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Clinical Study ReportTitle: Clinical study on the reduction of the body fat by intake of food containing Ashitaba ChalconeProject number: 21565Submitted on November 18, 2009 to Japan Bio Science Laboratory Co., Ltd.Medical institution: Medical corporation Yukokai, Meguro Medical ClinicPrincipal investigator: Dr. Hiromaru Ogata Contract research organization: TTC Co., Ltd.Representing Director Mr. Tetsuro YamamotoTable of Contents TOC \o "1-1" \h \z \u 1. Summary PAGEREF _Toc245454922 \h 22. Background and object of the study PAGEREF _Toc245454923 \h 43. Organisations PAGEREF _Toc245454924 \h 44. Methods PAGEREF _Toc245454925 \h 85. Results PAGEREF _Toc245454926 \h 176. Discussion PAGEREF _Toc245454927 \h 237. Conclusions PAGEREF _Toc245454928 \h 248. References PAGEREF _Toc245454929 \h 241. SummaryTo examine the reduction of the body fat when food containing Ashitaba Chalcone is taken, we conducted a double-blind, placebo-controlled study on slightly obese male and female adults with BMI equal to or more than 25 and less than 30. The subjects, after dinner, took one capsule of either a test food containing 200 mg of Ashitaba Chalcone or a placebo food without Ashitaba Chalcone for 56 days. Outcome measures included the weight, BMI, the body fat area (the visceral fat area, the subcutaneous fat area and the total fat area), the waist circumference, the hip circumference, the clinical test data, the special test (PAI-1 antigen, tPA activity, ECLT, adiponectin, resistin, leptin), blood pressure, heart rate and diet.Based on the result of pre-screening, we registered 26 participants and randomly assigned them into either the placebo group (male: 9, female: 4) or the test group (male: 9, female 4). There was no dropout in the study. There was no significant difference between the placebo group and the treatment group in the primary end points, namely, the visceral fat area and the body weight, because these values decreased in both groups. However, only in the treatment group, compared to the baseline (i.e., before the intake of the test food), a significant reduction of the visceral fat area at 8th week and the body weight at 4th and 8th week was confirmed.Like the body weight, the secondary end point, BMI, did not differ significantly between the groups. However, the significant decrease was observed only in the treatment group when the value before the intake was compared to that of 4th and 8th week. Although there was no significant difference in the value of waist circumstance between the groups, each group showed the significant reduction at 4th and 8th week compared to that of the baseline. The body fat percentage of both group decreased at 4th and 8th week after the intake. However, the significant reduction was confirmed only in the placebo group at 8th week after the intake.Regarding the other end points, the total fat area decreased in the both groups at 8th week after the intake, but the significant reduction was confirmed only in the treatment group. The hip circumstance significantly decreased in the placebo group at 8th week and in the treatment group at 4th and 8th week after the intake.The significant reduction of the visceral fat area and the body weight were confirmed within the treatment group although the difference between the groups was not confirmed. Therefore, the reduction effect on the visceral fat area and the body weight by the intake of Ashitaba chalcone were what we could expect. A number of adverse events observed during the study period were 3 cases (1 case of loose stools, 1 case of the common cold and 1 case of contact dermatitis due to insects) in 3 of 13 subjects of the placebo group (23%) and 8 cases (2 cases of diarrhea with abdominal pain, 2 cases of symptoms of the common cold, 1 case of bronchitis, 1 case of bloating, 1 case of stiff shoulder and 1 case of strained back) in 5 of 13 subjects of the treatment group (23%). All of them were mild and unrelated to the test food. There was a significant change in some examination items (namely, the total cholesterol, LDL-cholesterol, ALP, the total protein, albumins, creatinine, the white blood cell count, MCV, MCH, MCHC and the platelet count in the placebo group and the pulse rate, the total protein, Na, K, the white blood cell count, MCV and MCH in the treatment group), but any of the change was small and not clinically significant. Taking the above into consideration, the safety of this study where 200 mg of Ashitaba chalcone was taken for 8 weeks was determined as safe.2. Background and objective of the studyAshitaba (Angelica keiskei) is a large perennial plant of the Apiaceae indigenous to Japan, rich in fiber, potassium, carotene and Vitamin E and is considered as a nutritious food. Ashitaba chalcone, which is the principal ingredient in the test food, is a type of polyphenol uniquely included in yellow sap exuding from leaves, stems and roots of Ashitaba and has unique bitterness. It can be discussed that Ashitaba has a sufficient history of consumption because the use of Ashitaba as food or medicine is described in an old literature of the Edo period (the period between 1603 to 1868) and it is widely available in the public now. In addition, "Specifications on the Range of Drugs" categorizes leaves of Ashitaba in non-pharmaceuticals. This study examined the reduction effect on the body fat by the intake of food containing Ashitaba chalcone in slightly obese adult males and females. 3. OrganizationsThis study was conducted under the organization below.3.1　Study conducting organization3.1.1 Study conducting medical institute1) Name: Medical corporation Yukokai, Meguro Medical ClinicAddress：Kamiosaki 3-11-18, Shinagawa-ku, Tokyo 141-0021TEL：03-3280-58772) Name: Medical corporation Yukokai, Akihabara Medical ClinicAddress：Asakaze No.2 Building 6F, Sotokanda 1-16-9 Sotokanda, Chiyoda-ku, Tokyo 141-0021TEL：03-3255-8805Main role: To conduct the study and various types of analysis. Also, managed the participants and organized the study conducting system. 3.1.2 Principal investigatorPrincipal investigatorName：Dr. Hiromaru OgataOrganization：Medical corporation Yukokai, Meguro Medical ClinicMain role: Supervised administration regarding the study, was responsible for the management, inform and instruct the participants, obtained the informed consent, checked interviews and adverse events, made a case report form and managed the study conducting system.3.1.3 Person in charge of assignmentName: Yoshihisa KihuneOrigination: Advisor, TTC, Co., Ltd.Main role: Made the assignment table and sealed, kept and opened documents. 3.1.4 ClientName: Japan Bio Science Laboratory Co., Ltd.住所：Ibaraki-Tanaka Building 4 F, Nakahozumi 1-1-59, Ibaraki, Osaka 567-0034TEL：072-631-1203Contact person：Dr. Katsunori OhnishiMain role: Ordered the study to the contract research organization, managed the quality of the test food, dealt with liability issues regarding the test food (e.g., to take insurance), supplied the test food and approved a study protocol. 3.1.5 Contract research organizationName: TTC Co., Ltd.Address: Ebisunishi 1-20-2, Sibuya-ku, Tokyo 150-0021 TEL：03-5459-5329 FAX：03-5459-5685Mail role: Made a study protocol, was responsible for the operation, management and budget of the study and appropriately operated and controlled the study under the close cooperation with all the stakeholders in accordance with the study protocol approved by an ethics committee. Those in charge of the management of the study: Muneaki Iizuka, Masae OonoMain role: Supported the selection and management of participants, confirmed measurement values, collected and statistical analyzed the measurement values and made the study report.3.1.6 Medical facility supporting instituteName: e-KencomAddress: Suzuki Building 2F, Ikebukuro 2-55-2, Toyoshima-ku, Tokyo 171-0014TEL：03-5953-0888Person in charge: Keiichiro Tanaka, Kazuto Itakura (emergency contact: 090-7215-1619)Main role: Under the supervision of the contract research organization, in accordance with the study protocol, recruited participants, contacted them, managed the study progress, supported the responsible doctor and distributed the test food. 3.1.7 Clinical test conducting instituteName: BMLAddress: Kouenjiminami 1-34-5, Suginami-ku Tokyo 166-0003TEL：03-3316-0013Mail role: Conducted clinical tests and reported the analysis result to the medical institution.3.1.8 Ethics committeeName: Akihabara Medical Clinic Ethics CommitteeMain role: Based on the reference regarding the protocol and the test food, made sure the safety of participants and assessed whether the study should be approved. 3.2　Ethical consideration3.2.1 Compliance with Declaration of Helsinki and ethical guidelinesThis study was conducted in compliance with “Declaration of Helsinki” (Tokyo, 2004) and “Ethical Guidelines for Epidemiological Research” (Ministry of Education, Culture, Sports, Science and Technology?Ministry of Health, Labor and Welfare, 2004) and in accordance with the study protocol.3.2.2Assessment and approval by the ethics committeeThe study was conducted after the assessment and approval by the ethics committee at the study location. 3.2.3 Protection of privacy and personal informationThe principal investigator anonymized adverse events and data related to the study result, and did not use any number or address specifying the identity and name of a participant. Those people involved in the present study paid considerable attention to the protection of personal information and conducted the study.3.2.4 Informed consentThe principal investigator provided the participants with the informed consent including the following information prior to the commencement of the study, explained the objective and content of the study and obtained the written informed consent of the participants based on their free will. （1）Objective and nature of the study（2）Content of the study (including the inclusion and exclusion criteria for participants)（3）Study method （4）Duration of the study（5）Potential advantages and disadvantages（6）Actions to any damage to your health during the study（7）Provision of new information（8）Cancellation of the participation to the study and the dropout(9) Protection of personal information when any data or results are reported(10) Storage and disposal of references(11) Appropriate plan and conduct of the study and its report (conflict of interest) (12) Fees for participation(13) Requesting party (contract research organization) (14) Principal investigator, affiliation of doctors(15) Ethical committee(16) Contact information3.2.5 Study periodThe study was conducted between April and September 2009. 4. Methods4.1　Study designDouble-blind, parallel-group, study.4.2　Number of participants26 people 4.3　Selection and exclusion criteria of participantsIn accordance with the regulations of the site management organization, we recruited participants and registered those who met the inclusion criteria and did not meet the exclusion criteria. (1) Inclusion criteria ① Age equal to or greater than 40 and below 65 years old. ② BMI equal to or greater than 25 and below 30. ③ Waist circumference equal to or greater than 85 cm. (2) Exclusion criteria ① Those who regularly eat health foods intended for sliming or the exercise for it. ② Those who regularly consumer medicines and/or FOSHU (Foods for specified health uses) that potentially affect body fat, serum lipid and fat metabolism. ③ Those who regularly eat the study the principal ingredient used in the study, Ashitaba Chalcone.④ Those with the body weight equal to or greater than 100 kg. ⑤ Any individual determined inappropriate as a participant by the response to a lifestyle questionnaire. ⑥ Those who are under treatment of severe diseases⑦ Those with a medical history of a severe disease like diabetes, liver diseases or heart diseases. ⑧ Those who have risk of allergy in relation to the study⑨ Those who are doing breast feeding, pregnant or planning to be pregnant during the study period. ⑩ Any individual determined inappropriate as a participant by the result of the blood analysis that is conducted as a pretest.? Those who are participating in other clinical trials at the start of the study. ? Any others whom the principal investigator determine inappropriate. 4.4　Withdrawal and dropout criteria(1) Withdrawal criteria The principal investigator decided that any participant should be withdrawn from the study when s/he is considered to face the following cases.① Case where the safety of the participant is likely to be damaged. ② Case where any clinically severe abnormality or accident take place and it is difficult to continue the study. ③ Case where any significant or continuing incompliance of participants is identified.④ Case where the withdrawal of the study is considered to be appropriate for any other reasons. (2) Dropout criteria The principal investigator determined that he can discontinue a trial of a participant if s/he leaves the study due to his/her own reason and/or will after s/he decided to take part in the study. ,4.5　Test food4.5.1 Name of the test food, and its type(1) Test food (2) Placebo food 4.5.2 Principal ingredient Ashitaba chalcone 4.5.3 Composition and nutrition fact of the test food (1) Test food① Composition: per 1 capsule (200 mg)FormTwo-piece capsuleIngredients98% Ashitaba Chalcone Powder (made by Japan Bio Science Laboratory Co., Ltd.)2% Ester （Product name: DK Ester F-20W, made by Dai-ichi Kogyo Seiyaku Co., Ltd.）Amount of the principal ingredient196 mg as Ashitaba chalcone（Chalcone content: about 16 mg）Shelf life24 monthsStorageAt room temperature (Measured values during the storage period: 19 to 29 degrees C)＊Chalcone is an active ingredient contained in Ashitaba and mainly means xanthoangelol and 4-hydroxyderricin.② Nutrition facts: per 1 capsule (200 mg)Energy0.90 kcalProtein　0.98 mgFat　22.36 mgCarbohydrates　174.05 mgSodium0.02 mg(2) Placebo food①Composition: per 1 capsule (200 mg)FormTwo-piece capsuleIngredients98% Cyclodextrin (Product name: Isoelite-P, made by Kansai Seito K.K. 2% Ester (Product name: DK Ester F-20W, made by Dai-ichi Kogyo Seiyaku Co., Ltd.)Amount of principal ingredient 0 mg as Ashitaba chalconeShelf life24 monthsStorageAt room temperature②Nutrition facts: per 1 capsule (200 mg)Energy0.78 kcalProtein0.20 mgFat4.14 mgCarbohydrates186.79 mgSodium0.00 mg4.5.4 Intake amount of the test foodDaily dosage: 1 capsule (200 mg)4.5.5 Method of taking the test food and the intake periodOne capsule (200 mg) per day was taken with a glass of water after dinner. When forgotten, it was taken within the same day. The intake period was 56 days (i.e., 8 weeks). 4.5.6 Basis of the determination of the intake amountIn an area like Hachijo Island, Ashitaba is often cooked as Tempura or simply boiled vegetable and normally 50 to 100 grams of the leaves are eaten. The amount of the active ingredient, chalcone included is about 10 to 20 mg, which determined the daily dosage of the study.4.6　Any food or medicines prohibitedThe use of any medicines or health foods fortified with the ingredient used in the study was prohibited. 4.7　Endpoints(1) Primary end points Visceral fat area, body weight(2) Secondary end pointsBMI, waist circumference, body fat ratio(3) End points for safety① Subjective symptoms (conforming body condition)② Clinical tests (blood test, blood biochemistry test, urinary test) ③ Physical examination (blood pressure, heart rate)4.8　Observation and test scheduleThe study schedule is shown below. After the informed consent, a pre-check was performed and those 26 participants who met the inclusion criteria and did not meet exclusion criteria were registered. After the pre-intake test, the participants were randomly assigned to two groups (each group consist of 13 participants). Each participant received assigned foods and started the intake from the determined date. The participants came to the hospital at 4th and 8th week after the intake, where several tests (e.g., measurement of the body fat) were performed. Study scheduleルTest item　　datePre-checkTest food intake periodBefore intake4th week8th weekSelection●Lifestyle questionnaire ●Interview●●●●Physical measurements●●●●Physical examination●●●●Measurement of body fat ●＊● ●＊●Clinical laboratory tests at fasting state●●●Special test items ●＊＊ ●＊＊ ●＊＊Diet survey●●●DiaryTest food intake period＊：Conducted only the measurement of body fat ratio (impedance method)＊＊：About 2 mL (1 x 2 sets) of blood plasma was sent to Hamamatsu University School of Medicine and about 2 mL (1 x 2 sets) of blood plasma and 2 mL (1 x 2 sets) of serum were sent to Kobe University4.9　Cautions regarding the tests① Blood draw was performed at a certain time period during the morning of each test day. Especially, in the test before the intake and at 8th week, the participants were made to come to the hospital in the same time period and the blood was drawn (about within 1 hour). ② At the hospital, a participant was made to rest and the blood was drawn after conforming that s/he neither run or did exercise between getting up and arriving at the hospital. ③ Immediately after the blood draw, it was inverted more than 5 times. Then, refrigerated centrifugation of blood plasma and serum were carried out. 4.10　Restrictions on the participationBoth the principal investigator and those who supported the study instructed the participants to have a normal life and to respect the following restrictions during the study.① Do not change the lifestyle like exercise, sleeping or smoking. ② Those who do regular exercise do not excessive exercise. Those who do not do regular exercise do not start exercise. ③ Do not take any FOSHU foods that will influence the serum lipid concentration and fat metabolism.④ Keep the diary and record of the diet survey on that day.⑤ Do not drink alcohol a day before the test. Finish eating and drinking before 10 pm and do not eat or drink anything (water is ok) afterward. In addition, any fatty meal should be avoided. ⑥ On the day of the test, do not take breakfast and the test food. Be at the hospital at the scheduled time in the morning. Take the test after conforming the fasting for more than 8 hours since the last night. Do not eat any gum, candy or beverage until the test finishes (water is ok). 4.10　Content of the testItemContentLifestyle questionnaireDisease history, use of medicines and health foods, allergy, smoking, drinkingBody condition checkCheck on subjective symptomsBody measurements＊Height＊＊, weight, BMI, waist circumference , hip circumferencePhysical examinationSBP, DBP, heart rateBody fat measurementAbdominal CT scanning (visceral fat area, subcutaneous fat area, total fat area), body fat ratio (impedance method)Clinical laboratory test at fasting stateHematology: white blood cell count, red blood cell count, Hb, Ht, blood plateletBlood chemistry: AST, ALT, LDH, ALP, γ-GTP, T-Bil, TP, Alb, creatinine, BUN, uric acid, glucose, HbA1C＊＊＊, TG, T-C, LDL-C, HDL-C, Na, K, ClUrinalysis: urine protein (qualitative), urine sugar (qualitative), urine occult blood reaction (qualitative) Special test itemsPAI-1 antigen, tPA activity, ECLT, Adiponectin, resistin, leptinDiet surveyParticipants keep a record of the diet for 3 days before the test date and the energy, protein, fat and carbohydrates are calculated. DiaryStatus of the test food intake, any changes in health and status of any drug intake＊：A hospital gown is used in the body measurement. ＊＊：Only a pre-check is conducted.＊＊＊：Conducted in the pre-check and the test at 8th week 4.11　Evaluation method(1) Background of participantsComputed the descriptive statistics (the mean and standard deviation) on age, height, body weight and BMI.(2) A number of days of test-food intake and the intake rateChecked a number of days the test food was taken in the record of the diary and computed the intake rate.(3) Evaluation of the efficacy ① ParticipantsOf those participants who completed the study, those who met the following exclusion criteria were excluded from the analysis. 【Exclusion criteria】?Those who have the intake rate of the test food below 80%.?Those who show any sign of decreasing the reliability of the test result, e.g., poor record.?Those who meet the exclusion criteria of the study and/or are unable to comply the restrictions after the start of the study.② Evaluation methodPerform a between-groups (treatment group vs. placebo group) t-test on the change amount 8 weeks after the intake. Similarly evaluate the change amount 4 weeks after the intake as a reference. In addition, perform a one-sample t-test on the change amount at each time period from the baseline. Any additional analysis is performed as needed.(4) Safety evaluation① Participants?Adverse eventsAny participants who have taken the test food are included.?The mean of observed values and test scoresThe same as those used for the efficacy analysis.② Evaluation method of adverse events“Adverse events” were defined as subjective symptoms occurred during the intake period and any abnormal changes of values in physical examinations and clinical laboratory tests. When any adverse event occurred, an appropriate treatment was performed and various things, e.g., its symptoms, findings, the severity of the adverse event, whether it is serious or not, its relation to the test food, the date of occurrence, the date of disappearing, whether or not any treatment was performed (content of the treatment) and outcomes, were recorded in a case report form. The evaluation of adverse events was determined by the following criteria.【Severity】Light：Not affect the everyday life.Mild：Affect the everyday life.High：Everyday life is difficult.【Seriousness】If an observed adverse event meets any of the following criteria, it is coded as a serious adverse event.?Death?Any event potentially leading to death (life-threatening event)?Event requiring hospitalization for treatment or its extension?Impairment (any showing a dysfunction in everyday life)?Event potentially leading to impairment?Event close to the one described above (impairment)?Any congenital disease or abnormality in the next generation【Relation to the test food】No: Causes other than the test food can be clearly specified.Maybe no: There is no logical time-related relation to specify causes other than the test food.Maybe yes: A logical time-related relation of the test food is observed but some other causes can be suggested.Yes: A logical time-related relation is confirmed and the other causes are not suggested. ③ Evaluation method of the mean valueEvaluated the test value of each group by one-sample t-test of the change after the intake(5) Significance levelThe significance level for both the efficacy and the safety evaluation was 5%, one-tailed. 5. Results5.1　Participants in each groupA total of 26 adult males and females with BMI equal to and greater than 25 and below 30 were registered based on the pre-check. Considering the result of the pre-test, we randomly assigned 13 participants to both the placebo group and the treatment group. There was no dropout or withdrawal. All the 13 participants in the placebo group (9 males and 4 females) and all the 13 participants in the treatment group (9 males and 4 females) completed the study.5.2　Deviation from the study protocol5.2.1 Prohibited medicines and foodsAny participants did not use a prohibited medicine or food.5.2.2 Intake rate of the test foodThe intake rate of the test food is shown in Table 1. The average intake rate of the placebo group was 99.1% (100% = 11, 95% = 1, 93%=1). The average intake rate of the treatment group was 98.2% (100%=8, 98%=1, 96%=2, 93%=2) 5.3　Evaluation of the efficacy5.3.1 ParticipantsAll the 13 participants in the placebo group (9 males and 4 females) and all the 13 participants in the treatment group were evaluated. 5.3.2 Background of the participantsThe mean ± standard deviation of extraneous factors of the participants was shown in Table 2. In the placebo group, these were age 52.4±6.9 years old, height 165.00 ± 8.94 cm, body weight 72.47 ± 7.11 kg, and BMI 26.59 ± 1.08. In the treatment group, these were age 47.3±5.9 years old, height 165.60 ± 6.57 cm, body weight 73.85 ± 6.36 kg, and BMI 26.92 ± 1.41.5.3.3 Analysis of the primary endpoints①Visceral fat areaThe mean ± standard deviation, the amount of change and the rate of change are shown in Table 3, and their transition is shown in Fig. 1-1-1 to 1-2-3.The visceral fat area decreased 8 weeks after the intake in both groups, but the difference between the two groups was not significant. However, the amount of the reduction (i.e., the change amount and the change rate) was large and significant compared to that of the baseline (the baseline → 8th week: 107.00±43.56 → 96.98±38.41 cm2, a reduction of 7.94％). On the other hand, the reduction was not significant in the placebo group. There was no significant difference in the change amount and the change rate.In addition, when the subgroup analysis of male and female was performed, there was a significant reduction in the male participants of the treatment group at 8th week compared to the baseline (the baseline → 8th week: 123.30±43.27→107.32±42.31cm2, a reduction of 13.51％). ② Body weightTable 4-1 shows the mean ± standard deviation of the body weight and the table 4-3 to 4-4 show the change amount and the change rate. The transition is shown in Fig 2-1-1 to 2-2-3.There was a reduction at 4th week and 8the week in both groups, but it was significant only in the treatment group (the baseline → 4th week → 8th week: 73.86±6.15→73.14±5.98→73.05±6.21kg, a reduction of 0.81 kg at 8th week). There was no significant group difference in the change amount and in the change rate.When the subgroup analysis of male and female was conducted, the male participants of the treatment group showed a significant reduction at 4th and 8th week (the baseline → 4th week → 8th week: 76.49±5.49→75.67±5.32→75.79±5.29kg, a reduction of 0.70 kg at 8th week). The reduction in the female participants of the treatment group was not significant but it was –1.07 kg at 8th week and larger than that of the male participants. 5.3.4 Analysis of the secondary end points① BMIThe mean ± standard deviation of BMI is shown in Table 4-1. The change amount and the change rate are shown in Fig. 2-3-1 to 2-4-3. The BMI, like the body weight, decreased in both groups, but the reduction was significant at 4th and 8th week only in the treatment group (the baseline → 4th week → 8th week: 26.92±1.36→26.67±1.41→26.64±1.45, a reduction of 0.28 at 8th week). When the subgroup analysis of male and female was performed, there was a significant reduction in the male participants of the treatment group at 8th week (the baseline → 8th week: 27.21±1.37→27.00±1.49, a reduction of 0.21 at 8th week). Like the body weight, the reduction was not significant in the female of the treatment group but it was –0.42 at 8th week and a larger than that of the male participants. ② Waist circumferenceThe mean ± standard deviation of the waist circumference is shown in Table 4-2. The change amount and the change rate are shown in Fig. 4-3 to 4-4. The transition is shown in Fig 2-5-1 to 2-6-3.There was a significant reduction at 4th and 8th week in both groups. The significant group difference was not observed but the decrease of the treatment group at 8th week (-1.13 cm) was greater than that of the placebo group (-0.73 cm). ② Body fat ratioThe mean ± standard deviation of the body fat ratio is shown in Table 4-1. The change amount and the change rate are shown in Fig. 4-3 to 4-4. The transition is shown in Fig 2-7-1 to 2-8-3.The body fat ratio decreased at 4th and 8th week in both groups, but it was significant only in the placebo group at 8the week. 5.3.5 Analysis of other end points① Subcutaneous fat area and total fat areaTable 3 show the mean ± standard deviation of the subcutaneous fat area and the total fat area, the change amount and the change rate. The transition is shown in Fig 1-3-1 to 1-6-3.The subcutaneous fat area decreased at 8th week in both groups, but it was not significant. The difference between groups was not significant, but the reduction of the placebo group at 8the week was 1.13% while that of the treatment group was 3.21%. The male participants of both groups did not show a reduction, but the female participants of the placebo group and the treatment group had a reduction of 7.16% and 8.30%, respectively. This suggested that the rate of the decrease was greater in the female participants.In the total fat area, both group showed a reduction at 8th week, but it was significant only in the treatment group compared to the baseline (baseline → 8th week: 330.27±59.57→311.12±66.26cm2, a reduction of 5.99％).In addition, when a subgroup analysis of male and female was conducted, the male participants of the treatment group showed a significant reduction at 8th week compared to the baseline (baseline → 8the week: 331.59±65.83→310.70±68.49cm2, a reduction of 6.36％).② Hip circumference and W/H (waist to hip ratio)The mean ± standard deviation of the hip circumference and the W/H are shown in Table 4-2. The change amount and the change rate are shown in Table 4-3 to 4-4. The transition is shown in Fig 2-9-1 to 2-10-3. The hip circumference decreased at 4th and 8th week in both groups. It was significant at 8th week in the placebo group (Baseline → 8th week: 98.48±3.22→98.02±3.14cm, a reduction of 0.46cm at 8th week) and at 4the and 8th week in the treatment group (baseline → 4th week → 8th week: 100.07±3.29→99.61±3.23→99.38±3.20cm, a reduction of 0.69 cm at 8th week).The W/H decreased at 4th and 8th week in both group. It was significant at 4th week in the placebo group and at 8th week in the treatment group. ③ Blood analysis (special items)The mean ± standard deviation of PAI-1 antigen, ECLT, tPA activity, adiponectin, leptin and resistin are shown in Table 5-1. The change amount and the change rate are shown in Table 5-2 to 3. The transition is shown in Fig 3-1-1 to 3-5-6.The results of PAI-1, measured at two facilities, are presented, but neither shows a significant change.ECLT significantly extended at 8th week only in the placebo group. The result excluding the samples showing aggregation or cloudiness is also shown, but, like the previous analysis, it significantly extended at 8th week only in the treatment group. However, the group difference was not observed.tPA activity of the treatment group compared to the placebo group decreased, but none of the differences between and within groups approached statistical significance. There was no significant change in adiponectin.Leptin significantly decreased at 8th week in both group. Although the significant difference between groups was not observed, the reduction of 30.9% in the treatment group was greater than that of the placebo group of 14.4%.Resistin significantly decreased at 4th and 8th week in both groups and the rate of reduction (i.e., the change rate) was almost the same. 5.3.6 Conclusion on efficacyIn the primary end points, namely, the visceral fat area and the body weight, the significant difference between the placebo group and the treatment group was not observed, but only the treatment group showed the significant reduction in the visceral fat area at 8the week and in the body weight at 4th and 8th week.A significant group difference was not observed in BMI, a secondary end point, but the reduction of the treatment group at 4th and 8th week compared to the baseline were significant. Both groups showed the significant reduction of waist circumference at 4th and 8th week after the intake, but the group difference was not observed. The body fat ratio of both groups decreased at 4th and 8th week, but it was significant only in the placebo group at 8th week compared to the baseline.Regarding other end points, the total fat area of both groups decreased at 8th week, but only the treatment group showed a significant reduction. There was a significant reduction of the hip circumference in the placebo group at 8th week and in the treatment group at 4th and 8th group.In the analysis of PAI-1 antigen, ECLT, tPA activity, adiponectin, leptin and resistin, the significant extension of ECLT of the treatment group at 8th week, the significant reduction of leptin of both groups at 8th week and the significant decrease of resistin of both group were observed. From the result above, the significant reduction of the visceral fat area and the body weight were confirmed only in the treatment group although the difference between groups was not confirmed. Therefore, the reduction effect on the visceral fat area and the body weight by the intake of Ashitaba chalcone were what we could expect.5.4　Evaluation of safety5.4.1 ParticipantsNo participants withdrew and dropped out so that there were, like that of the efficacy evaluation, 13 participants in the placebo group (male = 9, female = 4) and in the treatment group (male = 9, female = 4).5.4.2 Adverse eventsOccurrence of adverse events is shown in Table 6-1 to 6-2.In the placebo group, 3 adverse events occurred in 3 of the 13 participants (23%) (1 case of loose stools, 1 case of the common cold and 1 case of contact dermatitis due to insects). The treatment group showed 8 adverse events in 5 of the 13 participants (38%) (2 cases of diarrhea with abdominal pain, 2 cases of symptoms of the common cold, 1 case of bronchitis, 1 case of bloating, 1 case of stiff shoulder and 1 case of strained back).Each seriousness was light so that any relation to the test food was determined as “no” in all cases. 5.4.3 Changes in physical examinations(1) Blood pressure and heart rateThe mean ± standard deviation of blood pressure and heart rate were shown in Table 7.The mean of the heart rate significantly increased at 4th week in the treatment group compared to the baseline. However, it was a mild change and was not clinically a problem.Any other significant changes were not confirmed. 5.4.4Changes in the blood analysis(1) Blood chemistry analysis① FatThe mean ± standard deviation of the total cholesterol, HDL-cholesterol, LDL-cholesterol and the neural fat are shown in Table 8-1. The transition is shown in Fig. 4-1 to 4.4,Compared to the baseline, the total cholesterol and the LDL-cholesterol significantly increased at 4th week in the placebo group. However, it was a small change and nor a clinically problem. ② Liver functionsTable 8-2 shows the mean ± standard deviation of AST, ALT, LDH, T-Bil (total bilirubin), γ-GTP and ALP. Figs 5-1 to 5-6 show the transition.There was a reduction of ALP in the placebo group at 4th and 8th week compared to the baseline, but it was a small change and not a clinically a problem. ③ Serum protein, nitrogen compounds and kidney functionTable 8-3 shows the mean ± standard deviation of total protein, albumin, creatinine, BUN (urea nitrogen) and urine acid. Fig 6-1 to 6-5 shows the transition.The items that showed a significant change compared to the baseline were the total protein (a reduction at 4th and 8th week in the placebo group and at 4th week in the treatment group), albumin (a reduction at 4th week in the placebo group) and creatinine (an increase at 8th week). However, these were small and not clinically problems. ④ SugarTable 8-4 shows the mean ± standard deviation of glucose and HbAlc. Fig. 7-1 to 7-2 show the transition. Any significant change was not observed. ⑤ ElectrolyteTable 8-5 shows the mean ± standard deviation of Na, K and Cl.Na and K showed a significant increase at 8th week in the treatment group compared to the baseline, but it was a small change and not clinically a problem.（2）Hematology testsTable 9-1 to 9-2 show the white blood cell count, the red blood cell count, hemoglobin, hematocrit, MCV, MCH, MCHC and the blood platelet. Fig. 8-1 to 8-8 show the transition. The items that showed a significant change compared to the baseline were the white blood cell count (a reduction at 4th week in the placebo group and at 4th and 8th week in the treatment group), MCV (an increase at 4th and 8th week in the placebo group and at 8th week in the treatment group), MCH (an increase at 8th week in both groups), MCHC (a reduction at 4th and 8th week) and the blood platelet (a reduction at 4th and 8th week in the placebo group). Each change was small and not clinically a problem.（3）General urine testsTable 10 shows the result of urinary protein, urine sugar and urine occult blood reaction.There was no problem confirmed. 5.4.5 Conclusion on safetyAdverse events occurred during the intake period were 3 cases in 3 of the 13 participants (23%) in the placebo group (1 case of loose stools, 1 case of the common cold and 1 case of contact dermatitis due to insects) and 8 cases in 5 of the 13 participants (38%) in the treatment group (2 cases of diarrhea with abdominal pain, 2 cases of symptoms of the common cold, 1 case of bronchitis, 1 case of bloating, 1 case of stiff shoulder and 1 case of strained back). All were light and not related to the test food.There was a significant change in some test items (namely, the total cholesterol, LDL-cholesterol, ALP, the total protein, albumins, creatinine, the white blood cell count, MCV, MCH, MCHC and the platelet count in the placebo group and the pulse rate, the total protein, Na, K, the white blood cell count, MCV and MCH in the treatment group), but any of the change was small and not clinically significant. Taking the above into consideration, it was determined that there is no safety issue in this study where 200 mg of Ashitaba chalcone was taken for 8 weeks.5.5　Diet surveyTable 11 shows the mean intake.The intake of energy, protein, fat and carbohydrates for 3 days before each test were computed.There was no significant change of the energy intake in both groups. The protein intake at 8th week after the start of the intake significantly increased at 8th week in the all cases and the male participants of the treatment group. A significant increase of the fat intake at 4th week in the male participants of the treatment group was observed. Any significant change of the carbohydrate intake was observed in both groups.Each change in the treatment group was small and not an issue in the analysis of the evaluation items. 6．DiscussionIt is know that Ashitaba contains two types of chalcones as the main components, xanthoangelol and 4-hydroxyderricin. Various bioactive effects have been reported, e.g., anti-bacterial activity, vasodilating action, anti-tumor activity, inhibition of gastric acid secretion, anti-inflammatory and effects on blood coagulation. Recently, effects such as inhibiting transfer of tumor cells by suppressing the proliferation and inducing the apoptosis have also been reported. In addition, some other functions of chalcones, e.g., solving cellulite 1,2) and those related to dieting, and some animal studies showing the promotion of the fat metabolism 3) and the inhibition of the fat accumulation 4) have been identified, which receive much attention. In this study, where slightly obese adult males and females took a test food containing 200 mg of Ashitaba Chalcone for 8 weeks, a significant difference between groups was not observed but a significant reduction of the visceral fat area and body weight was confirmed only in the treatment group compared to the baseline.It is discussed that a number of the participants was small and the intake period of 8 weeks was not long so that a group difference was not confirmed. In the future, it is considered that an increase in a number of participants or an extension of an intake period will further illustrate and clarify the body fat-reducing effect. Cellulite is an aggregate of enlarged fat, due to poor blood circulation in subcutaneous tissues and poor fat metabolism, surrounded by body waste and water. It is considered that Ashitaba chalcone solves cellulite by improving the blood flow in the cellulite area by the validation effect and by promoting the fat metabolism. The facilitation of lipolysis is necessary for solving the depo fat and the mechanism is related to solving general obesity 1). When the reduction of the visceral fat was compared to that of the subcutaneous fat in the current study on the intake of Ashitaba chalcone, the former was large in the male participants and the latter was, although the sample is small and no significant difference was not observed, large in the female participants. It is argued, although it is a subsequent research topic, that the body fat decreases by the same or similar mechanism to that of cellulite solution and that the body weight reducing effects are present. 7. ConclusionIn the slightly obese male and female participants who took the test food containing 200 mg of Ashitaba chalcone for 8 weeks (i.e., the treatment group), the significant decrease of the visceral fat area, total fat area and the body weight (BMI) were confirmed. There was no issue in the safety when the test food containing 200 mg of Ashitaba chalcone as the principal ingredient was taken for 8 weeks.The significant reduction of the visceral fat area and body weight were confirmed only in the treatment group so that the visceral fat-reducing effect by the intake of Ashitaba chalcone can be expected. 8. References1) Nagata, J. (2004). About Ashitaba – a collection of commentaries in the efficacy evaluation project of the food ingredient and the health evaluation. National Institute of Health and Nutrition (In Japanese) Retrieved from ) Minami. H., Taniguchi, M., Shibano, M., & Baba, K. (2008). Study on the function of Ashitaba and the trend of the patent application. Report of Tokyo Metropolitan Agriculture And Forestry Research Center. 3: 81-87. (In Japanese). Retrieved from ) Ogawa, H., Okada, Y., Kamisako, T., & Baba, K. (2007). Beneficial effect of xanthoangelol, a chalcone compound from Angelica keiskei, on lipid metabolism in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 34: 238-43.4) Ogawa, H., Ohno, M., & Baba, K. (2005). Hypotensive and lipid regulatory actions of 4-hydroxyderricin, a chalcone from Angelica keiskei, in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 32: 19-23.Clinical study report prepared by Muneaki Iizuka, TTC Co.,Ltd. ................
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