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.