A Standardized Extract of Cultured Lentinula Edodes Mycelia (AHCC®) as Immune Modulator in Cancer Patients Treated With Immunotherapy: a Phase 2 Double-blind, Randomized, Placebo-controlled Trial
Phase: NA
Conditions: Liver Cancer, Hepatocellular Carcinoma
Sponsor: National Cheng-Kung University Hospital

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1 
A standardized extract of cultured Lentinula edodes 
mycelia (AHCC®) as immune modulator in cancer 
patients treated with immunotherapy: a phase 2 
double-blind, randomized, placebo-controlled trial 

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Table of Contents   
 
 
 
 
 
 
 
 
 
 
       page  
1. Abstract ................................................................................................3 
2. Background ...........................................................................................4 
3. Study objectives ....................................................................................9 
4. Study design..........................................................................................9 
5. Patient selection .................................................................................. 10 
6. Screening and registration .................................................................... 10 
7. Treatment and follow-up plan ............................................................... 11 
8. Assessment of treatment efficacy and safety .......................................... 12 
9. Analysis of predictive markers............................................................... 18 
10.Criteria for discontinuation of study drug treatment ............................... 19 
11.Statistical consideration ....................................................................... 19 
12.Institutional review board .................................................................... 23 
13.Records to be kept ............................................................................... 23 
14.References .......................................................................................... 24 
15.Appendix ............................................................................................ 24 
 
 
 
 

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1. Abstract 
This is a prospective double-blind, randomized, placebo-controlled trial aims to investigate 
whether add-on of a standardized extract of cultured Lentinula edodes mycelia (AHCC®) can 
enhance the effect of immunotherapy in cancer patients. 
AHCC is a newly developed functional food. In vitro studies have demonstrated that AHCC 
enhances natural killer cell activity and may serve as a potent biological response modifier for 
cancer treatment. Previous research involving 269 HCC patients found that 113 patients who took 
AHCC orally after curative surgery (AHCC group) experienced significantly longer recurrence-free 
survival (hazard ratio [HR], 0.639; 95% confidence interval [CI], 0.429-0.952; P = 0.0277) and 
overall survival (HR, 0.421; 95% CI, 0.253-0.701; P = 0.0009) compared to the control group. 
This trial will adopt a two-arm Bayesian optimal phase 2 (BOP2) design (Zhao, 2020). The 
study will simultaneously evaluate efficacy and toxicity. The null hypothesis assumes a true 
response rate of 0.27 and a grade 3/4 toxicity rate of 0.57, while the alternative hypothesis 
assumes a true response rate of 0.42 and a grade 3/4 toxicity rate of 0.36. The trial will be 
conducted in two stages. In the first stage, 36 patients will be recruited and randomized using 
block randomization with a block size of 4. The study will be terminated early if fewer patients 
respond in the AHCC group than in the control group or if 2 or more patients in the AHCC group 
experience grade 3/4 acute toxicity compared to the control group. Otherwise, the second stage 
will proceed with the recruitment of an additional 58 patients, bringing the total sample size to 
94. If, among the 47 patients in the AHCC group, at least 2 more patients respond compared to 
the control group or if 2 or fewer patients experience grade 3/4 toxicity, we will reject the null 
hypothesis and conclude that the treatment is promising. This design controls the type I error rate 
at 0.1 and achieves a power of 0.75. Considering a 5% dropout rate, each group will enroll 49 
patients, resulting in a total sample size of 98. 
Following the Screening period to confirm eligibility, 98 study participants, who meet the 
entry criteria, will be 1:1 randomized to study intervention (3g of AHCC oral per day or matching 
placebo) and will be stratified by AFP (<400 vs. ≥400). Enrollment is anticipated to be completed 
within 2 years, with each participant followed for 6 months since treatment. Therefore, the total 
duration of the study is expected to be approximately 2.5 years from the time of Institutional 
Review Board approval. All enrolled participants will receive AHCC or placebo 3g per day until 
disease progression, intolerance or patient or physician decision to discontinue. Tumor tissue and 
peripheral blood samples will be collected from all participants for biomarker analysis.  
 
2. Background 
Immune checkpoint inhibitors 
 
In recent years, significant progress has been made, particularly in the areas of personalized 
medicine and cancer therapeutics. Immunotherapy, including adoptive cell transfer and immune 
checkpoint inhibitors (ICIs), harnesses the body's immune system to combat tumor cells1. Both as 
standalone treatments and in combination with traditional therapies like radiotherapy and 
chemotherapy, immunotherapy has achieved notable success in treating various cancers. Co-
inhibitory receptors, such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 

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4 (CTLA-4), are expressed on T cells and negatively regulate T cell-mediated immune responses. 
Tumor cells exploit these receptors to induce immune tolerance and T cell exhaustion. ICIs, such 
as anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies, target these receptors to reactivate the 
immune system against tumors. Three major groups of ICIs—PD-1 inhibitors (Nivolumab, 
Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and 
CTLA-4 inhibitors (Ipilimumab)—have been approved by the US Food and Drug Administration 
(FDA) for the treatment of various cancers. However, only a subset of patients (20–40%) benefit 
from this therapy, underscoring the need for reliable predictive biomarkers. Factors such as tumor 
mutational burden (TMB), PD-L1 expression, the microbiome, hypoxia, interferon-γ, extracellular 
matrix (ECM), and the molecular and cellular composition of the tumor microenvironment (TME) 
are all associated with immunotherapy outcomes.  
 
The approval of ipilimumab in 2011 marked the beginning of ICIs as a novel treatment option, 
revolutionizing cancer therapy. These therapies have provided long-lasting results with relatively 
low toxicity in certain cases. Unlike traditional treatments, ICIs work by reactivating the immune 
system to combat tumor cells. Immune checkpoints regulate the balance between pro-
inflammatory and anti-inflammatory signals in the body’s immune system under normal 
conditions. These checkpoints are a collection of inhibitory and stimulatory pathways that control 
immune cell activity. In recent years, antibodies targeting immune inhibitory receptors such as 
CTLA-4, PD-1, and PD-L1 have become the most widely used immunotherapeutic agents. 
 
A standardized extract of cultured Lentinula edodes mycelia (AHCC®) 
AHCC® is a standardized extract of cultured shiitake or Lentinula edodes mycelia (AHCC®) 
which contains a mixture of nutrients including oligosaccharides, amino acids, and minerals 
obtained through the liquid culture process of shiitake mycelia. It is produced by Amino Up Co., 
Ltd. (Sapporo, Japan) under the trademark “AHCC®.” The shiitake mycelia used for AHCC® are 
cultured in a liquid medium where the mycelia proliferate and form globular fungal bodies but 
not fruiting bodies. AHCC® is produced through the unique manufacturing process of culturing 
the mycelia followed by separation, sterilization, and freeze-drying. The most abundant 
component of AHCC® is oligosaccharides which comprise about 74% of the dry weight of AHCC®. 
Polysaccharides are ubiquitous among fungi from yeast to mushroom, and these 
compounds impart structural properties to the organisms. Although the polymeric compositions 
of various fungal polysaccharides are unique and specific to each organism, the structural 
configurations are highly conserved2. Due to the ubiquitous presence of fungus in the 
environment and diet, mammalian immune systems have developed innate pattern recognition 

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systems for fungal polysaccharides. The interaction between fungal derived glucans and various 
cells of the immune system results in immunostimulatory effects, which in-turn prime the 
immune system for defense against potential invading microorganisms. The unique capacity of 
fungal derived glucans to act as biological response modifiers of the immune system has 
stimulated wide-spread research into their uses as functional foods. The immunological effects 
of AHCC have been investigated in numerous publications, and the product has been utilized as 
an immunostimulatory food for over 15 years in Japan. AHCC has been reported to improve the 
prognosis of patients with postoperative hepatocellular carcinoma3, and improvements in the 
quality of life of patients with advanced liver cancer also have been reported. In studies 
conducted in rodents, AHCC has been shown to reduce metastasis of rat mammary 
adenocarcinoma2, and to ameliorate the side-effects evoked by cisplatin chemotherapy in 
tumor-bearing mice. AHCC also may find utility against viral and microbial infections, and has 
been reported to increase survival in rodents following various viral and bacterial challenges.  
The mechanism(s), and specific receptor mediated interaction(s) by which AHCC affects 
the immune system are not completely understood; however, studies in healthy subjects 
administered AHCC daily for a period of 4 weeks indicate that AHCC can modulate dendritic cell 
number and activity4. Thus, the utility of AHCC in cancer subjects and in various infectious 
models in rodents may be mediated through its ability to stimulate dendritic cells, which are 
potent antigen presenting cells that are able to prime T-cells. Finally, recent evidence also has 
suggested that the functional properties of AHCC may be multi-factorial; in addition to direct 
modulation of the immune system, AHCC also has been observed to attenuate inflammation in 
rats with hapten-induced colitis via prebiotic effects on the colonic microflora. 
 
 

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Safety profile of AHCC in preclinical model2 
Figure 1. Body weight changes in male rats treated orally with AHCC for 90 days. 
 
Table 1. Hematology results for male and female rats following daily gavage administration of 
AHCC-FD for a period of 90 days. 
 
 
 

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Table 2. Urinalysis results for of male and female rats following 90-day gavage administration of 
AHCC-FD. 
 
Table 3. Results of Ames reverse mutation experiments conducted with AHCC-FD in the absence 
(-S9) and presence of metabolic activation (+S9). 
 
Safety profile of AHCC in phase 1 clinical trial4 
Table 4. Lab results in 26 health volunteers 

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3. Study objectives 
Primary objective:  
• To investigate whether add-on of AHCC can enhance the effect of immunotherapy in cancer 
patients. 
Secondary objectives: 
• To evaluate the progression-free survival of patients who receive AHCC along with 
immunotherapy. 
• To evaluate the overall survival of patients who receive AHCC along with immunotherapy. 
• To evaluate the safety profile in cancer patients who receive AHCC along with immunotherapy. 
• To evaluate the Quality of life in patients who receive AHCC along with immunotherapy. 
 
 
4. Study design. 
This is a prospective double-blind, randomized, placebo-controlled trial.  
 

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5. Patient selection 
6.1 Inclusion criteria 
6.1.1 Liver cancer patient who will receive immunotherapy 
6.1.2 At least one measurable tumor, according to RECIST version 1.1, that has not been 
treated with any local procedure. 
6.1.3 Age  20 years old. 
6.1.4 ECOG performance status 0 or 1. 
6.1.5 White blood count  2,000/L ; platelet count  60,000/L.  
6.1.6 Liver transaminases (ALT and AST)  5 times upper limit of normal values (ULN); total 
bilirubin  2 times ULN; creatinine clearance or eGFR > 50 mL/min (either Cockcroft-
Gault or MDRD is acceptable, whichever is higher).  
6.1.7 Subjects with chronic hepatitis B virus infection (HBV surface antigen (HBsAg) positive) 
must start antiviral therapy with nucleoside analogs (e.g., entecavir or tenofovir, 
according to current practice guidelines) before start of study drug treatment 5,6. 
6.2. Exclusion criteria 
5.2.1 Major systemic diseases that the investigator considers inappropriate for 
participation. 
5.2.2 Any active autoimmune disease or history of known autoimmune disease except for 
vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in 
the absence of an external trigger are permitted to enroll.  
5.2.3 Dementia or significantly altered mental status that would prohibit the 
understanding or rendering of informed consent and compliance with the 
requirements of this protocol.  
5.2.4 Prior therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody (or any other 
antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).  
5.2.5 Requirement of systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease.  
5.2.6 Prior organ allograft or allogeneic bone marrow transplantation. 
5.2.7 Other severe acute or chronic medical or psychiatric condition, or laboratory 
abnormality that may increase the risk associated with study participation and in the 
judgment of the investigator would make the patient inappropriate for entry into 
this study. 
6. Screening and registration 
6.1 The following examinations must be done to check the patients’ eligibility: 
7.1.1. Tumor assessment (according to RECIST 1.1); histological proof of HCC; viral hepatitis 
serology (HBsAg, anti-HBs, anti-HCV), HBV DNA level (for HBsAg (+) or anti-HBc (+) 
subjects), HCV RNA level (for anti-HCV (+) subjects). 

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7.1.2. Within 1 week of registration: physical examination (including performance status), 
hematology/ biochemistry. 
6.2 The following procedures must be done and data recorded at registration: written informed 
consent, demography, medical history, tumor staging (BCLC, AJCC), tumor assessment 
(according to RECIST 1.1), Child-Pugh score, hematology/biochemistry, viral hepatitis status.  
 
7. Treatment and follow-up plan 
7.1 All enrolled patients will receive AHCC or placebo 3g every day until disease progression, 
intolerance or patient or physician decision to discontinue.  
7.2 During treatment the subjects will be followed according to the follow-up plan summarized 
in the following table: 
7.2.1 Hematology and biochemistry levels will be checked within 72 hours before each 
administration of study drug treatment. 
7.2.2 A window of +/- 7 calendar days is allowable for imaging examination for tumor 
assessment. 
7.3 Prohibited treatment during the study drug treatment period includes the following: 
7.3.1 Investigational agents for the treatment of cancer; 
7.3.2 Systemic steroids > 10 mg within 14 days of dosing (with a few exceptions eg, steroids 
for adrenal insufficiency, steroids if taken as part of prophylaxis for CT prep). 
Screen Treatment Cycles (21-day 
cycles) 
End-of-treatment 
(EOT) evaluation a 
Week 
 
C1 C2 
C3 
C4 
C5 4 weeks after last 
treatment 
C6 C7 
C8 
C9 
C10 
⁞ 
⁞ 
⁞ 
⁞ 
⁞ 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demography/ tumour staging 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
X 
Blood test b 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
X 
X 
HBV/HCV serology markers c 
X 
 
 
 
 
 
X  
Performance status 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
X 
 
 
 
 
 
X 
Tumor assessment d 
X 
 
 
 
 
X 
 
Treatment 
 
X 
X 
X 
X 
X 
 
Pregnancy test e 
X 
 
 
 
 
 
 
Immunological study f 
X 
 
 
 
 
X 
X 
Thyroid function g  
X 
 
 
 
 
 
X 
Tolerability/AE reporting 
 
X 
X 
X 
X 
X 
X 
QOL questionnaire 
X 
 
 
X 
 
X 
X 

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11 
 
a) 
The EOT assessment will take place at approximately 1 month after last treatment. 
b) 
Blood tests will include CBC/DC, albumin, total and direct bilirubin, transaminases (AST and ALT), ALP, AC sugar, 
sodium, blood urea nitrogen (BUN), creatinine, amylase, lipase, Troponin-T(or hs-cTnT), pro-BNP (brain 
natriuretic peptide), and creatinine kinase (CK) or CK-MB isoform (CK-MB). Other biochemistry tests may be 
done at the discretion of individual investigators. 
c) 
HBV and HCV serology markers, including HBsAg, anti-HBs, anti-HBc, and anti-HCV, will be checked at baseline 
only. Subjects who test positive for HBsAg are categorized as chronic HBV infection. Subjects who test positive 
for anti-HCV are categorized as chronic HCV infection. For subjects with chronic HBV infection, HBV DNA levels 
should be checked at baseline and at EOT evaluation. For subjects with chronic HCV infection, HCV RNA levels 
should be checked at baseline and at EOT evaluation. 
d) 
Tumor assessment (according to RECIST 1.1) will be done every 12 weeks. Computed tomography is the 
preferred imaging modality and should include imaging of chest and abdomen at baseline and follow-up.  
e) 
For women with childbearing potential. 
f) 
In brief, 20ml blood and tumor sample will be collected. Please refer to Sec. 10 for detailed description for 
collection of each type of samples. 
g) 
Including serum T3, T4 and TSH. 
h) 
Quality of life is assessed using the EORTC QLQ-C30 and QLQ-HCC18 at baseline, every 6 weeks and EOT. 
8. Assessment of treatment efficacy and safety 
8.1 Assessment of treatment efficacy  
8.1.1 All enrolled patients will receive assessment of tumor response by imaging studies 
every 12 weeks, according to RECIST version 1.1. Computed tomography is the 
preferred imaging modality and should include imaging of chest and abdomen at 
baseline and follow-up. 
8.1.2 For subjects who are considered suitable for surgical resection, the actual surgical 
procedure will be determined by individual treating surgeons and will be recorded. 
The time frame for holding the study drug prior to surgery will be determined by the 
treating physician. Participants may resume the study drug after recovery from 
surgery, at the physician’s discretion. 
8.2 
Management of immune-related adverse events (irAE) 7,8 
8.2.1 The definition of the most irAE and according management recommendation are 
summarized in the following table. 
8.2.2 For the definition of hepatitis grading, only ALT (alanine aminotransferase) level is 
used because it is more specific to liver inflammation. 
8.2.3 Definition of study drug-induced liver injury (DILI) was listed below, according to the 
amendment #8 of the CA209040 protocol: 
8.2.3.1 Concurrent ALT ≥ 10 x ULN AND total bilirubin ≥ 2 x ULN or baseline value 
(if elevated bilirubin at study entry), AND 
8.2.3.2 No other immediately apparent possible causes of ALT elevation and 
hyperbilirubinemia, including, but not limited to, tumor progression, acute 
viral hepatitis, cholestasis, pre-existing hepatic disease or the 
administration of other drug(s), herbal medications and substances known 
to be hepatotoxic. 
8.2.3.3 Management 
of 
hepatic 
events, 
including 
dose 
delay 
and/or 
discontinuation as well as intervention with steroid treatment, will follow 
the recommendation listed below, will not be impacted by the definition of 
DILI. 

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Types of irAE 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hepatitis 
ALT up to 3 x ULN 
AND > 2x baseline 
• Monitor weekly 
• Look for other 
causes of hepatitis 
(e.g., viral 
infections other 
than HBV/HCV, 
hepatotoxic drugs) 
ALT 3 to 5 x ULN 
AND > 2x baseline 
• If patient is well, 
re-check liver 
function every 2-3 
days. Steroid 
treatment (e.g., 
prednisolone 1–2 
mg/kg/day or IV 
equivalent) if no 
improvement or 
worsening.  
• Taper steroids over 4 
weeks once liver 
function G1 or at 
baseline 
ALT 5 to 20 x ULN:  
• As per Grade 2  
• Delay study drug 
treatment if ALT≤ 
8X ULN and bilirubin 
≤ 5X ULN. 
Discontinue if worse 
• Steroid treatment 
(e.g., prednisolone 
1–2 mg/kg/day or IV 
equivalent) 
• Consider liver 
biopsy 
• Consider 
prophylactic 
antibiotics for 
opportunistic 
infection 
ALT >20 x ULN:  
• Discontinue study 
drug 
administration 
• As per Grade 3 
(Steroid treatment 
at prednisolone 2 
mg/kg/day or IV 
equivalent). 
• Consult 
immunologists for 
additional 
immunosuppressive 
therapy (e.g. 
infliximab, 
mycophenolate, 
immunoglobulins). 
 
Diarrhea/ 
enterocolitis 
<4 bowel actions 
per day over 
baseline; mild:  
• Supportive measures 
such as increasing 
• Oral fluid 
• Anti-motility agents 
such as loperamide 
4–6 bowel actions 
per day over 
baseline; moderate:  
• Delay stud drug 
administration.  
• As per Grade 1 if 
patient is well.  
• Steroid treatment 
(e.g., prednisolone 
0.5–1 mg/kg/day or 
IV equivalent) if no 
improvement in 5-7 
days, or if 
worsening of 
symptoms; 
continue until 
symptoms improve 
to G1. Steroids can 
be tapered over 2–
4 weeks. 
• If no improvement 
> 3-5 days with oral 
steroids, manage as 
per G3.  
• Consider 
sigmoidoscopy and 
biopsy 
≥7 bowel actions 
per day over 
baseline; severe 
symptoms: 
• Discontinue study 
drug administration. 
• Hospitalization and 
intravenous 
hydration 
• Steroid treatment 
(e.g., prednisolone 
1–2 mg/kg/day or IV 
equivalent.  
• If no improvement 
in 2–3 days, consult 
immunologists for 
additional 
immunosuppressive 
therapy (e.g. 
infliximab, 
mycophenolate, 
immunoglobulins). 
• If improving, taper 
steroids over 
minimum 1 month 
(up to 3 months for 
severe cases). 
• Consider 
sigmoidoscopy and 
biopsy 
Life threatening 
consequences (e.g., 
perforation) 
• Urgent intervention 
indicated: as per G3.  
• Involve 
gastroenterologist 
and surgeon in 
management.  
Pneumonitis 
Asymptomatic; 
• Clinical observations;  
• Consider delaying 
study drug 
administration. 
• Consider steroids 
(e.g. prednisone 1 
mg/kg/day PO or 
methylprednisolone 
1 mg/kg/day IV).  
• Re-image at least 
Symptomatic; 
limits instrumental 
ADLs: 
• Delay study drug 
administration. 
• Consider 
hospitalization, 
daily monitoring of 
symptoms.  
• Steroid treatment 
(prednisone 1 
mg/kg/day PO or IV 
Severe symptoms; 
limits self-care 
ADLs; oxygen 
indicated: 
• Discontinue study 
drug administration. 
• Hospitalization. 
• Steroid treatment 
(prednisone 2-4 
mg/kg/day PO or IV 
equivalent). 
Life-threatening 
respiratory 
compromise; 
• Urgent intervention 
indicated (eg 
intubation): as per 
Grade 3.  
• Intensive care 
support required 

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13 
every 3 weeks. 
equivalent). 
• Consider empiric 
antibiotics  
• Follow-up: reassess 
management every 
1–3 days. If 
improving taper 
steroids. 
• May continue study 
drug treatment if 
symptoms resolve 
completely.  
• Consider high-dose 
steroid treatment 
(e.g. methyl-
prednisolone 1 
g/day IV) (Spain L, 
et al. Cancer Treat 
Rev 2016).  
• Add prophylactic 
antibiotics for 
opportunistic 
infections. 
• Consider 
bronchoscopy with 
biopsy.  
• Reassess 
management daily. 
If not improving 
after 48 h or 
worsening, consult 
immunologists for 
additional 
immunosuppressive
therapy (e.g. 
infliximab, 
mycophenolate, 
immunoglobulins). 
If improving, taper 
steroids.  
Endocrine 
dysfunction 
Asymptomatic 
• Monitor only 
• Consider endocrinology 
consultation 
Symptomatic  
• Consult 
endocrinologist 
• Levothyroxine 
replacement for 
hypothyroidism 
• Cortisol 
replacement for 
hypoadrenalism 
• Consider β-blockers 
for 
hyperthyroidism-
related symptoms  
• Consider steroids 
or carbimazole for 
hyperthyroidism 
Severe symptoms:  
• As per grade 2.  
• Delay study drug 
administration. 
• Steroid treatment 
(e.g., prednisolone 
1–2 mg/kg/day or IV 
equivalent) 
Life threatening 
consequences 
• As per Grade 3. 
• Delay or discontinue 
study drug 
administration. 
 
Nephritis 
Creatinine > 1X ULN 
and ≤1.5 X baseline; 
proteinuria 1+, 
<1.0g / 24 h:  
• Monitor renal 
function weekly; 
hydration  
Creatinine > 1.5–3.0 
X baseline; 
proteinuria 2+, 1.0–
3.4 g/24 h: 
• Steroid treatment 
(e.g., prednisolone 
0.5–1 mg/kg/day or 
IV equivalent)   
• Delay study drug 
administration. 
Monitor renal 
function every 2-3 
days; If worsens, 
manage as per grade 
3 
• Exclude non-immune 
causes 
Creatinine > 3.0 X 
baseline to ≤ 6X 
ULN; proteinuria ≥ 
3.5 g/24 h:  
• As per Grade 2 
• Consider renal 
biopsy 
• If elevations persist 
> 7 days or worsens, 
manage as per 
grade 4 
 
 
Creatinine > 6.0 X 
ULN:  
• Steroid treatment 
(e.g., prednisolone 
1–2 mg/kg/day or IV 
equivalent)  
• Consider renal 
biopsy 
• Discontinue study 
drug treatment  
Skin rash 
<10% BSA: 
10–30% BSA:  
>30% BSA:  
Life threatening 

 (V1.2 2025.05.23) 
14 
• Antihistamines and 
topical steroid for 
pruritus 
• As per G1 if tolerable 
• If intolerable, steroid 
treatment (eg 
prednisolone 0.5–1 
mg/kg/day with a 1–
2 week wean) 
• Delay study drug 
treatment until G1 
and steroids <10 mg/ 
day  
• Consider skin biopsy 
if symptoms persist 
or recur  
• Consult 
dermatologist and 
consider skin biopsy 
• Steroid treatment 
(e.g., prednisolone 1 
mg/kg/day or IV 
equivalent). 
• Delay study drug 
treatment until G1 
and steroids <10 
mg/ day 
consequences 
• As per Grade 3. 
  
 
 
8.2.4 When irAE improved to Grade 1 after steroid treatment, may taper steroid dosage 
over at least 1 month. 
8.2.5 For other grade 3-4 toxicities (according to CTCAE version 4) that are considered to 
be related to study drug treatment, study drug treatment should be held if the 
toxicities last for 3 days or more under best supportive care. Further study drug 
treatment may be considered when toxicity has resolved to ≤ grade 1, after 
discussion with the principal investigator. 
8.2.6 Recent review of irAE indicated the clinical significance of the rare but potentially 
fatal cardiac toxicity for patients who received combination immunotherapy 9,10. 
Cardiac exam (echocardiography or radionuclide ventriculography (MUGA scan)) 
will be done at baseline, at the first imaging assessment, and at the end-of-
treatment (EOT) evaluation. Troponin-T(or hs-cTnT), pro-BNP (brain natriuretic 
peptide), and creatinine kinase (CK) or CK-MB isoform (CK-MB) will be checked every 
3 weeks before each administration of study drug treatment and at EOT evaluation. 
8.2.7 When cardiac toxicity is suspected, cardiologists will be consulted for further 
diagnostic work-up. High-dose steroid and other immunosuppressive treatment will 
be used according to the most recent expert recommendation. 
8.3 
Patients will be followed every 3 weeks to evaluate the occurrence and severity of adverse 
events, according to CTCAE version 4. 
8.4 
The Institution and the Principal Investigator shall report any Adverse Events arising out of 
or in connection with the Study to the Regulatory Authority in accordance with applicable 
laws and regulations. 
8.5 
Serious adverse events (SAE) must be reported in written forms to the institutional review 
boards of the participating centers and Department of Health, Taiwan, within 7 working 
days. SAE is defined as any event that 
8.5.1 Results in death;  
8.5.2 Life-threatening (defined as an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe); 
8.5.3 Results in hospitalization or prolong inpatient hospitalization;  
8.5.4 Results in persistent or significant disability/incapacity;  
8.5.5 Results in congenital anomaly of offspring;  

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15 
8.5.6 Requires treatments for permanent injuries;  
8.5.7 Results in development of second malignancy. Second malignancy includes any 
second primary malignancy, regardless of causal relationship to the study drug, 
occurring at any time for the duration of the study, from the time of signing the 
informed consent up to 3 months after withdrawal from the study drug.  
8.5.8 An important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.  
8.5.9 Results in suspected transmission of an infectious agent (e.g., pathogenic or 
nonpathogenic) via the study drug is an SAE. 
8.5.10 Although pregnancy, overdose, potential drug-induced liver injury (DILI) and cancer 
are not always serious by regulatory definition, these events must be handled as 
SAEs. Overdose is defined as the accidental or intentional administration of any dose 
of study drugs that is considered both excessive and medically important. 
8.6 If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to IRB. All SAEs 
should be followed to resolution or stabilization. 
8.6.1 An SAE report should be completed for any event where doubt exists regarding its 
seriousness. 
8.6.2 If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE Report Form. 
8.6.3 If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially 
reported.) 
8.6.4 
Definition of SAE is listed in Section 10.5. Additional description of SAE, as required 
by the study drug supplier, is listed below. 
8.6.4.1 
Any component of a study endpoint that is considered related to study therapy 
should be reported as an SAE (eg, death is an endpoint, if death occurred due 
to anaphylaxis, anaphylaxis must be reported). 
8.6.4.2 
The following hospitalizations are not considered SAEs in this study: 
8.6.4.3 
A visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life-
threatening event) 
8.6.4.4 
Elective surgery, planned prior to signing consent 
8.6.4.5 
Admissions as per protocol for a planned medical/surgical procedure 
8.6.4.6 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy) 

 (V1.2 2025.05.23) 
16 
8.6.4.7 
Medical/surgical admission other than to remedy ill health and planned prior 
to entry into the study. Appropriate documentation is required in these cases 
8.6.4.8 
Admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols) 
8.6.5 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation participant 
administered study drug and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(such as an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of investigational product, whether or not considered 
related to the investigational product. 
8.6.6 
The causal relationship to study drug is determined by a physician and should be 
used to assess all adverse events (AE). The casual relationship can be one of the 
following: 
8.6.6.1 
Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
8.6.6.2 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
8.6.6.3 
The term "reasonable causal relationship" means there is evidence to suggest 
a causal relationship. 
8.6.6.4 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific 
occurrence of one or more AEs.) 
8.6.6.5 
Nonserious AE information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline 
status for the subjects. 
8.6.6.6 
The collection of nonserious AE information should begin at initiation of study 
drug. All nonserious adverse events (not only those deemed to be treatment-
related) should be collected continuously during the treatment period and for 
a minimum of 30 days following the last dose of study treatment. 
8.6.6.7 
Nonserious AEs should be followed to resolution or stabilization, or reported 
as SAEs if they become serious. Follow-up is also required for nonserious AEs 
that cause interruption or discontinuation of study drug and for those present 
at the end of study treatment as appropriate. 
8.6.7 
All laboratory test results captured as part of the study should be recorded 
following institutional procedures. Test results that constitute SAEs should be 
documented and reported as such. The following laboratory abnormalities should 
be documented and reported appropriately: 
8.6.7.1 
any laboratory test result that is clinically significant or meets the definition of 
an SAE 
8.6.7.2 
any laboratory abnormality that required the participant to have study drug 
discontinued or interrupted 

 (V1.2 2025.05.23) 
17 
8.6.7.3 
any laboratory abnormality that required the subject to receive specific 
corrective therapy. 
8.6.8 
Other Safety Considerations: Any significant worsening noted during interim or 
final physical examinations, electrocardiograms, X-rays, and any other potential 
safety assessments, whether or not these procedures are required by the protocol, 
should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
 
9. Analysis of predictive markers 
9.1 Biomarker study of the pre-treatment biopsy tumor tissue 
9.1.1 Five 10-micrometer-thick slides will be obtained from paraffin-embedded tumor 
specimens for DNA/RNA extraction and subsequent whole exome sequencing and 
RNA sequencing. 
9.1.2 Ten 4-micrometer-thick slides will be obtained from paraffin-embedded tumor 
specimens for tissue staining. Immunohistochemistry or multiplex staining will be 
done in paraffin-embedded tumor specimens if enough tissue samples are available 
to confirm the proportion and distribution of immune cells in different tumor 
microenvironment. 
9.2 Biomarker study of peripheral blood samples during study drug treatment 
9.2.1 For the immunology study, peripheral blood samples will be collected before the 
start of the first cycle of study drug treatment, at the time of tumor response 
assessment, and at the end-of-treatment assessment. 
9.2.2 Blood samples will be put in BD Vacutainer®CPT™ cell preparation tubes and EDTA 
tube respectively, and centrifuged within 6 hours after sampling. 
9.2.3 The mononuclear cell layer will be stored in liquid nitrogen for flow cytometry and 
DNA/RNA extraction studies. 
9.2.4 Flow cytometry and transcriptomic analysis will be done to analyze the proportion 
of different immune cells in peripheral blood and the results will be correlated with 
efficacy of study drug treatment. 
9.2.5 Plasma will be used for blood biomarker research including but not limited to cfDNA, 
cytokine and lipid profiling. 
9.3 
Biomarker study of the resected tumor tissue from subjects who undergo surgery 
9.3.1 Samples from the same tumor(s) will be obtained from formalin-fixed, paraffin-
embedded tumor specimen for relevant studies 
9.3.2 The genetic study to be done include but not limited to whole exome sequencing.  
9.3.3 Transcriptomic analysis will be done to analyze the composition (e.g., the proportion 
of different immune cells) of the immune microenvironment by using RNA-Seq and 
the results will be correlated with efficacy of study drug treatment. 
9.3.4 The biomarker studies of tumors and peripheral blood samples will be done at the 
National Health Research Institutes. The relevant information of the responsible 
laboratory is as follows: 
Name of the institution/laboratory: National Institute of Cancer Research. 
Mailing address: No. 367, Sheng-Li Road, Tainan 704, Taiwan (R.O.C.)  

 (V1.2 2025.05.23) 
18 
Name of the person responsible for specimens storage: Yung-Yeh Su  
Place of specimens storage: National Institute of Cancer Research, National Health 
Research Institutes. 
Estimated period of time for specimens storage: 10 years 
 
10. Criteria for discontinuation of study drug treatment 
Discontinuation of study drug treatment is when a patient no longer receives study drug but 
continues to be followed up for tumor status and survival according to local treatment guidelines 
for up to half year, unless consent is withdrawn. Patients may be discontinued from study drug 
treatment and assessments at any time. When study drug treatment is discontinued due to the 
reasons listed below, no further AHCC/placebo treatment will be provided by this study and 
further anticancer therapy will be decided by the investigators according to current treatment 
guidelines. Specific reasons for discontinuation of study drug treatment include: 
10.1 Voluntary discontinuation by the subject who is at any time free to discontinue his/her 
participation in this study, without prejudice to further treatment.  
10.2 When the investigator(s) consider other treatment modalities (surgery, others) are more 
suitable for the subjects according to assessment of tumor response specified in the 
protocol.  
10.3 Safety reasons as judged by the investigator. Severe non-compliance to protocol as judged 
by the investigator.  
10.4 Incorrect enrollment, in the opinion of the investigator or study delivery team physician, 
which will compromise the patient’s health if study drug treatment or assessments are 
continued.  
10.5 Dose delay or interruption of study drug treatment for more than 3 weeks. 
 
11. Statistical consideration 
11.1 The primary endpoint is ORR in AHCC arm compared to placebo arm. The secondary 
endpoints include, incidence and severity of adverse events according to CTCAE version 4, 
progression-free survival and overall survival. 
11.2 Exploratory endpoints will include correlation of treatment response (tumor shrinkage, 
objective response rate, etc.) with immune biomarkers in subjects’ samples from tumor 
tissue and peripheral blood. 
11.3 We simultaneously monitor efficacy and safety endpoints using the 2-arm Bayesian 
optimal phase 2 (BOP2) design (Zhao et al., 2020).  
11.3.1 Specifically, let 𝑛 denote the interim sample size and 𝑁 denote the maximum sample size. Let 
𝐸 and 𝐶 denote the experimental arm and the control arm, respectively. For arm 𝑡, 𝑡= 𝐸, 𝐶, 
let 𝑌𝑒𝑓𝑓,𝑡 and 𝑌𝑡𝑜𝑥,𝑡 respectively denote the efficacy and toxic endpoints, with 𝑌𝑒𝑓𝑓,𝑡= 1 and 
𝑌𝑡𝑜𝑥,𝑡= 1 respectively indicating that patients experience efficacy and toxicity. We assume that 
the joint distribution of (𝑌𝑒𝑓𝑓,𝑡, 𝑌𝑡𝑜𝑥,𝑡) follows a multinomial distribution with four elementary 
outcomes: (𝑌𝑒𝑓𝑓,𝑡, 𝑌𝑡𝑜𝑥,𝑡) = (1, 1), (1, 0), (0, 1) and (0, 0). Let 𝐩𝐭= (𝑃11,𝑡, 𝑃10,𝑡, 𝑃01,𝑡, 𝑃00,𝑡) 

 (V1.2 2025.05.23) 
19 
denote the probabilities of observing the four outcomes, and let 𝑝𝑒𝑓𝑓,𝑡= 𝑃𝑟(𝑌𝑒𝑓𝑓,𝑡= 1) , 
𝑝𝑡𝑜𝑥,𝑡= 𝑃𝑟(𝑌𝑡𝑜𝑥,𝑡= 1) and 𝑝𝑒𝑓𝑓𝑡𝑜𝑥,𝑡= 𝑃𝑟(𝑌𝑒𝑓𝑓,𝑡= 1, 𝑌𝑡𝑜𝑥,𝑡= 1). 
11.3.2 The experimental arm is deemed as unacceptable if 𝐻0: 𝑝𝑒𝑓𝑓,𝐸≤𝑝𝑒𝑓𝑓,𝐶 or 𝑝𝑡𝑜𝑥,𝐸> 𝑝𝑡𝑜𝑥,𝐶 , i.e., 
the experimental treatment is inefficacious or overly toxic, with respect to the control. We employ 
the following Bayesian rule to make a go/no-go decision: (Futility and toxicity stopping) stop 
enrolling patients and claim that the experimental arm is unacceptable if 
𝑃𝑟(𝑝𝑒𝑓𝑓,𝐸> 𝑝𝑒𝑓𝑓,𝐶|𝑑𝑎𝑡𝑎) < 𝜆(𝑛
𝑁)
𝛼
, 
OR 
𝑃𝑟(𝑝𝑡𝑜𝑥,𝐸≤𝑝𝑡𝑜𝑥,𝐶|𝑑𝑎𝑡𝑎) < 𝜆(𝑛
𝑁)
𝛼
, 
where 𝜆=0.68 and 𝛼=0.84 are design parameters optimized to maximize the probability of 
correctly concluding an efficacious and safe treatment as acceptable when 𝑝𝑒𝑓𝑓,𝐸= 0.42, 
𝑝𝑡𝑜𝑥,𝐸= 0.36 and 𝑝𝑒𝑓𝑓𝑡𝑜𝑥,𝐸= 0.15, while controlling that the probability of incorrectly 
claiming an inefficacious and toxic treatment, with 𝑝𝑒𝑓𝑓,𝐶= 𝑝𝑒𝑓𝑓,𝐸= 0.27, 𝑝2,𝐶= 𝑝2,𝐸=
0.57  and 𝑝3,𝐶= 𝑝3,𝐸= 0.15 , as acceptable is 10 %. This optimization is performed 
assuming a vague Dirichlet prior 𝐷𝑖𝑟(0.25,0.25,0.25,0.25) for 𝐩.The prior is chosen such 
that it corresponds to a prior effective sample size of 1. The above decision rule leads to the 
optimal stopping boundaries shown in following tables. The trial stops when either the 
efficacy endpoint or the toxicity endpoint crosses the stopping boundaries. 
Optimized stopping boundaries for efficacy endpoint 
Interim (no. 
in control) 
Interim (no. in 
experimental) 
No. response (eff) 
in control 
Stop for futility if no. of response in 
experimental - no. of response in 
control <= 
18 
18 
0 
Never 
18 
18 
1~2 
-1 
18 
18 
3~16 
-2 
18 
18 
17~18 
-1 
47 
47 
0~2 
0 
47 
47 
3~12 
1 
47 
47 
13~32 
2 
47 
47 
33~44 
1 
47 
47 
45~47 
0 

 (V1.2 2025.05.23) 
20 
 
 
Optimized stopping boundaries for toxicity endpoint 
Interim (no. 
in control) 
Interim (no. in 
experimental) 
No. toxicity (tox) 
in control 
Stop for unsafety if no. of toxicity in 
experimental - no. of toxicity in 
control >= 
18 
18 
0~1 
1 
18 
18 
2~15 
2 
18 
18 
16~17 
1 
18 
18 
18 
Never 
47 
47 
0~3 
0 
47 
47 
4~14 
-1 
47 
47 
15~34 
-2 
47 
47 
35~45 
-1 
47 
47 
46~47 
0 

 (V1.2 2025.05.23) 
21 
 
Based on the above tables and figures, we perform the interim analysis when the number of 
enrolled patients reaches 36. When the total number of patients reaches the maximum sample 
size of 94, we reject the null hypothesis and conclude that the experimental arm is acceptable, 
compared to the control, if both the futility and toxicity stopping boundary are not crossed. 
Below are the operating characteristics of the design based on 10000 simulations using the 
BOP2 web application, which is available at http://www.trialdesign.org. 
Operating characteristics 
Scena
rio 
Pr(Eff
) for 
Contr
ol 
Pr(To
x) for 
Contr
ol 
Pr(Eff 
& 
Tox) 
for 
Contr
ol 
Pr(Eff) for 
Experime
ntal 
Pr(Tox) 
for 
Experime
ntal 
Pr(Eff & 
Tox) for 
Experime
ntal 
Early 
Futilit
y 
Stoppi
ng (%) 
Claim 
Promisi
ng (%) 
Avera
ge 
Sampl
e Size 
1 
0.27 
0.57 
0.15 
0.37 
0.47 
0.17 
23.58 
44.40 
80.3 
2 
0.27 
0.57 
0.15 
0.42 
0.36 
0.15 
9.79 
75.93 
88.3 
 
11.4 The primary endpoint analysis and other secondary endpoints will be based on the intent-
to-treat population and per-protocol population, while the safety data will be summarized 
based on the intent-to-treat population.  
11.4.1 Intent-to-treat population refers to all enrolled patients regardless of their 
compliance with the study drug treatment.  
11.4.2 Per-protocol population refers to all patients who have received at least 6 weeks (2 cycles) of 
study medication and received the first scheduled assessment of tumor response. 
11.5 Disease stabilization rate (complete response + partial response by RECIST + stable disease 
by RECIST that last for  8 weeks), objective response rate (complete response + partial 

 (V1.2 2025.05.23) 
22 
response by RECIST), and down-staging rate will be calculated with their 95% confidence 
intervals.  
11.6 Progression-free survival, time-to-tumor progression, and overall survival will be calculated 
by the Kaplan-Meier method.  
11.6.1 Progression-free survival is defined as the duration from the date of the first dose of study drug 
treatment to the date of documented disease progression or death of any cause.  
11.6.2 Time-to-tumor progression is defined as the duration from the date of the first dose of study drug 
treatment to the date of documented tumor progression by imaging studies. 
11.6.3 Overall survival is defined as the duration from the date of the first dose of study drug treatment 
to the date of death of any cause.  
11.7 The baseline and changes in immune-related biomarkers after study drug treatment will be 
correlated with the patients’ treatment outcome, including disease stabilization, best 
radiographic response, time to tumor progression, progression-free survival, and overall 
survival. 
11.8 For the endpoint of the safety assessment, the tabulations will count the number of subjects 
reporting individual adverse events. Incidence of adverse events and serious adverse events 
will be summarized. 
11.9 The demographic features of the subjects will be summarized by descriptive statistics. 
Comparison between sub-groups, for examples,  
subjects with vs. without objective tumor response/AFP response/disease stabilization 
subjects with vs. without surgery after study drug treatment 
by using Mann-Whitney tests/ one-way ANOVA (continuous variables) or chi-
square/Fisher’s Exact tests (categorical variables). 
12. Institutional review board 
12.1 The study will be conducted in accordance with the Declaration of Helsinki on Ethical 
Principles for Medical Research Involving Human Subjects (revised in 2013) the 
International Conference on Harmonization guideline on Good Clinical Practice (GCP), and 
applicable local regulatory requirements and laws. 
12.2 The investigator of each participating center is responsible for submission and obtaining 
approval of the study protocol, protocol amendments, informed consent forms, and other 
relevant documents from the institutional review board or research ethics committee of 
each participating center. 
13. Records to be kept 
13.1 The investigator of each participating center is responsible for keeping the following records, 
according to the GCP guidelines and applicable local regulatory requirements and laws: 
13.1.1 Identity of all participating subjects (sufficient information to link the source documents (hospital 
records) and the case record forms); 
13.1.2 All original signed informed consent forms; 
13.1.3 Source documents; 
13.1.4 Copies of all case record forms; 
13.1.5 Serious adverse event forms; 
13.1.6 All correspondence with the institutional review board. 
 

 (V1.2 2025.05.23) 
23 
14. References  
 
1. 
Shiravand Y, Khodadadi F, Kashani SMA, et al. Immune Checkpoint Inhibitors in Cancer 
Therapy. Curr Oncol. 2022;29(5):3044-3060. 
2. 
Fujii H, Nishioka N, Simon RR, Kaur R, Lynch B, Roberts A. Genotoxicity and subchronic 
toxicity evaluation of Active Hexose Correlated Compound (AHCC). Regul Toxicol 
Pharmacol. 2011;59(2):237-250. 
3. 
Matsui Y, Uhara J, Satoi S, et al. Improved prognosis of postoperative hepatocellular 
carcinoma patients when treated with functional foods: a prospective cohort study. 
Journal of hepatology. 2002;37(1):78-86. 
4. 
Spierings EL, Fujii H, Sun B, Walshe T. A Phase I study of the safety of the nutritional 
supplement, active hexose correlated compound, AHCC, in healthy volunteers. J Nutr Sci 
Vitaminol (Tokyo). 2007;53(6):536-539. 
5. 
Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the 
management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1-98. 
6. 
EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. 
Journal of hepatology. 2017;67(2):370-398. 
7. 
Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. 
Cancer treatment reviews. 2016;44:51-60. 
8. 
Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the Immune-Related Adverse 
Effects of Immune Checkpoint Inhibitors: A Review. JAMA oncology. 2016;2(10):1346-
1353. 
9. 
Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J. Immune checkpoint inhibitors and 
cardiovascular toxicity. The Lancet Oncology. 2018;19(9):e447-e458. 
10. 
Wang DY, Salem J, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint 
inhibitors: A systematic review and meta-analysis. JAMA oncology. 2018. 
 
15. Appendix 
15.1 Improved prognosis of postoperative hepatocellular carcinoma patients when treated 
with functional foods: a prospective cohort study. J Hepatol. 2002 Jul;37(1):78-86. 
15.2 A Phase I study of the safety of the nutritional supplement, active hexose correlated 
compound, AHCC, in healthy volunteers. Nutr Sci Vitaminol (Tokyo). 2007 Dec;53(6):536-
9.