Randomized Controlled Selection Trial of Cryotherapy vs. Compression Therapy for the Prevention of Taxane-induced Peripheral Neuropathy in Breast Cancer Patients
Phase: NA
Conditions: CIPN - Chemotherapy-Induced Peripheral Neuropathy
Sponsor: Columbia University

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 02Mar2021 
1 
CUMC IRB#: AAAR9515 
Version Date: 02Mar2021 
TITLE: Randomized controlled selection trial of cryotherapy vs. compression therapy for 
the prevention of taxane-induced peripheral neuropathy in breast cancer patients 
Coordinating Center: 
Columbia University Medical Center 
Principal Investigator: 
Melissa Accordino 
Columbia University 
Herbert Irving Pavilion 
161 Fort Washington Avenue, HIP 10 
New York, NY 10032 
Phone: 212-305-1945 
FAX: 212-305-0178 
E-mail: mkg2134@cumc.columbia.edu 
Co-Investigators: 
Dawn L. Hershman 
Columbia University 
Herbert Irving Pavilion 
161 Fort Washington Avenue, HIP 10 
New York, NY 10032 
Phone: 212-305-1945 
Fax: 212-305-0178 
E-mail: dlh23@cumc.columbia.edu 
Katherine Crew 
Columbia University 
Herbert Irving Pavilion 
161 Fort Washington Avenue, HIP 10 
New York, NY 10032 
Phone: 212-305-1945 
Fax: 212-305-0178 
E-mail: kd59@cumc.columbia.edu 
Kevin Kalinsky 
Columbia University 
Herbert Irving Pavilion 
161 Fort Washington Avenue, HIP 10 
New York, NY 10032 
Phone: 212-305-1945 
FAX: 212-305-0178 
E-mail: kk2693@cumc.columbia.edu 
NCT03873272

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 02Mar2021 
2 
Meghna S. Trivedi 
Columbia University 
Herbert Irving Pavilion 
161 Fort Washington Avenue, HIP 10 
New York, NY 10032 
Phone: 212-305-1945 
FAX: 212-305-0178 
E-mail: mst2134@cumc.columbia.edu 
Statistician: 
Shing M. Lee 
Department of Biostatistics 
Columbia University 
722 W 168th St, 6th Floor, Room 645 
Phone: 212-342-1266 
Email: sml2114@columbia.edu 
Cheng-Shiun Leu 
Department of Biostatistics 
Columbia University 
722 W 168th St, 6th Floor, Room 650 
Email: cl94@columbia.edu 
Initial version: 6/12/2018 
Amended: 
2/26/2019 
Amended: 
9/3/2019 
Amended: 
1/16/2020 
Amended 
3/2/2021 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 02Mar2021 
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Protocol Signature Page 
 
 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol. I have read and understand 
the information in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks 
and potential benefits. I will promptly submit the protocol to the applicable IRB for review and 
approval. Once the protocol has been approved by the IRB, I understand that any modification 
made during the course of the study must first be approved by the IRB, prior to implementation 
except when such modification is made to remove an immediate hazard to the subject. I certify 
that I, and the study staff, have received the requisite training to conduct this research protocol. I 
agree to maintain adequate and accurate records in accordance with Columbia University and 
Herbert Irving Comprehensive Cancer Center policies, Federal, state and local laws and 
regulations. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator 
Date 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
 
Name of Institution 
Instructions to Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder. 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 02Mar2021 
4 
 
 
 
Protocol Synopsis 
 
Title 
Randomized controlled selection trial of cryotherapy vs. compression 
therapy for the prevention of taxane-induced peripheral neuropathy in 
breast cancer patients 
Short Title 
The CONTRoL Trial: Cryotherapy vs. cOmpression Neuropathy TRiaL 
Protocol Number 
AAAR9515 
Phase 
Phase 2B 
Methodology 
Randomized, placebo-controlled, clinical selection trial 
Study Duration 
18 months 
Study Center(s) 
Single-center - Columbia University Medical Center 
Objectives 
To select the best intervention from cold therapy, compression therapy 
and placebo at reducing neuropathic pain as measured by the change in 
the Neurotoxicity (NTX) component of the Functional Assessment of 
Cancer Therapy (FACT) -Taxane questionnaire, following 12 weeks of 
neoadjuvant/adjuvant chemotherapy with paclitaxel or docetaxel 
among breast cancer patients. 
Number of Subjects Up to 100 subjects 
Diagnosis and Main 
Inclusion Criteria 
Stage I-III breast cancer receiving adjuvant or neoadjuvant nab 
paclitaxel, paclitaxel or docetaxel for at least 12 weeks. 
Study Product, 
Dose, Route, 
Regimen 
Product #1: Frozen garment on hands and feet worn at least 15 minutes 
before chemotherapy infusion, during infusion and at least 15 minutes 
after infusion (total time 1.5-2 hours). 
Product #2: Compression garment for hands/arms and feet/legs worn at 
least 15 minutes before chemotherapy infusion, during infusion and at 
least15 minutes after infusion (total time 1.5-2 hours). 
Product #3: “Loose” garment for hands/arms and feet/legs worn at 
least 15 minutes before chemotherapy infusion, during infusion and at 
least 15 minutes after infusion (total time 1.5-2 hours). 
Duration of 
administration 
Products will be worn during each chemotherapy infusion for at least 12 
weeks of treatment. 
Reference therapy 
Not applicable 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 02Mar2021 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical 
Methodology 
Patients will be randomly assigned in triplets to receive either frozen 
gloves and socks, compression gloves and socks, or “loose” gloves and 
socks (placebo arm) during chemotherapy infusion. Randomization will 
be stratified by chemotherapy schedule (weekly vs q3week). The 
primary goal of the trial is to select the best intervention to be carried 
forward for further study, with a high probability of correct selection if 
one intervention is truly superior to the other two by a pre-specified 
effect size. Up to 100 patients will be enrolled in the study, using a novel 
sequential design based on the Levin-Robbins-Leu family of sequential 
selection procedures that allows for an early elimination of an apparently 
inferior arm. 
 
The primary endpoint of the study is the change in the neurotoxicity 
(NTX) component of the Functional Assessment of Cancer Therapy 
(FACT) -Taxane questionnaire at 12 weeks from baseline, with success 
being defined as a change in FACT NTX of less than 5 points from 
baseline. Each time an outcome is observed for all patients in a triplet 
(or, after elimination of one arm, a pair), those outcomes are added to a 
running tally of successes for each intervention. Pre-specified criteria 
for eliminating an inferior arm and for selecting the preferred 
intervention will be applied starting from the 15th patient. From that 
point forward, with this sequential procedure, the preferred intervention 
can be selected during the ongoing enrollment as soon as the pre- 
specified selection criteria are met, and further enrollment will cease. 

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Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 02Mar2021 
7 
 
 
 
Contents 
Protocol Signature Page ...................................................................................................................3 
1. 
Introduction ..........................................................................................................................9 
2. 
Study Objectives ..................................................................................................................9 
2.1 
Primary Objective ....................................................................................................9 
2.2 
Secondary Objectives ...............................................................................................9 
3. 
Background ..........................................................................................................................9 
4. 
INVESTIGATIONAL AGENT .........................................................................................10 
4.1 
Preclinical Data - N/A ............................................................................................10 
4.2 
Clinical Data to Date ..............................................................................................10 
4.3 
Other Agent(s)- N/A ..............................................................................................11 
5. 
Study Design ......................................................................................................................11 
5.1 
General Design .......................................................................................................11 
5.2 
Dose Limiting Toxicities - N/A .............................................................................13 
5.3 
Number of Patients .................................................................................................13 
6. 
Subject Selection and Withdrawal .....................................................................................13 
6.1 
Inclusion Criteria ....................................................................................................13 
6.2 
Exclusion Criteria ..................................................................................................13 
6.3 
Inclusion of Women and Minorities ......................................................................13 
6.4 
Subject Recruitment ...............................................................................................14 
6.5 
Early Withdrawal of Subjects .................................................................................14 
6.6 
CUMC Research Participant Registration ..............................................................15 
7. 
TREATMENT PLAN ............................................................................................................ 17 
7.1 
Agent Administration .............................................................................................17 
7.2 
General Concomitant Medication and Supportive Care Guidelines- N/A..............18 
7.3 
Duration of Therapy ...............................................................................................18 
7.4 
Duration of Follow Up ...........................................................................................18 
7.5 
Criteria for Removal from Study ...........................................................................18 
8. 
DOSING DELAYS/DOSE MODIFICATIONS - N/A ......................................................18 
9. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................. 18 
9.1 
Adverse Events ...................................................................................................................19 
9.2 
Definitions ..............................................................................................................19 
9.3 
Recording of Adverse Events .................................................................................22 
9.4 
Reporting of Serious Adverse Events ....................................................................22 
9.5 
Reporting Process ...................................................................................................23 

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Herbert Irving Comprehensive Cancer Center 
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9.6 
Description .............................................................................................................23 
9.7 
Treatment Regimen ................................................................................................23 
9.8 
Method for Assigning Subjects to Treatment Groups ............................................24 
9.9 
Preparation and Administration of Study Drug ......................................................24 
9.10 
Subject Compliance Monitoring ............................................................................24 
9.11 
Prior and Concomitant Therapy .............................................................................24 
9.12 
Packaging ...............................................................................................................24 
9.13 
Blinding of Study Drug ..........................................................................................24 
9.14 
Receiving, Storage, Dispensing and Return ...........................................................24 
9.15 
Other Agent(s)- N/A ..............................................................................................25 
10. 
STUDY CALENDAR ............................................................................................................ 25 
11. 
MEASUREMENT OF EFFECT ........................................................................................27 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................28 
12.1 
Data Collection .......................................................................................................28 
12.2 
Data Reporting .......................................................................................................29 
12.3 
Data and Safety Monitoring Committee ................................................................29 
12.4 
Quality Control and Quality Assurance .................................................................29 
12.5 
Confidentiality .......................................................................................................30 
12.6 
Source Documents .................................................................................................31 
12.7 
Case Report Forms .................................................................................................31 
12.8 
Records Retention ..................................................................................................31 
13. 
STATISTICAL CONSIDERATIONS ...............................................................................31 
13.1 
Study Implementation: ...........................................................................................31 
13.2 
Size/Accrual Rate ...................................................................................................37 
13.3 
Stratification Factors ..............................................................................................37 
13.4 
Analysis of Secondary Endpoints ..........................................................................37 
13.5 
Reporting and Exclusions .......................................................................................38 
14. 
Protection of Human Subjects ............................................................................................38 
15. 
Study Finances ...................................................................................................................39 
15.1 
Conflict of Interest ..................................................................................................... 39 
15.2 
Subject Stipends or Payments ................................................................................39 
16. 
Publication Plan .................................................................................................................39 
17. 
References ............................................................................................................................... 39 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 02Mar2021 
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1. INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Columbia University Medical Center institutional research policies and procedures. 
 
2. STUDY OBJECTIVES 
 
2.1 Primary Objective 
To select the best intervention from cold therapy, compression therapy and placebo at reducing 
neuropathic pain as measured by the change in the Neurotoxicity (NTX) component of the 
Functional Assessment of Cancer Therapy (FACT) -Taxane questionnaire , following 12 weeks 
of neoadjuvant/adjuvant chemotherapy with paclitaxel or docetaxel among breast cancer 
patients. 
 
2.2 Secondary Objectives 
 To estimate the change in severity of neuropathy as determined by the NCI-CTCAE by 
therapy. 
 To evaluate objective sensory and motor function change from baseline with the Neuropen, 
tuning fork, timed get up and go test, and tandem/unipedal stance test by therapy. 
 To assess cutaneous toxicity and onycholysis using the National Cancer Institute Common 
Toxicity Criteria (Version 2) by therapy. 
 To assess adherence to the intervention by therapy 
 To assess patient comfort to the intervention by therapy 
 To compare the degree of neuropathy among our intervention arms with historical control 
data 
 
3. BACKGROUND 
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect resulting from the 
administration of cytotoxic chemotherapeutic agents.  The incidence of CIPN can vary on the 
type of agent used, the frequency with which it is given, and the cumulative dose. Unfortunately, 
for some patients, symptoms may persist even after discontinuation of the drug due to 
irreversible nerve damage [1].  Furthermore, dose reduction or early termination of effective 
anti-cancer treatment may ultimately affect overall survival.  Despite multiple trials investigating 
various agents for the treatment of established CIPN, only duloxetine is recommended, based on 
efficacy data from a large randomized placebo-controlled trial [2]. Numerous trials have studied 
the efficacy of various pharmacologic agents and chemoprotectants in the prevention of CIPN 
including acetyl-l-carnitine (ALC), amifostine, amitriptyline, calcium and magnesium, 
diethyldithio-carbamate (DDTC), glutathione (GSH), nimodipine, org 2766, all-trans-retinoic 
acid, rhuLIF, vitamin E, N-acetylcysteine, carbamazepine, glutamate, goshajinkigan (GJG), 
omega-3 fatty acids, and oxycarbazepine. These agents have not shown any consistent and/or 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 16Jan2020 
 
 
conclusive clinically meaningful benefits when compared with placebo controls.  As of now, 
there are no established agents for CIPN prevention [3]. 
The taxanes, such as nab paclitaxel, paclitaxel or docetaxel, are effective chemotherapeutic 
agents used in a variety of malignant diseases such as breast, ovarian, prostate and lung cancer 
[4]. Clinical trials where patients received taxane-based therapy have reported up to 33% grades 
3-4 sensory neuropathy and up to 14% of motor neuropathy [5].  The sensory symptoms 
associated with taxane-induced peripheral neuropathy often begin in a "stocking-glove" pattern 
and is characterized by pain, numbness and tingling in the hands and feet. Patients may also 
experience motor deficits such as weakness, difficulty walking or dropping items [6].  Activities 
of daily living are often affected and can greatly impair a patient's quality of life [7]. Often 
patients who experience CIPN require dose reductions or cessation of the offending agent. 
Peripheral neuropathy is a disabling adverse effect of taxane therapy and no effective 
preventative treatment currently exists.  The purpose of this study is to directly compare the 
efficacy of compression therapy and cryotherapy to a control arm for the prevention of CIPN. 
We hope to overcome some of the study limitations and biases of the prior clinical trials with the 
current study design. Given the safety and tolerability of cold therapy and compression therapy, 
it is reasonable to test the efficacy of these non-pharmacological interventions in women with 
Stage I-III breast cancer receiving adjuvant or neoadjuvant paclitaxel or docetaxel for 12 weeks. 
 
 
4. INVESTIGATIONAL AGENT 
 
4.1 
Preclinical Data - N/A 
 
4.2 
Clinical Data to Date 
 
 
There have been several studies investigating potential pharmaceutical agents, herbal 
supplements and other modalities for the prevention and treatment of CIPN [8].  Recently, scalp 
cooling has been shown in a randomized clinical trial to reduce the incidence of chemotherapy- 
induced alopecia in breast cancer patients receiving taxanes and/or anthracyclines [9]. The 
rationale behind this therapy is cold temperature causes vasoconstriction, decreasing blood flow 
to the hair follicles and therefore reducing the amount of drug that reaches the follicles. This 
concept was applied by Scotté, et al. who evaluated frozen glove use in the prevention of 
docetaxel-induced nail and skin toxicity.  In this case control study, onycholysis and cutaneous 
toxicity was significantly lower in the hand with the frozen glove compared with the control 
hand (P = .0001).  Eleven percent of patients withdrew from the study due to cold intolerance 
[10]. 
In another prospective study, forty breast cancer patients were treated with weekly paclitaxel for 
12 cycles and wore frozen gloves and socks on the dominant side for 90 minutes [11]. 
Symptoms on the treated sides were compared to the untreated (non-dominant) side, which 
served as the control arm.  The primary endpoint assessed was tactile disturbance using a 
monofilament test.  Secondary endpoints included thermosensory disturbance, vibration 
perception, performance speed, patient neurotoxicity questionnaire (PNQ), electrophysiological 
10 

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signs, and pharmacokinetics. Tactile deterioration was significantly lower for the intervention 
side compared to the control side (hand: 27.8% vs. 80.6%, P < .001; foot: 25.0% vs. 63.9%, P < 
.001).  In addition, the incidence of severe CIPN (PNQ grades D or E) occurred less with 
cryotherapy (hand: 2.8% vs. 41.7%, P < .001; foot: 2.8% vs. 36.1%, P = .007). No patients 
dropped out due to cold intolerance.  Limitations of the study included no randomization, each 
subject acting as their own control, and lack of long term follow-up. 
Similar to cryotherapy, compression therapy can also decrease microvascular flow in the 
extremities.  In a self-controlled clinical trial, 42 patients with breast cancer wore two surgical 
gloves (one size smaller than the size that fit their dominant hand) for 90 minutes while receiving 
nab-paclitaxel [12].  The rates of grade 2 or higher sensory and motor neuropathy was 
significantly lower in the hand with the surgical gloves compared to the control hand (sensory 
neuropathy 21.4 vs. 76.1%; motor neuropathy 26.2 vs. 57.1%).  Furthermore, compression 
gloves significantly decreased the temperature of each fingertip by 1.6-2.2°C (P<.0001).  There 
were no withdrawals from the study due to intolerability of compression gloves. In this trial, 
peripheral neuropathy was only evaluated using subjective measures (CTCAE, PNQ) and feet 
were not addressed. 
 
4.3 Other Agent(s)- N/A 
 
5. STUDY DESIGN 
 
5.1 
General Design 
This is a randomized, placebo-controlled clinical selection trial of interventions for CIPN in 
patients treated with docetaxel every 3 weeks or paclitaxel on a weekly schedule.  Patients will 
be randomly assigned to receive either frozen gloves and socks, compression gloves and socks, 
or “loose” gloves and socks (placebo arm) during chemotherapy infusion.  The primary goal of 
the trial is to select the best intervention to be carried forward for further study, with a high 
probability of correct selection if one intervention is truly superior to the other two by a pre- 
specified effect size.  Up to 100 patients (with expected sample sizes between 60-70 patients for 
the most likely scenarios) will be enrolled in the study, using a novel sequential design that 
allows for an early elimination of an apparently inferior arm.  Initially the randomization will be 
blocked in triplets of patients within chemotherapy strata (every three weeks or weekly).  Each 
time an outcome is observed for all patients in a triplet, those outcomes are added to a running 
tally of successes for each intervention.  There is a pre-specified criterion in terms of the success 
tallies for eliminating arms as evidence of apparent inferiority accumulates. If and when one arm 
is eliminated, pairs of patients are thereafter randomly assigned to the two remaining 
interventions, and the trial continues until one of the remaining interventions is subsequently 
eliminated, at which time the apparently superior intervention is selected as the preferred 
intervention.  In the event that two arms are simultaneously eliminated at any given examination 
of triplet tallies, the trial terminates at that time with the selection of the apparently superior 
intervention.  With this sequential procedure, the preferred intervention can be selected during 
the ongoing enrollment as soon as the pre-specified selection criteria are met, and further 
enrollment will cease.  To ensure that there will be some unbiased estimates of the proportion of 
patients with a good outcome available for each intervention arm (a secondary goal of the study), 

Columbia University Medical Center 
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the elimination and selection criteria will not be applied until 15 patients per arm have been 
observed.  Fifteen patients per arm will provide a 95% confidence interval no wider than 0.52 
(+/- 0.26) percentage points for the estimate of the proportion of patients with a good outcome 
based on the Clopper Pearson method. 
 
This novel approach based on the Levin-Robbins-Leu family of sequential selection procedures 
[18-23] will a) allow a rational selection of the CIPN intervention to be carried forward for 
confirmatory testing in a future phase 3 trial; b) provide preliminary concurrent control estimates 
for the placebo arm that can be used for sample size estimation in that future trial; and c) keep 
the trial small and efficient, consistent with a Phase 2B design, until sufficient evidence of 
promise accumulates to warrant the major investment in funds, time, and effort to complete the 
larger Phase 3 study. 
 
Upon enrollment, each study participant will complete a baseline questionnaire assessing 
demographic information (age, race, and tobacco use). Clinical characteristics (cancer staging, 
grade, concomitant morbidities, chemotherapy cumulative dose and current medications) will be 
documented as well.  Patients will be able to enroll in the trial and complete the baseline 
assessment up to the second chemotherapy infusion. 
 
During each study encounter (at baseline, week 12 +/- 14 days, and at week 24 +/- 21 days), 
study participants will complete a questionnaire assessing pain, severity of CIPN, function, and 
comfort with the intervention.  They will also undergo objective neurological assessments of 
sensory and motor neuropathy (see below). Further, adherence to the intervention will also be 
assessed by research staff. Patients will be evaluated at weeks 12 and 24 from baseline to 
determine clinical benefit of the intervention during treatment and to assess if the benefit is 
sustained after discontinuation of the intervention.  Outcome measures on week 12 from baseline 
will be evaluated before scheduled chemotherapy infusion.  Visits will be conducted within the 
below specified windows forbidding unexpected circumstances such as missed appointments or 
loss to follow-up. 
 
MEASURE 
Baseline 
Week 12 
(+/- 14 days) 
Week 24 
(+/- 21 days) 
History & Physical Exam 
X 
Chemotherapy Treatment Schedule 
X 
X 
X 
Self-Administered 
Questionnaires 
Baseline Demographics 
X 
FACT NTX 
X 
X 
X 
Comfort 
X 
X 
X 
PROMIS-29 
X 
X 
X 

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Staff administered 
History of Falls Assessment 
X 
X 
X 
Active Topical Agents, Medications, Supplements, and 
Interventions 
X 
X 
X 
128 Hertz Tuning Fork 
X 
X 
X 
Vibration Threshold Test 
X 
X 
X 
Neuropen Test (pressure/pain) 
X 
X 
X 
NCI-CTCAE 
X 
X 
X 
NCI-CTC (V2) (nail changes) 
X 
X 
X 
Timed get up and go 
X 
X 
X 
Tandem and unipedal stance test 
X 
X 
X 
Hand and fingertip color changes 
X 
X 
X 
Adherence 
X 
X 
 
 
5.2 
Dose Limiting Toxicities - N/A 
 
5.3 
Number of Patients 
Up to 100 patients.  The expected sample size is between 60-70 for the most likely scenarios. 
 
6. 
SUBJECT SELECTION AND WITHDRAWAL 
 
6.1 
Inclusion Criteria 
 
 Age ≥18. Because no dosing or adverse event data are currently available on the use of 
cold therapy and compression therapy in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials. 
 History of stage I-III breast cancer 
 Patient scheduled to be receiving adjuvant or neoadjuvant nab paclitaxel, paclitaxel, 
or docetaxel for at least 12 weeks 
 Signed informed consent 
 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
6.2 
Exclusion Criteria 
 Prior treatment with taxane or platinum based chemotherapy 
 Known history of neuropathy 
 Raynaud's phenomenon 
 Peripheral arterial ischemia 
 Cold intolerance 
 Current use of duloxetine which may mitigate CIPN 
 
*If a subject has any condition that limits the use of one out of four extremities, i.e. need for 
peripheral IV, previous amputation, etc, then no device (compression, cryotherapy, or loose 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 16Jan2020 
14 
 
 
gloves/socks) will be used on that specific extremity. 
 
 
6.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.  As most patients 
diagnosed with breast cancer are women, there will be more women accrued in the trial. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
30 
+ 0 
= 
Not Hispanic or Latino 
70 
+ 0 
= 
Ethnic Category: Total of all 
subjects 
100 
(A1) + 0 
(B1) = 100 
(C1) 
Racial Category 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4 
Subject Recruitment 
Patients will be recruited by their medical oncologist from the Breast Oncology Clinic of 
Columbia University Medical Center (CUMC). The estimated accrual is 6 patients per 
month for a period of 18 months. The CUMC Breast Oncology clinic sees approximately 
100 breast cancer patients each week. Approximately 8-12 patients per month are generally 
scheduled to receive adjuvant or neoadjuvant paclitaxel or docetaxel. Therefore, an accrual 
of up to 100 participants, with an expected accrual of 60-70 participants, is feasible. 
6.5 
Early Withdrawal of Subjects 
6.5.1When and How to Withdraw Subjects 
 Patients are not expected to develop progressive disease while receiving neoadjuvant or 
adjuvant therapy.  However, if at any time the patient develops progressive disease, 
he/she 
will be referred for alternative therapy. He/she will continue to be followed for the 
primary endpoint. 
American Indian or Alaskan Native 0 
+ 0 
= 
Asian 
5 
+ 0 
= 
Black or African American 
5 
+ 0 
= 
Native Hawaiian or other Pacific 
Islander 
0 
+ 0 
= 
White 
90 
+ 0 
= 
Racial Category: Total of all 
subjects 
100 
(A2) + 0 
(B2) = 100 
(C2) 
(A1 = A2) 
(B1 = B2) 
(C1 = C2) 

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15 
 
 
 If at any time the patient develops unacceptable neuropathy from the chemotherapy that leads 
to dose reduction/modification or treatment discontinuation, he/she will be counted as having 
a “poor” outcome for the primary endpoint. 
 If at any time the patient develops unacceptable toxicity from the chemotherapy unrelated 
to neuropathy, and needs to stop treatment, he/she will continue to be followed for the 
primary 
endpoint. 
 If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient 
will be removed from study. 
 If the patient withdraws consent for continued participation, he/she will be removed 
from study 
 
6.5.2Data Collection and Follow-up for Withdrawn Subjects 
 
Even though subjects may be withdrawn prematurely from the study, it is imperative to collect at 
least efficacy data on such subjects throughout the protocol defined follow-up period for that 
subject.  Such data are important to the integrity of the final study analysis since early withdrawal 
could be related to the safety profile of the study products.  If a subject withdraws consent to 
participate in the study, attempts will be made to obtain consent from the subject to record at least 
efficacy data up to the protocol-described end of subject follow-up period. It must be a high 
priority to try to obtain at least efficacy data on all subjects lost to follow-up and to note what 
methods should be used before one can state the subject is truly lost to follow-up (e.g. number of 
phone calls to subject, phone calls to next-of-kin if possible, certified letters, etc.). Subjects 
withdrawn because of unacceptable adverse events will be followed for the primary endpoint 
and/or until resolution or stabilization of the adverse event.  In order to preserve the intent-to-treat 
principle (“once randomized then analyzed”) we will impute a “poor” outcome for any patient 
who withdraws from the study and cannot or will not be evaluated at 12 weeks from baseline. 
 
6.6 
CUMC Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 

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Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office. 
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@columbia.edu or fax to 
212.305.5292, with the subject line “AAAR9515 Pending Subject Registration Request (PHI)”. 
Upon receipt, applicable subject information as well as a “pending eligibility” status will be 
entered into HICCC’s institutional database. This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
 
 
The completed/signed IRB approved HIPAA Authorization form 
 
 
Completed/signed CPDM ICF checklist 
 
 
Completed/signed HICCC personal census form 
 
 
Completed/signed CPDM Demographics Note to File 
 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
 
 
The completed/signed study specific Eligibility Checklist  (signed by an Physician level 
Investigator) 
 
Copies of source documentation necessary for each item to be verified on the CPDM 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent process 
information, along with providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms (e.g., positive 

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investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 
Please note: subject line of email or fax should include the following: “AAAR9515 
Complete Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional CTMS database by the Central Registration 
Registrar. Upon completion, an official subject registration notification email will be sent to the 
PI/research team which will include eligibility/enrollment status, as well as subject ID 
information.  Protocol therapy may not be initiated prior to receipt of this notification from the 
Central Registration Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
7. 
TREATMENT PLAN 
 
7.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for frozen mittens/socks and compression garments are described in Section 10. There are 
no dose modifications for the products. 
 
Cryotherapy: Study subjects will wear NatraCure flexible socks on bilateral hands and feet. The 
garments will be available in 3 sizes: small, medium, large.  The correct size will be determined 
during the initial visit and the same size used during each chemotherapy infusion.  The sock will 
act as a mitten and covers the entire hand until past the wrist. There are 2 gel packs inserted into 
the sock, to provide cooling to the dorsal and frontal aspect of the hand.  For the feet, the sock 
will cover the entire foot until above the ankle.  Garments will be refrigerated for at least 3 hours 
at -25 to -30°C prior to use.  With each infusion, patients will wear the frozen garments on their 
hands and feet for a total of 90-120 minutes, beginning at least 15 minutes (with the window 
being within 30 minutes prior to start) before the start of the infusion and until at least 15 
minutes after the end of the infusion.  Two sets of socks will be used during each session for 45- 
60 minutes each to maintain a consistently low temperatures of the extremities. Patients may 
remove the garments for up to 10 minutes during treatment if they need to use the restroom. 
 
Compression therapy: Study participants will wear Sigvaris Secure Arm Sleeves and Gloves on 
bilateral upper extremities.  The sleeves and gloves provide 20-30mmHg of compression.  The 

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arm sleeves will be available in several sizes.  Subjects will wear Sigvaris CompreFlex Lite 
compression garments on the lower extremities which includes a transition liner with a 
compressive foot, providing 20-30mmHg of compression on the lower leg and 15mmHg on the 
toes and feet.  AccuTabs will be placed along the CompreFlex Lite to easily and accurately set 
the compression level at 20-30mmHg.  For the compression garments, the correct size will be 
determined during the initial visit and the same size and products used during each chemotherapy 
infusion.  With each chemotherapy infusion, patients will wear the sleeves/gloves and socks for a 
total of 90-120 minutes, beginning at least 15 minutes before the start of the infusion (with the 
window being within 30 minutes prior to start) and until at least 15 minutes after the end of the 
infusion. 
 
Control arm (Loose glove/sock): To minimize potential biases of patients receiving treatment in 
the intervention arms, we will have a control arm where patients will wear loose or comfortably 
fitting gloves/sleeves and socks on their hands and feet. 
 
Study subjects will wear a non-compressive sleeve and loosely fitting glove on bilateral arms and 
hands. They will also wear a non-compressive Sigvaris Basic Liner with the CompreFlex Lite 
loosely applied over it.  We will verify that no compression is applied via using an interface 
pressure sensor (PicoPress).  The maximum level of allowed pressure for garments on the upper 
and lower extremities will be 3mmHg.  If the pressure reading is >3mmHg, then a larger garment 
size will be used.  For the loose garments, the correct size will be determined during the initial visit 
and the same size and products used during each chemotherapy infusion.  If weight gain or 
swelling is noticed, then the patient may need to be refitted to ensure the correct placebo pressure 
is applied.  Measurements with the pressure sensor will be repeated as needed to ensure a low 
pressure level of less than 3mmHg. With each chemotherapy infusion, patients will wear the 
gloves/sleeves and socks for a total of 90-120 minutes, beginning 15 minutes before the start of the 
infusion and until 15 minutes after the end of the infusion. 
 
8.1.1 
Investigational Agent(s) - N/A 
8.1.2 Other Agent(s)- N/A 
7.1.3 Other Modality(ies) or Procedures -N/A 
7.2 
General Concomitant Medication and Supportive Care Guidelines- N/A 
 
7.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for until 
completion of all cycles or until one of the following criteria applies: 
 
 Disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse events(s) such as frostbite or cold intolerance 
 Patient decides to withdraw from the study 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 

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7.4 
Duration of Follow Up 
 
Patients will be followed for 24 weeks after completion or removal from study or until death, 
whichever occurs first. Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
7.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 8.5 applies. The 
reason for study removal and the date the patient was removed will be documented in the Case 
Report Form. 
 
 
8. 
DOSING DELAYS/DOSE MODIFICATIONS - N/A 
 
9. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
9.1 
Adverse Events 
 
Risk associated with frozen mitten and sock 
Very Likely 
-feeling cold 
Less Likely 
-sensory abnormalities including numbness and tingling 
-mild pain 
Very unlikely 
-frostbite 
 
Risk associated with compression therapy 
Less likely 
-sensory abnormalities including numbness and tingling 
Very unlikely 
-pain 
-skin changes 
 
Risk associated with control arm 
-none 
 
Patients will be assessed at baseline, 12 weeks and 24 weeks from baseline with an assessment 
of any skin color changes to evaluate for any signs of frostbite. 
 
9.2 
Definitions 
Adverse Event: 

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An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including abnormal sign, symptom or disease, temporally associated with the subject’s 
participation in research, whether or not considered related to the subject’s participation in the 
research. Abnormal results of diagnostic procedures are considered to be adverse events if the 
abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
 fatal 
 life-threatening 
 requires inpatient hospitalization/prolongation of existing hospitalization, unless 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (procedures such as central line placements, paracentesis, 
pain control) 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above/below and not resulting in hospital administrations 
o social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious events should be regarded as 
non-serious adverse events. 
 
Unanticipated Problem: 
An unanticipated problem is any incident, experience or outcome involving risks to subjects or 
others in any human subjects research that meets all of the following criteria: 
 Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approval protocol and informed consent document, and (b) the 
characteristics of the subject population being studied; 
 Related or possibly related to participation in such research (e.g., there is a reasonable 

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possibility that the incident, experience or outcome may have been caused by the procedures 
involved in such research); and 
 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. 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures (e.g., after the first dose of study treatment) to the end 
of the study treatment (e.g., last dose of study treatment) and/or follow-up.  For this study, the 
study treatment follow-up is defined as 21 days following 24 weeks after baseline visit, or 30 
days following the decision to remove the subject from study treatment, whichever is 
earliest. 
Baseline/Preexisting Condition 
A baseline/preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or if the character of 
the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met: 
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc.). 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 

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adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition. Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
 
9.3 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded in the source document, though should be 
grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 
9.4 
Reporting of Serious Adverse Events 
9.4.1 
IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the principal investigator’s 
acquiring knowledge of the unanticipated problem in accordance with IRB policy. Additionally, 
the sponsor-investigator will submit a summary of all Unanticipated problems that occurred since 
the beginning of the study at the time of continuing review. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Regulatory binder. 
 
9.4.3FDA Notification by Sponsor-Investigator- N/A 
 
9.4.4DSMC Reporting by the Sponsor Investigator 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring at our 
institution or affiliate sites. 
 
9.4.5Reporting to Drug Manufacturer by Sponsor-Investigator 
The Sponsor-Investigator will report to investigational agent manufacturer any serious adverse 
events that meet the reporting criteria to the Institutional Review Board as described in section 

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9.4 and/or to the FDA as described in section 9.4 within 24 hours of becoming aware of it, so 
that these reports can be evaluated and included in the Investigator’s Brochure and for IND 
safety submissions per regulations. Reporting will occur by sending the reporting form along 
with any additional documentation sent to the regulatory authorities. 
 
At the time of IRB renewal or at the request of the manufacturer, the Sponsor- Investigator will 
submit a summary of all Serious Adverse Events that have occurred inclusive of all sites to 
manufacturer. 
 
9.5 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A, the HICCC DSMC Serious Adverse 
Event Reporting Form, or in a narrative format. If supplied as in a narrative format, the minimum 
information to be supplied is noted above at the beginning of section 10. 
 
Study Products 
 
9.6 
Description 
 
Cryotherapy: Study subjects will wear NatraCure flexible socks on bilateral hands and feet. The 
garments will be available in 3 sizes: small, medium, large.  The correct size will be determined 
during the initial visit and the same size used during each chemotherapy infusion.  The sock will 
act as a mitten and covers the entire hand until past the wrist. There are 2 gel packs inserted into 
the sock, to provide cooling to the dorsal and frontal aspect of the hand.  For the feet, the sock 
will cover the entire foot until above the ankle. 
Compression therapy: Study participants will wear Sigvaris Secure Arm Sleeves and Gloves on 
bilateral upper extremities.  The sleeves and gloves provide 20-30mmHg of compression. The 
arm sleeves will be available in several sizes.  Subjects will wear Sigvaris CompreFlex Lite 
compression garments on the lower extremities which includes a transition liner with a 
compressive foot, providing 20-30mmHg of compression on the lower leg and 15mmHg on the 
toes and feet.  AccuTabs will be placed along the CompreFlex Lite to easily and accurately set 
the compression level at 20-30mmHg.  For the compression garments, the correct size will be 
determined during the initial visit and the same size and products used during each chemotherapy 
infusion. 
Control arm (Loose glove/sock): Study subjects will wear a non-compressive sleeve and loosely 
fitting glove on bilateral arms and hands.  The will also wear a non-compressive Sigvaris Basic 
Liner with the CompreFlex Lite loosely applied over it. We will verify that no compression is 
applied via using an interface pressure sensor (PicoPress). The maximum level of allowed 
pressure for garments on the upper and lower extremities will be 3mmHg.  If the pressure 
reading is >3mmHg, then a larger garment size will be used. For the loose garments, the correct 
size will be determined during the initial visit and the same size and products used during each 
chemotherapy infusion. 
 
9.7 
Treatment Regimen 
Cryotherapy: Products will be refrigerated for at least 3 hours at -25 to -30°C prior to use. With 
each infusion, patients will wear the frozen socks on both hands and feet for a total of 90-120 

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minutes, beginning at least 15 minutes before the start of the infusion (with a window of 30 
minutes prior to infusion) and until at least 15 minutes after the end of the infusion.  Two sets of 
socks will be used during each session for 45-60 minutes each to maintain a consistently low 
temperature of the extremities. 
 
Compression therapy/Control arm: With each chemotherapy infusion, patients will wear the 
gloves/sleeves and socks for a total of 90-120 minutes, beginning at least 15 minutes before the 
start of the infusion (with a window of 30 minutes prior to infusion and until at least 15 minutes 
after the end of the infusion. 
 
Control arm (Loose glove/sock): With each chemotherapy infusion, patients will wear the 
gloves/sleeves and socks for a total of 90-120 minutes, beginning at least 15 minutes before the 
start of the infusion (with a window of 30 minutes prior to infusion and until at least 15 minutes 
after the end of the infusion. 
9.8 
Method for Assigning Subjects to Treatment Groups 
 
Randomization will be centralized by the CPDM. Randomization will be stratified by the 
chemotherapy intervention schedule (every 3 weeks versus weekly). Patients will be randomized 
in triplets at the start of the trial until the outcomes of 15 triplets have been observed. If and when 
one arm is eliminated, the randomization will proceed in pairs until a terminal decision is reached 
or enrollment is truncated at 99 or 100 patients. 
 
9.9 
Preparation and Administration of Study Drug 
The study coordinator will assist patients in wearing the cold therapy, compression, and loose, 
garments. 
 
9.10 
Subject Compliance Monitoring 
The study team will track subject compliance with the frozen, compression and placebo products 
during each treatment.  Subjects who are significantly non-compliant with the study treatment 
regimen will be asked to withdraw from the study. 
 
9.11 
Prior and Concomitant Therapy 
 Concomitant chemotherapy or antibody therapy is permitted during the study with taxane 
drug 
 Prior taxane or platinum therapy is not permitted during the study 
 
9.12 
Packaging 
CompreFlex Lite compression garments including Transition Liners will be packaged in lot 
traceable units. Secure Arm Sleeves and Gloves will be packaged in lot traceable units. Medical 
device labeling and instructions for use are provided within the packaging of each device. These 
are Class 1 registered devices. Devices are shipped in bulk and may be used for up to 6 months. 
 
9.13 
Blinding of Study Drug 
 
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Participants will not be blinded if they are assigned to the cryotherapy. However, if randomized 
to the compression versus loose gloves group they will be blinded to their assignment. 
 
 
9.14 
Receiving, Storage, Dispensing and Return 
 
9.14.1 
Receipt of Product Supplies 
PolyGel and Sigvaris will directly ship the products to the Herbert Irving Pavilion. Upon receipt 
of the study treatment supplies, an inventory will be performed and a device receipt log filled out 
and signed by the person accepting the shipment. The designated study staff will count and verify 
that the shipment contains all items noted in the shipment inventory. Any damaged or unusable 
devices in a given shipment will be documented in the study files. The study team will notify 
device manufacturer of any damaged or unusable devices that were supplied to the study site. 
 
9.14.2 
Storage 
All products will be stored in a locked and secure location on the 10th floor of Herbert Irving 
Pavilion.  Each subject's frozen garments, compression garments or loose gloves and socks will 
be placed in a bag marked with the patient's study ID number and then placed in a locked and 
secure storage area on the 10th floor of Herbert Irving Pavilion. 
 
9.14.3 
Dispensing of Study Products 
The study coordinator will assist patients in wearing the compression, loose, cold therapy 
garments. 
 
9.14.4 
Return or Destruction of Study Products 
At the completion of the study, the used and unused products will be discarded appropriately. 
 
9.15 
Other Agent(s)- N/A 
 
10. 
STUDY CALENDAR 
 
Study protocol and schedule of evaluation: Upon enrollment, each study participant will 
complete a baseline questionnaire assessing demographic information (age, race, and tobacco 
use).  Clinical characteristics (cancer staging, grade, concomitant morbidities, chemotherapy 
cumulative dose and current medications) will be documented as well. Patients will be able to 
enroll in the trial and complete the baseline assessment up to the second chemotherapy infusion. 
During each encounter, study participants will complete a questionnaire assessing pain, severity 
of CIPN and function, and self-reported comfort with the study intervention.  They will also 
undergo objective neurological assessments of sensory and motor neuropathy (see below). 
Further, research staff will assess adherence to the treatment intervention. Patients will be 
evaluated at weeks 12 and 24 from baseline to determine clinical benefit of the intervention 
during treatment and to assess if the benefit is sustained after discontinuation of the 
intervention.  Outcome measures on week 12 from baseline will be evaluated before scheduled 
chemotherapy infusion.  Visits will be conducted within the below specified windows 
 
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forbidding unexpected circumstances such as missed appointments or loss to follow-up. 
 
MEASURE 
Baseline 
Week 12 
(+/- 14 days) 
Week 24 
(+/- 21 days) 
History & Physical Exam 
X 
Chemotherapy Treatment Schedule 
X 
X 
X 
Self-Administered 
Questionnaires 
Baseline Demographics 
X 
FACT NTX 
X 
X 
X 
Comfort 
X 
X 
X 
PROMIS-29 
X 
X 
X 
Staff administered 
History of Falls Assessment 
X 
X 
X 
Active Topical Agents, Medications, Supplements, and 
Interventions 
X 
X 
X 
128 Hertz Tuning Fork 
X 
X 
X 
Vibration Threshold Test 
X 
X 
X 
Neuropen Test (pressure/pain) 
X 
X 
X 
NCI-CTCAE 
X 
X 
X 
NCI-CTC (V2) (nail changes) 
X 
X 
X 
Timed get up and go 
X 
X 
X 
Tandem and unipedal stance test 
X 
X 
X 
Hand and fingertip color changes 
X 
X 
X 
Adherence 
X 
X 
 
 
11. 
MEASUREMENT OF EFFECT - 
 
Primary endpoint: 
Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane) Neurotoxicity (NTX): 
We will assess neurotoxicity using the 11-item neurotoxicity component of the Functional 
Assessment of Cancer Therapy- Taxane symptom module. Each item is measured on a 0-4 
scale (1, not at all; 4, very much). Questions pertain to sensory neuropathy, motor 
neuropathy, hearing neuropathy, and dysfunction associated with neuropathy. The FACT 
NTX was initially developed with input of expert clinicians and patients who reported 
symptoms of CIPN within the past month.[13] The questionnaire was validated in patients 
with cancer who received taxane and platinum chemotherapy, drugs known to cause 
CIPN.[14, 15]. The FACT NTX has been shown to have internal consistency reliability on 
the basis of Cronbach α coefficients of 0.84-0.88 and the scale is also responsive to changes 
 
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in patient reported CIPN over time [15]. The FACT NTX has been used in prior clinical trials 
evaluating intervention for treatment and prevention of CIPN.[16-19] 
The primary endpoint is the change in FACT NTX at 12 weeks from baseline from the start of 
chemotherapy. The change in FACT NTX will be dichotomized into a good outcome (change in 
FACT NTX<5 from baseline to week 12) versus a poor outcome (change in FACT NTX≥5  from 
baseline to week 12).[16] This dichotomy will be the primary outcome for monitoring in the 
selection procedure.  Patients who experience dose reductions/modifications and/or treatment 
discontinuation for their chemotherapy treatment due to neuropathy are considered to have a 
”poor” outcome. 
 
Secondary endpoints: 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
grading scale: The NCI-CTCAE is a subjective method to evaluate CIPN which is performed 
by a healthcare professional.  The patient's peripheral sensory neuropathy, peripheral motor 
neuropathy, dysestheia, paresthesia and neuralgia will be graded on a scale of 1 to 5 
depending on severity [20]. 
Skin/nail toxicity: Cutaneous toxicity and onycholysis will be assessed by a healthcare 
professional using the National Cancer Institute Common Toxicity Criteria (Version 2), 
specifically nail changes.  Grade 1 includes discoloration, ridging (koilonychia), or pitting of 
the nails and Grade 2 is partial or complete loss of nail(s) or pain in the nail beds. 
Comfort with Intervention: Comfort with the study intervention will be assessed on a 4-point 
scale, (0=dissatisfied; 1=not satisfied; 2=satisfied; 3=very satisfied). This scale was used to 
assess comfort of cryotherapy previously, comfort to compression therapy was not previously 
assessed.[10] 
Tuning fork (vibration): Study participants will be assessed for development of sensory 
neurological dysfunction. Vibration perception will be assessed using a tuning fork [21]. 
 
Vibration threshold will be tested on the bilateral dorsum of the distal interphalangeal joint of 
the index finger and dorsum of the interphalangeal joint of the hallux. Subjects will be asked 
to indicate when the vibration stimulus is initially felt (perception threshold) and when the 
stimulus disappears (disappearance threshold.) The vibration perception threshold is the 
average of three paired measurements. 
Neuropen (pressure/pain): Evaluation of other sensory endpoints including touch, pressure 
and pain will be evaluated using a Neuropen.  Touch and pressure sensation will be assessed 
using a 10-g monofilament on the subject's dominant foot. Pain and subjective sharpness 
sensation will be assessed using the Neuropen on the dominant foot.  The spring mechanism 
is calibrated to exert a force of 40 grams to help identify subjects with loss of pain sensation. 
Timed get up and go: The ‘timed get up and go’ test is a rapid and widely used clinical 
performance-based measure of lower extremity function, mobility, and fall risk [22]. Subjects 
are asked to stand up from a standard chair (seat height between 44 and 47 cm), walk a 
distance of 3 m (marked on the floor) at a comfortable pace, turn, walk back and sit down. 
Subjects are permitted to use routine walking aids and are instructed not to use their arms to 
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stand up. No physical assistance is given. The time to complete the task is measured with a 
stopwatch. Timing commences on the command ‘go’ and stops when the subject's back is 
positioned against the back of the chair after sitting down. Shorter times indicate better 
performance. Patients who are wheelchair-bound will not be required to complete this 
assessment. Training on the use of this tool is available online 
(https://www.youtube.com/watch?v=grrYoBucNPE). 
Tandem and Unipedal stance test: Balance will be assessed using the tandem and unipedal 
stance test [23].  In this assessment, the subject stands with one foot in front of the other (heel 
to toe) (30 seconds), then on one leg with: eyes open (60 seconds), eyes closed (30 seconds), 
and eyes open with head rotation (30 seconds) with arms held comfortably at the side. 
Participants are allowed one practice trial for each of the balance tests. Tests are recorded as 
achieved or not. The test was accepted failure when the stance foot shifted in any way or the 
nonstance foot touched the ground. If the subject did not reach the maximum time, the best 
time was recorded. 
Adherence to the Study Intervention: Adherence will be defined as wearing the assigned 
gloves and socks for ≥ 80% of infusions 
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements). The Data Safety Monitoring Plan is 
described in Section 12.2. 
 
12.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be 
built into the CTMS for data entry. The system has full auditing capabilities which is web-based 
and housed on a server in a fully HIPAA compliant server room with restricted access and video 
camera monitoring. All users must login with their own application username and password. 
Users off campus must first access the Virtual Private Network with their assigned campus 
username and password and then use their application credentials. Users are only able to see 
study information if they are indicated as study personnel in our electronic IRB system. Users 
are limited to access based on the role assigned in their corresponding protocol. Subject data is 
entered directly into the system, which (in the case of Columbia subjects) confirms the correct 
identity of patients via an interface with the electronic medical patient index. Staff with the 
appropriate IRB defined roles can run reports within the system for reporting purposes. 
 
12.2 
Data Reporting 
 
Case Report Forms will be completed for each subject enrolled into the clinical study through the 
CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the corresponding CRFs are complete, accurate and authentic. 
 
 
12.3 
Data and Safety Monitoring Committee 

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The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol will adhere to the policies of the currently approved 
HICCC Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and 
CUMC-IRB policy and guidelines. The committee is chair is appointed by the HICCC Director. 
The committee consists of HICCC faculty and staff with expertise in oncology, research 
pharmacy, research nursing, and data management. The DSMC convenes twice a month to 
review patient safety and the conduct of the trial. The PI will submit data and safety monitoring 
reports to the DSMC at a frequency to be determined by the DSMC based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB. All 
study data reviewed and discussed during these meetings will be kept confidential. 
 
12.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC. Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 
study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints 
(e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled meetings. 
 
Internal On-site Monitoring: 
 
 
Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
remote clinical sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 
 
The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
 
The Compliance Coordinator will communicate with the site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to study materials 
and documentation. 
 
 
The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 

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first subject is enrolled and throughout the life of the study to ensure that the study is being 
conducted in accordance with the protocol, GCP, applicable federal and local regulations, and 
per all applicable SOPs. The Compliance Coordinator is responsible to notify the PI and 
CRNP/CRN/CRC of upcoming monitor visits and convey what information and documentation 
will be required for the visit(s).  The Compliance Coordinator is responsible for verifying that 
informed consent is properly obtained, eligibility is met (via the central registration process), 
and all study procedures are conducted according to the study protocol. The Compliance 
Coordinator will also verify that the data reported in the CRF’s accurately reflect source 
documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a timely 
and efficient manner.  The Compliance Coordinator will also monitor for applicable regulatory 
compliance and research pharmacy compliance (if applicable) and communicate any 
deficiencies as appropriate. 
 
12.5 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (e.g., that the subject is alive) at the end 
of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator and study staff will have access to the file. 
 
12.6 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
12.7 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the 
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CRF is left blank because the procedure was not done or the question was not asked, write “N/D”. 
If the item is not applicable to the individual case, write “N/A”. 
 
12.8 Records Retention 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 
CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies 
whether or not any subjects were enrolled in the study. 
If the research is FDA regulated, records should be retained for at least two years after approval 
of the investigational agent by FDA; if it is not approved, records should be retained at least two 
years after the study is terminated and FDA is notified (note the additional requirement below for 
clinical research studies); 
Clinical records, including consent forms that document clinical intervention or clinical 
diagnostic procedure research-related procedures, must be retained in medical records by the 
institution for at least seven years, per CUMC and NYP policy which is based on state law. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Implementation: 
This is a randomized, placebo-controlled clinical selection trial of interventions for CIPN in 
patients treated with paclitaxel or docetaxel every 3 weeks or on a weekly schedule.  The study 
design is described in detail in section 5.1. 
 
The identification of a preferred treatment will be done using an innovative sequential selection 
procedure, which will substantially reduce the number of patients in comparison to a hypothesis 
test procedure. The data will be examined each time a triplet (or, after elimination of one arm, a 
pair) of randomized patients completes follow-up. 
 
The goal of the procedure is to make a correct selection, i.e. to select the intervention that yields 
the greatest true probability of change in FACT NTX<5, assuming one exists, with high 
probability.  The procedure follows the preference zone / indifference zone approach, wherein 
we require the selection procedure to guarantee a probability of at least 80% correct selection (of 
the truly best intervention), assuming that one is truly superior to the others by a pre-specified 
amount.  This pre-specification defines a region in the parameter space called the preference 
zone.  If the best intervention does not exceed the next best by the pre-specified amount, the 
success probabilities are said to lie in the indifference zone, where we shall be indifferent to the 
fact that the probability of correct selection may be less than 80%.  For this trial, the preference 
zone consists of all parameter vectors (p1, p2, p3) of success probabilities where the odds ratio 
comparing the largest to the next largest is greater than or equal to 2.0. 
 
The selection procedure is specified by the sampling rule, the elimination rule, the stopping rule, 
and the terminal decision rule, as follows. 
 
Sampling rule: 
Vector-at-a-time sampling will be used.  Patients will be randomized in triplets within 
 
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chemotherapy strata to one of the three intervention arms.  If and when one arm is eliminated, 
patients will be randomized in pairs to the remaining interventions. 
 
Success tallies: 
Each time the follow-up for each patient in a triplet is complete and a “good” or “poor” outcome 
is determined for each (change in FACT NTX<5 or >=5, respectively), the triplet becomes 
“observed” and is available for sequential monitoring by adding to a running tally of the “good” 
outcomes for each intervention. These success tallies are used for the elimination criterion. 
 
Elimination criterion: 
The criterion for elimination of an intervention is a difference of 4 between the currently greatest 
and smallest success tallies.  That is, the first time that the success tally for the intervention (or 
interventions) with the largest tally exceeds the success tally of the intervention (or 
interventions) with the smallest tally, we eliminate the intervention (or interventions) with that 
smallest tally.  By “elimination” of an intervention arm we mean that no further patients will be 
randomized to such an arm.  Thereafter, the trial continues with the remaining interventions 
whose success tallies resume at their current values. The trial then continues randomizing 
additional pairs of patients until the difference in success tallies again equals 4, at which time the 
intervention with the smaller success tally is eliminated. 
If at any time two arms should happen 
to be tied with 4 fewer successes than the intervention currently in the lead, then both trailing 
interventions are eliminated at that time. 
 
Stopping rule: 
Stop the first time two intervention arms have been eliminated, if this occurs at or before 100 
patients’ outcomes have been observed.  If the criterion for the second elimination has not been 
reached at or before 100 outcomes have been observed, the trial will stop by truncation.  The 
maximum number of triplets or pairs at time of truncation is determined as follows.  If no early 
elimination occurs, a total of 99 patients in 33 triplets will be randomized.  If an early 
elimination of one intervention occurs after N triplets have been observed, the maximum 
number of subsequent pairs will be (100−3N)/2 if N is even or (99−3N)/2 if N is odd. (There is 
no truncation if an early elimination of two interventions occurs at or before 33 triplets have 
been observed because the trial stops in that case with a criterion decision.) 
 
Decision rule: 
If the second elimination criterion is reached, the remaining intervention with the largest success 
tally is selected as the preferred intervention.  If the trial stops by truncation, the intervention 
with the largest success tally among the remaining competitors is selected.  If there are ties for 
the largest success tally at time of truncation, we will select the intervention according to other 
considerations (safety, ease of compliance, etc.).  By construction of the elimination rule, there 
can be no ties for best success tally if the trial stops before truncation. 
 
Incomplete triplets and overrunning: 
If at the time of first elimination there are partially filled or partially observed triplets of patients 
that have been randomized and have started their intervention, we will allow each patient in each 
such triplet to complete their follow-up even if the arm to which they were randomized is 

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eliminated. Outcomes collected from these incomplete triplets will contribute to the secondary 
goal of obtaining unbiased estimates of the success probabilities and in interpreting the results of 
the study as explained below.  However, the data from patients in incomplete triplets randomized 
to eliminated arms will not be considered in applying the criterion to eliminate a subsequent 
intervention, in order to preserve the validity of the sequential stopping procedure. 
 
Similarly, if there are partially observed triplets or pairs of patients at the stopping time with a 
selection decision prior to truncation, we will allow the patients to complete their follow-up in 
order to observe their outcomes.  As for incomplete triplets at time of first elimination, data from 
such overrun triplets or pairs will be used to weigh the evidence concerning success 
probabilities, but they will not be used to alter the stopping time and terminal selection decision, 
in order to preserve the validity of the sequential stopping procedure. 
 
Operating characteristics of the Study Design: 
The elimination criterion of a lead of 4 between largest and smallest success tallies was chosen to 
achieve a probability of correct selection of at least 80% for any true success probabilities lying 
in the preference zone characterized by an odds ratio of 2.0 or greater between the true success 
probabilities of the best two interventions.  For example, true success probabilities of 26/33 
(approximately 0.79), 0.65, and 0.65 with an odds ratio of 2.0 comparing 26/33 and 0.65 is a 
least favorable configuration lying on the boundary between the preference and indifference 
zones.  For any such least favorable configuration with p1 > p2 = p3 and {p1/(1− p1)}/{p2/(1− p2)} 
= 2.0, the selection procedure will result in a correct selection with at least 80% probability. 
Based on published studies [12,13] [12] [12] evaluating frozen and compression gloves, the 
observed rates were 72% and 79%, respectively, and experience suggests a 40% success rate for 
the control arm is plausible.   We shall refer to the configuration of success probabilities of 79%, 
65% and 40% as the design alternative and it too is inside the preference zone. Under the design 
alternative, the probability of correct selection is over 90%.  Table 1 shows the operating 
characteristics of the selection procedure under various scenarios of true success probability 
configurations for the three arms. 

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TABLE 1 
Operating characteristics of the selection procedure 
 
Scenario 1 
0.79, 0.65, 0.65 
Scenario 2 
0.79, 0.65, 0.40 
Scenario 3 
0.75, 0.65, 0.40 
Scenario 4 
0.65, 0.65, 0.40 
Scenario5 
0.65, 0.65, 0.65 
P[cs] 
83.8% 
91.2% 
83.1% 
49.8% 
33.6% 
P[as] 
83.8% 
91.2% 
99.9% 
99.7% 
100% 
Mean[N] 
75.2 
65.7 
69.8 
74.8 
83.1 
Median[N] 
76 
59 
65 
75 
99 
Mean[N at first elim 57.4 
46.5 
47.2 
49.6 
63.2 
P[truncation] 
30.3% 
16.3% 
23.1% 
32.4% 
48.9% 
P[cs at N=45] 
68.1% 
79.2% 
71.7% 
48.7% 
33.7% 
P[as at N=45] 
68.1% 
79.2% 
86.3% 
83.2% 
100% 
P[N=45] 
13.4% 
27.2% 
21.4% 
15.3% 
7.5% 
P[N<80] 
53.4% 
71.9% 
63.8% 
53.7% 
36.2% 
P[N<60] 
32.2% 
51.4% 
43.5% 
34.3% 
20.1% 
 
P[cs] is the probability of correct selection overall, either by reaching the criterion difference at or before 100 
patients, or at the 100th patient without having reached the early stopping criterion. 
P[as] is the probability of an acceptable selection overall, either by reaching the criterion difference at or before 
100 patients, or at the 100th patient without having reached the early stopping criterion. 
Mean[N] is the mean of the distribution of the (random) total number of patients. 
Median[N] is the median of the distribution of the total number of patients. 
 
Mean[N at first elim] is the mean number of outcomes observed at time of first elimination. If no arms 
are eliminated, the number at first elimination is the number at truncation (i.e. 99). 
P[truncation] is the probability that the trial will be truncated before the second elimination time. 
P[cs at N=45] is the probability of correct selection after 45 patients have been randomized (15 patients in each 
of the three arms). 
P[as at N=45] is the probability of acceptable selection after 45 patients have been randomized (15 patients in each 
of the three arms). 
P(N=45) is the probability of reaching a decision after exactly 45 patients have been randomized. We are 
evaluating the operating characteristic at this point given that this is the point from which we will start to compare 
the tallies and represents the earliest stopping time with the minimum number of outcome observations. 
P(N<80] is the probability that the total number of patients is less than 80 
P(N<60] is the probability that the total number of patients is less than 60 
 
 
The first scenario corresponds to success probabilities in the least favorable configuration in 
the preference zone with an odds ratio of 2.0. The second scenario corresponds to the 
abovementioned design alternative based on the observed rates from previously conducted 
studies (where we have adjusted those rates to have more conservative effect sizes to account 
for a potential placebo effect). The third and fourth scenarios describe the operating 
characteristics of the selection procedure inside the indifference zone, assuming smaller 
differences in the success rates for the two interventions. The third scenario assumes that both 
interventions are superior to the placebo with a smaller difference between them (such that the 
odds ratio between the best and second best intervention is less than 2.0).  The fourth scenario 

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assumes that both interventions are superior to the placebo with no difference between them 
(an odds ratio of 1.0). The fifth scenario illustrates a case where there is no true difference in 
the rates for all three arms.  The first row displays the probability of selecting the first 
intervention (which is the best in scenarios 1-3, and tied for the best in scenarios 4-5). The 
second row of the table shows the probability of an acceptable selection.  For parameter values 
inside the indifference zone, it is deemed acceptable to select any intervention whose success 
probability has an odds ratio compared to the best treatment no less than 1/2.0 = 0.5. Thus in 
the third and fourth scenarios, it is acceptable to select either of the first two interventions.  In 
the fifth scenario, it is acceptable to select any of the three interventions. For configurations in 
the preference zone, only correct selections are deemed acceptable. 
 
In scenarios 1-3 where there is a superior arm, the design chooses the superior arm over 83% of 
the time across these scenarios with average sample sizes between 65.7 and 75.2 (median of 59 
to 76). The average time to first elimination ranges from 46.5 to 57.4.  At least 45 patients are 
required to ensure at least 15 patients per arm. Under the design alternative, there is 27.2% 
probability that we will stop the trial with 15 patients per arm. The probability of having to 
truncate the study ranges from 16.3% to 30.3%, with the lowest probability for our design 
alternative.  The probability of selecting the superior arm after 45 patients are enrolled is 
between 68.1% and 79.2% in these scenarios, which explains the need to continue enrollment to 
ensure that the correct dose is selected with high probability. 
 
In scenario 4, both interventions are equally efficacious and superior to the placebo.  In that 
setting there is not a single superior treatment and selecting either one of the superior 
interventions would be acceptable.  In that scenario, the probability of selecting either of the 
superior interventions is 99.7%. The average total sample size is similar to that under the least 
favorable configuration and the probability of truncation is slightly larger because there is no 
superior arm after a first elimination of the placebo arm. 
 
In scenario 5, there is no difference among the three arms. Thus, the design randomly selects 
one of them with a probability of 0.33.  However, given that they are all the same, it is  
acceptable to select any of them and thus the probability of selecting an acceptable intervention 
is 100%. Because there is no superior intervention in this scenario, evidence of an apparent 
advantage accumulates more slowly than under other scenarios and thus the procedure incurs a 
larger average sample size, average sample size to first elimination, and probability of truncation. 
 
Thus, under the design alternative the average sample size is 66 (median is 59), and it is more 
likely than not that the sample size is under 60. Under scenario 3, which assumes a smaller 
difference, the average sample size is 70 and the median is 65.  Under all scenarios considered 
except scenario 5 in which there is no difference among the three arms, it is more likely than not 
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X 
( n ) 
X
( n ) 
i
i 
j 
i 
j 
Analysis of the Primary Endpoint: 
For reporting purposes, we will calculate the sample proportion of patients along with the 
corresponding exact binomial 95% confidence interval after 15 patients have been randomized to 
each arm.  The final sample proportion with a change in FACT NTX<5from baseline to week 12 
for each arm will also be reported.  In general, a selection procedure, unlike a hypothesis test 
procedure, is not specifically designed to provide a p-value below a conventional level of 
significance.  Indeed, in this phase 2 trial, we will not be declaring any differences statistically 
significant, as that is explicitly not the goal of the present selection trial, i.e., we are explicitly not 
interested in testing the null hypothesis of no differences between the three interventions.  Instead, 
because the adaptive sequential selection procedure can be described as a procedure that samples 
until there is a pre-specified weight of evidence for making correct selections, assuming there is a 
minimum true degree of superiority as measured by the design odds ratio, we will quote the 
likelihood ratio (LR) measure of weight of evidence in various ways as follows. 
 
At the end of the trial, we will calculate the likelihood of the success tallies for the intervention 
selected together with the first runner-up.  This likelihood is given by 
L( p , p | X (n) , X (n) ) 

( n ) 
p i (1 p )nXi 
 
( n ) 
p  
j (1 p )
nX j , 
i 
j 
i 
j 
i 
i 
j 
j 
 
where X (n) and 
(n) 
j 
are the observed success tallies for the selected and first runner-up 
intervention and where pi and pj are the respective true success probabilities.  We will also 
calculate the likelihood of the observed success tallies under the assumption that we erred in our 
selection and that the true success probabilities are those for the two interventions transposed, 
namely, L( pj , pi | X ( n) , X ( n) ) . The likelihood ratio LR is the ratio of these two likelihoods. It can 
be shown that LR, equals the true odds ratio raised to the fourth power, 
 
L( p , p | X (n) , X (n) ) 
4 
p  (1 p ) 
LR 
i 
j 
i 
j 

i 
i    , 
L( p , p | X (n) , X (n) ) 
p (1 p ) 
j 
i 
i 
j 
j 
j 
 
in the case where the trial ends meeting the selection criterion.  In the case of truncation, the 
exponent 4 is replaced by X (n)  X (n) .  We will evaluate LR at the maximum likelihood estimates 
i 
j 
of pi and pj, which are the adjusted sample proportions ( X (n)  0.5) (n 1) and ( X (n) 0.5) (n 1) . 
The values of success tallies used in LR are those used in the elimination and selection criteria, i.e., 
without follow-up data from incomplete triplets or overrun triplets or pairs. However, for the 
values of pi and pj used in LR, we will use the corresponding sample proportions using all of the 
available outcome data including data from incomplete triplets and overrun triplets or pairs. 
X 

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For example, suppose after an early elimination of the placebo arm, the success tally for the 
frozen gloves and socks is 18 and that of the compression gloves and socks is 14, each with 27 
patients observed at stopping time. Then the maximum likelihood estimate of the true odds ratio 
comparing the two interventions (adding one-half to each frequency) is (18.5/9.5) / (14.5/13.5) = 
1.813, so that the likelihood ratio weight of evidence is 1.813 raised to the fourth power which is 

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10.8.  Likelihood ratios in excess of 8 or 10 are generally considered to be moderate to strong 
evidence [24].  For example, the usual “significant at p<0.05” corresponds to a LR of only 6.8 in 
large samples. 
 
We will also report the LR at the time of first elimination, measuring the weight of evidence that 
the intervention eliminated by the leading success tally was correctly eliminated as opposed to 
mistakenly eliminated with transposed true success probabilities.  In the above example, suppose 
that the placebo was eliminated after 20 triplets with a success tally of 7 compared with the other 
two interventions’ tallies tied at 11 successes each.  Then the odds ratio comparing the leading 
tally to the trailing tally is (11.5/9.5) / (7.5/13.5) = 2.179. Then the LR is 2.179 raised to the 
fourth power, which is 22.5. Thus, we would have strong evidence that the placebo was 
correctly eliminated at that time. 
 
As a sensitivity analysis we will restrict the sample proportions used in LR to the same success 
tallies used in LR, i.e., excluding data from incomplete triplets or overrun triplets or pairs. 
 
The LR may offer strong evidence of correct selection (if LR>10) or only weak evidence, and the 
LR weight of evidence will be taken account of in evaluating whether or not to mount a 
subsequent phase 3 trial.  If, for example, the placebo arm should be the selected intervention 
arm, there would presumably be either weak or even strong evidence against either active 
intervention being the best. 
 
13.2 
Size/Accrual Rate 
Patients will be recruited by their medical oncologist from the Breast Oncology Clinic of 
Columbia University Medical Center (CUMC). The estimated accrual is 6 patients per month 
for a period of 18 months. The CUMC Breast Oncology clinic sees approximately 100 breast 
cancer patients each week. Approximately 8-12 patients per month are scheduled to receive 
adjuvant or neoadjuvant paclitaxel or docetaxel. Therefore, an accrual of 100 patients, 
expected to be around 60 to 70, is feasible. 
 
13.3 
Stratification Factors 
Randomization will be stratified by the chemotherapy intervention schedule (every 3 weeks 
versus weekly). 
 
13.4 
Analysis of Secondary Endpoints 
Proportions of patients with a change in FACT NTX of less than 5 and a worsening in neuropathy 
as determined by the NCI-CTCAE grading, who reported satisfied or very satisfied in the comfort 
scale, who discontinued intervention will be reported by type of therapy. Moreover, we will report 
the descriptive statistics (mean, median, interquartile range) for the changes from baseline with 
the Neuropen, tuning fork, timed get up and go test, and tandem/unipedal stance test by therapy, 
as well as, changes in FACT NTX,. The proportion of patients with cutaneous toxicity and 
onycholysis using the National Cancer Institute Common Toxicity Criteria (Version 2) will also 
be estimated by therapy. Graphical display of the data will also be done. 
13.5 
Reporting and Exclusions 
 
37 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 16Jan2020 
 
If at the time of first elimination there are partially filled or partially observed triplets of patients 
that have been randomized and have started their intervention, we will allow each patient in each 
such triplet to complete their follow-up even if the arm to which they were randomized is 
eliminated. Outcomes collected from these incomplete triplets will contribute to the secondary 
goal of obtaining unbiased estimates of the success probabilities and in interpreting the results of 
the study as explained below.  However, the data from patients in incomplete triplets randomized 
to eliminated arms will not be considered in applying the criterion to eliminate a subsequent 
intervention, in order to preserve the validity of the sequential stopping procedure. 
 
Similarly, if there are partially observed triplets or pairs of patients at the stopping time with a 
selection decision prior to truncation, we will allow the patients to complete their follow-up in 
order to observe their outcomes.  As for incomplete triplets at time of first elimination, data from 
such overrun triplets or pairs will be used to weigh the evidence concerning success 
probabilities, but they will not be used to alter the stopping time and terminal selection decision, 
in order to preserve the validity of the sequential stopping procedure. 
13.5.1 
Evaluation of toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study 
products. 
 
Evaluable for primary endpoint 
All patients randomized will be evaluable for the primary endpoint.  Patients who progress or 
stop chemotherapy due to toxicity should continue to be followed for the primary endpoint. 
 
14. 
PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct. 
The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be obtained before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject or legally acceptable surrogate, as outlined in the IRB approved protocol, 
and the investigator-designated research professional obtaining the consent. 
15. STUDY FINANCES 
 
15.1 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
38 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 16Jan2020 
39 
 
 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the Columbia University Conflict of Interest Committee with a Committee- 
sanctioned conflict management plan that has been reviewed and approved prior to participation 
in this study.  All CUMC investigators will follow the University conflict of interest policy. 
 
15.2 Subject Stipends or Payments 
There are no subject payments or stipends. 
 
16. PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
17. REFERENCES 
1. 
Armstrong, T., L. Almadrones, and M.R. Gilbert, Chemotherapy-induced peripheral 
neuropathy. Oncol Nurs Forum, 2005. 32(2): p. 305-11. 
2. 
Smith, E.M., et al., Effect of duloxetine on pain, function, and quality of life among 
patients with chemotherapy-induced painful peripheral neuropathy: a randomized 
clinical trial. JAMA, 2013. 309(13): p. 1359-67. 
3. 
Hershman, D.L., et al., Prevention and management of chemotherapy-induced peripheral 
neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical 
practice guideline. J Clin Oncol, 2014. 32(18): p. 1941-67. 
4. 
Minisini, A.M., et al., Taxane-induced nail changes: incidence, clinical presentation and 
outcome. Ann Oncol, 2003. 14(2): p. 333-7. 
5. 
Argyriou, A.A., et al., Peripheral nerve damage associated with administration of 
taxanes in patients with cancer. Crit Rev Oncol Hematol, 2008. 66(3): p. 218-28. 
6. 
Park, S.B., et al., Chemotherapy-induced peripheral neurotoxicity: a critical analysis. 
CA Cancer J Clin, 2013. 63(6): p. 419-37. 
7. 
Mols, F., et al., Chemotherapy-induced peripheral neuropathy and its association with 
quality of life: a systematic review. Support Care Cancer, 2014. 22(8): p. 2261-9. 
8. 
Schloss, J., M. Colosimo, and L. Vitetta, New Insights into Potential Prevention and 
Management Options for Chemotherapy-Induced Peripheral Neuropathy. Asia Pac J 
Oncol Nurs, 2016. 3(1): p. 73-85. 
9. 
Nangia, J., et al., Effect of a Scalp Cooling Device on Alopecia in Women Undergoing 
Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial. JAMA, 2017. 
317(6): p. 596-605. 
10. 
Scotte, F., et al., Multicenter study of a frozen glove to prevent docetaxel-induced 
onycholysis and cutaneous toxicity of the hand. J Clin Oncol, 2005. 23(19): p. 4424-9. 
11. 
Hanai A., I.H., Sozu T., Tsuda M., Yano I., Nakagawa T., Imai S., Hamabe Y., Toi M., 
Arai H., Tsuboyama T., Effects of cryotherapy on objective and subjective symptoms of 
paclitaxel-induced neuropathy: prospective self-controlled trial. J Natl Cancer Inst, 2018. 
110(2). 
12. 
Tsuyuki, S., et al., Evaluation of the effect of compression therapy using surgical gloves 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 16Jan2020 
40 
 
 
on nanoparticle albumin-bound paclitaxel-induced peripheral neuropathy: a phase II 
multicenter study by the Kamigata Breast Cancer Study Group. Breast Cancer Res Treat, 
2016. 160(1): p. 61-67. 
13. 
Calhoun, E.A., et al., Psychometric evaluation of the Functional Assessment of Cancer 
Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for 
patients receiving systemic chemotherapy. Int J Gynecol Cancer, 2003. 13(6): p. 741-8. 
14. 
Huang, H.Q., et al., Validation and reduction of FACT/GOG-Ntx subscale for 
platinum/paclitaxel-induced neurologic symptoms: a gynecologic oncology group study. 
Int J Gynecol Cancer, 2007. 17(2): p. 387-93. 
15. 
Cella, D., et al., Measuring the side effects of taxane therapy in oncology: the functional 
assesment of cancer therapy-taxane (FACT-taxane). Cancer, 2003. 98(4): p. 822-31. 
16. 
Hershman, D.L., et al., Randomized double-blind placebo-controlled trial of acetyl-L- 
carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant 
breast cancer therapy. J Clin Oncol, 2013. 31(20): p. 2627-33. 
17. 
Greenlee, H., et al., Randomized sham-controlled pilot trial of weekly electro- 
acupuncture for the prevention of taxane-induced peripheral neuropathy in women with 
early stage breast cancer. Breast Cancer Res Treat, 2016. 156(3): p. 453-464. 
18. 
Han, X., et al., Acupuncture combined with methylcobalamin for the treatment of 
chemotherapy-induced peripheral neuropathy in patients with multiple myeloma. BMC 
Cancer, 2017. 17(1): p. 40. 
19. 
Zimmer, P., et al., Eight-week, multimodal exercise counteracts a progress of 
chemotherapy-induced peripheral neuropathy and improves balance and strength in 
metastasized colorectal cancer patients: a randomized controlled trial. Support Care 
Cancer, 2018. 26(2): p. 615-624. 
20. 
USDoHaH, S., Common Terminology Criteria for Adverse Events (CTCAE). 
21. 
Martina, I.S., et al., Measuring vibration threshold with a graduated tuning fork in 
normal aging and in patients with polyneuropathy. European Inflammatory Neuropathy 
Cause and Treatment (INCAT) group. J Neurol Neurosurg Psychiatry, 1998. 65(5): p. 
743-7. 
22. 
Herman, T., N. Giladi, and J.M. Hausdorff, Properties of the 'timed up and go' test: more 
than meets the eye. Gerontology, 2011. 57(3): p. 203-10. 
23. 
Cimbiz, A. and O. Cakir, Evaluation of balance and physical fitness in diabetic 
neuropathic patients. J Diabetes Complications, 2005. 19(3): p. 160-4. 
24. 
Rugo, H.S., et al., Association Between Use of a Scalp Cooling Device and Alopecia 
After Chemotherapy for Breast Cancer. JAMA, 2017. 317(6): p. 606-614. 

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AAAR9515 
ON STUDY FORM 1 
Protocol Version Date: 16Jan2019 
 
 
Patient Initials 
(L, F M) 
TREATMENT REGIMEN 
 BREAST   
Using or 
Planned? 
Regimen 
Standard Taxane Dose 
Frequency 
☐ 
P x 4 
Paclitaxel 175 mg/m2 
Every 2 weeks for 4 cycles 
☐ 
P x 12 +/- Carboplatin (AUC 2 for weekly 
or AUC 5-6 for every 3 weeks) 
Paclitaxel 80 mg/m2 
Every week for 12 cycles 
☐ 
TC x 4 or TC x 6 
Docetaxel 75 mg/m2 
Every 3 weeks for 4 or 6 cycles 
☐ 
TAC x 6 
Docetaxel 75 mg/m2 
Every 3 weeks for 6 cycles 
☐ 
T x 4 
Docetaxel 100 mg/m2 
Every 3 weeks for 4 cycles 
☐ 
T/Carboplatin (AUC6) 
Docetaxel 75 mg/m2 
Every 3 weeks for 6 cycles 
☐ 
Other, specify:  
 
Taxane:  Docetaxel/Paclitaxel 
Dose: 
_mg/m2 
Every 
weeks for 
cycles 
Abbreviations: dd, dose-dense; A, doxorubicin; C, cyclophosphamide; P, paclitaxel; T, docetaxel 
Trastuzumab and/or pertuzumab may be added to any of the regimens. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 

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AAAR9515 
ON STUDY FORM 2 
Protocol Version Date: 16Jan2020 
(continued on next page) 
Page 2 of 3 
 
 
 
 
Patient Initials 
(L, F M) 
 
 
 
 
Does the patient currently have neuropathy? 
☐No 
☐Yes 
If yes, select all causes that apply: 
☐Diabetic neuropathy 
☐Idiopathic neuropathy (also called cryptogenic neuropathy) 
☐Chronic inflammatory demyelinating polyradiculoneuropathy 
☐Neuropathy associated with B12 deficiency 
☐Neuropathy associated with other vitamin or mineral deficiency (e.g. Niacin deficiency (pellagra), B1 
deficiency, B6 deficiency, Copper deficiency, Vitamin E deficiency) 
☐Neuropathy associated with alcohol abuse 
☐Charcot Marie Tooth 
☐Hereditary neuropathy (sensory and autonomic neuropathy, motor neuropathy, or with tendency to 
pressure palsy) 
☐Neuropathy associated with a genetic disorder (Adrenomyeloneuropathy, MNGIE [mitochondrial 
neuropathy, with gastrointestinal symptoms and encephalopathy], NARP [neuropathy ataxia retinal 
pigmentosa], CANOMAD [chronic ataxic neuropathy, with ophthalmoplegia, monoclonal protein, 
cold agglutins and disialosyl antibodies]) 
☐Amyloid associated neuropathy (Transthyretin familial amyloid polyneuropathy, AL amyloidosis, 
POEMS (polyneuropathy, organomegaly, endocrinopathy, m protein, skin changes)) 
☐Neuropathy associated with other autoimmune disorder (e.g. Anti myelin associated glycoprotein 
(MAG) neuropathy, Anti-sulfatide antibody neuropathy, Multifocal motor neuropathy, Guillain 
barre syndrome, Celiac disease) 
☐Neuropathy associated with rheumatologic autoimmune disease (e.g. Systemic lupus 
erythematosus, Vasculitis, Sjogren’s disease, Wegener’s granulomatosus, Churg-Straus, 
cryoglobulinemia, Sarcoidosis, Rheumatoid arthritis) 
☐Toxic neuropathy (e.g. Pyridoxine (B6) toxicity, Amiodarone, Colchicine, Isoniazid, Dapsone, 
Phenytoin, disulfiram, Dideoxynucletides, Metronidazole, Nitrofurantoin, Arsenic, Lead, 
Mercury, Thallium, Acrylamide, N-hexane) 
☐Neuropathy associated with infectious etiology (e.g. HIV, Leprosy, Lyme disease, Hepatitis C, 
Diphtheria) 
☐Paraneoplastic neuropathy (e.g. associated with Anti-hu antibodies or Anti-CV2 (crmp5) antibodies) 
☐Critical illness neuropathy 
☐Uremic Neuropathy 
☐Neuropathy associated with thyroid disease (Hyperthyroidism or Hypothyroidism) 
☐Other cause of neuropathy, specify:_  
 
☐Unknown cause of neuropathy 
CAUSES OF NEUROPATHY 

AAAR9515 
ON STUDY FORM 2 
Protocol Version Date: 16Jan2020 
 
 
Patient Initials 
(L, F M) 
ALCOHOL USE 
PRIOR TREATMENT 
Has the patient ever received the following therapies? 
Taxane 
☐No 
☐Yes 
Platinum agent 
☐No 
☐Yes 
Vinca alkaloid 
☐No 
☐Yes 
Bortezomib-based chemotherapy 
☐No 
☐Yes 
Has the patient received any prior oncologic treatment for this cancer? 
Chemotherapy (e.g., adriamycin, cyclophosphamide, ifosfamide, 
Hormonal therapy (e.g., anastrozole, letrozole, exemestane, tamoxifen) 
☐ 
Biologic therapy (e.g., trastuzumab, pertuzumab, bevacizumab) 
☐ 
Immunotherapy (e.g., pembrolizumab, nivolumab, ipilimumab) 
☐ 
Molecular therapy (e.g., palbociclib, ribociclib, erlotinib) 
☐ 
Surgery 
☐ 
Radiation therapy 
☐ 
Other 
☐ 
If yes, specify:_  
 
No 
☐Yes 
No 
☐Yes 
No 
☐Yes 
No 
☐Yes 
No 
☐Yes 
No 
☐Yes 
No 
☐Yes 
Comments: 
 
 
 
 
Page 3 of 3 

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(continued on next page) 
Page 2 of 3 
Protocol Version Date: 16Jan2020 
AAAR9515 
SUPPLEMENTS, TOPICAL AGENTS, AND OTHER TREATMENTS FORM 
 
 
 
Patient Initials 
(L, F M) 
Date of Assessment: 
/ 
/ 
VITAMINS AND SUPPLEMENTS 
Indicate whether the patient took each vitamin or supplement since the last time point (Baseline only: indicate whether 
the patient is currently taking each vitamin or supplement). Also indicate dosage per pill and frequency, using the fre- 
quency codes below. If vitamins or supplements were not taken in pill form, explain in comments. 
Vitamin or Supplement 
Taken 
Dosage (per 
pill) 
Frequency 
Code 
Taken for neuropathy symptoms? 
Vitamin E 
 Yes   
No 
 Yes   
No 
IU 
Glutamine 
 Yes   
No 
 Yes   
No 
mg 
Vitamin B6 
 Yes   
No 
 Yes   
No 
mg 
Fish Oil 
 Yes   
No 
 Yes   
No 
mg 
TOPICAL AGENTS 
Application Site 
Frequency 
Used for neuropathy 
Topical Agent 
Used 
(check all that 
apply) 
Code 
symptoms? 
 Upper extremity (ies) 
Menthol 

Yes   
No 

Yes   
No 
 Lower extremity (ies) 
Other topical agent, 
Upper extremity (ies) 
 Yes   
No 

Yes   
No 
specify: 
Lower extremity (ies) 
 Frequency codes:   
Code 
Pills 
Topical Agents, 1 application: 
1 
< 1 pill per week 
1-3 times per week (or fewer) 
2 
2-3 pills per week 
4-6 times per week 
3 
4-6 pills per week 
Daily 
4 
1 pill per day 
Twice daily 
5 
> 1 pill per day 
> Twice daily 

AAAR9515 
SUPPLEMENTS, TOPICAL AGENTS, AND OTHER TREATMENTS FORM 
Protocol Version Date: 16Jan2020 
Page 3 of 3 
 
 
 
 
 
Patient Initials 
(L, F M) 
Date of Assessment: 
/ 
/ 
 
 
 
Since last contact, has the patient used acupuncture (Baseline: has the patient ever used acupuncture)? 
 Yes 

No 
If yes, did the patient use acupuncture for neuropathy symptoms? 
 Yes 

No 
Since last contact, has as the patient used cooling gloves or socks (Baseline: has the patient ever used 
cooling gloves or socks)? 
 Yes 

No 
If yes, did the patient use cooling gloves or socks for neuropathy symptoms? 
 Yes 

No 
Since last contact, has as the patient used compression gloves or socks (Baseline: has the patient ever used 
com- pression gloves or socks)? 
 Yes 

No 
If yes, did the patient use compression gloves or socks for neuropathy symptoms? 
 Yes 

No 
Since last contact, has the patient used any other complementary or alternative therapies for neuropathy symp- 
toms (Baseline: has the patient ever used any other complementary or alternative therapies for neuropathy symptoms)? 
 Yes 

No 
If yes, specify:_  
 
 
Did the patient feel these therapies improved their symptoms? 
 Yes 

No 
 
Comments 
 
 
COMPLEMENTARY AND ALTERNATIVE MEDICINES 

AAAR9515 
NEUROPATHY ASSESSMENT FORM 
Protocol Version Date: 16Jan2020 
Page 1 of 2 
 
 
 
Patient Initials 
 
(L, F M) 
Date of Assessment: 
/ 
/ 
Time point: 
Baseline 
12 Weeks  
24 Weeks 
Instructions: Submit this form at the time points listed above. All dates are MONTH, DAY, YEAR. Explain any 
blank dates or fields in the Comments section. Place an X in appropriate boxes. 
Test Performed by: 
Signature: x  
 
 
 
Baseline, 24 weeks, and 52 weeks only. 
Timed Get Up and Go: 
. 
sec 
 
 
Baseline, 24 weeks, and 52 weeks only. 
Did the patient have a history of falls within the past six months?  
Yes 

No 
 
DOMINANT SIDE 
Dominant hand/arm (side with which patient writes): 
 Left 
 Right 
Dominant foot (side with which patient kicks a ball): 
 Left 
 Right 
NEUROPEN 
All time points. 
Indicate whether sensation is detected at the following sites on the patient’s dominant foot. 
 
 
ess 
cted? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sites: 
TIMED GET UP AND GO 
FALLS 
2 
2 
3 
3 
4 
4 
1 
5 
5 
1 
6 
6 
7 
7 
Left foot 
8 
8 
Right foot 
9 
9 
10 
10 
Site 
Touch and pressure (Monofilament): 
Sensation detected? 
1. 
 Yes 
 No 
 Yes 

No 
2. 
 Yes 
 No 
 Yes 

No 
3. 
 Yes 
 No 
 Yes 

No 
4. 
 Yes 
 No 
 Yes 

No 
5. 
 Yes 
 No 
 Yes 

No 
6. 
 Yes 
 No 
 Yes 

No 
7. 
 Yes 
 No 
 Yes 

No 
8. 
 Yes 
 No 
 Yes 

No 
9. 
 Yes 
 No 
 Yes 

No 
10. 
 Yes 
 No 
 Yes 

No 

AAAR9515 
NEUROPATHY ASSESSMENT FORM 
Protocol Version Date: 16Jan2020 
Page 2 of 2 
 
 
 
Patient Initials 
(L, F M) 
Date of Assessment: 
/ 
/ 
128 Hz TUNING FORK 
All time points. Report time, in seconds, until vibration is no longer felt at each of the following 
sites: Lower extremity testing 
 
*Complete only if measurement of interphalangeal joint of the great toe < 15 sec. 
Upper extremity testing 
 
Comments 
 
 
Dominant side 
Normal value 
Interphalangeal joint of the great toe 
 > 15 sec 
sec 
. 
Middorsal foot* 
sec 
OR 

N/A 
 > 15 sec 
Medial Mallelolus* 
sec 
OR 

N/A 
 > 15 sec 
Midfibular region* 
sec 
OR 

N/A 
 > 15 sec 
Patellar region* 
sec 
OR 
N/A 
 > 15 sec 
Dominant side 
Normal value 
Distal interphalangeal joint of the 
index finger 
. 
sec 
> 25 sec 
Ulnar styloid of wrist 
. 
sec 
 > 15 sec 
Lateral epicondyle of elbow 
. 
sec 
 > 15 sec 

AAAR9515 
SOLICITED NEUROPATHY FORM 
Protocol Version Date: 16Jan2020 
Page 1 of 1 
 
 
 
Patient Initials 
(L, F M) 
Date of Assessment 
/ 
/ 
Time point: 
12 Weeks  
24 Weeks 
Instructions: Submit this form at the time points listed above. Using CTCAE 5.0 Grade definitions, please grade abnormalities or conditions present 
PRIOR to taxane administration for this time point (if applicable. If the condition is not present, enter grade 0. Do not code a condition existing prior to 
registration as an adverse event unless it worsens. Indicate if the adverse event results in inpatient hospitalization or prolongation of existing hos- 
pitalization for 24 hours. Follow instructions in Section 16.0 of the protocol for expedited reporting requirements on this study. Category lists may not 
include all adverse events from that category. All dates are MONTH, DAY, YEAR. Explain any blank dates or fields in the Comments section. Place 
an X in appropriate boxes. 
Were solicited events assessed during most recent period? ☐ Yes 
☐ No 
Solicited event term 
 
Attribution to study 
Hospitalization (at least 24 
(CTCAE v5.0) 
Solicited event grade (0-5) 
 
intervention* 
 
hours) 
Dysesthesia 
☐ 
Neuralgia 
☐ 
Paresthesia 
☐ 
Peripheral motor neuropathy 
☐ 
Peripheral sensory neuropathy 
☐ 
 
*Attribution codes: 1 - unrelated   2 - unlikely   3 - possible   4 - probable   5 - definite 
 
 
 

Protocol Version Date: 16Jan2020 
Page 1 of 1 
AAAR9515 
OFF PROTCOL NOTICE 
 
 
 
Patient Initials 
(L, F M) 
Instructions: Submit this form within 14 days after completion (or discontinuation) of protocol participation as outlined 
in Section 7.0 of the S1714 Protocol. All dates are MONTH, DAY, YEAR. Explain any blank fields or blank dates in the 
Comments section. Place an X in appropriate boxes. 
VITAL STATUS 
Vital Status: 
Alive 
Dead 
Date of last contact: 
/ 
/ 
(submit Notice of Death form) 
If dead, date of death: 
/ 
/ 
OFF PROTOCOL 
Off protocol reason (select one): 
Completion of 52 weeks of protocol participation 
Patient did not receive at least one cycle of taxane-containing chemotherapy within 30 days after registration 
Patient received another chemotherapy regimen containing neurotoxic agents 
Patient refusal 
Death 
Off protocol date (date of completion, death, or decision to discontinue participation): 
/ 
/ 
 
 
Comments: 
 
 

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Protocol Version Date: 16Jan2020 
Page 1 of 2 
 
 
AAAR9515 
CIPN FORM 
 
 
Participant ID 
 
Visit Date (MM/DD/YYYY)    
 
 
Visit: 
BASELINE / 12 WEEKS / 24 WEEKS 
 
 
 
Vibration Perception Threshold Test 
Perception Threshold: when vibration stimulus is initially felt 
Disappearance Threshold: when the stimulus disappears 
 
Distal Index Finger 
 
 
Trial 
Right Hand 
Left Hand 
Perception 
Threshold 
Disappearance 
Threshold 
Perception 
Threshold 
Disappearance 
Threshold 
1st 
2nd 
3rd 
Avg 
 
 [Normal Finger Tip: 0.420]  
 
 
Big Toe 
 
 
Trial 
Right Foot 
Left Foot 
Perception 
Threshold 
Disappearance 
Threshold 
Perception 
Threshold 
Disappearance 
Threshold 
1st 
2nd 
3rd 
Avg 
 
[Normal Toe Base: 0.616] 
 
 

AAAR9515 
Protocol Version Date: 16Jan2020 
Page 2 of 2 
 
 
CIPN FORM 
 
Participant ID 
Visit #:  
 
 
TANDEM AND UNIPEDAL STANCE TEST 
 
Successfullycompleted? 
Test 
Max time 
YES 
NO, (seconds) 
Tandem (heel to toe) 
30 sec 
( 
_. ) 
One leg (eyes open) 
60 sec 
( 
_. ) 
One leg (eyes closed) 
30 sec 
( 
_. ) 
One leg (eyes open, head rotated) 
30 sec 
( 
_. ) 
 
HANDS AND FEET COLOR CHANGES 
 
 
NORMAL 
RED 
WHITE 
BLUE 
BLACK 
 
ADHERENCE WITH STUDY INTEVERNTION 
 
Cycle 1 
Yes 
No 
N/A 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
 
Performed by:   
 

AAAR9515 
BASELINE TUMOR DESCRIPTION (BREAST CANCER) 
Protocol Version Date: 16Jan2020 
Page 1 of 2 
 
 
 
 
 
Participant ID 
 
Visit Date (MM/DD/YYYY)    
 
Instructions: Submit this form within 7 days after initial registration. Explain any blank fields or blank dates in the Comments sec- 
tion. Place an X in appropriate boxes. 
 
Date of current pathologic diagnosis: 
 
/ 
/ 
Primary tumor size at diagnosis: 
. 
cm 
AJCC clinical stage: 
T: ☐T1 ☐T1mi  ☐T1a 
☐T1b ☐T1c ☐T2 ☐T3 
☐T4 ☐T4a ☐T4b ☐T4c 
☐T4d 
N: ☐cN0  ☐cN1 ☐cN1mi  ☐cN2 ☐cN2a  ☐cN2b ☐cN3 ☐cN3a  ☐cN3b ☐cN3c ☐cNX 
M: ☐cM0  ☐cM1 
☐pM1 
ER status: 
☐Positive 
☐Negative 
PgR status: 
☐Positive 
☐Negative 
HER-2 status: 
☐Positive 
☐Negative 
☐Equivocal 
Clinical Prognostic Stage group: 
☐IA 
☐IB 
☐IIA ☐IIB 
☐IIIA  ☐IIIB  ☐IIIC  ☐IV 
Pathological Prognostic Stage group: 
☐IA 
☐IB 
☐IIA ☐IIB 
☐IIIA  ☐IIIB  ☐IIIC  ☐IV 
 
Select planned taxane-containing treatment regimen (if dose or frequency varies from standard, select closest 
regimen and indicate dose and frequency below): 
Using or 
Planned 
Regimen 
Standard Taxane Dose 
Frequency 
☐ 
P x 4 
Paclitaxel 175 mg/m2 
Every 2 weeks for 4 cycles 
☐ 
P x 12 +/- Carboplatin (AUC 2 for weekly 
or AUC 5-6 for every 3 weeks) 
Paclitaxel 80 mg/m2 
Every week for 12 cycles 
☐ 
TC x 4 or TC x 6 
Docetaxel 75 mg/m2 
Every 3 weeks for 4 or 6 cycles 
☐ 
TAC x 6 
Docetaxel 75 mg/m2 
Every 3 weeks for 6 cycles 
☐ 
T x 4 
Docetaxel 100 mg/m2 
Every 3 weeks for 4 cycles 
☐ 
T/Carboplatin (AUC6) 
Docetaxel 75 mg/m2 
Every 3 weeks for 6 cycles 
☐ 
Other, specify:  
 
Taxane:  Docetaxel/Paclitaxel 
Dose: 
_mg/m2 
Every 
weeks for 
cycles 
Abbreviations: dd, dose-dense; A, doxorubicin; C, cyclophosphamide; P, paclitaxel; T, docetaxel 

AAAR9515 
BASELINE TUMOR DESCRIPTION (BREAST CANCER) 
Protocol Version Date: 16Jan2020 
Page 2 of 2 
 
 
 
 
 
 
Comments: 
 
 
Is taxane planned to be delivered at the standard dose for the regimen shown in the table above? 
☐Yes 
☐No, reduced dose 
If no, specify dose: 
mg/m2 
Is taxane planned to be delivered at the standard frequency for the regimen shown in the table 
above? 
☐No 
If no, indicate frequency: 
☐Weekly 
☐ > Triweekly 
Will patient be taking HER-2 targeted therapy? 
☐No 
Will the platinum agent be delivered at the standard dose? 
☐Yes 
☐No, reduced dose☐Not Applicable (regimen does not contain a platinum agent) 

AAAR9515 
SOLICITED NEUROPATHY EVENTS FORM 
Protocol Version Date: 16Jan2020 
Page 1 of 1 
 
 
 
 
 
Comments