Topical Cannabidiol (CBD) for the Treatment of Chemotherapy-Induced Peripheral Neuropathy: A Randomized Placebo-Controlled Pilot Trial
Phase: PHASE2
Conditions: Chemotherapy-Induced Peripheral Neuropathy, Malignant Solid Neoplasm
Sponsor: Mayo Clinic

 
 
 
 
 
MC211003 / 21-011969 
 
 
Topical Cannabidiol (CBD) for the Treatment of Chemotherapy-
induced Peripheral Neuropathy: A Randomized Placebo-
controlled Pilot Trial 
 
 
NCT05388058 
 
 
Document Date: 05/10/2023 

MC211003 
Protocol Version Date: 21Apr2023 
 
 
Mayo Clinic Cancer Center 
Topical cannabidiol (CBD) for the treatment of chemotherapy-induced peripheral neuropathy: a 
randomized placebo-controlled pilot trial 
     Principal Investigator: 
  
 
 
Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
Statisticians: 
 
   
  
 
FDA IND #: 157457 
 
Trial Supported by: The Minnesota Cancer Clinical Trials Network (MNCCTN) 
Funding: The Breast Cancer Research Foundation (BCRF) 
 
Drug Availability:  
Commercial Agents: Nightingale Remedies, Portland OR  
 
Participating sites: Sutter Medical Center Sacramento, Mayo Clinic Rochester, MNCCTN Partners 
 
Document History 
(Effective Date) 
Activation 
26May2022 
MCCC Amendment 1 
26May2022 
MCCC Amendment 2 
26Jul2022 
MCCC Amendment 3 
17Apr2023 
MCCC Amendment 4 
10May2023 
 
 
 
 
 
 

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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
Serious Adverse Event Reporting 
 
  
*No waivers of eligibility allowed 
 
 

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Table of Contents 
Topical cannabidiol (CBD) for the treatment of chemotherapy-induced peripheral neuropathy: a 
randomized placebo-controlled pilot trial ..................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 8 
3.0 
Registration Patient Eligibility ...................................................................................................... 9 
4.0  
Test Schedule .............................................................................................................................. 11 
5.0 
Stratification Factors: .................................................................................................................. 12 
6.0 
Registration/Randomization Procedures ..................................................................................... 12 
7.0 
Protocol Treatment ...................................................................................................................... 14 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 15 
9.0 
Ancillary Treatment/Supportive Care: ........................................................................................ 15 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 15 
11.0     Treatment Evaluation/Measurement of Effect ............................................................................ 24 
12.0 
Descriptive Factors: Not applicable. ........................................................................................... 24 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 24 
14.0 
Body Fluid Biospecimens – None. ............................................................................................. 24 
15.0 
Drug Information ........................................................................................................................ 24 
16.0 
Statistical Considerations and Methodology ............................................................................... 26 
17.0  
Records and Data Collection Procedures .................................................................................... 29 
18.0  
Budget ......................................................................................................................................... 29 
19.0 
References ................................................................................................................................... 30 
Appendix I: EORTC QLQ-CIPN20 Instrument ......................................................................................... 32 
Appendix II: Patient Global Impression of Change .................................................................................... 34 
Appendix III: Chemotherapy Induced Peripheral Neuropathy Assessment Tool                        
(Quantitative Items) .................................................................................................................................... 35 
Appendix IV: Peripheral Neuropathy Question .......................................................................................... 36 
Appendix Va: Symptom Experience Diary –Baseline ................................................................................ 37 
Appendix Vb: Symptom Experience Diary ––During Treatment ............................................................... 38 
Appendix VII: PRODUCT AND PLACEBO INFORMATION ................................................................ 40 
Appendix VIII ECOG Performance Status ................................................................................................. 43 
Appendix IX: Patient Suicidal Thoughts Assessment and Evaluation for Skin Toxicity ........................... 44 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle length = 14 days 
 
 
Registration/ 
Randomization 
End of Study 
Placebo Cream: Cycle1 1  
followed by 
CBD Cream: Cycle1 2 
CBD Cream: Cycle1 1  
followed by 
Placebo Cream: Cycle1 2 

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1.0 
Background  
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose and age-dependent side-effect 
associated with six main antitumor agent drug classes: platinum-based drugs, (e.g., oxaliplatin), taxanes 
(e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vincristine), epothilones (e.g., ixabepilone), the 
proteasome inhibitors (e.g., bortezomide) and immunomodulatory drugs (e.g., thalidomide)[1]. In a 
review of over 30 clinical studies, CIPN prevalence was reported to be approximately 68% when 
measured in the first month after finishing a variety of chemotherapy agents, most of which had been 
associated with CIPN; it was 60% at three months and 30% at 6 months or more [2]. 
CIPN remains a challenge to treat, as most agents used in practice, such as tricyclic 
antidepressants, anticonvulsants (gabapentin and pregabalin), or serotonin-norepinephrine reuptake 
inhibitors (SNRIs), primarily duloxetine, provide limited benefit to most patients and can have significant 
side effects[3-5]. 
The mechanism of CIPN broadly includes the production of neuronal toxicity and 
inflammation[6]. The six main classes of antitumor agents, discussed above, cause damage to peripheral 
sensory, motor, and autonomic neurons, through such mechanisms as microtubule disruption, oxidative 
stress and mitochondrial damage, altered ion channel activity, and myelin sheath and DNA damage [7]. In 
addition, the cumulative damage leading to increased activation of the immune system ultimately 
promotes cell damage and death in peripheral neurons, leading to a sensitization to nociceptive 
responses[6]. 
The cannabinoids, delta-nine-tetrahydrocannabinol (THC) and cannabidiol (CBD), derived from 
the plant Cannabis sativa (Cannabis) have shown some efficacy in the treatment of pain [8, 9], including 
neuropathic pain[3, 10]. THC interacts with the endocannabinoid system primarily through the activation 
of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors[11]. CBD does not efficiently interact to 
activate known cannabinoid (CB1 and CB2) receptors [12]. CBD, however, can antagonize the activity of 
CB1 and CB2 receptor agonists [13]. 
THC and additional CB1 and CB2 receptor agonists, have been shown to be effective at reducing 
CIPN in multiple preclinical models [6, 14]. THC and additional cannabinoids, through CB1 and/or CB2 
receptors, have the potential to modulate pain through a variety of mechanisms, including inhibition of 
calcium channel activity, transient receptor potential (TRP) channels, serotonin, GABA and glutamate 
receptor signaling, and modulation of the immune system, leading to anti-inflammatory activity [15-17]. 
Inhaled cannabis has also been reported to be effective for treating HIV-associated neuropathy, possibly 
via CB1 agonism [18]. 
Neuropathic pain may also involve abnormal hyper-excitability in skin afferent nerves. Skin cells 
express CB2 and endothelin receptors, and when activated, they release B-endorphin, which can reduce 
hyperalgesia, that is mediated by pro-inflammatory pathways [19, 20]. 
CBD has been shown to have pleotropic effects that ultimately lead to reduction in oxidative 
stress and inflammation [21]. Increasingly, preclinical evidence demonstrates that CBD has anti-
neuropathic pain effects in multiple rodent models, including models of CIPN [21-25]. Also, there is 
significant overlap with mechanisms controlling pain when CBD and THC are compared. CBD has been 
shown to inhibit pain through modulation of calcium and TRP channels, serotonin receptors, glycine 
receptors, and modulation of the immune system [6], in particular, microglia and macrophage function 
[26], leading to anti-inflammatory activity. 
Similar to CB1 and CB2 receptor agonists, the neuroprotective and anti-inflammatory properties 
of CBD provide a potential mechanism for the protective effects of CBD in neuropathic pain, including 
CIPN [27]. For example, CBD has been shown to directly or indirectly modulate several receptors 
involved in modulating pain signaling, including 5-HT1A [25], and transient receptors TRPV1 and TRPA1 

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[16, 22]. TRPV1 receptors are present in sensory peripheral nerves as well as in keratinocytes and are 
activated by capsaicin, as well as by endogenous cannabinoids [28]. Capsaicin is a TRPV agonist that has 
been extensively studied in pain and appears to have activity in treating neuropathic pain. This agonist 
leads to overstimulation and desensitization of nociceptors and may lead to nerve regeneration and 
restoration [29]. A placebo-controlled, double-blinded, cross-over trial of a capsaicin cream demonstrated 
that it substantially decreased chronic post-surgical scar pain and its benefit persisted after stopping the 
capsaicin [30].  
CBD can also act as a neuroprotective agent as a result of direct antioxidant activity [31]. During 
secondary injury, CBD can reduce intracellular calcium levels and have neuroprotective effects [32]. 
CBD reduces mitochondrial damage during events of cellular stress, thereby diminishing generation of 
inflammatory and oxidative products [33]. CBD also inhibits microglial proliferation and pro-
inflammatory cytokines and increases anti-inflammatory cytokine production in vivo [22, 23, 34]. 
Given that many patients do not have access to systemic Cannabis, and/or want to avoid the 
psychoactive effects of THC, a more local means of providing cannabinoids might be preferable. 
Cannabinoids happen to be lipophilic agents and, thus, can permeate skin [35, 36]. Taking advantage of 
this delivery technique, a small pilot clinical trial evaluated a topical cannabinoid cream, reporting data 
that supported that it improved neuropathic pain [37]. 
In addition to the promising-appearing data noted above, we recently analyzed data from a case 
series of 22 patients with chemotherapy-induced peripheral neuropathy, who reported symptomatic 
benefit from using topical cannabinoid-based creams containing the delta-nine-tetrahydrocannabinol 
(THC) and/or cannabidiol (CBD), derived from Cannabis sativa (manuscript submitted for publication). 
These cases are summarized in the following table. 
 
Table 1. Patients reporting benefit from topical cannabis.  
Pt 
Cancer type 
Chemotherapy 
Location of 
symptoms 
Treatments 
tried/failed 
Cannabis type 
1 
Myeloma 
RVD/transplant 
Feet 
Duloxetine, 
Gabapentin, 
pregabalin, 
acupunture 
CBD  
 
2 
Breast  
AC-T 
Feet 
Gabapentin 
CBD/THC 
1:1  
3 
Pancreatic 
FOLFOXIRI 
Hands/feet 
 
CBD/THC 
1:1  
 
4 
Primary 
peritoneal 
Taxol/carboplatin 
Feet 
 
CBD 
 
5 
Breast 
Capecitabine/eribulin 
Feet 
 
CBD/THC 
6 
Lymphoma 
R-CVAD 
Hands and feet 
 
CBD 
7 
Breast 
AC-T  
Feet 
Gabapentin 
CBD  
 
8 
Breast  
AC-T  
Feet, legs 
 
CBD/THC 
9 
Ovarian 
Paclitaxel/carboplatin 
/bevacizumab 
 
Feet 
 
CBD oil 
10 
Breast  
AC-T 
Feet 
Acupuncture 
CBD 
11 
 
Uterine  
Paclitaxel                        Hands 
 
CBD/THC 
1:1 

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12 
Colorectal 
FOLFOX 
Burning in feet, 
hands 
gabapentin 
CBD/THC 1:1 
13 
Ovarian 
Paclitaxel/carboplatin  
Hands/feet 
gabapentin  
CBD/THC  
1:1 
14 
Pancreas 
FOLFOX 
Feet 
 
CBD oil  
15 
Pancreas 
FOLFOX 
Hands 
 
CBD/THC  
1:1 cream  
16 
Breast 
Paclitaxel/carboplatin 
Feet 
 
CBD/THC 
17 
Ovarian 
Paclitaxel/carboplatin 
Hands and feet 
Gabapentin 
CBD 
18 
Breast  
TC 
Hands 
 
CBD 
19 
Primary 
peritoneal 
cancer 
Paclitaxel/carboplatin 
Feet 
 
CBD oil  
20 
Breast 
AC-T 
Hand and feet 
Duloxetine, 
acupuncture, 
hydrotherapy 
CBD oil 
21 
Pancreatic 
FOLFOXIRI 
Feet 
 
CBD 
22 
Ovarian  
Paclitaxel 
Hands and feet 
 
CBD/THC 
Abbreviations: RVD-lenalidomide/bortezomib/dexamethasone; AC-T: doxorubicin, 
cyclophosphamide/paclitaxel; TC:docetaxel and cyclophosphamide; FOLFOXIRI: 5-
florouracil/leucovorin/oxaliplatin/irinotecan; FOLFOX: 5-florouracil/leucovorin/oxaliplatin 
 
 
As this table indicates, patients in this case series were using either a topical CBD alone or a 
topical combination of CBD/THC. Given that CBD is a negative modulator of CB1, it would seem that 
topical THC, working via a CB1 mechanism, might not be needed for the benefit observed with anti-
nociception.  
 
The data reported above, supporting that topical-based cannabis products decrease CIPN pain in 
humans, call for the conduct of a prospective trial to evaluate a topical cannabis-based product as a 
treatment of established painful CIPN. We have chosen to study a cream with CBD alone, as opposed to a 
product that contains THC. This should simplify the conduct of this trial, given the barriers to conducting 
studies using THC products and varying laws and regulations regarding the use of THC in different states 
in the USA. 
 
 

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2.0 
Goals  
This is a pilot randomized double blinded placebo controlled cross-over trial. This pilot study will 
randomize 40 patients with chemotherapy-induced peripheral neuropathy to receive, for 14 days, 
either 1) a CBD cream or 2) a placebo. Patients initially receiving the placebo will cross over to 
receive the CBD cream, while those receiving the CBD creams will cross over to receive the 
placebo, for 14 days. Patients will apply cream to the affected area (hands and/or feet) twice daily 
(morning and evening). This cross-over will allow all patients to eventually receive the CBD 
cream and will allow us to determine whether any benefit derived from a CBD preparation will 
diminish or persist after the CBD preparation is stopped (that is in the patients who initially 
received the CBD product and then were changed to receive a placebo, while still being blinded 
to what they received).  
 
No washout period is planned with the cross-over because a) no washout is needed in patients 
going from placebo to CBD cream, and b) we want to determine what happens after patients stop 
cannabis cream, i.e., do the effects persist after the patient starts the placebo portion, as was 
prominently seen in a prior trial of ours evaluating capsaicin cream [30].  
2.1 
Primary Objective 
The aims of the proposed project include: 
1. To evaluate whether topical CBD improves chemotherapy-induced peripheral 
neuropathy (CIPN), compared to placebo 
2. To evaluate side effects from topical CBD cream use, compared to placebo 
The data obtained from this trial are designed to provide information to allow for a larger 
phase III, placebo-controlled, randomized, clinical trial. 
Primary endpoint 
The primary endpoint is change in CIPN from baseline to the end of week 2. CIPN will 
be measured by the sensory subscale of the EORTC QLQ-CIPN20 which is composed of 
9 individual items. 
2.2 
Secondary Goals 
 
Secondary endpoints include other measures of neuropathy as measured by the EORTC 
QLQ CIPN20 motor subscale, the EORTC QLQ CIPN20 autonomic scale, and the total 
CTCAE neuropathy scale. Adverse event profiles will also be assessed using symptom 
questionnaires and CTCAE v5.0. 
 

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3.0 
Registration Patient Eligibility 
3.1 
Registration - Inclusion Criteria 
3.11 
Age ≥18 years 
3.12 
English speaking 
3.13 
Cancer diagnosis of any tumor type with chemotherapy-induced neuropathy 
3.14 
At least 4 out of 10 severity of neuropathy pain and/or tingling per appendix IV 
3.15 
Stable for at least 7 days prior to registration on medications for neuropathy, if 
any are being used 
3.16 
ECOG Performance Status (PS) 0, 1 or 2 (Appendix VIII).  
3.17 
Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
NOTE: If a urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  
3.18 
Able to provide written informed consent 
3.19a 
Ability to complete questionnaire(s) by themselves or with assistance. 
3.19b     No evidence of residual cancer 
3.19c 
Required Initial Laboratory Values: Following completion of chemotherapy, 
patients must have had a CBC and serum chemistries, including the following: 
• 
Platelet count > 100,000/mm3 
• 
Absolute neutrophil count (ANC) ≥ 1,000/mm3 
• 
Hemoglobin > 11 g/dL 
• 
Serum transaminase [ALT or AST] ≤ 1.2 x upper limit of normal 
(ULN) 
• 
Alkaline phosphatase≤ 1.2 x ULN 
• 
Serum creatinine ≤ 1.2 x ULN 
3.2 
Registration - Exclusion Criteria 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant persons 
• 
Nursing persons 
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception 
3.22 
Any medical condition that would prohibit use of a topical cream (skin infection 
or open wound in the area of the neuropathy)  
3.23 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 

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3.24 
Pre-existing neuropathy prior to chemotherapy that would confuse the issue of 
CIPN 
3.25 
Currently on chemotherapy or received chemotherapy treatment within the prior 
3 months.  
3.26 
Use of other cannabis products within 30 days prior to registration 
3.27 
History of allergy to cannabis products 
 

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4.0  
Test Schedule 
4.1 
Test schedule for Chemotherapy-Induced Peripheral Neuropathy  
Study Visit 
1 
2 
3 
4 
5 
6 
7 
Study Time Point 
Screening 
/Baseline 
(Day -30 
to 
Day 1) 
Day 1 
End of 
Week 1 
End of 
Week 2c 
(+3 Days) 
End of 
Week 3 
End of 
Week 4 
 
 
End of 
study 
CLINCAL ASSESSMENTS 
Informed consent  
X 
 
 
 
 
 
 
Inclusion/exclusion 
criteria  
Xg  
 
 
 
 
 
 
Demographics/ 
Medical history  
X 
 
 
 
 
 
 
Pregnancy testing a 
X 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
Dispense Study 
Product/Placebo  
 
X 
 
X 
 
 
 
Collect 
questionnaires  
 
 
 
 
 
 
X 
Adverse event 
assessment b 
 
 
X 
X 
X 
X 
 
STUDY TESTING 
EORTC QLQ-
CIPN 20 instrument  
(Appendix I) 
X 
 
X 
X 
X 
X 
 
Global impression 
of change 
(Appendix II) 
 
 
X 
X 
X 
X 
 
Chemotherapy 
Induced Peripheral 
Neuropathy 
Assessment Tool       
(Appendix III) 
X 
 
X 
X 
X 
X 
 
Symptom 
experience diary  
(Appendix Va & 
Vb) 
Xd 
 
Xe 
Xe 
Xe 
Xe 
 
NCI-CTCAE 
neuropathy scale f 
(Appendix VI) 
X 
 
X 
X 
X 
X 
 
Cycle = 14 days 
a For individuals of childbearing potential. Must be done ≤7 days prior to registration. 
b Research nurse or clinician to call patient. Including inquiry about skin toxicity and to assess for 
suicidal thoughts (Appendix IX). Ask the patient if they have missed any doses of the study 

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medication and provide education if necessary. Note any other pertinent information that the 
patient provides. 
c After subject completes week 2 they will turn in completed questionnaire diary and start the 
next supply of cream within 1-3 days after completing the first 2 weeks, ideally. 
d Appendix Va: System Experience Diary used for baseline assessment. Must be completed prior 
to application of study medication. 
e Appendix Vb: System Experience Diary used for weekly assessments. Must be completed at the 
end of each week. 
f To be completed during research nurse or clinician call to patient per Appendix VI. 
g Required Initial Laboratory Values per inclusion criteria 3.19c can be done any time after the 
patient has completed their chemotherapy and prior to study registration.  
 
 
 
5.0 
Stratification Factors:  
• 
Gender (Male, Female, or Other) 
 
6.0 
Registration/Randomization Procedures 
6.1 
Registration (Step 1):  
6.11 
Registering a patient 
To register a patient, access the Registration Application at 
 The 
Registration Application is available 24 hours a day, 7 days a week. If unable to access 
the application, contact the Mayo Clinic Research Registration Office 
between the hours of 8am and 4:30 pm Central 
Time, Monday through Friday. Prior to initiation of protocol treatment, this process must 
be completed in its entirety and a MCCC Subject ID number (R######) must be 
assigned. It is the responsibility of the individual registering the patient to confirm the 
process has been successfully completed prior to release of the study agent. 
6.2 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
). If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted, and the patient may not be 
enrolled in the protocol until the situation is resolved. 

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When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.4a 
Study drug 
Study drug is available on site. Each site will have a supply of both investigational 
product and placebo that will be sent from Nightingale Remedies. After randomization at 
Mayo, the local site pharmacist will re-label the product per randomization instructions. 
Research staff, other than pharmacy, are blinded, and will dispense the cream to the 
patient at the site.  
 
6.4b 
Patient questionnaire booklets need to be available for patients 
Patient questionnaire should be ordered using the Patient Questionnaire Order Form. PDF 
versions of the questionnaires will be sent electronically for printing. 
 
Patient questionnaire booklets should be provided to the patients. They may be provided 
to the patient during a routine visit, via mail or electronically.  They will be available as 
follows:  
 
• 
Questionnaires for Baseline (this should be completed prior to 
application of study medication)  
• 
Questionnaires for week 1 & 2 (a self-addressed and stamped envelope 
should be provided the patient to mail this back at the end of week 2)  
• 
Questionnaires for week 3 & 4 (a self-addressed and stamped envelope 
should be provided the patient to mail this back at the end of week 4)  
  
Before the questionnaires are provided to the patient, the patient initials and appropriate 
dates of when they are to be completed should be written on each of the questionnaires. 
 
6.4c 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations. 
6.4d 
Randomization Procedures: The factor defined in Section 5.0 (gender) will be used as the 
only stratification factor  
6.4e 
Procedures for Double-Blinding the Treatment Assignment 

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6.4e1 
After the treatment assignment has been ascertained by the   
registration/randomization application, the registration specialist will notify the 
designated unblinded data manager/nurse/pharmacist at the patient’s institution. 
The name of this contact person is to be entered in the designated space on the 
eligibility checklist at the time of registration. Make sure this contact person will 
be available at the time of registration so he or she can be contacted by the 
registration specialist if necessary. This contact person may not be involved in 
assessing adverse events or any other outcome measure and should not be the 
same person listed on page one of the Eligibility Checklist Form as the person 
completing the form. The last page of the Eligibility Checklist Form should 
provide the sources of communication, either fax or e-mail, and the appropriate 
contact information. The registration specialist will then communicate the 
treatment assignment to the designated contact at the patient’s institution. 
 
6.4e2 
The treatment assignment will be to active or placebo. The unblinded pharmacist 
should only give one supply of study cream at a time according to the treatment 
assignment from the registration specialist.  Each participating institution will be 
responsible for monitoring drug supplies. The bottles will be labeled by the 
unblinded pharmacist as “CBD or placebo cream” so that the contents are not 
discernible to the person administering the treatment. At the time of cross-over, 
the patient will be given the alternative medication (CBD or placebo), again in a 
blinded manner. 
 
6.4e3 
The unblinded pharmacist will maintain records that indicate the identity of the  
patient and their corresponding treatment assignment.  
 
7.0 
Protocol Treatment 
7.1 
Treatment Plan:  
Patients will be instructed to apply the CBD or placebo cream in a thin layer 
(approximately 4-5 pumps of product) to affected areas twice daily for 14 days.  
CIPN in hands:  apply 4-5 pumps to hands twice a day 
CIPN in feet:  apply 4-5 pumps to feet twice a day 
After two weeks of using the designated treatment participants will cross over to the other 
treatment. The other treatment will be applied as described above, twice daily for another 
two weeks.  
7.2 
Breaking Code:  
During the study, codes should only be broken in emergency situations, which are not 
expected in this study.  In the event of an emergency, call the MCCC Registration Office 
at 
to break the code on Monday through Friday, 8:00 a.m. to 4:30 p.m. 
Central Time. Alternatively, email the Registration Office 
If the 
code must be broken after hours, assume the patient was assigned to active treatment and 
treat accordingly. Place a call to the MCCC Registration Office and leave a message 
informing them of the need to un-blind a patient. Provide your contact information so that 
MCCC Registration Office personnel can return the call the next business day. 
7.3        After the patient has completed the study and the questionnaires have been completed and 
sent in, the code can be broken, so that the patient can choose whether to continue to use 
CBD on their own if they felt it gave them benefit.   To do this, the MCCC Registration 

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Office may 
to find out 
which study therapy the patient was receiving. 
 
8.0 
Dosage Modification Based on Adverse Events  
There are no dosage modifications. If patients develop any intolerance or bothersome enough 
side-effect, they are to stop the study drug/placebo.  Ideally, they will still complete the study 
questionnaires. 
9.0 
Ancillary Treatment/Supportive Care:  
This protocol should not interfere with appropriate supportive care measures unrelated to a 
patient’s CIPN, unless use of CBD is specifically restricted. 
 
10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
 
 

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Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
Will automatically be sent to 
 
Non Mayo sites – complete and 
forward to 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form:  
 
Will automatically be sent to 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting 
Form
 
AND attach 
MedWatch 3500A: 
 
Will automatically be sent to 
 
 
 
 
Non-Mayo 
Clinic Sites 
MedWatch 3500A:  
 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 

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Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0 A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site: 
 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 

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Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
 
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment 
on this trial 
● Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was 
in place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of 
the cancer. 
 
 

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10.4 
Expedited Reporting Requirements for IND Agents  
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND within 30 Days of the 
Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below.  
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
 

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10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
or investigational agents or 
commercial/investigational agents on the same arm.  
Non-MCCC Institutions: Submit copies to 
 
 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table 10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 

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Clinic Cancer Center Expedited Event Report form 
 
he Mayo Clinic Compliance Unit will 
review and process the submission to the Mayo Clinic IRB and work with the 
IND Coordinator for submission to FDA. 
Non-MCCC Institutions:  
Submit to your IRB as required by your institutional policies. 
Submit copies to
 
 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND requires expedited 
reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 

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o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 

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10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
Neurotoxicity Evaluation to be completed at baseline and each evaluation per NCI-
CTCAE v5.0 grading in Appendix VI. 
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions do not need to be graded.  
10.62 All other AEs 
All other AEs will be addressed during the weekly phone calls with the research 
nurse or clinician.  Patient questionnaire booklets are not collected until the end 
of the study, therefore, will not be used to collect & document AEs. 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
Deviation Reporting Instructions 
For Non-MCCC institutions All deviations must be reported in the Medidata Rave®  
EDC system via appropriate Case Report Forms. Mayo Clinic Cancer Center (MCCC) 
Institutions will report via institutional standards.  
 
 

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11.0     Treatment Evaluation/Measurement of Effect  
See statistical details in Section 16.  
12.0 
Descriptive Factors: Not applicable. 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
Physicians can use the unblinded study data, for the individual patient, to help determine 
subsequent therapy for individual patients.  
14.0 
Body Fluid Biospecimens – None. 
15.0 
Drug Information 
Placebo and creams will be provided by Nightingale Remedies. This product has been tested by 
an independent lab for content and has 0% THC (testing attached). The study cream contains 
CBD isolate; both creams are odorless. 4-5 pumps of product will cover hands/feet and contains 
approximately 4 mg of CBD isolate. Patients with CIPN only on hands or feet would then get 
approximately 8 mg of topical CBD per day.  Patients with CIPN on both locations would get 
approximately 16 mg of topical CBD per day.  See appendix VII for product ingredients. See 
investigator brochure for detailed information about drug product and safety issues.  
Shipping, handling, and storage 
Creams should be stored at room temperature (59°-77°F). Product will be shipped from 
Nightingale Remedies to participating sites.  They will not be blinded to their local pharmacist 
who must keep all of the other clinical partners blinded to the study product and placebo.   
IND number: 157457 
15.1 
CBD Cream 
15.11 Drug procurement: 
Nightingale Remedies will supply all drug. Each institution will order the drug 
from Nightingale Remedies. Submit the Drug Order Form request to: 
 
 
 
 
 
 
Outdated or remaining drug is to be destroyed on-site per procedures in place at 
each institution. 
The investigator is responsible to ensure supervision of accurate monitoring of 
the receipt, storage and allocation of the study product. Copies of all invoices of 
shipments must be retained. Accurate study product inventory, dispensing and 
accountability logs must be obtained and stored in the Pharmacy Binder. 
15.111 Each participating institution may ship Study Product/Placebo directly to 
their patients if the site standards allow. All local site procedures should 
be followed and accurate accountability logs should be maintained. 
15.12 Nursing guidelines 
Educate patient regarding this protocol and address questions.  

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1. Instruct patients to report any rash or burning with application  
2. Instruct patients to avoid eye contact after applying lotion 
3. Agent should be stored at room temperature 
 

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16.0 
Statistical Considerations and Methodology  
16.1 
Primary  
This is a randomized, two arm, placebo-controlled, double-blind, pilot study of whether 
CBD can improve CIPN more than a placebo. The purpose of this pilot study is to 
estimate the treatment effects of CBD compared to the placebo arm. These preliminary 
efficacy estimates will aid in the design of a large-scale randomized phase III clinical 
trial.  
The primary endpoint is the change in CIPN from baseline to week 2. CIPN will be 
measured by the sensory subscale of the EORTC QLQ-CIPN20 which is composed of 9 
individual items. Secondary endpoints include other measures of neuropathy as measured 
by the EORTC QLQ CIPN20 motor subscale, the EORTC QLQ CIPN20 autonomic 
scale, and the CTCAE neuropathy scale. Adverse event profiles will also be assessed 
using symptom questionnaires and the CTCAE 5.0. 
As this is a pilot study, descriptive statistics and statistical plots will be utilized to 
summarize and estimate the primary and secondary endpoints. Statistical hypothesis 
testing will be used in an exploratory manner and will be interpreted accordingly. 
 
For the primary analysis, changes in sensory neuropathy from baseline to week 2 will be 
compared between arms using two-sample, two-sided t-tests. The CBD arm will be 
compared to the placebo arm. We will construct 95% confidence intervals for the mean 
difference in sensory neuropathy score between arms. Repeated measures mixed models 
will be applied to the sensory scores over all time points to determine longitudinal effects 
and to adjust for confounding factors. Graphical results will include profile plots over 
time, stream plots of individual changes over time, and forest plots of the 95% confidence 
intervals by arm. 
 
For logistical and financial reasons, the sample size for this pilot study is set at 40 
patients (20 per treatment group). While this is only a descriptive study and is not 
powered to detect significant differences between arms, the following table provides 
power analyses for various effect sizes based on a two-sided, two-sample t test at α = 
0.05 for a fixed sample size of 20 patients per arm. 
 
Effect size, Δ = | μ 1 - μ 2| / σ 
0.5 
0.6 
0.7 
0.8 
0.9 
1.0 
Power 
0.34 
0.46 
0.58 
0.69 
0.79 
0.87 
 
For example, we will have 79% power to detect an effect size of 0.9 in EORTC QLQ-
CIPN20 with a sample size of 40 patients (20 per arm). This effect size is the mean 
difference divided by the common standard deviation within each arm. 
 
16.2 
Analysis Plan for Secondary Outcome and Translational Endpoint  
Analyses for secondary endpoints will also be descriptive in nature. Due to the 
exploratory nature of this research, we will not adjust for multiple comparisons for the 
secondary analyses. Analyses of the motor and autonomic subscales will be identical to 
the analyses of the primary endpoint. Analyses of CTCAE grades and the symptom 
questionnaire individual items will compare the incidence and maximum (worst) values 
between arms. Fisher’s exact tests will be used to compare incidence rates and Wilcoxon 
rank-sum tests will be used to compare maximum values between arms. 

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16.3 
Data & Safety Monitoring 
16.31 Safety review 
The principal investigator(s) and the study statistician will review the study 
monthly to identify accrual, adverse event, and any endpoint problems that might 
be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least biannually, based on reports provided by the MCCC Statistical Office. 
16.32 Adverse Event Stopping Rules  
Patients who report > grade 2 rash, pain, allergic reaction, or any other > grade 2 
side effects attributed to the study medication will stop study drug/placebo and be 
monitored. Appropriate local care should be administered by the treating 
physician.  
 
The PI has the right to discontinue this study at any time for reasonable medical 
or administrative reasons. The DSMB may also terminate study per early 
stopping rules.  
 
16.4 
Subset Analyses for Minorities 
16.41 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin.  
16.42 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.43 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Expected sizes of racial by gender subsets are 
shown in the following table: 
 
 

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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
18 
18 
36 
Ethnic Category: Total of all subjects 
20 
20 
40 
Racial Category 
American Indian or Alaskan Native 
1 
 
1 
Asian 
 
1 
1 
Black or African American 
2 
2 
4 
Native Hawaiian or other Pacific Islander 
1 
 
1 
White 
16 
17 
33 
Racial Category: Total of all subjects 
20 
20 
40 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

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17.0  
Records and Data Collection Procedures  
17.1 
Submission Timelines:  
Baseline information should be provided within 2 weeks of patient registration, while 2 
and 4 week data should be provided within 2 weeks of patient submission of such.     
17.2 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
17.3 
Site responsibilities 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient names must be 
removed. 
17.4 
Overdue items 
A member of the Mayo Clinic study team (e.g. Protocol specialist, data manager, PI, etc.) 
may contact site personnel via email regarding overdue forms and outstanding queries. 
 
18.0  
Budget 
18.1 
Costs charged to patient: routine clinical care 
18.2 
Tests to be research funded: 
CBD cream & placebo will be provided from research funds. 
 
 
 

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19.0 
References 
1. 
Starobova, H. and I. Vetter, Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy. 
Front Mol Neurosci, 2017. 10: p. 174. 
2. 
Seretny, M., et al., Incidence, prevalence, and predictors of chemotherapy-induced peripheral 
neuropathy: A systematic review and meta-analysis. Pain, 2014. 155(12): p. 2461-2470. 
3. 
Lee, G., et al., Medical Cannabis for Neuropathic Pain. Curr Pain Headache Rep, 2018. 22(1): p. 
8. 
4. 
Gewandter, J.S., et al., Painful chemotherapy-induced peripheral neuropathy: lack of treatment 
efficacy or the wrong clinical trial methodology? Pain, 2017. 158(1): p. 30-33. 
5. 
Flatters, S.J.L., P.M. Dougherty, and L.A. Colvin, Clinical and preclinical perspectives on 
Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review. Br J Anaesth, 2017. 
119(4): p. 737-749. 
6. 
Blanton, H.L., et al., Cannabinoids: Current and Future Options to Treat Chronic and 
Chemotherapy-Induced Neuropathic Pain. Drugs, 2019. 79(9): p. 969-995. 
7. 
Zajaczkowska, R., et al., Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. Int J 
Mol Sci, 2019. 20(6). 
8. 
Johnson, J.R., et al., An open-label extension study to investigate the long-term safety and 
tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal 
cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage, 2013. 
46(2): p. 207-18. 
9. 
Brown, D., M. Watson, and J. Schloss, Pharmacological evidence of medicinal cannabis in 
oncology: a systematic review. Support Care Cancer, 2019. 27(9): p. 3195-3207. 
10. 
Nugent, S.M., et al., The Effects of Cannabis Among Adults With Chronic Pain and an Overview 
of General Harms: A Systematic Review. Ann Intern Med, 2017. 167(5): p. 319-331. 
11. 
Pertwee, R.G., Cannabinoid pharmacology: the first 66 years. Br J Pharmacol, 2006. 147 Suppl 
1: p. S163-71. 
12. 
Showalter, V.M., et al., Evaluation of binding in a transfected cell line expressing a peripheral 
cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J 
Pharmacol Exp Ther, 1996. 278(3): p. 989-99. 
13. 
Thomas, A., et al., Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and 
CB2 receptor agonists in vitro. Br J Pharmacol, 2007. 150(5): p. 613-23. 
14. 
Masocha, W., Targeting the Endocannabinoid System for Prevention or Treatment of 
Chemotherapy-Induced Neuropathic Pain: Studies in Animal Models. Pain Res Manag, 2018. 
2018: p. 5234943. 
15. 
Vuckovic, S., et al., Cannabinoids and Pain: New Insights From Old Molecules. Front 
Pharmacol, 2018. 9: p. 1259. 
16. 
Muller, C., P. Morales, and P.H. Reggio, Cannabinoid Ligands Targeting TRP Channels. Front 
Mol Neurosci, 2018. 11: p. 487. 
17. 
Donvito, G., et al., The Endogenous Cannabinoid System: A Budding Source of Targets for 
Treating Inflammatory and Neuropathic Pain. Neuropsychopharmacology, 2018. 43(1): p. 52-79. 
18. 
Abrams, D.I., et al., Cannabis in painful HIV-associated sensory neuropathy: a randomized 
placebo-controlled trial. Neurology, 2007. 68(7): p. 515-21. 
19. 
Peppin, J.F., et al., Skin Matters: A Review of Topical Treatments for Chronic Pain. Part One: 
Skin Physiology and Delivery Systems. Pain Ther, 2015. 4(1): p. 17-32. 
20. 
Yesilyurt, O., et al., Topical cannabinoid enhances topical morphine antinociception. Pain, 2003. 
105(1-2): p. 303-8. 
21. 
Fernández-Ruiz, J., et al., Cannabidiol for neurodegenerative disorders: important new clinical 
applications for this phytocannabinoid? Br J Clin Pharmacol, 2013. 75(2): p. 323-33. 

MC211003 
31  
 
Protocol Version Date: 21Apr2023 
 
 
22. 
Costa, B., et al., The non-psychoactive cannabis constituent cannabidiol is an orally effective 
therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol, 2007. 
556(1-3): p. 75-83. 
23. 
Toth, C.C., et al., Cannabinoid-mediated modulation of neuropathic pain and microglial 
accumulation in a model of murine type I diabetic peripheral neuropathic pain. Mol Pain, 2010. 
6: p. 16. 
24. 
Xiong, W., et al., Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha3 
glycine receptors. J Exp Med, 2012. 209(6): p. 1121-34. 
25. 
Ward, S.J., et al., Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) 
receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol, 
2014. 171(3): p. 636-45. 
26. 
Booz, G.W., Cannabidiol as an emergent therapeutic strategy for lessening the impact of 
inflammation on oxidative stress. Free Radic Biol Med, 2011. 51(5): p. 1054-61. 
27. 
Zuardi, A.W., Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. 
Braz J Psychiatry, 2008. 30(3): p. 271-80. 
28. 
Caterina, M.J., TRP channel cannabinoid receptors in skin sensation, homeostasis, and 
inflammation. ACS Chem Neurosci, 2014. 5(11): p. 1107-16. 
29. 
Anand, P., et al., Rational treatment of chemotherapy-induced peripheral neuropathy with 
capsaicin 8% patch: from pain relief towards disease modification. J Pain Res, 2019. 12: p. 2039-
2052. 
30. 
Ellison, N., et al., Phase III placebo-controlled trial of capsaicin cream in the management of 
surgical neuropathic pain in cancer patients. J Clin Oncol, 1997. 15(8): p. 2974-80. 
31. 
Hampson, A.J., et al., Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective 
antioxidants. Proc Natl Acad Sci U S A, 1998. 95(14): p. 8268-73. 
32. 
Ryan, D., et al., Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J 
Neurosci, 2009. 29(7): p. 2053-63. 
33. 
Rajesh, M., et al., Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and 
inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol, 
2010. 56(25): p. 2115-25. 
34. 
Kozela, E., et al., Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation 
and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br J Pharmacol, 2011. 163(7): 
p. 1507-19. 
35. 
Paudel, K.S., et al., Cannabidiol bioavailability after nasal and transdermal application: effect of 
permeation enhancers. Drug Dev Ind Pharm, 2010. 36(9): p. 1088-97. 
36. 
Stinchcomb, A.L., et al., Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol 
and cannabinol. J Pharm Pharmacol, 2004. 56(3): p. 291-7. 
37. 
Xu, D.H., et al., The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of 
Peripheral Neuropathy of the Lower Extremities. Curr Pharm Biotechnol, 2020. 21(5): p. 390-
402. 
38. 
Tofthagen, C.S., S.C. McMillan, and K.E. Kip, Development and psychometric evaluation of the 
chemotherapy-induced peripheral neuropathy assessment tool. Cancer Nurs, 2011. 34(4): p. E10-
20. 
 
 
 
 

 
 
Appendix I: EORTC QLQ-CIPN20 Instrument 
 

 
 
 

 
 
Appendix II: Patient Global Impression of Change 
 
 
1. Since starting this study, my overall quality of life is: (please circle one) 
 
-3 
-2 
-1 
0 
1 
2 
3 
Very much 
worse 
Moderately 
worse 
A little 
worse 
About the 
same 
A little 
better 
Moderately 
better  
Very much 
better 
 
2. Since starting this study, the numbness, tingling or pain in my hands and/or feet is: (please 
circle one) 
 
-3 
-2 
-1 
0 
1 
2 
3 
Very much 
worse 
Moderately 
worse 
A little 
worse 
About the 
same 
A little 
better 
Moderately 
better  
Very much 
better 
 
 
3. Would you recommend this therapy, to try to prevent or treat neuropathy, to other patients 
with problems similar to yours? 
 
 
 No 
 
 Yes 
 
 Unsure 
 
Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 

 
 
Appendix III: Chemotherapy Induced Peripheral Neuropathy Assessment Tool                        
(Quantitative Items) 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Appendix IV: Peripheral Neuropathy Question 
 
 
 
1. How much of a problem has tingling or pain in your fingers and/or toes been in the past week? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No tingling or pain 
in fingers and/or 
toes 
 
 
 
 
 
 
 
Tingling or pain in 
fingers and/or toes 
as bad as you can 
imagine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Appendix Va: Symptom Experience Diary –Baseline  
 
 
Please circle ONE number for each item that best describes you over the past 7 days.   
 
1. Over the past week, please rate your quality of life: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad 
as it can 
be 
 
 
 
 
 
 
 
 
 
As good 
as it can 
be 
 
 
 
2. Do you have any skin rash on your hands or feet: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None     
 
 
 
 
 
 
 
 
 
As bad 
as it can 
be 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Appendix Vb: Symptom Experience Diary ––During Treatment  
 
 
Please circle ONE number for each item that best describes you over the past 7 days.   
 
1. Over the past week, please rate your quality of life: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad 
as it can 
be 
 
 
 
 
 
 
 
 
 
As good 
as it can 
be 
 
2. Do you have any skin rash on your hands or feet: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None     
 
 
 
 
 
 
 
 
 
As bad 
as it can 
be 
 
3. How many doses of the study medication do you think that you missed over the past week? 
(Circle one answer) 
 
0 times             
1-2 times  
     3-4 times 
More than 5 times 
 
4. Did you have any skin side effects from the study product? 
 
____ No 
 
____ Yes, if so, please describe the symptom(s) and severity:  
 
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________ 
 
5. Did you have any other side effects from the study product? 
 
____ No 
 
____ Yes, if so, please describe the symptom(s) and severity:  
 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
 
 

 
 
Appendix VI: CTCAE Criteria 
Neurotoxicity Evaluation 
 
Grade 
I 
II 
III 
IV 
NCI-CTCAE 
v5.0 
Asymptomatic 
Moderate 
symptoms; 
limiting 
instrumental ADL 
Severe 
symptoms; 
limiting self-care 
ADL 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Questions 
Sample answers for each toxicity grade 
Do you have 
problems tying 
your shoe laces, 
buttoning your 
shirts, fastening 
buckles or 
pulling up 
zippers? 
“No, I might feel 
some tingling in 
my hands, but I 
have no problems 
tying laces, 
buttoning shirts, 
fastening buckles 
or pulling up 
zippers” 
“It is a bit harder 
than before, but I 
can still tie laces, 
button shirts, 
fasten buckles or 
pull up zippers” 
“I have severe 
difficulties tying 
shoe laces, 
buttoning shirts, 
fastening buckles 
or pulling up 
zippers” or “I 
cannot tie laces, 
button shirts, 
fasten buckles or 
pull up zippers 
anymore” 
“I haven’t been 
able to tie laces, 
button shirts, fasten 
buckles or pull up 
zippers for weeks” 
Do you have 
problems 
writing? 
“No, I might feel 
some tingling in 
my hands, but I 
have no problems 
writing” 
“It is a bit harder 
than before, but I 
can still write” 
“I have severe 
difficulties 
writing” or “I 
cannot write 
anymore” 
“I haven’t been 
able to write for 
weeks” 
Do you have 
problems putting 
on your jewelry 
or your watch? 
“No, I might feel 
some tingling in 
my hands, but I 
have no problems 
putting on my 
jewelry or my 
watch” 
“It is a bit harder 
than before, but I 
can still put on my 
jewelry or my 
watch” 
“I have severe 
difficulties 
putting on my 
jewelry or my 
watch” or “I 
cannot put on my 
jewelry or my 
watch anymore” 
“I haven’t been 
able to put on my 
jewelry or my 
watch for weeks” 
Do your have 
problems 
walking? 
“No, I might feel 
some tingling in 
my feet, but I have 
no problems 
walking” 
“It is a bit harder 
than before, but I 
can still walk” 
“I have severe 
difficulties 
walking” or “I 
cannot walk 
anymore” 
“I haven’t been 
able to walk for 
weeks 
 
 
 
 
 
 
 
 

 
 
Appendix VII: PRODUCT AND PLACEBO INFORMATION 
 
I. 
Source of Hemp: The source of the Hemp is USA grown from pesticide-free farms. 
Manufacturer: Nightingale Remedies, Portland OR 
 
 
II. 
Method of CBD extraction: CBD isolate is extracted using Super Critical C02 Extraction 
method. This process is described below:  
 
An extractor chamber is filled with ground cannabis/hemp material (called trim). A pump 
forces pressurized carbon dioxide gas at the optimum temperature (ScCO2) into the extractor 
chamber. The supercritical carbon dioxide interacts with the cannabis, dissolving the 
cannabinoid compounds it contains. The supercritical CO2 carries the cannabis oil particles 
past a pressure release valve to a cyclonic separator. In the separator, the pressure is lower 
and the carbon dioxide and cannabis oil separates. The carbon dioxide rises and is routed 
back to the CO2 tank for reuse in the case of a closed loop system. The cannabis oil, waxes 
and resins descend in the separator where they are captured by a collection vessel. The 
resulting substance is processed further into various products, such as CBD-rich “cannabis 
oil”, free of any solvents. 
 
III. 
Manufacturing Process: The manufacturing process is in a certified facility (see attachments). 
All ingredients are pre-screened with COA's for each ingredient. Production standards of 
cGMP are followed in every step of the process. The manufacturing process is a controlled 
environment and FDA / cGMP certified. 
 
IV. 
Ingredients 
 
Placebo: 
Water, Organic Coconut Oil, Grapeseed Oil, Emulsifying Wax, Stearic Acid, Glycerin, 
Xanthan Gum, Phenoxyethanol, Tetrasodium Glutamate Diacetate, isopropyl palmitate, 
caprylic/capric triglyceride, propylene glycol, ceteareth-20, cetearyl alcohol, glyceryl 
stearate, PEG-100 stearate, dimethicone, octyldodecanol, hydroxyethyl acrylate/sodium 
acryloyldimethyl taurate copolymer, lecithin, phenoxyethanol, ethylhexylglycerin, trolamine. 
 
Experimental Cream: 
Water, CBD Isolate* (Hemp Extract), Organic Coconut Oil, Grapeseed Oil, Emulsifying 
Wax, Stearic Acid, Glycerin, Xanthan Gum, Phenoxyethanol, Tetrasodium Glutamate 
Diacetate, isopropyl palmitate, caprylic/capric triglyceride, propylene glycol, ceteareth-20, 
cetearyl alcohol, glyceryl stearate, PEG-100 stearate, dimethicone, octyldodecanol, 
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, lecithin, phenoxyethanol, 
ethylhexylglycerin, trolamine. 
*Active Product: Added CBD isolate to placebo base, 250 mg per 1.7 oz 
 
V. 
Certificate of Analysis: COA showing full panel test results is included in the current 
Investigator’s brochure. The COA shows that there is 0% THC in the final CBD Isolate 
product. 
 
VI. 
Study Product: The study product is being manufactured specifically for this study. It 
contains the ingredients listed above and will not have the herbals that are contained in the 

 
 
marketed Nightingale Remedies product “CBD Relief Cream”. COA for the study product is 
included in the current Investigator’s Brochure.   
 
VII. 
Product Safety:  No formal PK studies have been done on this particular product however the 
literature supports safety of topical cannabis creams. The dose of CBD isolate is 
approximately 4 mg BID, and a very small amount may be systemically absorbed. Similar 
creams have been used with no reported adverse effects. The CBD product that we propose 
using is currently available commercially (with additional added herbal products) without 
need for a prescription from a health care provider.  In a case series of 26 patients who had 
tried a variety of topical cannabis creams for CIPN (D’Andre, submitted to Integrative 
Cancer Therapies, 2021) there was not any toxicity that could be clearly attributed to the 
topical CBD therapy. One patient had a transient increase in CIPN symptoms, so the topical 
CBD was stopped and the symptoms subsequently returned to baseline. It is not clear to us 
whether the worsening CIPN symptoms were a result of the CBD cream of just a case of 
CIPN symptoms waxing and waning, as is frequently observed in clinical practice.  In the 
literature, there are no reports of toxicity in patients using topical cannabinoids similar to 
what we are proposing to use in the currently proposed trial. This includes a trial from Xu et 
al, whereby CBD 250 mg/3fl oz/emu oil was studied; no adverse events were noted (1). 
Maida et al. reported three patients that used topical cannabis for pyoderma gangrenosum.  
These patients reported less pain, and there were no side effects noted. The dose used was 5-7 
mg THC, 6-9 mg CBD (2). Maida et al also reported two more case series using a CBD based 
cream for non-healing ulcers in 2 patients and 14 patients, noting improved wound healing 
and pain control. In patients with open wounds, the systemic absorption of topicals is 
enhanced, and even in this situation there were no side effects noted (3,4). Three patients self-
initiated use of CBD oil for the treatment of pediatric epidermolysis bullosa. All patients 
reported improved skin condition, less pain, and no adverse effects were noted (5).  
Additionally, 50 patients with inflammatory skin diseases were treated with a cream that 
contained cannabis, macadamia, and rosa moschata seed oils. Thirty had complete healing in 
12 weeks and 20 had partial healing. The authors were trying to substitute this cream instead 
of using chronic steroid creams.  One patient with radiation induced dermatitis, had complete 
healing.  No side effects were noted (6). Another 11 patients were treated with a 3% seed 
extract CBD cream for acne and had decreased erythema and sebum production, compared to 
a base cream; no side effects were noted (7). Lastly, in a study of 35 patients with alopecia, a 
high dose (108 mg/2 oz) of a topical CBD cream was used to promote hair growth for six 
months; there were no reported adverse effects (8).   
 

 
 
 

 
 
 
Appendix VIII ECOG Performance Status  
  
ECOG PERFORMANCE STATUS*  
Grade  ECOG  
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours.  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair.  
5  
Dead  
*As published in Am. J. Clin. Oncol.:  
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982.  
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.  
  
 
 
 

 
 
Appendix IX: Patient Suicidal Thoughts Assessment and Evaluation for Skin Toxicity 
 
Nurse/clinician Phone Call Questions to address regarding suicidal thoughts and potential skin toxicity. 
Patients will be asked at the end of each week.   
1. Given an abundance of precaution, we want to ask you about whether you have had any 
thoughts of suicide since starting this protocol?  
 
 
If the answer is ‘no’, please record. 
 
If the answer is ‘yes’, please record then physician contact is required, and appropriate 
intervention is to be provided. 
 
2. Do you have skin irritation on your hands and/or feet in the location of the cream application? 
3. Do you have any rash, blisters, or open areas of skin in the location of the cream application? 
 
 
Please record responses. 
 
If the answer is ‘yes’ to any of the above two questions, the patient will be asked to come 
in to be seen by a provider for a skin examination. 
Additionally: 
4. At the end of weeks 2 and 4, please remind patients to mail in or bring in their questionnaires 
from the prior 2 weeks. 
5. Please note any other pertinent information that the patient provides.