8 1.0 48.6 48.3 49.0 　 48.1 0.9 48.3 47.9 48.7

ΔLean mass (kg) − − 　 − − 　 0.3 0.1 0.3 −0.1 0.6 　 0.7 0.4 0.7 0.4 1.1 　 0.5 0.1 0.5 0.2 0.9 　 0.3 0.1 0.3 −0.1 0.6 　 0.5 0.1 0.5 0.1 0.8 　 0.1 0.1 0.1 −0.2 0.5

Muscle mass (kg) 45.6 1.0 　 45.2 0.9 　 45.9 1.0 45.7 45.2 46.1 　 45.6 0.9 45.8 45.3 46.2 　 46.1 1.0 45.9 45.4 46.3 　 45.4 0.9 45.6 45.2 46.1 　 46.0 1.0 45.8 45.4 46.3 　 44.8 1.0 45.0 44.6 45.5

ΔMuscle mass (kg) − − 　 − − 　 0.3 0.1 0.3 −0.2 0.7 　 0.4 0.1 0.4 0.0 0.8 　 0.5 0.1 0.5 0.1 0.9 　 0.3 0.1 0.3 −0.2 0.7 　 0.4 0.1 0.5 0.0 0.9 　 −0.3 0.5 −0.4 −0.8 0.1

T-Cho (mg/dL) 223.7 3.8 　 228.3 3.6 　 226.5 3.9 228.4 224.1 232.8 　 226.3 3.6 224.4 220.0 228.7 　 223.0 4.1 224.9 220.6 229.2 　 224.7 3.6 222.7 218.3 227.0 　 220.5 3.9 222.3 218.0 226.6 　 220.8 3.5 219.0 214.7 223.4

ΔT-Cho (mg/dL) − − 　 − − 　 2.8 2.2 2.4 −1.9 6.7 　 −2.0 2.3 −1.7 −6.0 2.7 　 −0.8 2.0 −1.1 −5.4 3.2 　 −3.6 2.3 −3.3 −7.7 1.0 　 −3.2 2.7 −3.7 −8.1 0.6 　 −7.5 2.2 −7.0 −11.3 −2.6

HDL-Cho (mg/dL) 61.6 1.6 　 63.8 1.9 　 62.6 1.5 63.6 62.2 65.0 　 63.9 1.9 62.9 61.5 64.3 　 61.7 1.5 62.7 61.3 64.1 　 62.9 1.8 61.9 60.5 63.3 　 60.3 1.4 61.3 59.9 62.7 　 62.4 1.9 61.4 60.0 62.8

ΔHDL-Cho (mg/dL) − − 　 − − 　 1.0 0.7 0.9 −0.5 2.3 　 0.1 0.7 0.2 −1.2 1.6 　 0.1 0.8 0.0 −1.4 1.4 　 −0.9 0.8 −0.8 −2.2 0.6 　 −1.2 0.8 −1.4 −2.8 0.0 　 −1.4 0.8 −1.3 −2.7 0.1

LDL-Cho (mg/dL) 136.8 3.3 　 140.3 3.4 　 139.5 3.6 140.9 136.9 144.9 　 135.9 3.3 134.5 130.5 138.5 　 136.6 3.6 138.1 134.1 142.1 　 135.6 3.5 134.1 130.1 138.1 　 135.9 3.4 137.2 133.2 141.2 　 134.2 3.2 132.8 128.8 136.8

ΔLDL-Cho (mg/dL) − − 　 − − 　 2.7 2.0 2.4 −1.6 6.4 　 −4.3 2.3 −4.0 −8.0 0.0 　 −0.2 1.7 −0.4 −4.4 3.6 　 −4.6 2.3 −4.4 −8.4 −0.4 　 −0.9 2.3 −1.3 −5.3 2.7 　 −6.1 2.0 −5.7 −9.7 −1.7

TG (mg/dL) 127.0 7.8 　 127.2 9.2 　 128.6 8.0 128.7 112.0 145.4 　 144.6 15.9 144.5 127.7 161.3 　 125.6 6.9 125.7 109.0 142.4 　 133.9 11.9 133.9 117.1 150.7 　 123.5 6.7 123.6 106.8 140.3 　 126.6 8.2 126.6 109.8 143.4

ΔTG (mg/dL) − − 　 − − 　 1.6 5.6 1.6 −15.1 18.3 　 17.4 14.0 17.4 0.6 34.2 　 −1.4 6.6 −1.4 −18.1 15.3 　 6.8 10.9 6.8 −10.0 23.6 　 −3.5 5.7 −3.5 −20.2 13.2 　 −0.5 9.1 −0.5 −17.3 16.3

1
 Data are presented as the mean ± SE.

2 Data are presented as the mean ± SE, EMM, and the 95%CI (95%CI−, 95%CI+).

3
 EMM of the difference was obtained by subtracting the value of the placebo group from that of the intervention group.

4
 Circumference at the level of the umbilicus was recorded.

5
 Minimum abdominal circumference was recorded.

Appendix 5. Measurement data of parameters obtained from physical examination and biochemical analysis.

Parameter (Unit)

Baseline
1

Placebo group (n

= 95)

Intervention

group (n = 94)
Placebo group (n = 95)

4 weeks
2

8 weeks
2

12 weeks
2

Placebo group (n = 95) Intervention group (n = 94)Placebo group (n = 95) Intervention group (n = 94) Intervention group (n = 94)



Page 6 of 11 

 

 

 

EMM
1 95%

CI−

95%

CI+
EMM

1 95%

CI−

95%

CI+
EMM

1 95%

CI−

95%

CI+
EMM

1 95%

CI−

95%

CI+

Body weight (kg) 69.6 67.7 71.5 69.4 67.5 71.3 69.3 67.4 71.2 69.0 67.1 70.9

BMI (kg/m
2
) 25.6 25.2 26.0 25.6 25.2 25.9 25.5 25.1 25.9 25.4 25.0 25.8

Abdominal circumference
2
 (cm) 92.1 90.8 93.4 91.7 90.5 93.0 92.0 90.7 93.3 91.4 90.2 92.7

Waist circumference
3
 (cm) 84.0 82.8 85.3 84.5 83.2 85.7 84.7 83.4 85.9 84.0 82.7 85.3

Body fat ratio (%) 30.9 29.4 32.5 30.3 28.7 31.8 29.8 28.3 31.4 29.6 28.1 31.2

Fat mass (kg) 21.3 20.2 22.3 20.8 19.7 21.8 20.4 19.4 21.5 20.2 19.2 21.3

Lean mass (kg) 48.3 46.3 50.3 48.6 46.6 50.6 48.9 46.9 50.9 48.8 46.8 50.8

Muscle mass (kg) 45.6 43.7 47.5 45.9 43.9 47.8 46.1 44.2 48.0 46.0 44.1 47.9

T-Cho (mg/dL) 223.7 216.0 231.5 226.5 218.8 234.3 223.0 215.2 230.7 220.5 212.8 228.3

HDL-Cho (mg/dL) 61.6 58.6 64.5 62.6 59.6 65.6 61.7 58.7 64.7 60.3 57.3 63.3

LDL-Cho (mg/dL) 136.8 129.9 143.7 139.5 132.6 146.4 136.6 129.7 143.5 135.9 129.0 142.7

TG (mg/dL) 127.0 112.5 141.6 128.6 114.1 143.2 125.6 111.1 140.2 123.5 109.0 138.1

Body weight (kg) 69.6 67.8 71.5 69.3 67.4 71.1 69.0 67.2 70.9 68.3 66.4 70.2

BMI (kg/m
2
) 25.7 25.3 26.1 25.5 25.2 25.9 25.4 25.1 25.8 25.2 24.8 25.6

Abdominal circumference
2
 (cm) 92.0 90.7 93.4 91.6 90.2 92.9 91.5 90.1 92.8 91.3 89.9 92.6

Waist circumference
3
 (cm) 84.7 83.3 86.1 84.7 83.2 86.1 84.1 82.6 85.5 84.1 82.7 85.5

Body fat ratio (%) 31.4 29.9 32.8 30.4 29.0 31.8 30.5 29.0 31.9 30.1 28.6 31.5

Fat mass (kg) 21.6 20.6 22.7 20.9 19.8 21.9 20.8 19.8 21.8 20.7 19.6 21.7

Lean mass (kg) 48.0 46.1 49.9 48.7 46.8 50.6 48.2 46.4 50.1 48.1 46.2 50.0

Muscle mass (kg) 45.2 43.4 47.0 45.6 43.8 47.4 45.4 43.6 47.2 44.8 43.0 46.6

T-Cho (mg/dL) 228.3 221.2 235.4 226.3 219.2 233.4 224.7 217.6 231.8 220.8 213.7 227.9

HDL-Cho (mg/dL) 63.8 60.1 67.5 63.9 60.2 67.6 62.9 59.2 66.6 62.4 58.7 66.1

LDL-Cho (mg/dL) 140.3 133.7 146.9 135.9 129.3 142.5 135.6 129.0 142.2 134.2 127.6 140.8

TG (mg/dL) 127.2 104.1 150.2 144.6 121.5 167.6 133.9 110.9 157.0 126.6 103.6 149.7

2
 Circumference at the level of the umbilicus was recorded.

3
 Minimum abdominal circumference was recorded.

Placebo group (n = 95)

Parameter (Unit)

Appendix 6. The EMM and the 95%CI of parameters obtained from physical examination and biochemical analysis for analysis of intragroup analysis.

Intervention group (n = 94)

1
 EMM of the difference was obtained by subtracting the value of the baseline from the reading at the time.

Baseline 4 weeks 8 weeks 12 weeks



Page 7 of 11 

 

 

Appendix 7. Adverse events during the study.

Subject ID Symptom
Occurrence day

in 2021

Disappearance day

in 2021
Severity Treatment

Progress and

outcome
Causality

54839 Eczema April 11 April 12 Mild Medication Recovery/ disappearance No association

56020 Common cold April 15 April 16 Mild Medication Recovery/ disappearance No association

April 11 April 15 Mild Medication Recovery/ disappearance No association

April 21 April 23 Mild Medication Recovery/ disappearance No association

Allergic rhinitis April 2 May 2 Mild Medication Recovery/ disappearance No association

Cough April 2 April 23 Mild Medication Recovery/ disappearance No association

Eye strain May 8 May 17 Mild Medication Recovery/ disappearance No association

Hemostasis May 8 May 13 Mild Medication Recovery/ disappearance No association

Mydriasis May 8 May 15 Mild Medication Recovery/ disappearance No association

57248 Back pain April 6 April 7 Mild Medication Recovery/ disappearance No association

57823 Muscle pain April 1 May 12 Mild Medication Recovery/ disappearance No association

57829 Allergic rhinitis March 29 April 11 Mild Medication Recovery/ disappearance No association

April 10 April 11 Mild Medication Recovery/ disappearance No association

April 13 April 14 Mild Medication Recovery/ disappearance No association

April 15 April 16 Mild Medication Recovery/ disappearance No association

Dysmenorrhea May 9 May 11 Mild Medication Recovery/ disappearance No association

56037 Joint pain May 2 May 5 Mild Medication Recovery/ disappearance No association

56829 Headache April 27 April 28 Mild Medication Recovery/ disappearance No association

56868 Diarrhea May 8 May 9 Mild Medication Recovery/ disappearance No association

April 15 April 18 Mild Medication Recovery/ disappearance No association

May 7 May 9 Mild Medication Recovery/ disappearance No association

57850 Common cold April 27 April 30 Mild Medication Recovery/ disappearance No association

April 5 April 9 Mild Medication Recovery/ disappearance No association

April 12 April 23 Mild Medication Recovery/ disappearance No association

April 27 May 1 Mild Medication Recovery/ disappearance No association

May 1 May 5 Mild Medication Recovery/ disappearance No association

May 10 May 11 Mild Medication Recovery/ disappearance No association

May 13 May 14 Mild Medication Recovery/ disappearance No association

Oral mucositis April 6 April 11 Mild Medication Recovery/ disappearance No association

April 21 April 24 Mild Medication Recovery/ disappearance No association

April 25 May 1 Mild Medication Recovery/ disappearance No association

May 3 May 8 Mild Medication Recovery/ disappearance No association

Hay fever April 10 April 12 Mild Medication Recovery/ disappearance No association

Gastroenteritis April 10 April 12 Mild Medication Recovery/ disappearance No association

Placebo group

Intervention group

56033 Headache

56285

56317

58102

56022
Headache

57336 Dysmenorrhea

58000

Constipation

Intestines



Page 8 of 11 

 

 

Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD

Systolic blood pressure

(mmHg)
123.7 14.8 125.0 13.9 0.542 121.0 13.2 126.0 16.6 0.021* 120.7 14.1 126.3 15.7 0.011* 122.8 13.7 125.3 14.4 0.212

Diastolic blood pressure

(mmHg)
81.4 11.4 82.7 11.7 0.438 80.4 10.6 82.1 11.6 0.292 79.2 10.7 82.0 12.1 0.086 80.9 11.0 82.5 11.1 0.318

Pulse rate (bpm) 72.8 9.8 73.9 9.0 0.407 73.4 9.2 74.3 10.2 0.528 74.2 9.9 73.6 10.0 0.691 73.0 9.9 74.1 9.5 0.429

Body temperature (°C) 35.8 1.1 35.8 1.0 0.841 36.2 0.3 36.2 0.3 0.777 36.3 0.2 36.3 0.2 0.388 36.3 0.2 36.3 0.2 0.902

Appendix 8. Physical parameters during the study (FAS and SAF).

Baseline 4 weeks

Data are presented as the mean ± SD and were compared between the two groups using the Student's t-test.

8 weeks 12 weeks

Parameter
P  value

* P  < 0.05.

Intervention

group

(n = 95)P  value P  value P  value

Placebo

group

(n = 96)

Intervention

group

(n = 98)

Placebo

group

(n = 95)

Intervention

group

(n = 97)

Placebo

group

(n = 95)

Placebo

group

(n = 96)

Intervention

group

(n = 98)



Page 9 of 11 

 

 

Appendix 9. Hematological and biochemical parameters during the study (FAS and SAF).

Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD

WBC (/μL) 3300–9000 6006.3 1336.4 5857.1 1475.6 0.462 6126.0 1436.1 5766.3 1453.1 0.085 6107.4 1502.6 5652.6 1231.4 0.023
b 5914.7 1399.5 5686.3 1321.4 0.249

RBL (×10
4
/μL)

Male, 430–570

Female, 380–500
482.9 44.4 477.6 38.7 0.377 480.9 45.0 471.5 37.7 0.118 475.0 46.1 468.0 40.9 0.264 472.1 46.1 467.4 38.1 0.448

Hb (g/dL)
Male, 13.5–17.5

Female, 11.5–15.0
14.5 1.4 14.5 1.3 0.843 14.3 1.4 14.3 1.3 0.809 14.2 1.4 14.2 1.4 0.916 14.1 1.4 14.2 1.3 0.786

Ht (%)
Male, 39.7–52.4

Female, 34.8–45.0
45.1 3.6 45.0 3.5 0.974 45.0 3.7 44.7 3.5 0.569 44.7 3.8 44.6 3.8 0.868 44.1 3.9 44.2 3.5 0.818

PLT (×10
4
/μL) 14.0–34.0 27.0 5.2 27.1 5.1 0.862 27.2 4.9 26.6 5.3 0.430 26.4 5.2 26.0 5.2 0.573 26.7 5.2 26.3 5.3 0.557

MCV (fL) 85–102 93.5 5.0 94.4 4.0 0.197 93.9 4.9 95.0 4.2 0.100 94.3 4.8 95.4 4.1 0.089 93.6 4.7 94.6 4.2 0.122

MCH (Pg) 28.0–34.0 30.1 1.9 30.5 1.7 0.129 29.8 1.9 30.3 1.7 0.067 30.0 1.9 30.4 1.7 0.165 29.9 1.9 30.3 1.8 0.153

MCHC (%) 30.2–35.1 32.2 1.0 32.3 1.0 0.458 31.8 1.1 31.9 1.0 0.410 31.8 1.1 31.8 1.1 0.896 32.0 1.1 32.0 1.0 0.816

NEUT (%) 40.0–75.0 59.4 8.2 57.9 7.5 0.178 59.2 8.2 57.6 8.1 0.178 59.1 8.8 57.2 7.8 0.114 58.7 8.1 57.4 7.8 0.241

LYMP (%) 18.0–49.0 31.2 7.9 32.9 6.9 0.117 31.8 8.0 33.2 7.5 0.226 32.0 8.3 33.5 7.4 0.168 32.2 7.6 33.5 7.5 0.236

MONO (%) 2.0–10.0 5.5 1.3 5.6 1.3 0.665 5.5 1.2 5.6 1.5 0.343 5.5 1.4 5.7 1.3 0.292 5.6 1.3 5.6 1.4 0.956

EOS (%) 0–8.0 3.0 2.2 2.8 1.9 0.551 2.8 1.8 2.9 2.1 0.736 2.6 1.6 2.7 1.8 0.602 2.7 1.8 2.8 1.7 0.731

BASO (%) 0–2.0 0.9 0.4 0.8 0.3 0.346 0.8 0.4 0.8 0.3 0.310 0.8 0.3 0.8 0.3 0.922 0.8 0.4 0.8 0.4 0.768

AST (U/L) 10–40 23.3 7.2 22.9 8.6 0.691 23.0 7.3 22.3 7.6 0.494 21.8 5.9 22.1 9.2 0.780 23.1 8.4 21.9 8.0 0.281

ALT (U/L) 5–45 26.4 14.4 25.6 15.7 0.689 26.0 17.2 24.2 15.1 0.440 23.4 12.5 23.3 15.5 0.936 23.4 12.4 22.5 14.8 0.656

γ-GT (U/L)
Male, <80

Female, <30
39.2 39.2 35.8 30.0 0.499 38.8 34.3 35.4 32.3 0.485 34.5 26.8 34.9 32.3 0.939 33.0 24.9 32.9 31.8 0.980

ALP (U/L) 100–325 209.1 60.1 213.2 56.3 0.623 73.6 20.5 73.6 19.2 0.986 72.7 19.6 73.3 17.2 0.830 72.5 20.3 73.2 18.5 0.808

LD (U/L) 120–240 192.1 27.9 191.5 28.4 0.889 195.3 26.7 202.3 72.2 0.372 196.6 29.7 196.9 27.5 0.943 203.3 26.0 200.5 29.2 0.493

LAP (U/L)
Male, 45–81

Female, 37–61
54.6 12.5 54.9 15.8 0.886 54.3 11.7 54.2 13.2 0.943 54.0 10.1 54.2 11.3 0.905 53.2 10.8 52.8 11.7 0.792

T-BIL (mg/dL) 0.2–1.2 0.8 0.3 0.8 0.3 0.853 0.8 0.2 0.8 0.3 0.766 0.8 0.3 0.8 0.3 0.651 0.8 0.3 0.8 0.3 0.682

D-BIL (mg/dL) 0–0.2 0.1 0.0 0.1 0.0 0.427 0.1 0.1 0.1 0.1 0.212 0.1 0.0 0.1 0.1 0.058 0.1 0.1 0.1 0.1 0.681

I-BIL (mg/dL) 0.2–1.0 0.7 0.2 0.7 0.3 0.958 0.7 0.2 0.7 0.3 0.948 0.7 0.3 0.7 0.3 0.888 0.7 0.3 0.7 0.3 0.587

ChE (U/L)
Male, 234–493

Female, 200–452
371.3 68.3 371.5 64.7 0.984 366.8 66.6 362.3 64.5 0.637 362.5 68.8 356.2 63.2 0.511 358.7 71.2 352.6 62.4 0.530

TP (g/dL) 6.7–8.3 7.2 0.4 7.2 0.3 0.267 7.2 0.3 7.2 0.4 0.783 7.2 0.4 7.2 0.4 0.721 7.2 0.4 7.3 0.4 0.276

BUN (mg/dL) 8.0–20.0 13.8 3.4 12.8 3.5 0.065 13.6 3.1 13.2 3.3 0.417 13.4 3.5 12.9 2.9 0.303 13.1 3.1 12.3 2.7 0.038*

Cre (mg/dL)
Male, 0.61–1.04

Female, 0.47–0.79
0.8 0.2 0.7 0.1 0.918 0.8 0.2 0.8 0.1 0.698 0.8 0.2 0.8 0.1 0.769 0.8 0.2 0.8 0.1 0.753

UA (mg/dL)
Male, 3.8–7.0

Female, 2.5–7.0
5.4 1.4 5.5 1.4 0.584 5.3 1.2 5.5 1.4 0.285 5.4 1.2 5.6 1.4 0.303 5.4 1.3 5.5 1.4 0.647

CK (U/L)
Male, 60–270

Female, 40–150
118.9 83.7 121.6 102.9 0.838 122.3 70.8 114.7 74.4 0.470 127.0 100.2 137.4 264.4 0.721 131.6 85.5 117.9 82.0 0.261

Na (mEq/L) 137–147 140.7 1.5 140.8 1.6 0.771 141.1 1.9 141.1 1.8 0.995 141.1 1.8 141.0 1.5 0.755 141.2 1.6 141.0 1.5 0.277

K (mEq/L) 3.5–5.0 4.2 0.4 4.1 0.3 0.132 4.1 0.3 4.1 0.4 0.879 4.0 0.3 3.9 0.3 0.207 4.0 0.3 4.0 0.3 0.229

Cl (mEq/L) 98–108 101.7 1.9 101.6 1.9 0.706 101.4 1.9 101.5 2.0 0.939 101.5 2.1 101.6 1.8 0.558 101.9 1.9 101.6 1.7 0.234

Ca (mg/dL) 8.4–10.4 9.4 0.3 9.4 0.3 0.290 9.4 0.3 9.4 0.3 0.937 9.3 0.3 9.3 0.3 0.718 9.2 0.3 9.3 0.3 0.680

IP (mg/dL) 2.5–4.5 3.3 0.5 3.2 0.5 0.565 3.5 0.7 3.4 0.6 0.498 3.7 0.7 3.6 0.6 0.596 3.4 0.6 3.3 0.5 0.607

Fe (μg/dL)
Male, 50–200

Female, 40–180
104.6 38.2 108.8 42.3 0.468 101.6 33.6 105.6 37.3 0.435 108.3 37.6 109.5 38.2 0.834 109.6 36.0 107.0 37.0 0.628

AMY (U/L) 40–122 78.5 24.7 74.8 22.2 0.279 76.8 25.8 74.3 23.0 0.481 73.5 21.3 74.2 23.2 0.828 72.9 19.4 72.1 20.0 0.771

Glucose (mg/dL) 70–109 88.5 12.7 87.7 9.9 0.636 87.7 9.6 87.4 10.7 0.859 87.9 9.5 88.1 11.3 0.879 89.0 13.5 88.2 8.7 0.637

HbA1c (NGSP) (%) 4.6–6.2 5.4 0.4 5.5 0.4 0.363 5.4 0.4 5.5 0.4 0.800 5.4 0.4 5.5 0.4 0.436 5.4 0.4 5.4 0.3 0.985

GA (%) 12.3–16.5 12.8 1.5 12.7 1.2 0.560 12.7 1.5 12.7 1.3 0.816 13.0 1.5 12.9 1.1 0.663 12.9 1.5 12.9 1.1 0.707

Intervention

group

(n = 98) P  value

Placebo group

(n = 95)

Intervention group

(n = 97) P  value

* P  < 0.05.

Data are presented as the mean ± SD and were compared between the two groups using the Student's t-test.

Parameter

Baseline 4 weeks 8 weeks

Placebo group

(n = 95)

Intervention group

(n = 95) P  value
Criteria

12 weeks

Placebo group

(n = 96)

Intervention group

(n = 98) P  value

Placebo group

(n = 96)



Page 10 of 11 

 

 

Appendix 10. Distribution of the number of participants outside the reference value (FAS and SAF).

Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside

WBC 92 4 94 4 1.000 90 6 93 5 0.766 89 6 95 2 0.167 90 5 94 1 0.211

RBC 84 12 93 5 0.079 86 10 91 7 0.457 87 8 92 5 0.404 86 9 87 8 1.000

Hb 88 8 93 5 0.404 89 7 93 5 0.566 85 10 90 7 0.456 86 9 90 5 0.406

Ht 83 13 88 10 0.512 80 16 85 13 0.550 81 14 85 12 0.677 82 13 87 8 0.355

PLT 87 9 91 7 0.611 86 10 92 6 0.308 84 11 91 6 0.213 88 7 89 6 1.000

MCV 89 7 93 5 0.566 88 8 91 7 0.794 88 7 91 6 0.781 90 5 89 6 1.000

MCH 88 8 92 6 0.591 87 9 88 10 1.000 85 10 88 9 0.813 86 9 85 10 1.000

MCHC 93 3 96 2 0.681 91 5 93 5 1.000 89 6 91 6 1.000 92 3 90 5 0.721

NEUT 94 2 97 1 0.619 93 3 95 3 1.000 91 4 95 2 0.442 91 4 95 0 0.121

LYMP 93 3 95 3 1.000 93 3 95 3 1.000 89 6 95 2 0.167 90 5 94 1 0.211

MONO 95 1 98 0 0.495 96 0 97 1 1.000 94 1 96 1 1.000 95 0 94 1 1.000

EOS 91 5 96 2 0.276 95 1 95 3 0.621 95 0 95 2 0.497 94 1 95 0 1.000

BASO 94 2 98 0 0.244 95 1 98 0 0.495 95 0 97 0 N. A. 95 0 95 0 N. A.

AST 91 5 93 5 1.000 92 4 96 2 0.442 95 0 95 2 0.497 93 2 92 3 1.000

ALT 87 9 88 10 1.000 87 9 93 5 0.280 87 8 92 5 0.404 87 8 91 4 0.372

γ-GT 71 25 78 20 0.397 74 22 82 16 0.280 76 19 82 15 0.453 77 18 84 11 0.226

ALP 90 6 95 3 0.328 88 8 92 6 0.591 88 7 95 2 0.099 89 6 92 3 0.497

LD 91 5 93 5 1.000 85 11 81 17 0.308 82 13 82 15 0.839 73 22 78 17 0.473

LAP 83 13 85 13 1.000 83 13 85 13 1.000 84 11 84 13 0.828 83 12 81 14 0.833

T-BIL 89 7 88 10 0.613 93 3 92 6 0.498 90 5 84 13 0.081 86 9 90 5 0.406

D-BIL 96 0 98 0 N. A. 95 1 96 2 1.000 94 1 95 2 1.000 93 2 94 1 1.000

I-BIL 89 7 87 11 0.459 91 5 91 7 0.767 87 8 83 14 0.258 84 11 89 6 0.309

ChE 89 7 91 7 1.000 91 5 92 6 1.000 90 5 91 6 1.000 89 6 92 3 0.497

TP 86 10 94 4 0.103 90 6 93 5 0.766 85 10 87 10 1.000 87 8 91 4 0.372

BUN 90 6 85 13 0.146 92 4 92 6 0.747 85 10 94 3 0.048* 92 3 90 5 0.721

Cre 90 6 90 8 0.783 88 8 93 5 0.404 89 6 91 6 1.000 89 6 88 7 1.000

UA 83 13 83 15 0.839 85 11 83 15 0.529 83 12 80 17 0.421 84 11 81 14 0.668

CK 88 8 91 7 0.794 90 6 94 4 0.535 86 9 90 7 0.611 82 13 88 7 0.237

Na 96 0 98 0 N. A. 95 1 97 1 1.000 95 0 97 0 N. A. 94 1 95 0 1.000

K 94 2 96 2 1.000 94 2 95 3 1.000 90 5 95 2 0.276 93 2 91 4 0.682

Cl 93 3 97 1 0.366 94 2 96 2 1.000 93 2 96 1 0.619 93 2 93 2 1.000

Ca 96 0 98 0 N. A. 95 1 98 0 0.495 95 0 97 0 N. A. 93 2 95 0 0.497

IP 93 3 92 6 0.498 89 7 96 2 0.099 83 12 89 8 0.353 86 9 89 6 0.592

Fe 90 6 88 10 0.435 91 5 89 9 0.407 90 5 89 8 0.568 90 5 88 7 0.767

AMY 88 8 90 8 1.000 89 7 89 9 0.795 91 4 88 9 0.250 92 3 90 5 0.721

glucose 89 7 95 3 0.211 90 6 94 4 0.535 91 4 91 6 0.747 89 6 93 2 0.279

HbA1c (NGSP) 91 5 94 4 0.746 92 4 93 5 1.000 92 3 93 4 1.000 90 5 93 2 0.444

GA 59 37 66 32 0.454 51 45 60 38 0.310 60 35 64 33 0.763 61 34 67 28 0.439

8 weeks 12 weeks

Placebo group

(n = 96)

Intervention group

(n = 98) P  value

Placebo group

(n = 96)

* P  < 0.05.

Intervention group

(n = 95) P  value

Data represent the number of applicable subjects; they  were compared between the two groups using the χ
2
 test.

N. A., Not Available.

Intervention group

(n = 98) P  value

Placebo group

(n = 95)

Intervention group

(n = 97) P  value

Placebo group

(n = 95)
Parameter

Baseline 4 weeks



Page 11 of 11 

 

 

 

Appendix 11. Parameters of the urine test during the study (FAS and SAF).

Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside Inside Outside

Protein (−) 94 2 86 12 0.010* 89 7 89 9 0.795 88 7 89 8 1.000 88 7 88 7 1.000

Sugar (−) 96 0 97 1 1.000 96 0 97 1 1.000 94 1 96 1 1.000 93 2 94 1 1.000

Urobilinogen (±) 96 0 97 1 1.000 96 0 98 0 N. A. 95 0 97 0 N. A. 95 0 94 1 1.000

Bilirubin (−) 96 0 98 0 N. A. 96 0 98 0 N. A. 95 0 97 0 N. A. 95 0 95 0 N. A.

pH 5.0–7.5 95 1 96 2 1.000 95 1 96 2 1.000 92 3 96 1 0.366 94 1 94 1 1.000

Hidden blood (−) 90 6 91 7 1.000 90 6 89 9 0.593 88 7 89 8 1.000 88 7 82 13 0.237

Ketone body (−) 96 0 97 1 1.000 95 1 97 1 1.000 92 3 96 1 0.366 93 2 93 2 1.000

Parameter Criteria

Baseline 4 weeks 8 weeks

N. A., Not Available.

* P  < 0.05.

12 weeks

Placebo

group

(n = 96)

Intervention

group

(n = 98) P  value

Placebo

group

(n = 96)

Intervention

group

(n = 98) P  value

Placebo

group

(n = 95)

Intervention

group

(n = 97) P  value

Placebo

group

(n = 95)

Intervention

group

(n = 95) P  value

Data represent the number of applicable subjects; they  were compared between the two groups using the χ
2
 test.


