Clinical trial NCT02486796
Conditions: Quality of Life
Sponsor: Midwestern Regional Medical Center
Start date: 2016-02-19; Completion date: 2017-03-03
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is examine the effect of the addition of naturopathic on immunologic and/or inflammatory parameters and/or quality of life in women receiving neoadjuvant chemotherapy for breast cancer.

Detailed description:

Arms: arm 1: Subjects will be dosed with Reishi mushroom extract, Coenzyme Q10 and Melatonin beginning with Cycle 1 Day 1 of their prescribed neoadjuvant chemotherapy. arm 2: Subjects will be dosed with Reishi mushroom extract, Coenzyme Q10 and Melatonin beginning with Cycle 3 Day 1 of their prescribed neoadjuvant chemotherapy.
Interventions: intervention 1: Reishi mushroom extract intervention 2: Coenzyme Q10 intervention 3: Melatonin
Intervention descriptions: intervention 1: Reishi mushroom preparation produced water-ethanol extraction. intervention 2: Preparation of coenzyme Q10 intervention 3: Preparation of melatonin

Protocol documents:
Prot_SAP_ICF_000.pdf: 
CONFIDENTIAL 
11NOV2015 
Page 1 of 33 
 
 
 
  
Protocol Title:              A Comparison Study to Assess the Value of     
Naturopathic Medicine Given Immediately and 
Continuously or Delayed Until Cycle 3 in Combination 
with Neo-Adjuvant Chemotherapy for Breast Cancer.  
 
Protocol Number:      MZ2014018_Neo-Adjuvant Study 
 
Principal Investigator: Christina M. Shannon, ND, FABNO 
 
Midwestern Regional Medical Center, Inc. 
 
2520 Elisha Ave Zion, IL 60099 
 
christina.shannon@ctca-hope.com 
 
 
(847) 731-5617 
 
 


CONFIDENTIAL 
11NOV2015 
Page 2 of 33 
 
Table of Contents 
 
A 
Introduction .......................................................................................................................................... 4 
Study Abstract ...................................................................................................................................... 4 
Primary Hypothesis ............................................................................................................................. 4 
B 
Study Objectives ................................................................................................................................. 8 
Primary Aim ........................................................................................................................................... 8 
Secondary Aim ..................................................................................................................................... 8 
Rationale for the Selection of Outcome Measures ..................................................................... 8 
Dose Rationale and Risk/Benefits ................................................................................................... 9 
C 
Study Design ..................................................................................................................................... 10 
Overview or Design Summary ........................................................................................................ 10 
Subject Selection and Withdrawal ................................................................................................. 11 
C1.a 
Inclusion Criteria ..................................................................................................11 
C1.b 
Exclusion Criteria .................................................................................................12 
C1.c 
Ethical Considerations .........................................................................................14 
C1.d 
Subject Recruitment Plans and Consent Process ................................................14 
C1.e 
Randomization Method ........................................................................................14 
C1.f 
Risks and Benefits ...................................................................................................14 
C1.g 
Early Withdrawal of Subjects ...............................................................................15 
C1.h 
When and How to Withdraw Subjects ..................................................................15 
C1.i 
Data Collection and Follow-up for Withdrawn Subjects ............................................15 
Study Drug ........................................................................................................................................... 15 
C1.j 
Description ..............................................................................................................16 
C1.k 
Treatment Regimen .............................................................................................16 
C1.l 
Method for Assigning Subjects to Treatment Groups ...............................................16 
C1.m 
Preparation and Administration of Study Drug .....................................................16 
C1.n 
Subject Compliance Monitoring ...........................................................................17 
C1.o 
Prior and Concomitant Therapy ...........................................................................17 
C1.p 
Packaging/Labeling..............................................................................................17 
C1.q 
Blinding of Study Drug .........................................................................................17 
D 
Study Procedures ............................................................................................................................. 17 
Screening for Eligibility .................................................................................................................... 17 
D1.a 
Visit 1 ...................................................................................................................17 
D1.b 
Visit 2 ...................................................................................................................18 
D1.c 
Visit 3 ...................................................................................................................18 
D1.d 
Visit 4 ...................................................................................................................18 
D1.e 
Visit 5 (End of Study Visit)....................................................................................18 
Safety and Adverse Events ............................................................................................................. 18 
D1.f 
Safety and Compliance Monitoring ..........................................................................18 
D1.g 
Medical Monitoring ...............................................................................................19 
D1.h 
Definitions of Adverse Events ..............................................................................19 


CONFIDENTIAL 
11NOV2015 
Page 3 of 33 
 
D1.i 
Classification of Events ...........................................................................................19 
D1.j 
Reporting Procedures..............................................................................................19 
E 
Statistical Plan .................................................................................................................................. 19 
Sample Size Determination and Power ........................................................................................ 19 
Interim Monitoring and Early Stopping ........................................................................................ 20 
F 
Data Handling and Record Keeping .............................................................................................. 20 
Confidentiality and Security ............................................................................................................ 20 
Training ................................................................................................................................................. 20 
Source Documents ............................................................................................................................ 20 
Records Retention ............................................................................................................................. 21 
Performance Monitoring .................................................................................................................. 21 
G 
Study Monitoring, Auditing, and Inspecting .................................................................................. 21 
Study Monitoring Plan ...................................................................................................................... 21 
Organization and Participating Center ......................................................................................... 21 
Funding Source and Conflicts of Interest ................................................................................... 21 
Committees .......................................................................................................................................... 21 
Subject Stipends or Payments ........................................................................................................ 21 
Study Timetable .................................................................................................................................. 21 
ATTACHMENT L1 Informed Consent Document .............................................................23 
 
 
 
 


CONFIDENTIAL 
11NOV2015 
Page 4 of 33 
 
A Introduction 
 
Study Abstract 
Most health care providers are now aware of the literature citing the use of complementary and 
alternative medicine (CAM) treatments by patients, whether or not they divulge this use to their 
providers. Many times, patients are self-prescribing these treatments, and may be unaware of the 
potential for interactions with their conventional medications and treatments, as well as the 
potential for being contraindicated with their condition. Naturopathic Doctors are extensively 
trained in the use of integrative medicine treatments, and the management of patients utilizing both 
complementary and conventional treatments concomitantly. Cancer Treatment Centers of America 
is pioneering this model by offering patients an integrated approach to oncology care with a 
combination of conventional, standard of care cancer treatment, by Medical, Surgical and Radiation 
Oncologists, as well as evidence based complementary treatments by clinicians with doctorates in 
naturopathic medicine. 
 A variety of complementary agents are used along with conventional treatments in hopes of 
helping to manage and alleviate side effects of treatment. One reason for doing this is to enable 
patients to better tolerate treatments so that they may have optimal response to their treatment 
regimen. There are numerous articles, exhibiting mixed results at times, regarding improvement in 
quality of life of patients and modification of side effects using complementary agents along with 
conventional regimens. We would like to further investigate this notion by examining how patients 
respond to a combination of complementary agents. Additionally, we would like to determine 
whether or not this combination will affect measures of inflammatory, immune or possibly cancer 
biomarkers.  
Primary Hypothesis 
The addition of naturopathic medicine will improve immunologic and/or inflammatory parameters 
and/or quality of life in women receiving neoadjuvant chemotherapy (neo-CTx) for breast cancer. 
Purpose of the Study Protocol 
This protocol seeks to measure specific clinical, physiologic and quality of life parameters in 2 
groups of breast cancer patients who receive neoadjuvant chemotherapy. This is a randomized, 
prospective, 2-arm, open label, exploratory study in which patients who give informed consent, will 
be randomized to receive standard neoadjuvant chemotherapy for breast cancer with naturopathic 
treatment given either (i) concomitant with the start of neoadjuvant chemotherapy (cohort 1); or, 
(ii) beginning at the start of the 3rd cycle of neoadjuvant chemotherapy (cohort 2). The goal is to 
conduct a battery of immunologic and quality of life (QoL) measurements longitudinally in both 
cohorts, prior to beginning therapy, at defined assessment points during neoadjuvant therapy, and 
at the end of neoadjuvant chemotherapy prior to a time when most patients will receive surgery. 
This protocol will determine: 1) whether the addition of Naturopathic Medicine Support (NMS) at 
the start of Neo-CTx for breast cancer affects immune status, inflammatory mediators and/or QoL 
apart from the effects produced by the neo-CTx alone; 2) whether the effects, if any, will also be 
produced in patients who begin NMS beginning at the 3rd cycle of neoadjuvant chemotherapy; 3) 
the magnitude, frequency, and kinetics of effects in both patient cohorts; and, 4) whether effects 


CONFIDENTIAL 
11NOV2015 
Page 5 of 33 
 
elicited by the addition of NMS to neo-CTx are beneficial (favorable) with respect to the study 
parameter(s).  
 
Prior Literature and Studies 
Coenzyme Q10 (CoQ10) 
Preclinical Data 
Cell studies indicate that CoQ10 can help to reduce activity of matrix metalloproteinase-2 (MMP-2), 
thereby limiting their ability to metastasize. (Bahar et al., 2010) 
Animal models of breast cancer indicate increased mitochondrial antioxidant and antitumor 
activity when treated concomitantly with Tamoxifen and CoQ10, riboflavin and niacin. (Perumal, 
Shanthi, & Sachdanandam, 2005) 
Clinical Data 
CoQ10 has been shown to reduce the cardio toxicity associated with Adriamycin chemotherapy 
treatment. (Conklin, 2005) 
CoQ10 has been shown to improve cancer biomarkers (serum CEA and 15-3) in women receiving 
standard treatment for breast cancer. (Premkumar, Yuvaraj, Vijayasarathy, Gangadaran, & 
Sachdanandam, 2007)  
A pilot study of patients with a variety of “end stage” cancers, including breast cancer, showed 
mean actuarial survival was 28.8 months versus 11.9 months for mean predicted survival with the 
addition of CoQ10. (and a variety of other anti-oxidants)(Hertz & Lister, 2009) 
Another study shows a potential mechanism for the beneficial effects of CoQ10, demonstrating that 
CoQ10, as part of the CoRN protocol, administered along with Tamoxifen, can lead to decreased 
serum levels of IL-1B, IL-6, IL-8, TNFa and VEGF. (Premkumar et al., 2007)  
CoQ10 was also shown to significantly increase DNA repair enzymes and decrease DNA methylation 
patterns. This has potential to lead to a reduction in tumor burden, and may suggest good prognosis 
and efficacy of the treatment. (Premkumar, Yuvaraj, Shanthi, & Sachdanandam, 2008) 
CoQ10 is also believed to have anti-angiogenic effects as demonstrated by lowering angiogenic 
marker levels of bFGF, HGF, EGFR, TGF-β1, dThdPase, PGE2 and TSP levels in women undergoing 
treatment with Tamoxifen. (Premkumar, Yuvaraj, Sathish, Shanthi, & Sachdanandam, 2008)  
CoQ10 has been shown to reduce recurrence rates, when used with standard treatment for other 
cancer types (melanoma). (Rusciani et al., 2007)  
Yet another study demonstrates that CoQ10 with Vitamin B6 can increase IgG production, as well as 
increase T4 lymphocytes. (Folkers, Morita, & McRee, 1993)  


CONFIDENTIAL 
11NOV2015 
Page 6 of 33 
 
Finally a review article discusses the recent clinical trials using cancer and non-cancer patients with 
chronic fatigue that have shown the benefit of molecular replacement plus antioxidants such as 
CoQ10 in reducing the damage to mitochondrial membranes, restoring mitochondrial electron 
transport function, and reducing fatigue. (Nicolson & Conklin, 2008)  
Melatonin 
Melatonin has been shown in both preclinical and clinical studies to modulate immune function and 
has been associated with improved outcomes and quality of life. 
Preclinical Data 
A study of melatonin-exposed human breast cancer cell lines published in 2011 indicated that 
melatonin plays a role in the regulation of cancer-related gene expression in human breast cancer 
cells. (Lee et al., 2011)  
A study published in 2010 indicated that melatonin is associated with the inhibition of proliferation 
of estrogen receptor α (ERα)-positive breast cancer cell lines. (Mao et al., 2010) 
A study published 2009 showed that melatonin inhibits aromatase activity and expression by 
regulating the gene expression of specific aromatase promoter regions. A possible mechanism for 
these effects would be the regulation by melatonin of intracellular cAMP levels, mediated by an 
inhibition of cyclooxygenase activity and expression. (Martinez-Campa et al., 2009)  
In an earlier study by Garcia-Maurino, et al., the results suggested that melatonin may be involved 
in the regulation of human immune functions by modulating the activity of Th1 cells and monocytes 
via nuclear receptor-mediated transcriptional control. (Garcia-Maurino et al., 1997)  
Clinical Data 
One study suggests that melatonin may enhance Tamoxifen anti-tumor efficacy in other solid 
cancer types. (Lissoni et al., 1996)  
Melatonin is associated with a significant decrease of IL-6 circulating levels, indicating that it 
modulates immune function in cancer patients in favor of Type 1 (cell-mediated antitumor 
immunity) responses. Furthermore, by activating the pluripotent cytokine system, direct growth-
inhibitory properties have been observed over a wide range of tumor cell types that utilize 
cytokines as growth factors. Furthermore, by stimulating the cytotoxic activity of macrophages and 
monocytes, melatonin plays a critical role in host defense against the progression of Neoplasia. 
(Neri et al., 1998)  
A study published in 2000 by Lissonni, et al. showed an increased response rate in patients with 
renal cell carcinoma treated with IL-2 combined with melatonin compared to patients treated with 
IL-2 alone. Moreover, patients who received concomitant IL-2/melatonin plus morphine achieved a 
better response than the group receiving IL-2 plus morphine without melatonin (4/14 vs. 1/16 
respectively, p<0.05). Moreover, the 3-year survival rate for the combined IL-2/melatonin cohort 
was significantly higher compared to patients with IL-2 alone (p<0.01). Interestingly, one basis for 


CONFIDENTIAL 
11NOV2015 
Page 7 of 33 
 
this study was the observation that the opioid substances (e.g. morphine) may suppress anticancer 
immunity and the efficacy of IL-2 itself. (Lissoni, Mandala, & Brivio, 2000)  
Another study of 14 patients with several different advanced solid neoplasms that were clinically 
resistant to IL-2, but became responsive to IL-2 with concomitant administration of the pineal hormone 
melatonin (MLT). It was suggested that MLT could act by enhancing the IL-2-stimulated antitumor 
immune effects and/or by increasing the susceptibility of cancer cells to lysis by the IL-2-induced 
cytotoxic lymphocytes. In that study, a 40 mg dose of melatonin was given to patients daily. (Lissoni 
et al., 1994)  
Melatonin has been shown to cause the release of cytokines from activated T-cell populations. A 
phase II study, in 1994, combined interferon treatment with melatonin given at 10 mg daily. Out of 
22 patients there were seven tumor responses (33%) with three Complete Responses (CR) and 4 
Partial Responses (PR) involving lung and soft tissue disease. The median duration of survival was 
reported as 16 months. Of the other patients studied, 9 patients achieved stable disease with 5 
showing progressive disease. (Neri et al., 1994)  
Reishi (Ganoderma lucidum) 
Ganoderma licidum (G. lucidum) has been shown in both preclinical and clinical trials to have 
immune modulating effects.    One clinical trial has also indicated a potential benefit on quality of 
life.  
Preclinical Data 
Preclinical data of G. lucidum include enhancing the proliferation and maturation of T and B 
lymphocytes, splenic mononuclear cells, NK cells and dendritic cells.   G. lucidum has also been 
shown to effect gene expression of IL-1β, IL-6, IL-10, and tumor necrosis factor (TNF)-α.  
Furthermore a polysaccharide fraction was shown to enhance both innate and adaptive immunities 
by triggering the production of cytokines, IL-1, IL-6, IL-12, IFN-γ, TNF-α, and colony stimulating 
factors (CSFs) from mouse splenocytes. (Wachtel-Galor, Yuen, Buswell, & Benzie, 2011)  
Clinical Data 
In a 1996 Cochrane Database Systematic Review included 5 RCTs.  The common primary outcomes 
were tumor response evaluated according to the World Health Organization (WHO) criteria, 
immune function parameters such as natural killer (NK)-cell activity and T-lymphocyte co-receptor 
subsets, and quality of life measured by the Karnofsky scale score.   The results showed that those 
patients given G. lucidum given along with chemotherapy and radiation were more likely to respond 
positively compared to chemotherapy or radiation therapy alone.  In addition immune parameters 
and quality of life were improved.  In regards to the immune system there were increases in the 
percentage of CD3, CD4, and CD8.   The CD4/CD8 ratio was also elevated.  In this review only one 
study reported mild side effects of insomnia and nausea. (Jin, Ruiz Beguerie, Sze, & Chan, 2012)  
 
In a 2003 study by Gao et al the effects of G. lucidum on the immune functions of advanced stage 
patients with cancer were evaluated.   34 patients with advanced cancer were given 1800 mg three 
times daily for 12 weeks.  Treatment with G. lucidum resulted in increases in the mean plasma 


CONFIDENTIAL 
11NOV2015 
Page 8 of 33 
 
concentrations of IL-2, IL-6 and interferon-gamma.  The levels of IL-1 and tumor necrosis factor 
alpha (TNF-alpha) were decreased.   There were also effects on the numbers of each lymphocyte 
subset.  The absolute number of CD56 cells was significantly increased after 12 weeks while CD3, 
CD4 and CD8 were marginally increased to baseline.  There was no change to the CD4:CD8 ratio.   
Finally there was a significant increase in NK cell activity to baseline. (Gao, Zhou, Jiang, Huang, & 
Dai, 2003)  
In a double blind randomized study by Wicks et al of 16 healthy adults the safety and tolerability of 
G. lucidum was tested.   After 10 days of oral administration of 2g twice daily no adverse events 
were reported.   This study also showed no obvious changes in CD4, CD8 and CD19 levels however 
CD56 cells were increased and returned to baseline after 10 days of cessation of supplementation.  
Due to the small size of the study the increase in CD56 cells did not achieve statistical significance. 
(Wicks et al., 2007)  
 
B Study Objectives 
 
Primary Aim 
1. Determine the impact of adding NMS to neo-CTx on hematologic and immunologic parameters 
relevant to general immunocompetence (e.g. White Blood Cell counts) and antitumor immunity (i.e. 
NK cell activity).  
2. Determine the impact of adding NMS to neo-CTx on the quality of life (QoL) of patients with 
locally advanced breast cancer receiving neoadjuvant therapy prior to surgery as measured by the 
M.D. Anderson Symptom Inventory (MDASI) tool. 
3. Determine whether such effects can be elicited and maintained throughout the course of neo-CTx 
when given continuously at the start of treatment. 
4. Determine whether such effects can be elicited in patients who have received 2 of 4 planned CTx 
treatment cycles prior to initiating concomitant NMS therapy. 
 
Secondary Aim 
1. Determine the impact of adding NMS to neo-CTx on measures of the inflammatory response and 
type 1 and 2 cytokines.  
2. Characterize the impact of adding NMS to neo-CTx on the concentration of circulating tumor cells.  
 
Rationale for the Selection of Outcome Measures 
As discussed in previous sections, CoQ10, Melatonin and Reishi have all been shown, individually to 
affect immune parameters and inflammatory cytokines. CoQ10 has been shown to improve 


CONFIDENTIAL 
11NOV2015 
Page 9 of 33 
 
measures of tumor response. Additionally, previous studies have associated all 3 agents with 
improvement of side effects and quality of life.  
The presence of circulating tumor cells has been correlated with early detection of disease 
progression. A novel method to detect very low concentrations of circulating tumor cells has been 
developed (ClearID; Cynvenio Biosystems, Inc.). In addition to the measurement of immunologic 
and inflammatory parameters, this study will also test blood samples from ten participants to 
observe the effect of neoadjuvant chemotherapy and/or naturopathic medicines on the detection of 
circulating tumor cells. Blood will be collected from ten participants before the start of neoadjuvant 
therapy cycles 1 and 3 for testing. 
Dose Rationale and Risk/Benefits  
Source for potential interactions was Naturaldatabase.com, a comprehensive database of herb-
drug-nutrient interactions.  
Melatonin: 
Most clinical studies showing benefit with melatonin have used a dose of 20 mg. No known toxicity 
or serious side effects were reported; however, long-term human studies have not been conducted. 
Some uncommon side effects that have been reported in studies or case reports include drowsiness, 
alterations in sleep patterns, altered mental status, disorientation, tachycardia, flushing, pruritus, 
abdominal cramps and headache. Excessive dosages beyond those that will be given in this study 
may cause morning sedation or drowsiness. Melatonin should be used with caution in individuals 
using central nervous system depressants as concurrent use may cause additive sedation. 
Theoretically, melatonin may affect the disposition of the following medications: Theophylline, 
caffeine, clozapine, haloperidol, tacrine, fluvoxamine, and other medications associated with 
metabolism by cytochrome P450 1A2 (CYP1A2). It may also affect the activity of non-steroidal anti-
inflammatory agents (e.g., aspirin, ibuprofen, Naproxen), phenytoin, warfarin, zafirlukast, 
fluvoxamine, and others affected by cytochrome P450 2C9 (CYP2C9). Melatonin may interact with 
calcium channel blockers. Concomitant use of melatonin and nifedipine may cause increases in 
blood pressure. Assessment and monitoring of any such effects is part of the standard of care at 
CTCA by naturopathic physicians treating patients and will continue to be the standard for patients 
entered on this study.  
Coenzyme Q10: 
CoQ10 is generally well-tolerated. In clinical studies, there have been no reports of significant 
adverse effects. Coenzyme Q-10 can cause gastrointestinal side effects such as nausea, vomiting, 
diarrhea, appetite suppression, heartburn, and epigastric discomfort in less than 1% of patients and 
the effects are all reversible. Some of these adverse effects can be minimized if total daily doses 
exceeding 100 mg are divided and administered two to three times per day. Allergic rash has also 
been reported but is extremely rare. Theoretically, CoQ10 may increase bleeding risk and may 
decrease response to warfarin. However, a small randomized controlled trial showed no effect on 
International Normalized Ratio (INR; a measure of blood clotting) with concurrent use of coenzyme 
Q10 (Engelsen, Nielsen, & Hansen, 2003). Potential adverse reactions include abdominal 
discomfort, headache, nausea and vomiting. There is a wide range of dosing for CoQ10 but most 
studies used a dose between 60 – 200 mg.  


CONFIDENTIAL 
11NOV2015 
Page 10 of 33 
 
Reishi: 
Side effects are uncommon however reported side effects include allergies, dryness of the mouth, 
throat and nasal area, itching, nausea, epistaxis. Bloody stools have been reported with use of over 
3-6 months. 
In regards to documented potential effects with botanicals and drugs the data is sometimes 
inconsistent.  In patients with type-2 diabetes however, information from clinical research is 
inconsistent. In patients with type 2 diabetes taking G. lucidum appeared to effect HA1C but not 
fasting glucose.  Therefore it may be possible to have additive effects with botanicals or herbs that 
can have hypoglycemic potential.   Clinical evidence also shows that G. lucidum may reduce blood 
pressure in some but not all patients with hypertension therefore additive affects might be possible 
for patients on anti-hypertensive medications or botanicals.  Finally a dose of higher than 3g daily 
may decrease platelet aggregation and therefore additive effects may occur with patients on 
medications or botanicals that have antiplatelet actions.  
In regards to dosing the two clinical studies noted above in “Prior Literature and Studies” 
section used dosing between 4g  - 5.4g daily.  In the study of healthy volunteers the dose 
was 2g twice daily and in the study of patients with advanced cancer a dose of 1800mg 
three times daily was used for a total dose of 5.4g daily. 4,3 
 
 
C Study Design  
 
Overview or Design Summary 
This is a randomized, prospective, 2-arm, immediate versus delayed, open label, exploratory study 
in which patients who give informed consent, will be randomized to receive standard neoadjuvant 
chemotherapy for breast cancer with either immediate and continuous naturopathic treatment, or 
delayed continuous naturopathic treatment. Twenty patients will be recruited into this 2-arm 
design wherein 10 patients will receive immediate and continuous NMS intervention, and 10 will 
receive delayed NMS starting at cycle 3. 
All patients will have adenocarcinoma of the breast and have been recommended to receive 
neoadjuvant chemotherapy. The patients can have estrogen receptor positive or negative disease, 
progesterone receptor positive or negative disease and HER-2 positive or negative disease. They 
will all receive neoadjuvant chemotherapy as per the medical oncologist and according to NCCN 
guidelines.  Chemotherapies that may be used in combination include doxorubicin, 
cyclophosphamide, gemcitabine, carboplatin, docetaxel and paclitaxel. . Trastuzumab and or 
pertuzumab may also be used as recommended by the medical oncologist. 
In one group NMS interventions will start with cycle 1 and continue through 4 cycles of 
neoadjuvant chemotherapy until the patient returns for blood work and evaluation following the 
4th treatment of chemotherapy which is approximately 2-3 weeks after the 4th treatment is given.  


CONFIDENTIAL 
11NOV2015 
Page 11 of 33 
 
The total time on NMS interventions is approximately 8 -12 weeks as the time between each cycle 
of chemotherapy is approximately 2- 3 weeks. The interventions will include coenzyme Q10, 
melatonin and reishi. The second group will start naturopathic interventions at cycle 3 and will 
continue through the 4th cycle of neoadjuvant chemotherapy until the patient returns for blood 
work and evaluation following the 4th treatment of chemotherapy which is approximately 2 - 3 
weeks after the 4th treatment is given. The total time on NMS interventions is approximately 4 -6 
weeks. The naturopathic interventions will be identical in each group except for the timing of the 
start of the intervention and the total time the patient will be taking NMS interventions. 
At the start of each treatment cycle beginning with cycle 1 both groups will be given the Modified 
MD Anderson Symptom Inventory (MDASI). A blood sample will be collected according to standard 
of care with each treatment cycle to include a complete blood count, chemistry panel and tumor 
markers (including CA 15-3, CA 19-9, CA 27.29, Chorioembryonic Antigen [CEA] and Circulating 
Tumor Cells [CTC], if available). In addition, a blood sample for measurement of inflammatory 
markers C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR) will be drawn. A tube 
containing preservative-free heparin (an anticoagulant) will be collected for assessment of NK cell 
activity isolated by a standard ficoll/hypaque gradient centrifugation. The serum will be collected 
and stored for potential assessment of type I and type II cytokines using a commercial multiplex 
cytokine assay. These assays will be conducted only if the NK assay and/or QoL results indicate the 
NMS therapies have measurable effects. These blood draws will be done before chemotherapy is 
given. The NK cell studies will be done in real time, while the collected plasma containing cytokines 
will be batch tested at end of study.  
Assessment and monitoring of any side effects will occur at every follow-up visit as part of the 
standard of care at CTCA.  For all patients at every visit vital signs are taken and recorded.  This 
includes temperature, blood pressure, heart rate and respiration rate.  In addition, at the patient’s 
initial visit, height and weight will be recorded and subsequently weight will be measured for all 
follow-up visits. 
Subject Selection and Withdrawal  
 
C1.a 
Inclusion Criteria 
 
i 
Participants will have signed an informed consent 
Inclusion Criteria: 
• 
Female 
• 
18 years or older 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
• 
Diagnosis of invasive adenocarcinoma of the breast made by core needle excisional 
or stereotactic biopsy. 
• 
All patients will have adenocarcinoma of the breast and have been recommended to 
receive neoadjuvant chemotherapy. The patients can have estrogen receptor 
positive or negative disease, progesterone receptor positive or negative disease and 


CONFIDENTIAL 
11NOV2015 
Page 12 of 33 
 
HER-2 positive or negative disease. They will all receive neoadjuvant chemotherapy 
as per the medical oncologist and according to NCCN guidelines.  Chemotherapies 
that may be used in combination include doxorubicin, cyclophosphamide, 
gemcitabine, carboplatin, docetaxel and paclitaxel. Trastuzumab and or pertuzumab 
may also be used as recommended by the medical oncologist.  
• 
Left Ventricular Ejection Fraction (LVEF) assessment by MUGA or Echocardiogram 
within 3 months of entering study 
• 
Blood counts must meet the following criteria: 
▪ 
ANC greater than or equal to 1200 cells/mm3 
▪ 
Platelet count greater than or equal to 100,000/mm3 
▪ 
Hemoglobin greater than or equal to 10g/dL 
▪ 
Serum creatinine less than or equal to ULN for the laboratory range 
• 
Adequate hepatic function by the following criteria: 
▪ 
Total bilirubin less than or equal to ULN for the laboratory range, unless the 
patient has an elevation greater than ULN to 1.5 times the ULN resulting from 
Gilbert’s disease or similar syndrome due to slow conjugation of bilirubin 
▪ 
Alkaline phosphatase less than or equal to 2.5 x ULN; and 
▪ 
AST less than or equal to 1.5 x ULN for the laboratory range 
• 
If skeletal pain present or alkaline phosphatase greater than ULN (but less than or 
equal to 2.5 x ULN), bone scan or PET scan must not demonstrate metastatic 
disease  
• 
If AST or alkaline phosphatase greater than ULN, liver imaging (CT, MRI or PET 
scan) must not demonstrate metastatic disease and the requirements for hepatic 
function must be met 
• 
Able to swallow oral medication 
• 
Willing to forego naturopathic treatment for the first 2 treatment cycles in the event 
that randomization assigns the patient to the delayed NMS group.  
• 
Willing to start and continue naturopathic interventions as prescribed for entire 
neoadjuvant treatment which includes approximately 8 - 12 weeks for one group and 
4 - 6 weeks for the other group.  
• 
Willing to forego the use of nutritional or botanical supplements during the time of the 
study shown to effect immune or inflammatory markers outside the use of the 
naturopathic agents being studied  
 
C1.b 
Exclusion Criteria 
 
i 
Participants are not able to understand or provide written informed consent 
ii 
The research team deems that the participant may not be able to follow the study 
protocol 
 
Exclusion Criteria: 


CONFIDENTIAL 
11NOV2015 
Page 13 of 33 
 
• 
Stage 4 disease  
• 
Present and continued treatment with Warfarin or any other anticoagulant therapy. 
• 
Synchronous bilateral invasive breast cancer 
• 
Treatment including radiation, chemotherapy, and/or targeted therapy for the 
currently diagnosed breast cancer prior to entering study.  
• 
Any sex hormonal therapy e.g. birth control, ovarian hormone replacement therapy, 
etc. (eligible if discontinued prior to entering study) 
• 
Continued therapy with any hormonal agent such as raloxifene, tamoxifen, or other 
SERM (eligible if discontinued prior to entering study) 
• 
Prior history of breast cancer, including Ductal Carcinoma In Situ (subjects with a 
history of Lobular Carcinoma In Situ are eligible) 
• 
Prior therapy with chemotherapy or targeted therapy agents for any malignancy. 
• 
Cardiac disease that would preclude the use of the chemotherapy drugs described 
above. This includes but is not confined to: 
▪ 
Active cardiac disease 
▪ 
Angina pectoris requiring the use of anti-angina medication 
▪ 
Ventricular arrhythmias except for benign premature ventricular contractions 
controlled by medication 
▪ 
Conduction abnormality requiring a pacemaker 
▪ 
Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled 
with medication 
▪ 
Clinical significant valvular disease 
▪ 
History of cardiac disease: 
▪ 
Myocardial infarction 
▪ 
Congestive heart failure 
▪ 
Cardiomyopathy 
• 
Uncontrolled hypertension, defined as blood pressure above 150/90 mm/Hg on 
antihypertensive treatment 
• 
History of, or current symptomatic interstitial pneumonitis or pulmonary fibrosis or 
definitive evidence of interstitial pneumonitis or pulmonary fibrosis described on CT 
or chest x-ray in asymptomatic patients 
• 
Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI’s 
CTCAE v4.03 
• 
Malabsorption syndrome, ulcerative colitis, resection of the stomach or small bowel, 
or other disease significantly affecting gastrointestinal function 
• 
Other non-malignant systemic disease that would preclude treatment with any of the 
treatment regimens or would prevent required follow up 
• 
Conditions that would prohibit administration of corticosteroids 
• 
Unwilling to forego the use of nutritional or botanical supplements during the time of 
the study shown to effect immune or inflammatory markers outside the use of the 
naturopathic agents being studied. Repletion of vitamins and minerals will be 
allowed.   
• 
Unwilling to forego naturopathic agents being studied for first 2 cycles of 
chemotherapy treatment.  


CONFIDENTIAL 
11NOV2015 
Page 14 of 33 
 
• 
Administration of an investigational agent within 30 days prior to entering study. 
• 
Administration of therapeutic doses of the supplements being studied including 
Reishi, melatonin and CoQ10 in the previous 30 days. 
• 
Administration of therapeutic doses of immune modulating botanicals in the previous 
30 days. 
• 
Pregnancy or lactation 
 
C1.c 
Ethical Considerations  
This study will be conducted following all local laws and regulations in the conduct of research, as 
well as the International Conference on Harmonization’s Good Clinical Practice Guidelines. These 
guidelines provide a unified standard for designing, conducting, recording, and reporting trials that 
involve the participation of human subjects. 
In addition, this study will be reviewed and approved by appropriate Institutional Review Boards 
prior to the initiation of any study procedures. The protocol will undergo continuing review and 
approval by designated IRB providing ongoing oversight of the study.  
C1.d 
Subject Recruitment Plans and Consent Process 
Subjects will be consented using a current informed consent form that has been approved by the 
respective study site’s Institutional Review Board. Subjects will be allowed adequate time to read 
the informed consent, discuss the consent with study staff and others (e.g., family members, friends, 
or any of their health care providers), and have their questions answered prior to signing the 
informed consent. 
  
C1.e 
Randomization Method  
A random number generator will be used to produce a randomization table. Randomization of 
patients will occur after the patient has signed the IRB consent form. 
C1.f 
 Risks and Benefits 
i 
Risks  
Potential physical risks include: 
There are minimal potential risks involved in this study. There will be additional tubes drawn for 
blood with each cycle; however the risk of this is minimal as patients will already be having their 
blood drawn. 
Potential risks of side effects with naturopathic interventions are outlined in Dose Rational and 
Risk/Benefits.  
Patients will already be scheduled to receive neoadjuvant chemotherapy treatment as per medical 
oncologist in order to qualify for the study so no change in conventional treatment will result as a 
part of this study.  
Potential psychological risks include: 
There are no known potential psychological risks with this study.  


CONFIDENTIAL 
11NOV2015 
Page 15 of 33 
 
 
Potential social risks include: 
There is a possible social risk of embarrassment or reputational standing while responding to 
questionnaires or interviews. This risk will be minimized by using trained interviewers and 
maintaining all study related records in locked cabinets or secure computer files. 
 
ii 
Benefits 
The benefits that the subject may get from being in this study are potentially improved quality of 
life with naturopathic interventions as coenzyme Q10 has been shown to help with fatigue. 
Melatonin has also been shown to improve quality of life for patients undergoing chemotherapy 
with reduced nausea. In addition, coenzyme Q10, reishi, and melatonin have been shown to affect 
inflammatory and immune modulating cytokines that may have a benefit with tumor response and 
quality of life with chemotherapy treatment.  
 
C1.g 
Early Withdrawal of Subjects  
Subjects may be withdrawn for the following reasons: 
i. 
Inability to comply with naturopathic treatment interventions 
ii. Inability to continue with conventional treatment 
iii. Side effects from naturopathic treatment interventions 
iv. A change in chemotherapy treatment by medical oncologist due to progression of 
disease or intolerable side effects 
v. Subject Safety 
vi. Non-compliance with study visit schedule or study regimen 
 
C1.h 
When and How to Withdraw Subjects 
If patients are withdrawn from study, data will be collected as to reason for the withdrawal. The PI 
will evaluate withdrawal and oversee withdrawal of all such subjects.  
There are no risks involved with stopping naturopathic interventions at any point in the study.  
C1.i 
Data Collection and Follow-up for Withdrawn Subjects  
Data will be collected on reasons for withdrawal and included in the final analysis of the study. 
Study Drug  
The study regimen will consist of three common Naturopathic medicine treatments – Co-Enzyme 
Q10, Melatonin and Reishi.  
Additionally, blood will be collected for analysis of circulating tumor cells using a new assay system 
called ClearID (Cynvenio Biosystems, Inc.). 


CONFIDENTIAL 
11NOV2015 
Page 16 of 33 
 
C1.j 
Description  
Melatonin, N-acetyl-5-methoxytryptamine, is synthesized by the pineal gland in response to the 
dark/light cycle and has been known to act as a synchronizer of the biological clock. Melatonin has 
a variety of therapeutic effects, such as immunomodulatory actions, anti-inflammatory effects, and 
antioxidant actions. Furthermore, melatonin is reported to have an anticancer function including 
suppression of the metabolism of tumor cells and induction of tumor suppressor genes in cancer 
cells, including breast cancer cells.  
Coenzyme Q-10 is a fat soluble, vitamin-like compound present in virtually all cells and in especially 
high concentrations in the heart, liver, kidney, and pancreas. The majority of intracellular CoQ10 is 
found in the mitochondria. Its primary functions include activity as an antioxidant, a membrane 
stabilizer, and as a cofactor in many metabolic pathways, particularly in the production of 
adenosine triphosphate (ATP) in oxidative respiration.  
Reishi is an edible mushroom that is used widely in Asia. It is used as both a food and medicinal 
agent.  Reishi has been shown to effect the proliferation and maturation of immune cells, increase 
gene expression and enhance NK cell activity.   
Pharmacodnamics/Kinetics 
 
C1.k 
Treatment Regimen  
The treatment regimen will include standard neoadjuvant conventional treatment for breast 
cancer.  Chemotherapies that may be used in combination include doxorubicin, cyclophosphamide, 
gemcitabine, carboplatin, docetaxel and paclitaxel. Trastuzumab and or pertuzumab may also be 
used as recommended by the medical oncologist.  An NMS regimen will be added to this, to include 
the following: Co-Enzyme Q10 at a dose of 100 mg capsule twice daily with food; Melatonin at a 
dose of 20 mg capsule once nightly at bedtime; Reishi at a dose of 1000 mg (in 2 capsules) three 
times daily for a total of 3g daily.  The patients in one group will start the NMS interventions with 
cycle 1 and will take daily for approximately 8 - 12 weeks or through 4 treatment cycles.  The 
patients in the second group will start the NMS interventions at the start of cycle 3 and will take 
daily for approximately 4 - 6 weeks or through 3 and 4 treatment cycles. 
C1.l 
Method for Assigning Subjects to Treatment Groups  
Eligible patients who sign the informed consent will be randomized by a standard randomization 
table method to either the immediate and continuous naturopathic treatment group, or the delayed 
start with naturopathic treatment.  
 
C1.m Preparation and Administration of Study Drug  
Preparation of the study drugs will be by the manufacturer, Vital Nutrients for coenzyme Q10, 
melatonin and Reishi. All study drugs will be prepared according to the strict quality standards set 
forth by Vital Nutrients and the CTCA Dietary Supplement Formulary Committee to ensure 
authenticity, accurate dosing and lack of contamination. Patients will self-administer the study 
drugs. The study drug will be provided free of charge to the patients.  


CONFIDENTIAL 
11NOV2015 
Page 17 of 33 
 
C1.n 
Subject Compliance Monitoring  
Compliance will be monitored by a Patient Supplement Study Schedule to be filled out daily by the 
patient and returned at each follow-up visit. Therefore compliance will be monitored by patient’s 
self-reported diary. Patients will be given appropriate doses of supplements in unopened bottles at 
the start of the study and will be be given refills as needed throughout the study at return visits.  
Patients are not required to return unused drug or containers.  
C1.o 
Prior and Concomitant Therapy  
Concomitant therapy will be conventional neoadjuvant treatment for breast cancer.  
C1.p 
Packaging/Labeling 
Bottles of the study drugs will be packaged and labeled by the manufacturers, CNCA and JHS to 
include the ingredients of the study drugs and the dosing.  
C1.q 
Blinding of Study Drug  
The study drugs will not be blinded for this randomized, 2-arm, open label exploratory study.  
 
D Study Procedures  
 
Screening for Eligibility 
We will be reviewing patient’s medical records prior to consenting patients to determine study 
eligibility. No patient information will be recorded prior to the informed consent process.   
 
D1.a 
Visit 1 
The study will be explained to prospective participants on or the day prior to the Visit 1. The 
consent discussion and signing of the consent form will occur prior to any study related tests or 
procedures. The first questionnaires may be administered prior to Visit 1, as part of the standard of 
care for treatment at Midwestern Regional Medical Center.  This baseline questionnaire will be used 
as part of the study and will not be re-administered after the consent forms.  
On visit 1, which is day 1 of cycle 1 of neoadjuvant chemotherapy or just prior to this visit as 
standard of care at Midwestern Regional Medical Center, the MDASI questionnaire will be 
administered to both groups. Labs will be drawn for both groups including a complete blood count 
and chemistry panel. Tumor markers (including CA 15-3, CA 19-9, CA 27.29, CEA and CTCs) will be 
recorded, if available. In addition, blood for analysis of inflammatory markers (CRP and ESR), NK 
assay and cytokine analysis will be drawn as described above.  
The NMS intervention will be started in the immediate and continuous group. No NMS treatment 
will be given to the NMS delayed group.  
In addition blood samples will be drawn from ten participants for ClearID detection of circulating 
tumor cells. Blood will be collected from ten participants before the start of neoadjuvant therapy 
cycles 1 and 3 for testing. 


CONFIDENTIAL 
11NOV2015 
Page 18 of 33 
 
 
D1.b 
Visit 2 
On visit 2, which is day 1 of cycle 2 of neoadjuvant chemotherapy and is approximately 2 - 3 weeks 
after cycle 1 was given, the MDASI questionnaire will be administered to both groups. Blood 
samples for usual care and study specific laboratory analysis will be drawn for both groups as 
described above.  
The NMS intervention will be evaluated and continued in the immediate and continuous group. No 
NMS treatment will be given to the NMS delay group.  
D1.c 
Visit 3 
On visit 3, which is day 1 of cycle 3 of neoadjuvant chemotherapy and is approximately 2 - 3 weeks 
after cycle 2 was given, the MDASI questionnaire will be administered to both groups. Blood 
samples for usual care and study specific analysis will be drawn for both groups as described above.  
The NMS intervention will be evaluated and continued in the immediate and continuous group. The 
NMS delay group will begin NMS treatment.  
In addition blood samples will be drawn from ten participants for ClearID detection of circulating 
tumor cells. Blood will be collected from the same ten participants that had samples taken prior to 
the start of neoadjuvant therapy cycle 1.  
D1.d 
Visit 4 
On visit 4, which is the start of cycle 4 of neoadjuvant chemotherapy and is approximately 2 - 3 
weeks after cycle 3 was given, the MDASI questionnaire will be administered to both groups. Blood 
samples for usual care and study specific analysis will be drawn for both groups as described above.  
 The NMS intervention will be evaluated and continued in the immediate and continuous group. The 
NMS delay group will be continued on NMS treatment.  
D1.e 
Visit 5 (End of Study Visit) 
On visit 5 approximately 2 - 3 weeks after cycle 4 was given, the End of Study blood samples will be 
collected for usual care and study specific analysis, The MDASI questionnaire will be administered 
to both groups. 
The patients will be scheduled for surgery or continue on to second neoadjuvant chemotherapy 
according to the judgment of the attending medical oncologist. Naturopathic interventions on study 
will be complete and analyses will be conducted.  
 
Safety and Adverse Events  
 
D1.f 
Safety and Compliance Monitoring 
The lead study investigator and sub-investigators responsible for patient treatment will monitor 
the safety and compliance of all study subjects at MRMC utilizing the Oncore ERM study 
management system. 


CONFIDENTIAL 
11NOV2015 
Page 19 of 33 
 
D1.g 
Medical Monitoring  
Medical Monitoring will consist of regular monitoring by medical oncologist in addition to 
monitoring by naturopathic oncology providers at each treatment visit for compliance and 
evaluation of NMS treatment side effects. At every visit vital signs will be taken and recorded.  This 
includes temperature, blood pressure, heart rate and respiration rate.  In addition, at the patient’s 
initial visit, height and weight will be recorded and subsequently weight will be measured for all 
follow-up visits. 
 
D1.h 
Definitions of Adverse Events 
The Common Terminology Criteria for Adverse Events (CTCAE; version 4.03) will be used to 
identify and quantify adverse events experienced by the patients. 
D1.i 
Classification of Events  
Possible side effects were outlined in Dose Rationale and Risks/Benefits sections. Any side effects 
will be described using the CTCAE handbook. 
D1.j 
Reporting Procedures 
Serious Adverse Events and adverse events that meet “severe” criteria must be directly reported 
within 24 hours to the designated IRB.  
 
E Statistical Plan  
 
Sample Size Determination and Power 
This exploratory study will be limited to 20 patients with 10 patients in the neo-CTx with 
immediate and continuous NMS cohort and 10 in the NMS delayed until cycle 3 plus neo-CTx 
cohort. Because this is an exploratory study, it is not expected that adequate statistical power can 
be achieved to detect an effect size of 20% in favor of either NMS group for any of the parameters of 
interest. If a trend in favor of a difference between cohorts is observed, the study can be extended 
to accrue sufficient numbers to detect a 20% difference between the cohorts. 
Comparison between cohorts with respect to tumor response will be judged by calculating the 
percentage of patients in each cohort who demonstrate a clinical and a pathologic response defined 
as Complete Response (CR), Partial Response (PR), or No Response (NR). Differences between the 
cohorts for proportion of patients who exhibit a clinical and pathologic CR, PR, or NR will be 
compared by logistic regression to determine multivariate odds ratios. We will examine the issue of 
response to be certain there is no “safety signal”, but not for the issue of efficacy.  
For immunologic parameters (i.e. leukocyte #s, serum cytokine levels, NK lytic function), and QoL 
parameters (i.e. MDASI QoL elements) descriptive statistics for each parameter at each assessment 
point will be calculated for both cohorts and multiple comparisons for all parameters undertaken 
using the non-parametric Mann Whitney test. Differences between the immediate and delayed NMS 
cohorts for all parameters will be considered significant at P<0.05.  


CONFIDENTIAL 
11NOV2015 
Page 20 of 33 
 
In addition, the effects of treatment on immunologic and QoL in each cohort will be assessed by 
calculating the following parameters for each treatment cycle: 1) baseline level of function; 2) 
maximum deviation (suppression) from baseline (e.g. nadir of leukocyte counts, NK function, QoL 
measures); 3) maximum recovery from nadir; and, 4) time to achieve maximum recovery from 
nadir.  
No statistical power is needed. 
 
Interim Monitoring and Early Stopping 
The addition of NMS to neo-CTx is practiced as a standard of care at CTCA. Neo-CTx alone is the 
standard of care for many patients with breast cancer at most other cancer treatment centers; 
unanticipated and/or intolerable toxicity is not expected in either cohort. Thus, except for 
difficulties in patient accrual, we do not anticipate a need for early study termination. 
 
This is an open label, randomized trial with quantitative metrics chosen as the outcome measures. 
Data will be monitored continuously by the investigators and subjected to interim analysis by the 
consultant statistician at 5 patients/cohort increments throughout the duration of the study. 
Patients are considered off study at the time of mastectomy and/or need for a different 
chemotherapy treatment regimen.  
 
F 
Data Handling and Record Keeping  
 
Confidentiality and Security 
Data pertaining to hematologic parameters and MDASI symptom elements will be abstracted from 
the electronic medical record of CTCA Midwestern by clinical data managers at Midwestern. In 
addition, NK function (expressed as lytic units), inflammatory markers, and cytokine levels 
(expressed as pg/mL serum) will be entered on the data collection forms following determination 
of activity in these assays at Midwestern. All Data collection forms will be stored in the protocol 
office within a locked cabinet in a locked research office. 
Study sites will observe Health Insurance Portability and Accountability Act (HIPAA) Privacy and 
Security Rule standards. 
Training  
All research team members will show evidence of completion of the CITI (Collaborative 
Institutional Training Initiative) accreditation program for human subjects research. 
Source Documents 
Source documents for the clinical parameters are in the electronic medical record of CTCA 
hospitals. The laboratory results for NK function and serum cytokine levels will be obtained in the 
translational research laboratory of Midwestern Regional Medical Center of CTCA, and entered onto 


CONFIDENTIAL 
11NOV2015 
Page 21 of 33 
 
the study data collection forms which are stored in the clinical research office of Midwestern 
Regional Medical Center.  
Records Retention 
Paper study records will be maintained for seven years from the end date of the study. At the end of 
this time period, study records will be shredded.  
Performance Monitoring  
The Principal Investigator in conjunction with the sub-investigators will be responsible for the 
conduct of all study procedures. The manager of MRMC’s Clinical Protocol Office will be responsible 
for overseeing data collection and entry into the case report forms for the study, and for reporting 
AEs to the designated IRB. Statistical analyses and reporting of the results will be the responsibility 
of the investigators in conjunction with the VP Clinical Research of CTCA. 
 
G Study Monitoring, Auditing, and Inspecting  
 
Study Monitoring Plan  
Principal Investigators at each site will monitor ongoing study performance. Auditing study 
performance will be conducted at least quarterly by the VPs of Integrative Medicine and Clinical 
Research of CTCA. 
 
Organization and Participating Center 
Principal Investigators from Midwestern CTCA hospital are listed on the title page of the protocol. 
They will be responsible for the conduct of the study at each site. The clinical protocol office at 
Midwestern CTCA hospital will support the PI and Sub-PIs in data collection, record keeping, and 
AE reporting to the respective IRBs. 
Funding Source and Conflicts of Interest 
This study is funded by Cancer Treatment Centers of America.  
Committees 
An executive committee consisting of the site Principal Investigators; the VP of Integrative 
Medicine; the VP of Clinical Research lead for integrative medicine at CTCA will be formed to 
oversee all aspects of the study. All issues pertaining to the study will be discussed and adjudicated 
by the executive committee. 
Subject Stipends or Payments  
Subjects who participate in the study will not receive a stipend. However, patients will be provided 
with the designated supplements for the duration of the period in which neoadjuvant 
chemotherapy is administered. 
Study Timetable 
The study will last for approximately 2 years. 
 


CONFIDENTIAL 
11NOV2015 
Page 22 of 33 
 
 
 
 


CONFIDENTIAL 
11NOV2015 
Page 23 of 33 
 
ATTACHMENT L1 
Informed Consent Document 
 
 
RESEARCH SUBJECT INFORMED CONSENT AND AUTHORIZATION 
FORM 
 
TITLE: 
A COMPARISION STUDY TO ASSESS THE VALUE OF THE ADDITION OF  
 
NATUROPATHIC MEDICINE IMMEDIATELY AND CONTINUOUSLY OR 
DELAYED, IN COMBINATION WITH NEO-ADJUVANT CHEMOTHERAPY 
FOR BREAST CANCER. 
 
PROTOCOL NO.: 
MZ2014018_Neo-Adjuvant Study 
 
WIRB® Protocol 20141800 
 
MZ2014018 
 
SPONSOR: 
Midwestern Regional Medical Center, Inc. 
 
INVESTIGATOR: 
Christina M. Shannon, ND, FABNO 
 
 
2520 Elisha Ave 
  
Zion, IL, 60099 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Christina M. Shannon, ND, FABNO 
 
(847) 872-6364  
 
(847) 479-5202 pager (24 Hours) 
 
Introduction 
This is a clinical trial, a type of research study. Your Naturopathic Oncology Provider will explain the 
clinical trial to you. Clinical trials include only people who choose to take part. This Informed Consent 
document describes the clinical research study that you are being asked to participate in and what the 
study will involve. Please take your time to make your decision about taking part in this clinical trial. 
Discuss your decision with your friends and family. You can also discuss it with your health care team. If 
you have any questions, you can ask your Naturopathic Oncology Provider for more information.  
Why is This Study Being Performed?  
The purpose of this study is to observe whether treatment with naturopathic medicine supplements, 
while you are receiving chemotherapy for breast cancer, has an effect on your immune system and your 
quality of life.  We will also test whether these supplements effect the gene expression by your tumor, 
and your response to chemotherapy. In addition if timing of your lab draw allows for you to be among 
the ten participants to test the effectiveness of a new process, called ClearID then samples of your blood 
will be used to test for circulating tumor cells.  


CONFIDENTIAL 
11NOV2015 
Page 24 of 33 
 
How Many People Will Take Part in the Study? 
 We hope to enroll 20 participants in this research study. 
What Will Happen if I Take Part in This Research Study?  
PROCEDURES 
After your Naturopathic Oncology Provider has answered all of your questions about the study and you 
have given written consent by signing this form, a physical examination will be conducted if it has not 
already been done by your medical oncologist as part of the normal care for treatment of your breast 
cancer. Laboratory tests will be done to be sure you are able to begin treatment and therefore enter the 
study. Some of the tests are the same as those you have had in the past to diagnose and treat your 
cancer. Some of these same tests will also be performed during your treatment in order to follow your 
progress. Additional laboratory tests will be performed as part of the study.  
Your participation in this study is divided into different visits: 
1. A Screening Visit (which may be the same day as your treatment visit) 
2. Treatment Visits 
3. A Post-Treatment Visit 
Different tests are run during each of these different visits as described below. 
Screening Visit  
This Screening Visit is necessary to determine if you are eligible to participate in the study. The 
Screening Visit will take place before you receive any study related treatment.  
During the Screening Visit:  
• 
The Naturopathic Oncology Provider or nurse or Medical Oncologist will ask you about your 
medical history and obtain a list of all medications that you are currently taking and the previous 
treatments for your cancer you have received.  
• 
A full physical examination will be performed and your height, weight and vital signs (heart rate, 
blood pressure, breathing rate and body temperature) will be recorded.  
• 
Blood will be drawn for routine lab tests 
• 
Your Naturopathic Oncology Provider will ask you to sign this consent form if you wish to 
participate in this study.  You need to sign this form before any study specific tests are 
performed. 
All of these tests may be completed over several clinic visits. If a recent test result is already available in 
your medical records, we may not need to do that test again. 


CONFIDENTIAL 
11NOV2015 
Page 25 of 33 
 
Treatment Visits  
Once your eligibility is confirmed after screening, you will be able to participate in the study. 
Treatment visits are necessary to receive the naturopathic medicine support.  The supplements you will 
be given are coenzyme Q10, melatonin, and reishi.  Co-Enzyme Q10 at a dose of 100 mg capsule twice 
daily with food; Melatonin at a dose of a 20 mg capsule once nightly at bedtime; and reishi at a dose of 
1000 mg 3 times daily for a total dose of 3,000 mg or 3 g.  You will be assigned to either the immediate 
treatment group or the delayed treatment group.  If you are in the immediate and continuous treatment 
group, you will start taking your naturopathic supplements with cycle 1 of your chemotherapy 
treatment and continue for approximately 8 - 12 weeks.  If you are in the delayed naturopathic medicine 
treatment group, you will start your supplement treatment at the beginning of your 3rd cycle of 
chemotherapy treatment and continue for approximately 4 - 6 weeks. All participants in the study will 
be given the Systems Inventory Tool (MDASI) at each treatment visit. The MDASI is a questionnaire that 
will take approximately 10 minutes to fill out electronically or on a paper version.  This questionnaire 
helps to measure quality of life factors. 
On the day you begin each cycle of chemotherapy treatment, we will perform the tests listed below.  
Please note: these tests will be completed over several hours during each Treatment Visit: 
• 
The doctor or nurse will ask you to tell them of any side effects that you may have felt since your 
last visit and to give them a list of all medications that you are currently taking.  
• 
A physical exam will be performed and your body weight and vital signs (heart rate, blood 
pressure, breathing rate and body temperature) will be recorded.  
• 
The naturopathic oncology provider will ask you to tell them of any side effects that you may 
have felt since your last visit and to give them a list of all medications that you are currently 
taking. 
• 
Your doctors will review your symptoms and ask you about your ability to perform your normal 
activities. 
• 
Blood will be drawn for routine lab tests.  
• 
Blood will be drawn for study specific lab tests (approximately 16 mL). If you are among the ten 
participants having labs drawn for ClearID CTCs, two additional tubes of blood (about 20 mL) will 
be collected before you start cycle 1 and 3 of your usual chemotherapy treatment.  
• 
Compliance will be monitored by pill count and liquid measure according to your self-reported 
supplement log that you will fill out between visits 
 
• 
You will be asked to fill out the MDASI Survey describing your symptoms.  
 
End of Treatment Visit  


CONFIDENTIAL 
11NOV2015 
Page 26 of 33 
 
• 
A physical exam will be performed and your body weight and vital signs (heart rate, blood 
pressure, breathing rate and body temperature) will be recorded.  
• 
A review of your symptoms and your ability to perform your normal activities will be performed. 
• 
Blood will be drawn for routine lab tests and for study specific tests.  
• 
The doctor or nurse and naturopathic oncology provider will ask you to tell them of any side 
effects that you may have felt since your last visit and to give them a list of all medications that 
you are currently taking.  
These procedures will happen after receiving cycle 4 of your chemotherapy.  
How Long Will I be in The Study? 
This research study is expected to take approximately 15 weeks of active participation. 
What side effects or risks can I expect from being in the study?  
You may have side effects from the supplements used in this study, and they will vary from person to 
person. Everyone taking part in the study will be watched carefully for any side effects. However, your 
doctor(s) and the researchers do not know all the side effects that may happen as a result of study 
participation; there may be unknown side effects that could occur. Side effects with these supplements 
have historically been very mild if at all.  
The following are side effects that have been seen with melatonin, coenzyme Q10 and reishi. 
Melatonin: 
• 
No known toxicity or serious side effects reported; however, long-term human studies have 
not been conducted. Some uncommon side effects that have been reported in studies or case 
reports include drowsiness, alterations in sleep patterns, altered mental status, disorientation, 
tachycardia, flushing, pruritus, abdominal cramps and headache. 
• 
Excessive dosages may cause morning sedation or drowsiness.  
 
Coenzyme Q10: 
• 
Generally well tolerated. In clinical studies, there have been no reports of significant adverse 
effects. Coenzyme Q-10 can cause gastrointestinal side effects such as nausea, vomiting, 
diarrhea, appetite suppression, heartburn, and epigastric discomfort (stomach ache) in less 
than 1% of patients. Some of these adverse effects can be minimized if total daily doses 
exceeding 100 mg are divided and administered two to three times per day  
• 
Theoretically, may increase bleeding risk and may decrease response to warfarin (a blood 
thinning drug). However, a small study (randomized control trial) showed no effect on blood 
clotting activity (INR) with concurrent use of coenzyme Q10.  
• 
Potential adverse reactions include abdominal discomfort, headache, nausea and vomiting.  
 
Reishi (G. lucidum) 
• 
Side effects are uncommon however reported side effects include allergies, dryness of the 
mouth, throat and nasal area, itching, nausea, epistaxis. Bloody stools have been reported 
with use of over 3-6 months. 


CONFIDENTIAL 
11NOV2015 
Page 27 of 33 
 
• 
In patients with type 2 diabetes taking G. lucidum appeared to affect HA1C but not fasting 
glucose.  Therefore it may be possible to have additive effects with botanicals or herbs that 
can have hypoglycemic potential.   
• 
Clinical evidence also shows that G. lucidum may reduce blood pressure in some but not all 
patients with hypertension therefore additive affects might be possible for patients on anti-
hypertensive medications or botanicals.   
• 
A dose of higher than 3g daily may decrease platelet aggregation and therefore additive 
effects may occur with patients on medications or botanicals that have antiplatelet actions.   
 
For more information about risks and side effects, ask your Naturopathic Oncology Providers. You 
should talk to your Naturopathic Oncology Providers about any side effects that you have while taking 
part in the study. The Naturopathic Oncology Providers will take steps to treat any side effects if they 
appear. If the naturopathic medicine support causes side effects they will be evaluated and discussed.  
As with any drug, unknown risks and side effects are also possible with supplements. You could 
experience a side effect that is more severe than those mentioned above or a side effect that has not 
been anticipated with this supplement regime. There is a chance that you could be allergic to the 
supplements or to one of the chemicals used in its formulation. There is also a chance that other 
medications you may be taking could interact with this treatment regime. For your safety, you must tell 
the Naturopathic Oncology Provider or nurse about all medications you are taking before you start the 
study. Also, please tell the Naturopathic Oncology Provider or nurse before starting any non-study 
medications while you are on the study, including any over the counter medicines such as cough and 
cold remedies. 
The risks of having blood drawn include pain, bruising, and rarely, infection. Blood will be drawn by 
experienced technicians and whenever possible it will be obtained at a time when blood is being 
obtained for other tests your Medical Oncologist has ordered. 
There is not enough medical information to know what the risks might be to you if you become 
pregnant, your breast fed infant or your unborn child. You cannot take part in this study if you are 
pregnant or lactating (breast feeding). Therefore, all women who are sexually active and can become 
pregnant must use birth control measures while in this study. Breast feeding mothers must stop breast 
feeding to take part in this study.  
The following birth control measures are acceptable: condoms or a diaphragm. Women who could 
possibly become pregnant must have a pregnancy test before taking part in this study. For the 
pregnancy test, a blood sample will be taken within 7 days before you receive your first dose of 
chemotherapy. You will be told the results of the pregnancy test. If the pregnancy test is positive, you 
will not be able to take part in the study. 
Are there benefits to taking part in this research study? 
If you agree to take part in this study, there may or may not be direct medical benefit to you. Your 
cancer may respond well to treatment or it may get worse. The information obtained from this study 


CONFIDENTIAL 
11NOV2015 
Page 28 of 33 
 
may help doctors better understand cancers and this may eventually be helpful to future cancer 
patients.  
What other choices do I have if I don’t take part in this research study? 
You do not have to be in this study to receive treatment for your condition. You can continue with 
conventional treatment with your Medical Oncologist and choose to not receive any naturopathic 
support, or to receive it without being part of the study. You should talk to the Naturopathic Oncology 
Provider and your Medical Oncologist about each of your choices before you decide if you will take part 
in this study.  
Can I stop being in the study? 
Study participation is voluntary. You can decide not to be in the study or you can decide to stop at any 
time. Tell the Naturopathic Oncology Provider if you are thinking about stopping or decide to stop. He or 
she will tell you how to stop safely.  
It is important to tell the Naturopathic Oncology Provider if you are thinking about stopping so any risks 
from stopping the naturopathic support can be evaluated. Another reason to tell your Naturopathic 
Oncology Provider that you are thinking about stopping is to discuss what follow up care and testing 
could be most helpful for you.  
Leaving the study will not affect your medical care. You can still get your medical care from our 
institution.  
Why Might I Be Taken Out of the Study Early? 
The Naturopathic Oncology Provider and/or study sponsor may decide to take you off this study without 
your consent if: 
• 
You fail to follow the Naturopathic Oncology Provider’s instructions. 
• 
You experience a serious adverse event (harmful side effect) that may require evaluation. 
• 
Your disease does not respond to your prescribed chemotherapy and your treatment needs to 
be changed by your Medical Oncologist. 
• 
You experience side effects that are considered to outweigh benefits of your participation. 
• 
You become pregnant. 
• 
The research physician feels it is in the best interest of your health and welfare. 
You may stop participating at any time. However, if you decide to stop participating in the study, we 
encourage you to talk to the Naturopathic Oncology Provider and your Medical Oncologist first.  
In the event that you withdraw from the study, we will ask you to continue to be followed and clinical 
data will continue to be collected from your medical records.  
Will I need to pay for the tests and procedures? 


CONFIDENTIAL 
11NOV2015 
Page 29 of 33 
 
Because all of the drugs used in this study are part of regular treatment for your cancer at Midwestern 
Regional Medical Center, Inc., you or your insurance company/third party payer will be billed for all 
routine procedures and drugs associated with this study including the cost of treating injuries resulting 
from such routine procedures. Routine procedures and drugs are those that you would likely receive 
whether or not you are in this study. You will be responsible for any deductibles or co-payments that are 
associated with your insurance coverage. Examples of procedures and drugs that may be billed to 
you/your insurance company include routine blood tests to be certain you can receive your 
chemotherapy, and the drugs used to treat your cancer. However, Midwestern Regional Medical Center, 
Inc. will pay for any procedures or tests being done as part of this study that are not part of your routine 
care.  All study supplements will be covered by Midwestern Regional Medical Center.  
Will I be paid for taking part in this study? 
No, you will not be paid for participation in this study. 
What happens if I am injured because I took part in this research study? 
If you get injured or sick as a direct result of being in this study, call the study doctor immediately. If you 
require immediate medical care to treat an illness or injury that is determined by the Investigator to be 
caused directly by participation in this study, and you were following the directions given to you as a 
study participant, then Midwestern Regional Medical Center agrees to pay the cost to cover this 
immediate medical care.  You understand that Midwestern Regional Medical Center  has no plans to 
cover the costs of further treatment beyond immediate and necessary care, nor do they have plans to 
give you money as compensation for such injury.  There are no plans to pay for the cost of long-term 
care for illness or injury. If you are injured, the study doctor will discuss the available treatment options 
with you. 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose either to take part or not to take part in the 
study. If you decide to take part in this study, you may leave the study at any time. No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits. 
Leaving the study will not affect your medical care. You can still get your medical care from our 
institution.  
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study in a timely manner.  
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH PURPOSES 
What information may be used and given to others? 
If you choose to be in this study, the study doctor will get personal information about you.  This may 
include information that might identify you. Your personal health information (PHI) from your original 
and current medical records and all data resulting from your participation in this research will be 


CONFIDENTIAL 
11NOV2015 
Page 30 of 33 
 
collected during the course of this study. This may include (but not be limited to): results of tests or 
examinations, medical procedures, tissue or blood sampling and medication records. 
Your PHI will be used for regulatory purposes, to conduct the study, and to analyze the results of this 
research study.  It may also be used in scientific presentations and publications, but in a way that will 
not identify you by name. Your PHI will be kept confidential, and unless required by law, will not be 
made publically available. 
The study doctor will get your personal and medical information.  For example:  
• 
Past and present medical records 
• 
Research records 
• 
Records about phone calls made as part of this research 
• 
Records about your study visits. 
 
Who may use and give out information about you? 
The following parties are authorized to use and/or disclose your PHI in connection with this study: 
• 
The Principal Investigator, Christina M. Shannon, ND, FABNO 
• 
Midwestern Regional Medical Center research personnel 
• 
Western Institutional Review Board body that ensures the protection of human subjects 
enrolled in research studies at Midwestern Regional Medical Center 
 
Who might get this information? 
The parties listed in the preceding paragraph may share this information with: 
• 
The Office for Human Research Protection in the U.S. Department of Health and Human Services 
(OHRP) 
• 
The Food and Drug Administration (FDA) 
• 
Sponsor representatives  
• 
Western Institutional Review Board 
• 
Midwestern Regional Medical Center  internal monitoring representative(s) 
 
These recipients may disclose your PHI to other parties, and are not required by law to protect your 
privacy. 
 
If the results of this study are made public, information that identifies you will not be used. 
What if I decide not to give permission to use and give out my health information? 
If you decide not to give permission to use and give out my health information, you will not be able to 
participate in this research study (or receive any research-related treatment). Signing this form is not a 
condition for receiving any medical care outside of the study. 
 
May I review or copy my information? 
To maintain the integrity of this research study, you may not have access to any health information 
collected and developed as part of this study until the study is completed. At that time, you would have 


CONFIDENTIAL 
11NOV2015 
Page 31 of 33 
 
access to such health information if it was used to make a medical decision about you (e.g., if included in 
your medical record). 
 
May I withdraw or revoke (cancel) my permission? 
You are free to withdraw your authorization of use and disclosure of PHI (and to discontinue 
participation in this study) at any time. If you withdraw your permission, your PHI will no longer be used 
or disclosed in the study, except to the extent allowed by law (e.g., necessary to maintain the integrity 
of the research). If you wish to withdraw authorization for the research use and disclosure of PHI in this 
study, you must write to: 
 
Christina M. Shannon, ND, FABNO 
2520 Elisha Ave. 
Zion, IL 60099 
 
When will this authorization end? 
This authorization does not expire. 
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your permission. 
What do I do if I have questions about the study? 
If you have any questions concerning your participation in this study, or if you experience a research 
related injury or become ill as a result of being in this study, contact the Naturopathic Oncology Provider 
Christina M Shannon, ND, FABNO at: (847) 872-6364 M-F 8:00am-5:30pm CST. 
If you have questions about your rights as a research subject, or if you have questions, concerns, input 
or complaints about the research, you may contact: 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, Washington  98374-2115 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail:  Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
WIRB will not be able to answer some study-specific questions, such as questions about appointment 
times. However, you may contact WIRB if the research staff cannot be reached or if you wish to talk to 
someone other than the research staff. Do not sign this consent form unless you have had a chance to 
ask questions and have received satisfactory answers to all of your questions. You will be given a copy of 
this signed and dated informed consent to keep. 
 


CONFIDENTIAL 
11NOV2015 
Page 32 of 33 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 


Revised 11 November 2015 
Page 33 of 33 
Neoadjuvant Chemotherapy Study 
Consent 
I have read this consent form (or it has been read to me) and understand it. All my questions about the 
study and my part in it have been answered to my satisfaction. I freely consent to be in this research 
study. 
 
I authorize the use and disclosure of my health information to the parties listed in the authorization 
section of this consent for the purposes described above. 
 
By signing this consent form, I have not given up any of my legal rights.  
 
I will receive a copy of this fully signed and dated consent form for my files. 
 
 
Printed Name of Patient 
 
 
 
Signature of Patient 
Date 
I, the undersigned, have fully explained this informed consent to the patient 
named above. 
 
 
Printed Name of Person Conducting Informed Consent Discussion 
 
 
 
Signature of Person Conducting Informed Consent Discussion 
Date