Evaluation of Cryotherapy and TRPA1 Receptors in Chemotherapy Induced Neuropathy
Phase: NA
Conditions: Peripheral Neuropathies
Sponsor: The University of Texas Health Science Center at San Antonio

 
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COVER PAGE  
 
 
 
 
 
Official Study Title: Evaluation of Cryotherapy and TRPA1 
Receptors in Chemotherapy Induced Neuropathy 
 
NCT number: NCT03329131 
 
IRB Approval Date: 07.05.2021 
 
 
Unique Protocol ID: CTMS # 17-0033 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Title:  Evaluation of Cryotherapy and TRPA1 Receptors in Chemotherapy Induced Neuropathy 
 
Coordinating Center: 
 
 
Mays Cancer Center, UT Health San Antonio  
 
Principal Investigators: 
      Virginia Kaklamani, MD 
Professor, Department of Medicine 
Mays Cancer Center 
7979 Wurzbach Rd, San Antonio, TX 78229 
Ofc. 210-450-3838 
 
 
kaklamani@uthscsa.edu 
 
 
 
Sub-Investigators: 
 
See FDA Form 1572 
 
Statistician: 
Jonathan Gelfond, PhD 
 
 
Assistant Professor 
 
 
Department of Epidemiology and Biostatistics 
 
 
UT Health San Antonio 
Ofc 210-567-0851 
Fax 210-567-0921 
gelfondjal@uthscsa.edu  
 
CTMS# 17-0033  
 
IND Exempt 
 
PROTOCOL Version 13 
DATE: 6/22/21 
 
 

 
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INVESTIGATOR’S AGREEMENT 
 
I have read and understand the contents of this clinical protocol for Protocol Title: Evaluation of Cryotherapy and 
TRPA1 Receptors in Chemotherapy Induced Neuropathy, CTMS# 17-0033 and will adhere to the study 
requirements as presented, including all statements regarding confidentially. In addition, I will conduct the study 
in accordance with current international conference on harmonization (ICH) guidance, Good Clinical Practice 
(GCP) guidance, the Declaration of Helsinki, US Food and Drug Administration (FDA) regulations and local IRB 
and legal requirements. 
 
Name of Clinical Investigator: Virginia Kaklamani, MD 
 
Institution: Mays Cancer Center  
 
 
 
___________________________________________________   
___________________________ 
Investigator Signature 
 
 
 
 
 
 
Date 
 
 
 
 

 
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 ABBREVIATIONS (sample list – please only use those that are relevant to your protocol) 
 
 
AE 
 
 
 
Adverse Event 
BPI  
 
 
 
Brief Pain Inventory  
CIPN  
 
 
Chemotherapy-Induced Peripheral Neuropathy 
DSM  
 
 
Data Safety Monitoring 
DSMB  
 
 
Data Safety Monitoring Board 
DSMC  
 
 
Data Safety Monitoring Committee  
DQA 
 
 
 
Director of Quality Assurance 
EORTC QLQ-CIPN20  
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Chemotherapy Induced Peripheral Neuropathy 20 
FDA 
 
 
 
Food and Drug Administration 
 
FEPS 
  
Familial Episodic Pain Syndrome 
GCP 
 
 
 
Good Clinical Practice 
ICH  
  
 International Conference on Harmonization  
IIS 
 
 
 
Investigator Initiated Protocol 
IND 
 
 
 
Investigational New Drug 
IRB 
 
 
 
Institutional Review Board 
NCI 
 
 
 
National Cancer Institute 
NCS 
 
 
 
Nerve Conductive Studies  
NGS   
 
 
Next Gen Sequencing 
NIH 
 
 
 
National Institutes of Health 
NPSI   
 
 
Neuropathic Pain Symptom Inventory  
PALS  
 
 
Priority of Audit Level Score 
PI 
 
 
 
Principal Investigator 
PRMS   
 
 
Protocol Review and Monitoring System 
QAD 
 
 
 
Quality Assurance Division 
QST 
 
 
 
Quantitative Sensory Testing 
SAE 
 
 
 
Serious Adverse Event 
TRPA1 
  
Transient Receptor Potential Cation Channel Subfamily A Member 1 
TRPM8  
  
Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) 
TRPV1  
  
Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1) 
UPIRSO 
 
 
Unanticipated Problem Involving Risks to Subjects or Others  
 
 

 
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Table of Contents 
 
 
Study Synopsis 
 
5 
Background 
 
5 
Statement of Study Objectives 
 
7 
Inclusion and Exclusion Criteria 
 
7 
Study Schedule  
 
8 
Study Design 
 
9 
Data Safety Monitoring Plan 
 
15 
References/Bibliography  
 
18 
Appendix 
 
21 

 
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Study Synopsis 
This is a therapeutic study investigating the use of cryotherapy in the prevention of chemotherapy-induced 
peripheral neuropathy (CIPN) and associated nail toxicities. The therapeutic intervention will involve patients 
wearing an Elasto-Gel cold glove and wrap on one hand and one foot (both on the right side or both on the left 
side).  The patients will wear the glove and wrap during each infusion of taxane chemotherapy. Infusion therapy, 
assessments and patient questionnaires will take place in the Mays Cancer Center and the Nerve Conduction 
Studies (NCS) will be performed at the Medical Arts and Research Center (MARC). The primary aim is to 
demonstrate if cryotherapy is a safe and effective intervention in preventing peripheral neuropathy and nail 
toxicity in patients receiving taxane chemotherapy. The secondary aim is evaluating the relation of CIPN with 
gene expression profiles of TRPA1, TRPV1 and TRPM8 in peripheral blood.  
 
Background 
Breast cancer is the second most common cause of death for women and is the most common cause of death 
for women ages 45 to 55 1. The incidence varies worldwide, being more prevalent in North America than in Africa, 
as a consequence of environmental factors such as diet and exercise 1. Multiple prognostic factors such as 
receptor status have been identified, therefore, making the treatment more effective due to better targeting. 
Women with node-positive disease and a significant percentage of node-negative women benefit from 
chemotherapy2. Although there are some well-known algorithms of treatments, the choice of which 
chemotherapy to use is based on variables like age, comorbidities, axillary node involvement and status of 
hormone receptors. For those patients receiving chemotherapy, multiple combinations are available; one 
commonly used is doxorubicin/cyclophosphamide and paclitaxel 3. Taxanes improve the disease-free and overall 
survival in patients with early breast cancer 4.  There are multiple taxane chemotherapies, but they all share the 
common mechanism of action of stabilizing microtubules assembly5-6 and thus preventing cell division.  Toxicities 
are also shared within the taxane class and include a higher rate of myelosuppresion, febrile neutropenia 5-6, 
polyneuropathy and cutaneous toxicities such as nail bed hyperpigmentation and oncholysis 7. Side effect 
incidence is related to the overall cumulative dose of taxanes8. Thus far, no specific genomic biomarker has 
been identified that can predict individual susceptibility to these know toxicities 9.  
 
Chemotherapy inducted peripheral Neuropathy is a common treatment-related adverse effect and affects long-
term quality of life16. CIPN is a dose-limiting side effect of many anti-cancer drugs including platinum drugs, 
taxanes, vinca alkaloids, epothilones, bortezomib, and lenolidamide17-19. The overall incidence of CIPN is 
estimated to be approximately 38% in patients treated with multiple agents16 although this percentage varies 
depending on the different chemotherapy regimens used and the duration of the exposure. These effects of 
chemotherapy drugs can resolve after treatment ceases but many patients are left with permanent sensory 
deficient or chronic pain syndromes18. Treatments for CIPN have been disappointing, with most agents 
demonstrating no significant analgesic effect. Therefore, interventions that can reduce the prevalence or severity 
of neuropathic symptoms in patients receiving chemotherapy will immediately have a significant impact on 
patient care.  
 
Breast cancer is a common malignancy that responds well to taxane-containing chemotherapeutic regimens1. 
Women who develop peripheral neuropathy as a result of treatment with taxane chemotherapy can have lasting 
side effects and significant decrease in their quality of life. Peripheral neuropathy can result in loss of ability to 
complete activities of daily living such as walking, standing and self-care, and can also lead to difficult to treat 
chronic pain syndromes 10-11. Unfortunately, studies exploring a variety of agents for the prevention of taxane-
induced peripheral neuropathy have so far been unsuccessful 12. For example, recent studies of Amifostine and 
recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) were shown to have no neuro-
protective effect against paclitaxel 13-15.  
 
In trials where neurosensory evaluation included electrophysiology or other quantitative sensory testing, the 
large majority of subjects receiving taxane containing chemotherapy regimens demonstrated physiologic 
changes indicative of peripheral neuropathy 8. In a small prospective trial in women receiving paclitaxel for breast 
cancer, neuropathy occurred after the first or second dose in 84% of patients and was progressive in 7% 20. In 
total, 97% developed signs of peripheral neuropathy when evaluated with quantitative sensory testing. In another 

 
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study, all patients receiving paclitaxel in combination with cisplatin, developed significant changes on 
electrophysiology measures 21. Furthermore, in another trial, 20 of 21 patients (95%) developed a sensory-motor 
neuropathy 1 to 21 weeks after the initiation of paclitaxel therapy and progressed with each additional course. 
The neuropathy was reported to be symmetrical, length dependent (neurons with longer axons were more likely 
to be affected) and was more evident in patients receiving higher doses of paclitaxel22.  
 
Recently, we have found that chemotherapy drugs directly activate peripheral sensory nociceptors in Drosophila 
and mice via the activation of Transient Receptor Potential Cation Channel Subfamily A Member 1 (TRPA1) 
resulting in a neuropathic pain syndrome similar to human patients. (Boiko, N., Medrano, G., Montano, E., Jiang, 
N., Williams, C. R., Madungwe, N. B., et al. (2017). TrpA1 activation in peripheral sensory neurons underlies the 
ionic basis of pain hypersensitivity in response to vinca alkaloids. PLoS ONE, 12(10), e0186888. 
http://doi.org/10.1371/journal.pone.0186888.g007).  Our working model based on our data and others is that the 
activation of TRPA1 during chemotherapy is a significant contributor to the neuropathic pain syndrome 
associated with CIPN.  Further, prolonged hyperexcitation of the sensory neuron by activation of TRPA1 could 
lead to excitotoxicity and neuropathy during chemotherapy treatment programs.   
 
TRPA1 is a well-studied and evolutionarily-conserved chemical nociceptor expressed throughout the body 
including sensory nociceptors23 ,  Importantly, a gain-of-function mutation in hTRPA1 has been linked to Familial 
Episodic Pain Syndrome (FEPS), a human pain syndrome associated with enhanced sensitivity to punctate 
stimuli and mustard oil 25. This mutation was shown to result in a 5-fold increase in the inward current in response 
to channel activation supporting that inappropriate activation of hTRPA1 channels in sensory neurons is sufficient 
to generate pain in humans 25.  Thus, the activation of hTRPA1 during chemotherapy may be responsible for the 
neuropathic pain experienced during chemotherapy treatment and represent an important pathogenic event 
during CIPN.  In addition to TRPA1, related genes in the Transient Receptor Potential Cation Channel Subfamily 
V member 1 (TRPV1) and Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) may 
also play a role in development of CIPN.  Currently, multiple clinical trials are studying TRPA1 antagonists 24. 
Showing the effect of activated TRPA1 in vivo and the subsequent development of CIPN, would provide support 
for targeting TRPA1 for the treatment and prevention of CIPN in patients receiving taxane based chemotherapy.  
In addition, it is predicted that baseline TRPA1 activity in patients could represent an important biomarker for the 
prognosis of CIPN,   
 
Recently, a form of cryotherapy using an Elasto-Gel frozen (4ºC) glove or wrap has been shown to reduce nail 
toxicity and oncholysis 30. Its role in preventing peripheral neuropathy has not been thoroughly studied but 
preliminary observations suggest a potential beneficial effect (31 - 32). Cryotherapy has been extensively studied 
and the proposed mechanism of action is that local vasoconstriction reduces blood flow to the extremity and 
consequently reduces the exposure to the taxane 30. This therapy has been shown to be effective in reducing 
toxicities within the oral cavity 33 and the scalp 32. In regards to the oncholysis, a study with patients treated with 
docetaxel served as their own controls with a glove placed on the right hand starting 15 minutes prior to 
treatment, and extending 15 minutes after the infusion ended. Nail changes where observed in 51% in the 
untreated hand versus 11% in the cold glove hand 35. In the second trial, patients wore a frozen sock on their 
right foot using the same protocol. Grade 1 and 2 nail toxicity was 0% in the treated side and 21% in the untreated 
extremity 36. The intervention was well tolerated with only one of fifty patients withdrawing due to cold 
intolerances. Therefore, extremity cooling therapy provides a potential opportunity to reduce both peripheral 
neuropathies and nail toxicities related to taxane based chemotherapy.  
 
The importance of the study relies on the high incidence of debilitating symptoms as a result of breast cancer 
treatment, which has a high clinical and public health significance 37-39. Additionally, after completing treatment 
only approximately 50-60% of the patients have improvement of the neuropathy; therefore, an important 
percentage of people remain affected by the symptoms. Furthermore there are no established agents that can 
be recommended for the prevention of CIPN in patients with cancer undergoing treatment with neurotoxic agents, 
and establishing a link between CIPN and activation of TRPA1, TRPV1 and TRPM8 genes allows for the 
exploration of prevention with TRPA1 agonists.  
 

 
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Statement of Study Objectives 
 
Specific Aims  
1. Evaluate the safety profile and efficacy of cryotherapy in the prevention of peripheral neuropathy during 
treatment with taxane chemotherapy.  
2. Evaluate the safety profile and efficacy of cryotherapy in the prevention of nail toxicity during treatment 
with taxane chemotherapy.  
3. Evaluate the role of TRPA1 in CIPN in patients receiving taxane-based chemotherapy  
 
Primary Endpoints:   
1. To determine rate and severity of chemotherapy induced neuropathy in extremities treated with cold 
gloves and wraps versus control extremities as measured by 
a. Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 
b. Brief Pain Inventory (BPI) 
c. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
Chemotherapy Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) 
d. the Neuropathic Pain Symptom Inventory (NPSI) 
e. To determine rate and severity of chemotherapy related oncholysis in extremities treated with 
cold gloves and wraps versus control extremities as measured using Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) Version 4.03 
 
 
Secondary Endpoints:   
1. Differences in amplitude and peak latency of Nerve Conduction Studies (NCS) at baseline, 3 weeks after 
completion of chemotherapy and 6 months follow up in treated and untreated extremities.  
2. Correlating rates and severity of CIPN and oncholysis with the gene expression profiles of TRPA1, 
TRPV1 and TRPM8 genes. Genetic material for sequencing will be isolated from peripheral blood. 
3. Correlating quantitative sensory testing of TrpA1 activation with rates and severity of CIPN.  
 
Inclusion and Exclusion Criteria 
 
Inclusion Criteria: 
• 
Histologically confirmed diagnosis of early stage breast cancer (stage I-III).  
• 
Planned to receive treatment with either adjuvant or neo-adjuvant taxane-based chemotherapy. 
• 
Age > 18 years. There is no upper age limit for participation in this study. 
• 
Patients may have received any of the following therapies: surgery, chemotherapy, hormones, 
biologics, or radiation. 
• 
Prior chemotherapies are permitted, except with prior treatments with taxanes, vinca alcaloids, 
gemcitabine, eribulin, ixabepilone, platinum drugs 
• 
All patients will have given signed, informed consent prior to registration  
• 
Patients must have a performance status of ECOG 0 or 1.  
 
Exclusion Criteria 
• 
Patients must not have received any prior taxane or platinum based chemotherapy.  
• 
Patients must not have a history of peripheral neuropathy (regardless of cause). 
• 
Patient must not have a history of Raynaud’s disease. 
• 
Patients with partial or complete limb amputations. 
• 
Known hypersensitivity to cold  
• 
Patient cannot be on the following medications: GABA analogues (such as Neurontin, Lyrica), tricyclic 
antidepressants (such as amitriptyline or nortriptyline) 
• 
As judged by the investigator, severe uncontrolled concurrent medical conditions, psychiatric illness or 
social condition that would limit compliance with study requirements.  
• 
Evidence of any significant clinical disorder or laboratory finding that makes it undesirable for the subject 
to participate in the clinical trial 

 
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• 
Must not be pregnant or breast feeding  
 
Study Schedule  
Screening 
C1D1 
D1 each cycle 
End of Tx (+/- 7 
days) 
6 month FU 
(+/- 7 days) 
Eligibility Criteria9  
X 
X 
 
 
 
History & Physical 8,9 
X 
X 
X 
X 
X 
Vital Signs, Height and Weight9 
 
X 
X 
X 
X 
ECOG8,9 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
CBC, CMP Serum 8,9 
X 
 
X 
X 
X 
TSH, Folate, B12, HbA1c, purple top for next 
gen sequencing 
X 
 
 
 
 
Pregnancy Test2 
X 
 
 
 
 
Adverse Events1,8 
Sensory neuropathy, nail toxicity, photo of hands and feet 
 
X 
X 
X 
X 
Concurrent medication review8,9 
X 
X 
X 
X 
X 
NCS4  
X 
 
 
X 
X 
Patient questionnaires 
BPI, EORTC-CIPN20, NPSI (verbal) 
 
X 
X 
X 
X 
Elasto-Gel treatment  
 
 
X7 
 
 
TrpA1 QST with mustard oil  
 
X5 
 
 
 
 
1 - NCI-CTCAE v4.03 will be used to document adverse events.   
2 - For women who are not post-menopausal for 1 year or more 
3-  Within 28 days of C1D1 
4 – NCS Screening/Baseline NCS is the same NCS. End of Treatment NCS to be done 3 weeks post last day of last chemo cycle (+1 week window allowed and 6 
months post last day of chemo),  
5 – Sensory Testing on C1D1 to be done 15 minutes prior to cryotherapy on arm to be treated with cryotherapy and 15 minutes post infusion on opposite non-
treated arm.  
6 – Also, to be done at C5D1 and C6D1 if applicable depending on SOC treatment schedule per treating oncologists discretion. 
7 - Will be worn each treatment day. Assessments done on Day 1 of each cycle. Elasto-Gel treatment worn on every day patient receives taxane infusion. 
8 - + 3 days between PE, ECOG, labs and taxane infusion 
9 – Can occur up to and including C1D1 
 

 
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Master Table of Study Assessments 
 
Baseline  C1D1 
C2D1  
C3D1 
C4D16 
End of Tx (+/- 
7 days) (i.e.3 
weeks post 
Last Day of 
Last Chemo 
Cycle)  
6 month FU (+/- 
7 days) (i.e.6 
months post 
Last Day of Last 
Chemo Cycle) 
Surveys/Observational Data  
Patient Information Questionnaire 
Appendix 1 
X 
 
 
 
 
 
 
CTCAE V4.03: Neuropathy  
Appendix 3 
 
X 
X 
X 
X 
X 
X 
CTCAE V4.03: Nail Toxicity 
Appendix 3 
 
X 
X 
X 
X 
X 
X 
Brief Pain Inventory (BPI) 
Appendix 4  
 
X 
X 
X 
X 
X 
X 
EORTC Quality of Life – CIPN 20 
Appendix 5  
 
X 
X 
X 
X 
X 
X 
Neuropathic Pain Symptom 
Inventory (NPSI)  
Appendix 6 
 
X 
X 
X 
X 
X 
X 
Quantitative Testing  
Quantitative Sensory Test (QST) 
Pre-chemo. Appendix 7 
X 
 
 
 
 
 
 
Quantitative Sensory Test (QST) 
Post-chemo. Appendix 8 
 
 
 
 
 
X 
X 
Nerve Conduction Study (NCS)4 
X 
 
 
 
 
X 
X 
Additional Assessments  
Blood Draw for Gene Expression 
Profiles  
X 
 
 
 
 
 
 
Sensory Testing for TrpA1 
Activation. Appendix 9 
 
X5 
 
 
 
 
 
 
Study Design  
 
Overview: 
This is a therapeutic study investigating the use of cryotherapy in the prevention of taxane-induced peripheral 
neuropathy and associated nail toxicities. Study subjects will be recruited primarily at the Mays Cancer Center 
Breast Oncology Clinic. Patients who are to receive taxane based chemotherapy regimens as part of their breast 
cancer treatment will be offered participation in the trial. Informed consent will take place at the Mays Cancer 
Center. A member of the patient’s medical team will introduce the coordinator, who will present the study and 
answer any questions or concerns of the patient. Once consented, the patient will complete the Patient 
Information Questionnaire and schedule a time for baseline data collection (Appendix 1). The questionnaire will 
cover: history of diabetes, peripheral vascular disease, Raynaud’s, smoking, alcohol use, recent weight changes, 
current medications, as well as history of surgery to the extremities, pre-existing neurological conditions, and 
current activity level. Several of these demographic characteristics are suspected to be risk factors in the 
development of CIPN (e.g., diabetes, and alcoholism). Other risk factors have been implicated in the 
development of peripheral neuropathy not related to CIPN (e.g., statins, weight loss, pre-existing neurologic 
conditions). 
 
Administration of therapy and assessments will take place in the Breast Oncology Clinic and Infusion Clinics at 
the Mays Cancer Center. A member of the research team will administer the neurological exams and 
questionnaires at each specified time point.  The therapeutic intervention will involve patients wearing an Elasto-
Gel cold glove and wrap on either their right or left side of their body, acting as their own controls. The treatment 
side will be determined by right or left side dominance and will be randomized based on dominance. Patients 

 
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will be given a randomization number once all screening procedures are performed. Patients with even study 
numbers will wear the gloves and wraps on their dominant hand and foot while patients with odd study numbers 
will wear the gloves on their non-dominant side. The patients will wear the glove and wrap during each taxane 
treatment session. Patients who do not start treatment will be given a screen fail number and not included in the 
randomization sequence.  
 
This is an ideal study for a paired design, as patients will be their own control as only the right or the left sided 
extremities will have the cold glove and wrap applied. The value of a paired design is that it reduces undesirable 
variability because data from the same subject are much less variable than data from different subjects. It also 
insures exact matching of the treatment and non-treatment sides with respect to race, gender, age, and other 
potentially confounding variable. The cold therapy treatment side will be assigned, according to the patients 
assigned study number at the time of eligibility. The purpose of stratifying by dominance is to make sure that we 
don’t end up with, for example, the treatment being more likely to be assigned to the non-dominant hand. Since 
the non-dominant hand gets less use and wear and tear than the dominant hand, it’s possible that neuropathy 
would tend to be less severe or less noticed in the non-dominant hand. 
  
The efficacy of cryotherapy will be assessed with evaluation of patient reported adverse events using version 
4.03 of the CTCAE for neuropathy and nail toxicities, validated patient symptom surveys, focused neurological 
evaluations and NCS’s.  Completion of these questionnaires will not require extra time outside of the patients 
scheduled appointments. Prior to beginning the cold therapy and taxane based chemotherapy, baseline data will 
be collected. If the patient is receiving anthracycline treatment, then this data can be collected during their last 
anthracycline infusion. If the patient is not receiving chemotherapy prior to starting on a taxane, then the baseline 
data with be collected at the clinic visit prior to starting taxane chemotherapy. The Post-Chemotherapy 
assessment will occur approximately 3 weeks (+ 1 week) after the patient’s last chemotherapy treatment cycle 
end date. It may require a separate trip to clinic at a time that is convenient for them. At all-time points, a member 
of the research staff will meet with the patient to complete the questionnaires and quantitative sensory tests. The 
Study Schedule outlines all of the assessments and the timing of those assessments during the study period. All 
assessment tools can be found in referenced section in the appendices section.  
 
Patient questionnaires will be completed prior to starting taxane based chemotherapy, every cycle of treatment, 
three weeks after last dose of taxane and 6 months after completion of taxane therapy.   
 
Assessments will be administered by a member of the research team who has personal qualifications to perform 
neurological exams.  
 
Nerve Conduction Studies (NCS)  will be completed at the neurology clinic at the MARC within 28 days of starting 
taxane chemotherapy for baseline, 3 weeks after completion of taxane chemotherapy, and again 6 months after 
completion of taxane chemotherapy. NCS will be completed and interpreted by a neurologist. One additional 
tube of blood (5ml) will be collected prior to starting on treatment for next-gen sequencing for TRPA1, TRPV1, 
and TRPM8 expression.  These expression profiles will be analyzed and correlated to patient symptom severity, 
sensory testing and NCS findings. Sensory testing for TrpA1 activation will also be completed prior to the first 
infusion of taxane chemotherapy. This pre-treatment assessment will be completed in the chemotherapy infusion 
clinic during the first chemotherapy session and involves the topical application of mustard oil to the patient’s 
forearm that is receiving the cold glove therapy. It will then be applied to the forearm not receiving cold glove 
therapy after taxane is completed. The first application is prior to taxane infusion to the treatment side receiving 
cold therapy, and the second is at the conclusion of the taxane infusion to the control side not receiving cold 
therapy. The degree of patient report punctate hyperalgesia. will be recorded by the researcher after each 
application of the mustard oil. The full protocol is listed in appendix 9 and is estimated to take appropriately 40 
minutes of active time. Patient will not have any additional time requirement as this test will be done while the 
patient is in the chemotherapy infusion clinic for their scheduled chemotherapy.  
 
Recruitment:  

 
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This study seeks to enroll patients diagnosed with breast cancer, who will be receiving taxane-based 
chemotherapy. Patient accrual will occur by clinician referral. The primary source of accrual will be dependent 
on clinician referrals to the study-coordinator. The study will be presented monthly at the Women’s Cancer Site 
Team meeting and potential study candidates will be identified and screened for eligibility during regular 
encounters for their breast cancer treatment.  
 
Informed consent will take place in clinic. A member of the patient’s medical team will introduce the coordinator, 
who will present the study and answer any questions or concerns of the patient.  
 
Once consented, the patient will complete the Patient Questionnaire and schedule a time for baseline data 
collection (Appendix 1). The questionnaire will cover: history of diabetes, peripheral vascular disease, 
Raynaud’s, smoking, alcohol use, recent weight changes, current medications, as well as history of surgery to 
the extremities, pre-existing neurological conditions, and current activity level. Several of these demographic 
characteristics are suspected to be risk factors in the development of paclitaxel-induced peripheral neuropathy 
(e.g., diabetes, and alcoholism). Other risk factors have been implicated in the development of peripheral 
neuropathy not related to paclitaxel (e.g., statins, weight loss, pre-existing neurologic conditions). 
 
Dosage: 
Since we are not administering a drug, the study team will be required to make no dose modifications. All the 
patients enrolled in this study are being administered a taxane based regimen as part of their specific 
chemotherapy regimen. Therefore, any dose changes in the patient’s chemotherapy regimen will be executed 
by the cancer care team based on standard practices. All dose changes or delays in the subject’s chemotherapy 
regimen will be recorded in the study log as such fluctuations will likely impact the subject’s neuropathy. This 
study recognizes the necessity of dose-adjustments in cases of severe and debilitating peripheral neuropathy 
secondary to taxane therapy. The signs and symptoms observed and reports should be examined for 
correlations with the dose administered on a particular date.  The total dose of the patient’s taxane therapy will 
be collected and recorded in the Patient Data file (Appendix 2).  
 
If the patient is able to wear the glove and wrap for at least half of the infusion time, they can continue on study 
with intervention time noted. Patients will be allowed to continue with the cold therapy at subsequent 
chemotherapy treatments. The length of time in which they are able to maintain the cold therapy will be recorded 
in the Patient data file (appendix 2). 
 
Cold Therapy Treatment  
Duration of treatment: Patients will receive the cold therapy during the taxane portion of chemotherapy. The 
glove and wrap will be worn at every infusion. The glove and wrap will be worn for the duration of treatment 
including an additional 15 minutes before (± 20 minutes to accommodate for infusion nurse staffing and after the 
taxane infusion. However if the patient is able to maintain the cold therapy for at least 15 min prior to infusion 
and 50% of the infusion time, they will be considered as having received the full treatment. If the patient is unable 
to maintain the cold therapy for 50% of the infusion time for 2 consecutive treatments, then the patient will be 
withdrawn from the study for cold intolerance. The duration of the cold therapy will be recorded in the patient 
data file (appendix 2). In the event of trauma, not related to the study, to one or both extremities of the treatment 
side, treatment will be performed as tolerated applying the same rules as stated above. 
 
Administration: The side being treated will be determined by dominance, alternating between the non-dominant 
and dominant side. Patients will be randomized based on the assigned study number. Patients with even study 
numbers will wear the gloves and wraps on their dominant hand and foot while patients with odd study numbers 
will wear the gloves and wraps on their non-dominant side. As a sanitary measure, patients will wear a disposable 
glove and sock liner each time they wear the glove and wrap. The glove and wrap will be secured by a Velcro 
strap at the wrist and ankle per manufacture instructions. The glove and wrap need to be kept at an approximate 
temperature of 4ºC (a range of 3 ºC - 6 ºC is acceptable). The gloves and wraps will be stored in a designated 
freezer check at approximately 4ºC.  The study member will verify freezer temperature prior to starting the cold 
treatments and record this on provided study forms. In order to maintain cold therapy, gloves and wraps will be 

 
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replaced every 30-40 minutes during treatment. A member of the research team will be present during treatment 
to switch the gloves and wraps as needed within the time window. This research team member can be a 
chemotherapy infusion nurse, medical assistant, or the study coordinator depending on staffing needs on 
particular days. Length of treatment will vary between eight weeks and twelve weeks depending on if patient is 
prescribed bi-weekly or weekly paclitaxel treatments.  
 
• 
Every patient will wear an Elasto-Gel glove and wraps for the duration of each neurotoxic chemotherapy 
agent infused that they have scheduled as part of their treatment plan at the infusion clinic at the Mays 
Cancer Center. The Elasto-Gel glove and wrap are made of a glycerin-based gel that maintains its 
flexibility at a temperature of 4ºC. The cover material is a water resistant four-way stretchable fabric with 
straps at the wrist and ankle to assure good position.  
• 
Storage and stability: The gloves and wraps will be kept in a freezer located on the chemotherapy infusion 
room at the Mays Cancer Center. Each glove and wrap will be kept in individual plastic bags with the 
time placed in the fridge.  
• 
Preparation: Gloves and wraps must be refrigerated for at least three hours prior to use. Each glove or 
wrap will be tagged on the plastic bag with the time and date recorded when it is placed in the refrigerator. 
The refrigerate temperature will be logged prior to removal of glove or wrap.  
• 
Protocol: Patients will wear the glove and wrap on either the dominant hand or foot OR non-dominant 
hand and foot for the duration of each of their chemotherapy treatment (infusion). The gloves and wraps 
will be worn 15 minutes (± 20 minutes) prior to the start of the taxane infusion and 15 minutes after the 
completion this infusion. New cold gloves and wraps will be switched every 30-40 minutes until the end 
of each individual infusion in order to maintain the extremity cold with an ideal temperature of 
approximately 4ºC.  
• 
Patients unable to wear the glove and/or wrap for 15 minutes prior to the start of taxane infusion and at 
least 50% of infusion time for 2 consecutive treatments will be considered “not tolerant of cold therapy” 
and cold therapy will not be continued with subsequent infusions on study. However, if able to wear the 
glove and wrap for 15 minutes prior to the start of taxane chemotherapy and at least 50% of the infusion 
time, patients will be allowed to continue the cold therapy at their next chemotherapy treatment.  
• 
Use of the Elasto-Gel glove and wrap will be provided free of charge to patients.  
 
Assessments [Neurological Exams and Questionnaires] 
Patient Questionnaires  
At each of the six time points the Brief Pain Inventory (BPI) (Appendix 4), European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire Chemotherapy Induced Peripheral Neuropathy 20 
(EORTC QLQ-CIPN20) (Appendix 5), Neuropathic Pain Symptom Inventory (NPSI) (Appendix 6), will be 
administered. All questionnaires have been reproduced with permission from their authors.  
 
To complement the patient-reported contributions to symptom evaluation, the researcher will complete the 
National Cancer Institute Common Toxicity Criteria version 4.03 (NCI-CTC v 4.03) neuropathy sub-scales 
(peripheral sensory neuropathy) and nail toxicities for both the treated and not treated hands and feet (Appendix 
3).  A picture will also be taken of both hands and feet pre-, and post-taxane treatments to access the changes 
that may occur as well as help evaluate the glove and wrap efficacy of preventing nail toxicities.  
 
Quantitative Sensory Tests 
The focused neurological examination will quantitatively measure the subject’s sensitivity to noxious semi-sharp 
pin-prick stimuli, fine motor skills/manual dexterity, as well as vibration detection threshold. These measures are 
currently used in a study looking into the prevalence of paclitaxel-induced peripheral neuropathy.  
 
Although no gold standard for QST assessment has been developed and accepted, an examination of the current 
literature reveals that when CIPN patients complete anatomical pain diagrams to visually characterize the 
location and intensity of their symptoms, the result is frequently a “stocking and glove” distribution[5]. The 
symptoms of this neuropathy are usually symmetrically manifested with no significant right-to-left difference 
[6,13].  

 
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There are currently a few protocols available which can assess CIPN in a clinical setting [5,7,11,12]. Rolke et al, 
has written a Quantitative Sensory Tests protocol that details non-invasive tests to determine the presence of 
neuropathy. The protocol is well-accepted and has been validated in numerous CIPN studies. It also serves as 
a guide in a current study looking into the prevalence of PIPN.  
 
To monitor the efficacy of the cold therapy, the following QST described below (with the exception of the fine 
motor tests) which will be administered on the right and left sides as well as both hands and feet.  
 
Monofilaments for Touch Stimulus 
To determine the subject’s sensitivity innocuous mechanical touch stimulation, we will use a set of Semmes-
Weinstein Monofilaments called The Touch-Test™ Sensory Evaluators ( .008 g - 300 g) produced by North 
Coast Medical, Inc. The monofilaments will be used to apply the stimulus via the “method of limits” on the 
patient’s right and left upper and lower extremity: the glabrous tip of the right and left index finger and at the tip 
of the hallux of the foot on both sides.  
 
To begin, we will ask the patient to place her right or left forearm on a stable surface with her palm up and face 
away with her eyes closed. The patient will be told to vocally say “Yes” to when she feels the stimulus. Nonverbal 
patients may tap the table lightly with the opposite hand (not being tested) when the stimulus is felt. The lightest 
monofilament in the set (.008 g) will be touched to the skin of the fingertip and depressed until it bows. Using a 
stopwatch for accuracy, the researcher holds the filament in this position for 2 seconds and then smoothly raises 
it. If the subject does not indicate that she felt a stimulus, then the researcher uses the next-lightest monofilament 
in the set (.02 g) and applies the stimulus in the same manner (gently depress until it bows), for the same amount 
of time (2 seconds) to a slightly different site on the fingertip. If the patient indicates that she felt the stimulus, 
then the researcher returns to the previous monofilament (.008 g). If the patient does not indicate that the 
stimulus was felt, then the researcher again moves to the next monofilament in the set (.04 g). This pattern is 
repeated until a total of five (5) stimuli have been applied. These data are recorded on the Monofilament Data 
Sheet, part of the Quantitative Sensory Test Data (Appendix 7) and then entered into a spreadsheet, which will 
determine the patient’s final threshold (the geometric mean of the five-recorded weights) and generate a 
graphical representation of this datum to be used later in analysis. If paclitaxel-induced peripheral neuropathy 
causes an increase in sensitivity, then a significant disparity will appear between the “before paclitaxel” threshold 
and the “after paclitaxel” threshold. 
 
25 –hole Pegboard test for Manual Dexterity 
To assess the subject’s manual dexterity, we will administer a 25-hole pegboard test manufactured by Lafayette 
Instrument Company. At each time point, the researcher will give the patient a practice test. The patient will be 
asked to use her dominant hand to pick up the pegs one at a time from the container and place them in the holes 
until all 25 holes are filled. This time will be recorded in 25-Hole Peg Test Data Sheet. 
 
Rydel-Seiffer tuning fork for Vibratory Detection Threshold 
The final sensory test will assess the patient’s ability to detect vibration. We will use the Rydel-Seiffer tuning fork 
produced by US Neurologicals. The tuning fork will be used on the following four regions of the patient’s right 
and left upper extremity and the right and left lower extremity: dorsum of index finger DIP joint, dorsum of IP of 
hallux (great toe) on both sides. 
 
The researcher will place the base of the tuning fork, with the dampers facing the researcher, on the bony 
prominences listed above. To create a vibration, the tynes are pressed together between the thumb and index 
finger then rapidly released. As the prongs start to oscillate, the illusion of two triangles is visible on each 
damper. These are black and white triangles on the dampers that are each marked with a scale from 0 to 8.  As 
the intensity of the vibration starts to diminish the two triangles move closer together again and their point of 
intersection moves slowly upward.  The intensity at which the patient no longer detects the vibration is read as 
the number adjacent the intersection of the vibrating triangles.  This number can be read off the white or black 
triangle depending on the amount of light available or which scale is more easily readable. According to 

 
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manufacturer instructions, the black triangle intersection from the base up and the white triangle intersection 
from the apex down seem to produce the most accurate readings between triangles for any particular moment 
in time.  
 
The patient will be told to vocally say “Yes” immediately once the vibration is no longer detected. (Reading the 
tuning fork assessment)This procedure will then be repeated four more times per region (fingertip and toe), with 
the first reading being discarded and the last three being recorded on the Vibration Test data section of the 
Quantitative Sensory Tests Data sheet. 
 
RESPONSE ASSESSMENT 
The primary objective of this study is to reduce or prevent paclitaxel-induced peripheral neuropathy. The primary 
focuses of concerns being the pain and oncholysis that often occur during the paclitaxel portion of the patient’s 
chemotherapy regimen. Therefore, the response assessment will involve a comparison of the patient’s treated 
hand and foot with the non-treated hand and foot. Allowing the patients to act as their own controls will reduce 
variability, ensuring the matching of the treated and non-treated sides with respect to demographic differences 
and potentially confounding variables. 
 
Data Management/Interpretation of Results 
Redcap and Velos will be used for data management and statistical analysis. All data will be coded and entered 
into a database by a research assistant and checked for errors by the principal investigator. Manipulation, 
analysis, and reporting of the data will be performed in an aggregate fashion and in no way will identify individual 
subjects. Data will be maintained by study personnel in a secure location, within a locked office and a password 
protected computer. Both databases are supported by UT Health Cancer Center and are password secured.  
 
Because the data will have statistically non-normal distributions, nonparametric statistical methods will be used 
to analyze the data. The analyses will be done separately for each time point. A 0.05 significance level will be 
used for all statistical two-sided tests 
 
Null and Alternative Hypotheses 
The test for the primary efficacy will be performed with respect to cryotherapy versus control. The untreated hand 
or feet will act as control for each patient. The difference between cryotherapy and control in NCI-CTC at 8 or 
12 weeks will be used for analysis for the primary endpoint.  
 
The null hypothesis tested for the primary efficacy analysis is that the difference between cryotherapy and control 
in NCI-CTC score at 8 or 12 weeks equals zero. The alternative hypothesis is that the difference in NCI-CTC 
score does not equal zero. To test the null hypothesis, one-sample paired t-tests will be used for continuously 
distributed outcomes and McNemar tests will be used for binary outcomes. 
 
Randomization for the Cold Gloves 
Determining right or left side dominance is important prior to the study in order to establish randomization. The 
purpose of stratifying by dominance is to avoid biasing the intervention to the dominant hand.  Since the non-
dominant hand utilized less for activity, it’s possible that neuropathy could be perceived as less severe in the 
non-dominant hand. Patients with even study numbers will wear the gloves and wraps on their dominant hand 
and foot while patients with odd study numbers will wear the gloves and wraps on their non-dominant side. 
 
Sample Size Calculation 
With regard to the occurrence of adverse events as assessed by the NCI-CTC method and dichotomizing this 
outcome to none or at least one, a sample size of 63 pairs achieves 80% power to detect an odds ratio of 2.9 
using a two-sided McNemar test with a significance level of 0.05. The odds ratio is equivalent to a difference 
between two paired proportions of 0.27 which occurs when the proportion in one off diagonal cell is 0.41 and 
the proportion in the other off diagonal is 0.14 and the proportion of discordant pairs is 0.55. Due to possibility 
of drop out, the target accrual is 65 patients.  
 

 
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Statistical Methods 
The significance of within-subject changes in the BPI and EORTC and NPSI scores will be assessed with paired-
tests.  Other continuously distributed secondary outcomes will be assessed similarly.  The significance of within-
subject changes in binary outcomes will be assessed with McNemar tests.  All statistical testing will be two-sided 
with a significance level of 5%.  SAS Version 9.4 or R will be used throughout. 
 
8.3 Infection Control Intervention: 
The same set of gloves and wraps will be used for multiple patients. Thus, preventive measures will be made in 
order to decrease the chances of infection spread between patients. After each use, the gloves and wraps will 
be wiped down with an antibacterial and antiseptic wipe, and patients will wear a disposable standard medical 
glove and a disposable shoe liner during each infusion.  
 
8.4 Dosage of Anti-Cancer Therapy 
Since we are not administering a drug, the study team will be required to make no dose modifications. All the 
patients enrolled in this study are being administered anti-drug therapy that is well known to cause CIPN like 
taxanes. Therefore, any dose changes in the patient’s chemotherapy regimen will be made by the adult medical 
oncology team and not by the clinical trial team. All dose changes or delays in the subject’s chemotherapy 
regimen will be recorded in the study log as these fluctuations will likely impact the subject’s risk of developing 
neuropathy. The total dose of the anti-cancer drug will be recorded in the Patient Data File (Appendix 2).  
 
This study recognizes the necessity of dose-adjustments in cases of severe and debilitating peripheral 
neuropathy secondary to anti-cancer therapy. The signs and symptoms observed should be examined for 
correlations with the dose administered on a particular date. Any dose reductions due to the occurrence of any 
toxicity from anti-cancer therapy will also be recorded in the same data file.  
 
8.5 Discontinuation of Cold Gloves Therapy 
• 
Patients will discontinue the cold glove and wrap therapy if they are not able to complete at least 50% of 
the infusion time for 2 consecutive treatments.  
• 
Development of grade 2 nail toxicities or neuropathy on the treated extremity that is not also present on 
the non-treatment extremity.  
• 
Discontinuation of taxane based chemotherapy regimen   
• 
Patients may withdraw consent at any time. 
 
8.6 Next-gen sequencing for Correlative Studies: Correlative studies will be conducted as secondary outcome 
measure to provide information on toxicity prediction. One purple top tube of peripheral blood (approximately 5 
cc) will be collected at baseline and sent for next-gen sequencing assays for TRPA1, TRPV1 and TRPM8 
which will take place at the lab of Dr Benjamin Eaton at UT Health San Antonio. This single tube will be placed 
on ice, marked with study ID number and delivered to Dr. Eaton’s lab for processing.  
 
Data and Safety Monitoring  
A Data and Safety Monitoring Plan (DSMP) is required for all an individual protocols conducted at The Mays 
Cancer Center. All protocols conducted at the Mays Cancer Center are covered under the auspices of the Mays 
Cancer Center Institutional Data Safety Monitoring Plan.   
 
The Mays Cancer Center Institutional DSMP global policies provide individual trials with:  
• 
institutional policies and procedures for institutional data safety and monitoring,  
• 
an institutional guide to follow, 
• 
monitoring of protocol accrual by the Mays Cancer Center Protocol Review Committee, 
• 
review of study forms and orders by the Forms Committee, 
• 
tools for monitoring safety events, 
• 
monitoring of UPIRSO’s by the Director of Quality Assurance and DSMC, 
• 
determining level of risk (Priority of Audit Level Score – PALS),  
• 
oversight by the Data Safety Monitoring Committee (DSMC), and 

 
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• 
verification of protocol adherence via annual audit for all Investigator Initiated Studies by the Mays 
Cancer Center Quality Assurance Division. 
 
Monitoring Safety: 
Due to the low risk associated with participation in this protocol, the Principal Investigator will perform primary 
assessment of adverse events, adverse event trends and treatment effects on this study.  The PI will conduct 
independent semi-annual review and report findings to the Mays Cancer Center Data Safety Monitoring Board 
(DSMB) and the UT Health San Antonio IRB.  
 
Baseline events and adverse events will be captured using the Mays Cancer Center Master Adverse Events 
Document for each patient using CTCAE V 4.03 for the grading and attribution of adverse events. Usage of the 
Mays Cancer Center Master Adverse Events Document centrally documents: 
• 
the event and grades the seriousness of it,  
• 
if the event was a change from baseline,   
• 
determines the relationship between the event and study intervention,  
• 
if the event was part of the normal disease process, and  
• 
what actions were taken as a result of the event.  
 
Safety Definitions: 
For this study, the following safety definitions will be applicable: 
 
Adverse Event Definition: An adverse event (AE) is defined as any untoward or unfavorable medical occurrence 
in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, whether or not 
considered related to the subject’s participation in the research  For this study, all adverse events will be 
documented starting with the first use of the cold therapy device  and ending 30 days after the last dose use of 
the cold therapy device, regardless of the length of time the device was used.  
 
Serious Adverse Event Definition: is any adverse event that: 
1. results in death; 
2. is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
3. results in inpatient hospitalization or prolongation of existing hospitalization; 
4. results in a persistent or significant disability/incapacity; 
5. results in a congenital anomaly/birth defect; or 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical 
or surgical intervention to prevent one of the other outcomes listed in this definition  
 
Unanticipated Problems Involving Risks to Subjects or Others Definition: Unanticipated problem involving risk to 
subjects or others includes any incident, experience or outcome that meets all of the following criteria: 
 
A. 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 (note: the 
unfounded classification of a serious adverse event as “anticipated” constitutes serious non-compliance); 
B. definitely related or probably related to participation in the research; and 
C. 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 
 
Reporting Requirements 
For this study, all Master Adverse Events Documents collected on patients for this protocol will be reviewed by 
the Principal Investigator on a monthly basis to determine if a serious safety problem has emerged that result in 
a change or early termination of a protocol such as: 
• 
suspending enrollment due to safety or efficacy, or 

 
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• 
termination of the study due to a significant change in risks or benefits.   
 
Endpoints for termination of the study are: frostbites. If there are more than 5% of patients with frostbites then 
the study will be terminated 
 
As per the Mays Cancer Center DSMP, any protocol modifications, problematic safety reports, unanticipated 
problems, and suspension or early termination of a trial must be reported to all members of the research team.  
Suspension and early termination of a trial must also be reported immediately to the Director of Quality 
Assurance (DQA) who will promptly notify the sponsor and the UT Health San Antonio IRB.  
 
The PI will review the Master Adverse Events document to determine the significance of the reported events and 
will file the Investigator Initiated Study Quarterly DSM Report Form on a semi-annual basis with the Mays Cancer 
Center DSMC.  The Investigator Initiated Study Quarterly DSMB Report Form includes information on adverse 
events, current dose levels, number of patients enrolled, significant toxicities per the protocol, patient status 
(morbidity and mortality), dose adjustments with observed response, and any interim findings.  Any trend 
consisting of three or more of the same event will be reported to the Mays Cancer Center DSMB for independent 
review outside of the quarterly reporting cycle, which begins three months following protocol start up. Conflict of 
interest is avoided by the independent review of the Mays Cancer Center DSMC and by ongoing independent 
review of adverse events trends by the Director of Quality Assurance.  
 
All SAE and UPRISO’s will be reported following the Mays Cancer Center and UT Health San Antonio institutional 
guidelines. 
UTHSCSA SAE/UPRISO REPORTING REQUIREMENTS 
Type Event 
Report to 
Timeframe 
All AE, SAE and UPIRSO 
Regulatory Affairs and DQA 
Same as other notification timeframes 
except for SAE/AE which should be 
reported on Monday for the prior week 
SAE 
Clinical Trial Sponsor 
within 24 hours 
AE/SAE 
UT Health San Antonio IRB 
Annually 
UPIRSO - all 
Clinical Trial Sponsor 
within 24 hours of the PI determining a 
UPIRSO exists 
UPIRSO - life threatening 
UT Health San Antonio IRB 
within 48 hours of the PI determining a 
UPIRSO exists 
UPIRSO - non-life threatening 
UT Health San Antonio IRB 
within 7 days of the PI determining a 
UPIRSO exists 
 
Sponsor-Investigators are responsible for investigating all safety concerns and reporting to both the FDA and 
the IRB as needed.  
 
An unanticipated adverse device effect is “any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects” (21 CFR 812.3(s)).  
 
Any unanticipated adverse device events must be reported to FDA and the reviewing IRB as well as all 
participating investigators within 10 working days after the Sponsor-Investigator is aware of the occurrence. The 
FDA and IRB may request additional reports. Such reports should be clearly labeled “IDE Safety Report 
 
AE’s and SAE events that occur in subjects enrolled in this clinical trial should be reported under the IDE program 
(21 CFR 812.150) using FDA's MedWatch Form 3500.  
  

 
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Assuring Compliance with Protocol and Data Accuracy 
As with all studies conducted at the Mays Cancer Center, the PI has ultimate responsibility for ensuring protocol 
compliance, data accuracy/integrity and responding to recommendations that emanate from monitoring 
activities.   Source verification of data will be performed every 12 weeks Protocol compliance, data accuracy and 
reporting of events is further ensured by an annual audit conducted by the Data Safety Officer, whose audit 
report is shared with the PI, the research team, and will be reviewed by the Mays Cancer Center DSMC.  
 
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27. Julius, D., 2013. TRP Channels and Pain. Annual review of cell and developmental biology, 29(1), 
pp.355–384. 
28. Li, Y. et al., 2015. The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory 
Neuron Responses to TRPV1 by Activation of TLR4. Journal of Neuroscience, 35(39), pp.13487–
13500. 
29. re, D.A.B. et al., 2012. Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced 
diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 
sensitization. Pain, 153(3), pp.553–561. 
30. McCarthy, Alexandra L., Ramon Z. Shaban, Kerri Gillespie, y Joanne Vick. “Cryotherapy for Docetaxel-
Induced Hand and Nail Toxicity: Randomised Control Trial”. Supportive Care in Cancer 22, num. 5 (May 
2014): 1375–83. doi:10.1007/s00520-013-2095-x. 
31. Scotte F, Tourani JM, Banu E, Peyromaure M, Levy E, Marsan S et al. (2005) Multicenter study of a 
frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. J Clin Oncol 
23:4424–4429 
32.  Can G, Aydiner A, Cavdar I (2012) Taxane-induced nail changes: predictors and efficacy of the use of 
frozen gloves and socks in the prevention of nail toxicity. Euro J Oncol Nurs 16:270–275 
33. Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athmann LM, Therneau TM, Sorensen JM, Gainey DK, 
Mailliard JA, Gusa NL et al (1991) Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin 
Oncol 9(3):449–452 
34. Katsimbri P, Bamias A, Pavlidis N (2000) Prevention of chemotherapy-induced alopecia using an 
effective scalp cooling system. Eur J Cancer 36(6):766–771 
35. Scotte, F. “Multicenter Study of a Frozen Glove to Prevent Docetaxel-Induced Onycholysis and 
Cutaneous Toxicity of the Hand”. Journal of Clinical Oncology 23, num. 19 (1 of July 2005): 4424–29. 
doi:10.1200/JCO.2005.15.651. 
36. Scotté, Florian, Eugeniu Banu, Jacques Medioni, Eric Levy, Christelle Ebenezer, Sandrine Marsan, 
Adela Banu, Jean Marc Tourani, Jean-Marie Andrieu, y Stéphane Oudard. “Matched Case-Control 
Phase 2 Study to Evaluate the Use of a Frozen Sock to Prevent Docetaxel-Induced Onycholysis and 

 
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Cutaneous Toxicity of the Foot”. Cancer 112, num. 7 (1 of April 2008): 1625–31. 
doi:10.1002/cncr.23333. 
37. Reyes-Gibby, Cielito, Phuong Khanh Morrow, Michael I. Bennett, Mark P. Jensen, y Sanjay Shete. 
“Neuropathic Pain in Breast Cancer Survivors: Using the ID Pain as a Screening Tool”. Journal of Pain 
and Symptom Management 39, núm. 5 (mayo de 2010): 882–89. 
doi:10.1016/j.jpainsymman.2009.09.020. 
38. Loprinzi, C. L., B. N. Reeves, S. R. Dakhil, J. A. Sloan, S. L. Wolf, K. N. Burger, A. Kamal, et al. 
“Natural History of Paclitaxel-Associated Acute Pain Syndrome: Prospective Cohort Study NCCTG 
N08C1”. Journal of Clinical Oncology 29, núm. 11 (10 of April 2011): 1472–78. 
doi:10.1200/JCO.2010.33.0308. 
39. Wood, Alastair J.J., Charles L. Shapiro, y Abram Recht. “Side Effects of Adjuvant Treatment of Breast 
Cancer”. New England Journal of Medicine 344, núm. 26 (28 of Junio 2001): 1997–2008. 
doi:10.1056/NEJM200106283442607. 

 
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Appendices 
 
1. Patient Information Questionnaire 
2. Patient Data File  
3. NCI-CTCAE Assessment for peripheral neuropathy and nail changes  
4. Brief Pain Index 
5. EORTC-CIPN 20 
6. NPSI Hand survey  
7. Quantitative Sensory Tests BASELINE 
8. Quantitative Sensory Tests POST CHEMO  
9. Quantitative Sensory Testing for TrpA1 Activation Protocol 
10.  Cold Glove and Cold Wrap Patient Dosing Record 
 
 

 
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Appendix 1: 
Patient ID: ___________________ 
Date: _______________________ 
Date of consent: _______________ 
 
Patient Information Questionnaire 
 
Thank you for participating in this study. This brief questionnaire will ask about your past health history. 
If any of the questions are unclear of you feel uncomfortable answering, please let me know. All 
answers will remain confidential and only be seen by those involved in this study.    
 
1.) Date of Birth (mm/dd/yyyy)  ____/_____/______ 
 
2.) Race: 
 
 
 American Indian or Alaska Native 
 
 Asian 
 
 Black or African American 
 
 Native Hawaiian or Other Pacific Islander 
 
 White (non-Hispanic) 
 
 White (Hispanic) 
 
 Other (please specify:) _______________ 
 
3.) Do you have a history of any of the following? (Please check all that apply) 
 
• Diabetes Year of diagnosis: ___________ 
• Peripheral Vascular Disease (numbness and tingling in your feet or hands) Year of diagnosis: 
_______________________ 
• Raynaud’s (Pain and color changes in hands and toes when exposed to cold) Year of 
diagnosis: _______________________ 
 
4.) Your particular chemotherapy regimen is often given to patients before or after surgery (i.e: 
lumpectomy, mastectomy or axial node dissection). Which applies to you? 
 
 I am receiving chemotherapy after surgery. 
 
 I am receiving chemotherapy before surgery. 
 
5.) How many alcoholic beverages do you consume per week (average): ________ 
For how many years have you been drinking? ____________ 
 
6.) Do you smoke?  Yes   No, I use to smoke  No, never smoked  

 
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If Yes, how many packs of cigarettes do you smoke each day: _____ 
 If you smoked in the past, Year Quit: ______________ 
 
For how many years have/did you smoked? _____ (Pack years:__________) 
 
7.) In the last six (6) months, approximately how much weight have you gained/lost:  
     (Please check one)         
           Gained: ______lbs 
 
Lost: _______lbs 
 
Virtually no change 
 
 
8.) Are you on a cholesterol-lowering statin drug?   
 
 
 I am not taking any statins 
 
 
     If Yes, please select which one(s) below: 
(If you have been on more than one, check each statin that applies and please write down how long 
you were taking that particular statin)  
 
 
 
Zocor (simvastatin)      _______ year(s) 
 
 
Lipitor (atorvastatin)     _______ year(s) 
 
 
Lescol (fluvastatin)       _______ year(s) 
 
 
Mevacor (lovastatin)     _______ year(s) 
 
 
Pravachol (pravastatin) _______ year(s) 
 
 
Crestor (rosuvastatin)    _______ year(s) 
        
9.) Past Surgical History 
 I have not had any surgeries 
Surgery: 
Date of Surgery: 
Carpal tunnel surgery 
 
Trauma surgery on arms 
 
Trauma surgery on legs 
 
Hip or knee replacement surgery 
 
Arthroscopic surgery on legs 
 
 
Surgery: 
Date of Surgery: Description: 

 
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Other 
surgery 
on 
Arm(s) or Hand(s) 
 
 
Other 
surgery 
on 
Leg(s) or Feet 
 
 
 
10.) What is your current physical activity level?    
Sedentary    Low    Moderate    Heavy 
What is your level of activity? 
 
Able to walk / run a mile in 15 minutes  
Able to walk 2 blocks without stopping  
Able to walk up a flight of stairs 
Able to complete normal activities of daily living 
 Unable to do any of the above activities 
 
11.) Do you have any skin problems? 
 
No 
Active Shingles 
Eczema 
Open Wound 
Ulcers 
New Rash 
Other________________________ 
 
 

 
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Appendix 2: 
 
PATIENT DATA FILE 
ID:  
 
 
Date of consent:  
 
 
 
 
CONTROL HAND/FEET: RIGHT or LEFT 
TREATED HAND/FEET: RIGHT or LEFT 
 
Lab Values: 
Chem Panel 
 
CBC 
Date: 
 
 
Date: 
 
Sodium 
 
 
White Cell 
 
Potassium 
 
 
Red Cell 
 
Chloride 
 
 
Hgb 
 
Glucose 
 
 
HCT 
 
BUN 
 
 
MCV 
 
Creatinine 
 
 
MCH 
 
Calcium 
 
 
MCHC 
 
 
 
 
RDW 
 
 
 
 
Plt 
 
 
Misc. Lab Values: 
TSH: 
 
 
Date drawn: 
 
Folate: 
 
 
Date drawn: 
 
HgA1c: 
 
 
Date drawn: 
 
B12:  
 
 
Date drawn: 
 
 
Current Weight:   
 
 lbs 
Date:  
 
 
 
Total Taxol Dose:   
 
mg/m2 
Paclitaxel dose: 
 
Paclitaxel 1 
Paclitaxel 2 
Paclitaxel 3 
Paclitaxel 4 
Date: 
 
 
 
 
Dose: 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
Dose: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 3 
 
 
4.03 

 
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V.4.03 

 
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V.4.03 

 
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Appendix 4: Brief Pain Index  
 
Patient ID:_______________ 
Date:____________________ 
Time point:_______________ 
 
BRIEF PAIN INVENTORY  
Copyright 1991 Charles S. Cleeland, Ph.D.  
Pain Research Group.  
Used by permission. 
 
 

 
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Patient ID:_______________ 
Date:____________________ 
Time point:_______________ 
 
 
 

 
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Appendix 5 
 
 
 
 

 
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Appendix 6 
 

 
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Appendix 7 
 
 
 
 
Performed by:________________________________     Date:____________ Time:___________ 

 
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Performed by:________________________________     Date:____________ Time:___________ 
 
 
Performed by:________________________________     Date:____________ Time:___________ 
 
 

 
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Appendix 8  
 
 
Performed by:________________________________     Date:____________ Time:___________ 
 

 
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Patient ID: ___________ 
 
Date:____________________ 
 
Performed by:______________________________________       Date:___________ Time:___________ 
 
 
 
Vibration Test using a Rydel-Seiffer tuning fork 
 
 
CONTROL: □ Right     □ Left 
 
 
Post-Chemo 
Hands 
Feet 
1 
 
 
2 
 
 
3 
 
 
average  
 
 
TREATED: □ Right     □ Left 
 
Post-Chemo 
Hands 
Feet 
1 
 
 
2 
 
 
3 
 
 
average  
 
 
Performed by:_______________________________________       Date:___________ Time:___________ 
 
 
 
Patient Satisfaction: 
 
On a scale from 0-4, how satisfied are you with the frozen glove and wrap treatment? 
 
0 being not at all satisfied to 4 being the most satisfied 
 
0 
1 
2 
3 
4 
 

 
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Appendix 9 
 
Quantitative Sensory Testing for TrpA1 activity 
 
Materials: 
500 ul Mustard Oil solution (400 ul mustard oil plus 100 ul olive oil) in 1.5 ml Eppendorf tube 
5-1.5 empty Eppendorf tubes 
5- square spot bandages (Band-Aid Tru-Stay Clear Spots) 
~5 inch strip of paper tape~5 inch strip of paper tape 
Von Frey fiber (4.0 g force) 
1 pencil or pen for patient 
 
Instructions: 
 
1) Prior to receiving chemotherapy, patient reports baseline arm pain on a scale of 1-10, 1=no pain and 10= 
worst pain ever to the treatment arm. Score is recorded on the MO data score sheet. 
 
2) The CIPN strip is prepared as follows: 
A. using a black Sharpie, write each number (1-5) on the back of the bandage. DO NOT write on the 
cotton pad. Number should be visible through paper tape. These can be made in advance.   
B. Attach numbered bandages side by side to the sticky side of a strip of paper tape. Remove bandage 
backing to expose cotton pads. 
C. Add 40 ul of appropriate test solution to the specific pad. A serial dilution is made as described 
below. 
D. Place a strip with wetted pads down on the ulnar region of the “treated: arm with spot #5 towards the 
wrist. Write numbers next to the appropriate bandage if needed for visualization.  
 
Serial dilution of Tube (#5 made first) for CIPN Strip:  
Tube # 
1 
2 
3 
4 
5 
Condition Veh only 1:250 dil 
1:50 dil 
1:10 dil 
1:2 dil 
Recipe  
100ul 
veh 
120ul 
veh + 
30ul #3 
120ul 
veh + 
30ul #4 
120ul veh 
+ 30ul #5 
100ul + 
100ul MO 
soln 
VEH=Olive Oil 
 
 
3)  After 10 minutes post-application, patients are asked to record responses on the data sheet 
 
4) The strip is removed and the technician records all spots with a visible flare by photograph. 
 
5) Patients are asked to look away and punctate hyperalgesia assayed using a single poke of Von Frey fiber 
(4g) beginning at spot #1 and moving towards spot #5.  Patients are asked to indicate when poke changes 
from a slight prick to something more painful.  Patients should also indicate which spots are numb to the poke. 
It is helpful for the patient if a couple of test pokes are administrated on the arm away from the test zone so 
they can get a sense of the baseline sensation. Scores are recorded on data sheet provided. 
 
6) After chemotherapy treatment, Steps 1-5 are repeated on opposite arm (the control arm). 

 
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MO Strip Data Sheet  
 
 
Patient: ____________________________________ 
A. To be completed prior to first chemotherapy  
drug infusion: Indicate the level of arm-specific pain today (1-10; 1=no pain and 10= worst pain ever): 
__________ 
 
 
Instructions: The MO strip is attached to the ulnar area of the patient's treatment arm. After 10 minutes the 
patient should answer the questions below (numbers refers to application spots on the strip):  
1) 
Indicate all numbers where you feel pain: 
 
 
1 
2 
3 
4 
5    NONE 
2) 
Indicate all numbers where you feel burning/stinging: 
1 
2 
3 
4 
5    NONE 
3) 
Indicate all numbers where you feel tingling/prickly:           1 
2 
3 
4 
5   NONE 
For the technician: 
4) 
Remove the MO strip and circle all numbers with a visible flare:  
1 
2 
3 
4 
5 
NONE 
 
Punctate hyperalgesia (4g Von Frey fiber) 
5) 
Indicate all numbers that feel painful to the touch of the fiber:       1 
2 
3 
4 
5 
NONE 
6) 
Indicate all numbers that feel numb to the touch fiber:                    1 
2 
3 
4 
5 
NONE 
Comments: 
 
 
 B. To be completed immediately after the first chemotherapy drug infusion: 
Indicate the level of arm-specific pain today (1-10; 1=no pain and 10=worst pain ever): ______ 
Instructions: The MO strip is attached to the ulnar area of the control arm. Incubate at room temp for 10 
minutes and then answer the questions below (numbers refer to application spots on strip): 
1) 
Indicate all numbers where you feel pain: 
 
 
1 
2 
3 
4 
5  NONE 
2) 
Indicate all numbers where you feel burning/stinging: 
1 
2 
3 
4 
5  NONE 
3) 
Indicate all numbers where you feel tingling/prickly:           1 
2 
3 
4 
5  NONE 
For the technician: 
4) 
Remove the MO strip and circle all numbers with a visible flare:  
1 
2 
3 
4 
5 
NONE 
 
Punctate hyperalgesia (4g Von Frey fiber) 
5) 
Indicate all numbers that feel painful to the touch of the fiber:      
1 
2 
3 
4 
5 
NONE 

 
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6) 
Indicate all numbers that feel numb to the touch fiber:                    1 
2 
3 
4 
5 
NONE 
Comments: 
 
 
 
 
 
 
 

 
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Appendix 10 
 
Cold Glove and Cold Wrap Patient Dosing Record 
 
Patient ID: _______________________ 
 
 
 
Treatment Date: 
Drug and Course #: 
Pre-med start time: 
Chemo Start time: 
□ Temp confirmed at approx. 4ᵒ C 
Actual Temp: 
Randomized to Dominant or Non-dominant 
side 
Corresponds to Left or Right side 
Glove 
Wrap 
Temp 
confirmed 
Time Applied 
Time 
Removed 
Temp 
confirmed 
Time applied 
Time 
removed 
#1 □ 
 
 
 
#1 □ 
 
 
#2 □ 
 
 
 
#2 □ 
 
 
#3 □ 
 
 
 
#3 □ 
 
 
#4 □ or 
□ N/A 
 
 
#4 □ or 
□ N/A 
 
 
#5 □ or 
□ N/A 
 
 
#5 □ or 
□ N/A 
 
 
#6 □ or 
□ N/A 
 
 
#6 □ or 
□ N/A 
 
 
#7 □ or 
□ N/A 
 
 
#7 □ or 
□ N/A 
 
 
Comments_______________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
_________________________________________________________________________ 
Name and Initials of Person(s) applying cryotherapy Treatment to Patient: 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
Date/Time of completion of cryotherapy: ________________________/__________________________