Alternative Approaches for Nausea Control
Phase: NA
Conditions: Nausea
Sponsor: University of Rochester

 
 
 
 
 
 
UNIVERSITY OF ROCHESTER CANCER CENTER  
 
 
 
 
 
Protocol 
 
for 
 
Alternative Approaches for Nausea Control 
UCCS1202 
 
 
 
 
 
 
 
 
 
 
 
 
Study Chairs: 
Joseph A. Roscoe, Ph.D. 
Michelle Shayne, M.D. 
Tracey O’Connor, M.D. (RPCI) 
Jeffrey Kirshner, M.D. (HOACNY) 
Peter Bushunow, M.D. (RGH-LCC) 
 
 
 
 
 
 
 
Protocol approved by NCCAM 9-17-2012 
 
 
 
 
    
      Protocol approved by RSRB 4-2-2012 
 
 
 
 
    Clarifications approved by NCCAM 10-1-2012 
 
 
 
 
      Clarifications approved by RSRB 10-26-2012 
 
 
 
 
 
  
 
 
 Amended 2-5-2013 
 
 
 
 
 
 
 
           Amended 5-23-2013 
 
 
 
 
 
 
                       Amended 3-19-2014 
Amended 1-9-2015 
Amended 1-26-2016 
Alternative Approaches for Nausea Control version 01/26/2016 
 

TABLE OF CONTENTS 
 
SECTION 
 
1.0 
Background and Study Design 
 
2.0 
Aims 
 
3.0 
Subject Eligibility 
 
4.0 
Registration and Randomization 
 
5.0 
Treatment Protocol 
 
6.0 
Treatment Evaluation 
 
7.0 
Statistical Considerations 
 
8.0 
Records to Be Kept 
 
9.0 
Patient Consent and Peer Judgment 
 
 10.0 
 
References 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          2 

 Abstract 
 
Nausea remains a significant clinical problem despite the use of the best available antiemetic medications.  
Several studies have shown that expectations of developing nausea are a significant determinant of whether 
patients actually develop treatment-induced nausea.  For example, we found that breast cancer patients (N = 
194) about to begin their first chemotherapy regimen containing doxorubicin who believed that they were “very 
likely” to experience severe nausea were five times more likely to experience severe nausea than those who 
believed that they were “very unlikely” to do so.  In addition, studies have shown that expectations of efficacy 
are largely responsible for the placebo effect and for many of the benefits derived from some CAM therapies.  
For example, in a multicenter study (N = 465) examining acupressure wristbands for control of chemotherapy-
induced nausea, we found that patients who expected the bands to be effective in nausea control experienced 
significantly less nausea than patients who did not expect them to be effective.  
 
 
As a test of whether the effectiveness of acupressure bands in reducing nausea could be enhanced by boosting 
patients’ expectations of the bands’ efficacy, we conducted a double-blind, randomized R21 pilot study 
examining the efficacy of acupressure bands with and without expectancy-enhancing supplementary materials 
in breast cancer patients beginning chemotherapy.  Patients were stratified by expected nausea (high, low).  
Patients in the active condition received a handout with expectancy-enhancing materials and a 12-minute 
relaxation CD that included a 30-second “suggestion” concerning the acupressure bands’ effectiveness.  Patients 
in the control group received a handout that had only neutral materials concerning the bands’ likely 
effectiveness and a relaxation CD that was identical to the active one except additional music was substituted 
for the 30-second suggestion concerning the bands’ effectiveness.  For the 26 patients expecting nausea, peak 
nausea on the 1-7 scale was an average of 1.2 points less in the patients randomized to the active condition 
of expectancy-enhancing supplementary materials compared to the control condition with neutral 
supplementary materials; this represents a large  effect size of 0.78 (Cohen’s D). 
 
 
The present study seeks to confirm and extend these findings in a multi-site, 3-arm, randomized, controlled 
study of 252 breast cancer patients beginning chemotherapy who expect to have nausea.  All patients will 
receive a standardized antiemetic regimen.  Arm 1: Neutral handout; Arm 2: Neutral handout + control 
relaxation MP3 + acupressure bands; Arm 3: Active handout + active relaxation MP3 + acupressure bands.  We 
hypothesize that acupressure bands provided with efficacy-enhancing materials will be more effective in 
controlling chemotherapy-induced nausea than acupressure bands provided with neutral materials.  We build 
upon a successful R21 study that was designed to refine methods and provide an effect size estimate for this 
application.   
 
 
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          3 

 
 
-----------------------  
1.0  Background 
----------------------- 
 
The shift towards patient-centered care has increasingly made communication between caregiver and patient a 
two-way street.  Healthcare professionals need to impart information about treatment to the patient while 
listening to the patient’s fears, hopes, and wishes.  Working together, a treatment plan is developed.  Patient and 
caregiver communication is crucial in the development of patients’ expectancies for treatment outcomes, termed 
“response expectancies.”  This anticipation can influence physical, emotional, and mental outcomes throughout 
the treatment process.1-4   
 
 
The effect of response expectancies can be considerable, and they frequently account for variance in 
chemotherapy-induced nausea above and beyond the emetogenicity of the chemotherapeutic agent and other 
known predictive factors for nausea such as gender and age.2-11  For example, Roscoe et al. studied 194 breast 
cancer patients about to begin chemotherapy with a doxorubicin-based regimen and found that patients who 
believed that they were “very likely” to experience severe nausea were five times more likely to 
experience severe nausea than those who believed that they were “very unlikely” to do so.8   
 
 
Although expectancies may represent an acknowledgement of one’s propensity to develop nausea based on past 
experience (e.g., nausea during pregnancy or susceptibility to motion sickness), these expectancies are also 
influenced by socio-cultural factors and what patients are told to expect from the range of information they 
receive from clinicians, hospital staff, other patients, family, friends, and the world at large.  Thus, nausea 
Prior to patient’s first chemotherapy treatment 
1. Assess nausea, emesis,  and antiemetic and concomitant therapy use for nausea, for 5 days by diary.  
2. Record the number of hours the acupressure bands were worn and the number of times the MP3 was listened to 
for five days by diary.  
3. Assess HRQL on Day 5. 
4.  Feedback questions on Day 5. 
Following patient’s first and second chemotherapy treatment 
1.  Give patients in 
Arms 2 and 3 the 
acupressure bands 
and put them on.  
 
2. Give patients the 
assigned handout. 
 
3.  Give patients in 
Arms 2 and 3 an 
MP3 player and the 
assigned relaxation 
MP3 and play it 
using earphones.  
 
4.  Assess expected 
efficacy of the 
acupressure bands 
and reassess 
expected nausea 
(Arms 2 and 3 only).  
-  Handout without expectancy- 
 enhancing component 
-  Handout without expectancy- 
enhancing component 
-  Relaxation MP3 without 
expectancy-enhancing component 
-  Acupressure bands  
            On-study 
 
1. Screen for patients with 
expected nausea > 3 on 
1-5 scale. 
 
2. Informed consent 
 
3. Complete on-study 
questions, which 
include expected 
nausea and nausea 
history questions. 
 
4. Assess HRQL. 
 
5. All patients receive a 
standardized 
antiemetic regimen and 
standard care. 
 
Arm 1 
Arm 2 
Arm 3 
-  Handout with expectancy- 
 enhancing component 
-  Relaxation MP3 with expectancy-
 enhancing component 
-  Acupressure bands  
S 
t 
r 
a 
t 
i 
f 
y 
& 
R 
a 
n 
d 
o 
m 
i 
z 
e 
 
Schema 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          4 

expectancies can be considered to have both internal and external sources, and it is these external sources that 
might provide a way of reducing chemotherapy-induced nausea.  Unlike other risk factors for nausea, nausea 
expectancies are malleable and provide an opportunity for intervention.    
 
 
Acupressure Bands and Expectancy:  Research done by our group and others provides evidence that 
acupressure bands are efficacious in reducing treatment-related nausea,12-17 and that acupressure bands are 
particularly effective for patients who expect nausea.18  Expectancy appears to play a dual role in the bands’ 
effectiveness, with research also showing that their effectiveness in controlling nausea can largely be accounted 
for by patients’ expectations of efficacy, i.e., a placebo effect.11,13,19,20  In this regard, in addition to any intrinsic 
efficacy for relieving nausea they may have, the acupressure bands can be considered an inert 
device/remedy that facilitates a change in nausea expectancies.  The interplay between patients’ expectations 
for developing nausea and their propensity to respond favorably to an intervention designed to increase positive 
expectations for nausea control leads to a logical question—can the effectiveness of acupressure bands in 
reducing nausea be enhanced by boosting patients’ expectations of the bands’ efficacy?   Stated another way, 
can the placebo effect be maximized and utilized for enhanced nausea control?   
   
 
We tested that question in an R21 pilot study of acupressure bands, with and without expectancy-enhancing 
supplementary materials, for control of nausea in breast cancer patients beginning chemotherapy (Preliminary 
Study 1).11  The active condition consisted of a handout and a specially made 12-minute relaxation CD, each 
with components to enhance patients’ expectations of the usefulness of the acupressure wristbands.  Patients in 
the control condition received acupressure bands along with a neutral handout concerning the bands’ likely 
effectiveness and a relaxation CD that had no information concerning the acupressure bands.  For the 26 
patients expecting nausea, peak nausea on the 1-7 scale was an average of 1.2 points less in the patients 
randomized to the active condition compared to the control condition.  The present study seeks to confirm and 
extend these findings in a multi-site, 3-arm, randomized, controlled study.  
 
 
Overview of Proposed Study:  252 Chemotherapy-naïve, female breast cancer patients about to begin 
chemotherapy without concurrent radiotherapy or interferon, treated at the University of Rochester James P. 
Wilmot Cancer Center (URCC), Rochester General Hospital's Lipson Cancer and Blood Center (RGH-LCC), 
Roswell Park Cancer Institute (RPCI), or at Hematology-Oncology Associates of Central New York 
(HOACNY), and who expect to have nausea, will be entered.  Participants will be randomized to one of three 
study arms: Arm 1: Neutral handout; Arm 2: Neutral handout + control relaxation MP3 + acupressure bands; 
Arm 3: Active handout + active relaxation MP3 + acupressure bands.   
 
Four common chemotherapy regimens will be allowed.  They are doxorubicin and cyclophosphamide with or 
without docetaxel, docetaxel with cyclophosphamide, and docetaxel with carboplatin.  Only patients receiving 
the antiemetic regimen described below will be eligible.  All patients will receive a standardized antiemetic 
regimen.  All ancillary treatments, as appropriate for control of symptoms caused by the cancer or its treatment, 
may be administered as clinically indicated and will be recorded.  As part of the consent process, patients will 
be told that we are studying the use of acupressure bands and a relaxation MP3 and how information is 
delivered.  At no point will we inform patients we are examining the role of expectancy and that we are testing 
an expectancy manipulation.   
 
Hypothesis:  Acupressure bands with efficacy-enhancing supplementary material will be more effective in 
controlling chemotherapy-induced nausea than acupressure bands with neutral supplementary material.  
 
---------------------- 
2.0  Aims 
----------------------- 
 
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2.1 
Primary Aim:  To determine whether acupressure bands provided with efficacy-enhancing 
supplementary material are more effective in controlling chemotherapy-induced nausea than acupressure 
bands provided with neutral supplementary material. (Arm 2 vs. Arm 3) 
 
2.2 
Secondary Aim:  To determine whether acupressure bands combined with a relaxation MP3 and 
supplementary material are a helpful adjunct to standard antiemetics in controlling nausea. (Arm 1 vs. 
Arm 3) 
 
 
 
---------------------------- 
3.0  Subject Eligibility 
---------------------------- 
 
Study Patients Must: 
 
3.1 
Be female. 
 
3.2 
Have a diagnosis of breast cancer, any stage. 
 
3.3 
Be chemotherapy naïve and about to begin her first course of chemotherapy. 
 
   3.4 
Be scheduled to receive one of the following four common chemotherapy regimens* with the specified 
 
antiemetic regimen.**ab  They are: 
 
1. Chemotherapy regimen: Doxorubicin/cyclophosphamide  
Antiemetic regimen: Aprepitant (125 mg p.o.) + palonosetron ** (0.25 mg I.V.) + dexamethasone on 
Day 1 and aprepitant (80 mg p.o.) + dexamethasone on Days 2 & 3.a   
Note: Fosaprepitant (150 mg I.V.) on Day 1 will be allowed in place of the three days of oral 
aprepitant. 
 
2. Chemotherapy regimen: Doxorubicin/cyclophosphamide/docetaxel  
Antiemetic regimen: Aprepitant (125 mg p.o.) + palonosetron ** (0.25 mg I.V.) + dexamethasone on  
Day 1 and aprepitant (80 mg p.o.) + dexamethasone on Days 2 & 3.a   
Note: Fosaprepitant (150 mg I.V.) on Day 1 will be allowed in place of the three days of oral 
aprepitant. 
 
3. Chemotherapy regimen: Docetaxel/carboplatin 
Antiemetic regimen: Palonosetron ** (0.25 mg I.V.) + dexamethasone on Day 1 + dexamethasone on 
Days 2 & 3.ab 
 
4. Chemotherapy regimen: Docetaxel/cyclophosphamide 
Antiemetic regimen: Palonosetron  ** (0.25 mg I.V.) + dexamethasone on Day 1 + dexamethasone on 
Days 2 & 3.ab 
 
*  In the study, Herceptin® (trastuzumab) is not classified as a chemotherapy agent and will be allowed 
at the oncologist’s discretion. 
 
** Granisetron or ondansetron, on one or more days, will be allowed in place of palonosetron.   Note: 
both granisetron and ondansetron may be given to the same patient if provided on different days. 
 
a  Providing dexamethasone on Day 2 and/or Day 3 is optional at the discretion of clinic personnel. 
 
b   Aprepitant or fosaprepitant, as described in regimens 1 and 2 above, may be provided with this 
antiemetic regimen at the discretion of clinic personnel.  
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and 
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Alternative Approaches for Nausea Control version 01/09/2015 
 
 
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3.5.   Have a response of > 3 on a question assessing expected nausea as assessed on a 5-point Likert-scale 
anchored at one end by 1 = "I am certain I WILL NOT have this," and at the other end by  
 
5 = "I am certain I WILL have this."   
 
3.6  
Be able to read English (since the assessment materials are in printed format). 
 
3.7 
Be 18 years of age or older and give written informed consent. 
 
Study Patients Must Not: 
 
3.8 
Have clinical evidence of lymphedema, current bowel obstruction, or symptomatic brain metastases, as 
 
determined by their treating oncologist. 
 
3.9 
Be receiving concurrent radiotherapy or interferon.  
 
---------------------------- 
4.0  Randomization 
---------------------------- 
 
 
4.1 
Patients who meet the eligibility criteria and who have signed the consent form will be randomized to 
one of three trial arms as described below. 
 
4.2 
Randomization will be stratified by whether or not patients receive a doxorubicin-based chemotherapy 
(yes, no) because it is more emetogenic than other chemotherapy regimens.10  We will also stratify by 
site (i.e., URCC, RGH-LCC, RPCI, HOACNY) as is customary in multicenter cancer studies.   
 
4.3 
A total enrollment of 252 patients is planned, with 84 patients in each treatment condition.   
 
4.3.1 Each of the four sites will have an accrual target range from 48 to 96 patients.  
 
4.3.2 Accrual at a given site will halt only when (1) at least 96 subjects have been enrolled at the site 
or (2) enrollment at all sites is closed since at least 252 subjects have been enrolled in the study. 
 
4.4 
Treatment Arms 
  
 
 
 
 
 
 
 
 
Arm 1: Neutral handout that has no mention of acupressure bands. 
Arm 2: Neutral handout concerning acupressure bands + control relaxation MP3 + acupressure bands. 
Arm 3: Active handout concerning acupressure bands + active relaxation MP3 + acupressure bands.  
 
4.5   
Because patients must actually receive the intervention prior to their initial chemotherapy, which is an 
extraordinarily busy and hectic time in cancer clinics, an expedited randomized system will be used 
which involves providing the study coordinator with the correct study materials for any given patient in 
advance of that patient providing consent.  Details for implementation are as follows: 
 
4.5.1 Research associates of Dr. Roscoe who will not be involved in study analyses and will not have 
patient contact will create randomization envelopes and study packets for each site in advance 
of patient recruitment. 
 
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Rev 
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and 
1/26/16 
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4.5.2 324 Study packets will be created and numbered sequentially with each packet containing the 
necessary questionnaires for the study with preprinted study ID numbers (i.e., 1-324) on all of 
the Teleform questionnaires within that packet.   
 
4.5.21 Study packets will be grouped in sequential blocks of 18, i.e., 1-18, 19-36, 37-54, etc. 
 
4.5.22  Each block of 18 study packets will be randomly assigned to Study Arms by means of a 
computer-generated random table using the Mersenne-Twister (Ref: Matsumoto, M. and 
Nishimura, T. (1998) Mersenne Twister: A 623-dimensionally equidistributed uniform 
pseudo-random number generator, ACM Transactions on Modeling and Computer 
Simulation, 8, 3–30.) with a random block size of 3 or 6.  
  
4.5.3 All study packets randomized to study Arm 1 will be yellow in color and will have the neutral 
handout with no mention of acupressure bands added.   
 
4.5.4 All study packets randomized to study Arm 2 will have an opaque, sealed, study-materials 
envelope added with the expectancy neutral handout and a piece of paper the same size as a 
prescription which says, “Use the acupressure bands in addition to your regular medication” 
inside.  The sealed study-materials envelope will also have a flash drive with the control 
relaxation MP3 on it. 
 
4.5.5 All study packets randomized to study Arm 3 will have an opaque, sealed, study-materials 
envelope added with the expectancy enhanced handouts inside.  The sealed study-materials 
envelope will also have a flash drive with the active relaxation MP3 on it. 
 
4.5.6 All study packets for study arms 2 and 3 from each randomization block of 18 packets will be 
placed in sequential order and included in a box with study arm 1 packets.  There will be a total 
of 18 study packets per box.  
 
4.5.61 Each site will initially receive two of these boxes, one with the additional marking, For 
Patients Receiving Doxorubicin, and the other with the additional marking, For 
Patients Not Receiving Doxorubicin.   
 
4.5.62 The remaining boxes will be stored at the URCC until needed at one of the sites.  These 
remaining boxes can later be marked either For Patients Receiving Doxorubicin or For 
Patients Not Receiving Doxorubicin, as necessary, and can go to any site.   
 
 
4.5.63 Note: This procedure will keep the study materials for these two conditions blinded from 
anyone with patient contact up to this point in the study.  Arm 1 is not blinded in this 
study. 
 
4.5.7 Additional sealed, opaque, randomization envelopes will be created for each of the four study 
sites (150 for RPCI, 150 for HOACNY, 114 for RGH-LCC, and 78 for URCC).  For 
stratification purposes, half of the randomization envelopes for each site will be marked 
“doxorubicin-based chemotherapy” on the outside, will have some red coloring (because 
doxorubicin is red), and will be labeled sequentially, i.e., 1-38 or 1-75.  The remaining half will 
be marked “non doxorubicin-based chemotherapy” and will also be labeled sequentially.  Two 
thirds of the envelopes in each group will have a sheet of paper saying “Active” inside.  The 
remaining envelopes will have a sheet of paper saying “Control” inside. The information in the 
envelopes will be randomized using the procedure outlined in Section 4.5.2 and adapted as 
Rev 
1/9/15 
 
Rev 
1/9/15 
 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          8 

appropriate for the 2-1 randomization.  The envelopes in each group will then be numbered 
sequentially and placed in a doxorubicin box or a non-doxorubicin box as appropriate.   
 
4.5.8 To randomize a patient who meet the eligibility criteria and who have signed the consent form, 
the study coordinator will take the next sealed randomization envelope out of the appropriate 
doxorubicin or non-doxorubicin box.  If the randomization envelope says Control, the study 
coordinator will take the next study packet labeled control for that patient from the box labeled 
Doxorubicin or from the box labeled as Not Receiving Doxorubicin, depending on the 
chemotherapy regimen the patient receives.  If the randomization envelope says Active, the 
study coordinator will take the study packet for that patient from the box labeled Doxorubicin or 
from the box labeled as Not Receiving Doxorubicin, depending on the chemotherapy regimen 
the patient receives.  
 
4.6 
Documentation of IRB approval and a copy of the institution's IRB-approved informed consent 
document form must be on file with Dr. Roscoe prior to entering participants on this protocol. 
 
Joseph A. Roscoe, Ph.D. 
Department of Radiation Oncology 
University of Rochester Medical Center 
265 Crittenden Blvd. 
CU 420658 
Rochester, NY  14642-0658 
Joseph_Roscoe@URMC.Rochester.edu 
 
4.7 
Within 24 hours following randomization, the following information needs to be sent to Dr. Roscoe: 
 
4.7.1 Site, i.e., URCC, RGH-LCC, RPCI, HOACNY 
 
4.7.2 Name of person consenting the study participant 
 
4.7.3 Verification that participants meet all eligibility requirements listed in Section 3.0 
 
 
4.7.4   Whether or not the patient will receive doxorubicin-based chemotherapy  
 
4.7.5 Verification that the consent form has been signed 
 
4.7.6 Initials of patient  
 
 
4.7.7 Ethnicity 
 
4.7.8 Race 
 
4.7.9 Age 
 
4.7.10 Randomization envelope number 
 
4.7.11 Study packet number  
 
4.7.12 Whether or not the patient will receive Herceptin® (trastuzumab).  
 
 
 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          9 

----------------------------- 
5.0  Treatment Protocol 
----------------------------- 
 
5.1 
All ancillary treatments, including antiemetic medications, as appropriate for control of symptoms 
caused by the cancer or its treatment may be administered as clinically indicated to all patients.  
 
5.1.1. The chemotherapy and/or antiemetic regimens may be altered at the patient’s second and 
subsequent chemotherapy cycles.  
 
5.2 
Recruitment and Informed Consent:  All data will be gathered from patients, 18 years of age or older, 
who are undergoing chemotherapy for breast cancer and who are able to read and understand English.  
Subjects will be recruited from the URCC, HOACNY, RPCI, and RGH-LCC.  Study personnel will 
monitor the clinic schedule.  If the study is deemed appropriate for the patient, and if the patient agrees 
to discuss it, a member of the research team will then explain the project to the potential subject and 
answer all questions.  After they sign the consent form, patients will be given a copy of the document, 
along with the phone numbers to call in case questions arise.    
 
5.3 
Procedures:  Prior to first chemotherapy, all patients will complete the on-study questionnaires (see 
Schema) and be given the handout appropriate for their randomization assignment.  The remaining 
procedures vary according to randomization assignment.   
 
5.3.1 Arm 1: Patients receive a neutral handout with no mention of acupressure bands.   
 
5.3.2 Arms 2 and 3: Patients will receive two acupressure wrist bands to be put on at that time.  
Patients will be told they are allowed to wear or remove the bands throughout the study period at 
their own discretion.  While still wearing the acupressure bands, patients will be given a sealed 
envelope with their assigned handout and asked to read the contents without letting any research 
or clinical personnel know the contents.  Patients will also be given, to keep, a portable MP3 
player and the assigned relaxation MP3.  They will listen to the MP3 at that time using provided 
earphones to ensure they hear it at least once.  Patients will also be encouraged to listen to the 
MP3 later if they found it helpful and to record how many times they did so.  The same 
procedures regarding the relaxation MP3 used for Arm 2 will then be followed.  A reassessment 
of expected nausea, including questions regarding expected efficacy of the acupressure bands, 
will then be completed.  Note: Patients will be instructed not to share information provided in the 
handouts and on the MP3 with the researcher or other patients. 
 
5.3.3 All patients, regardless of study arm, will be given a diary (Five-Day Home Record) to complete 
at home following their first and second treatments to assess frequency and severity of NV and 
use of antiemetic medications and concomitant therapies for nausea.  They will also receive a 
HRQL measure to complete on Day 5 following their first and second treatments.  In addition, 
logs, as appropriate, will be used to assess use of the wristbands and MP3s, as well as the effect 
of the intervention on patients’ levels of apprehension regarding treatment-related side effects, 
their sense of control over side effects, and the perceived credibility of the intervention following 
their first and second treatments.   
 
5.3.4 Patients will be contacted two to four days after their first and second chemotherapy treatments 
(i.e., Days 3, 4 or 5 of the cycle) to ask them to complete and return the questionnaires in the 
provided stamped, pre-addressed envelope.   
 
Rev 
5/23/13 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          10 

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In another study involving 386 chemotherapy patients, patients wearing the Seabands had 
much less nausea on the day they received their chemotherapy than patients who did not wear 
Seabands. 
 
The promising findings from these two studies suggest that the Seabands are well worth 
trying and that they may be very helpful to patients receiving chemotherapy.  
 N 
116 
   3 
    6 
    9 
   12 
   15 
  18 
N 
120 
 Seabands 
No Seabands 
Patients with Nausea 
0 
Only 3 of 30 patients wearing Seabands had nausea compared  
to 15 of 30 of patients not wearing Seabands. 
 
Thank you for taking part in this study.  We are excited about this study because we think it 
might help stop or reduce the nausea that could result from your treatments.  Previous studies 
show that the Seabands have been able to reduce nausea, and we are hopeful the Seabands 
will help you.  As you can see from the graph below, results from a previous study of 60 
surgical patients show that only 3 of the 30 patients wearing Seabands had nausea.  Many 
more patients (15 out of 30) had nausea without them. 
Part 1 of the expectancy enhancing handout for patients in Arm 3.   
The  prescription (shown above) will be paper clipped to the above handout and is 
intended to augment the efficacy enhancing potential of the handout. 
Part 2 of the expectancy enhancing handout for patients in Arm 3.   
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          12 

5.4.3 The expectancy neutral handout given to patients in Arms 1 and 2 will simply thank patients for 
participating in the study.  Handouts provided to these patients will not have a prescription 
attached and will not contain information on the efficacy of the acupressure bands nor positive 
statements concerning them.  The text is shown below and it will be printed on the appropriate 
Cancer Center letterhead and signed by a medical oncologist.  In addition, patients in Arm 2 will 
receive a piece of paper the size of a prescription that says, “Use the acupressure bands 
in addition to your regular medication.” 
 
 
 
 
5.4.4 Expectancy enhancing and expectancy neutral MP3s:  The basic script used in both the 
expectancy neutral and expectancy enhancing MP3s is about 12 minutes in length and utilizes 
guided imagery in which the individual visualizes pleasant, soothing images or scenes while 
relaxed.  It is based upon a published script.22,23 The MP3s differ from one another only in that 
the expectancy enhancing MP3 (for subjects randomized to Arm 3) will have additional 
language inserted concerning efficacy of the acupressure bands and control of nausea. This 
additional language is under one minute in length and is intended to strengthen patients’ beliefs 
that the acupressure bands will be effective by focusing patients’ attention on how effective the 
acupressure bands have been in reducing or eliminating nausea for other patients.  We believe 
that this focusing of attention will serve to more deeply imbed the idea that the acupressure 
bands will be helpful.  In addition, it will be suggested that since the acupressure bands were 
helpful to others, “we think that they will be helpful to you, as well.”  This use of a suggestion is 
a technique borrowed from suggestive/hypnosis therapy and is a non-deceptive psychological 
procedure to alter expectancy.24  Evidence suggests that both hypnotic and placebo effects share 
the common mechanism of response expectancy and that they are therapeutic because they 
change patients’ expectations of outcome.25  Both can be viewed as instances of the broader 
phenomenon of suggestion.26  Interventions that make use of suggestions (with or without the 
induction of a hypnotic trance) have been used successfully to control nausea related to 
chemotherapy,27-31 during pregnancy,32,33 and after anesthesia.34  In the proposed study, a 
hypnotic trance will not be induced.  We will simply make use of the therapeutic technique of 
providing a suggestion as a method that may be efficacious in increasing positive expectancies 
concerning the acupressure bands.  
 
The actual language that has been inserted in the expectancy enhancing MP3, but not in the 
control MP3, is as follows: 
 
“I’d like you to imagine feeling this way as you begin your treatment, and receive it …and then 
afterwards…you can call up these calm, pleasant feelings at any time…return whenever you 
wish to this special, safe place…and I wonder, too, if you might be able to use the wristband you 
now have as a reminder of these relaxed, pleasant sensations you are now experiencing…free of 
stress, nausea or other unpleasant sensations…I wonder if directing your attention to the 
 
Thank you for agreeing to participate in this study regarding the use of acupressure bands to 
control chemotherapy-related nausea.  The information you will provide is extremely 
valuable.  It is only with the assistance of individuals like you, who are willing to give their 
time, that we can learn new ways to better control the side effects of cancer treatment.  We 
are very appreciative of your contribution to this study.  
 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          13 

wristband in the future can call up these feelings for you…of being quiet, relaxed, with no 
queasiness…others who have had chemotherapy have found the wristbands useful in providing 
relief of that unpleasant feeling, and I wonder if you will too…knowing you can use the bands to 
call up the peace you feel now, the feeling of being free of nausea that you are hopefully feeling 
…and regain the sense of calm...peace and relaxation you have now.” 
 
5.4.5  Patients will be told that they may wear or remove the bands throughout the five days at their 
own discretion and to record when they were worn in the provided five-day diary.  Although 
patients will be given two acupressure bands, they may choose to wear only one band.  In this 
case, the band may be worn on either wrist or alternated between wrists, as the patient desires. 
 
5.4.6 Patients will be given the MP3, and an MP3 player, if necessary, to take home and told they may 
listen to it as much or as little as they would like. 
 
5.5 
No side effects are associated with use of the Seabands.  Patients susceptible to lymphedema, however, 
will be cautioned not to wear the band on the affected arm. 
 
5.6 
No side effects are associated with use of the MP3s.  
 
5.7  Any adverse event (AE) that is possibly, probably, or definitely related to the study intervention will be 
reported according to the guidelines below:   
 
5.7.1 A SAE refers to any event in which the outcome results in any of the following:  death*, a life-
threatening adverse drug experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability, incapacity, or a congenital anomaly/birth 
defect.  Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
 
* This includes all deaths within 30 calendar days of ending study participation regardless of 
attribution. 
 
5.7.1.1   Only SAEs that are possibly, probably, or definitely related to the study intervention 
will be recorded in this study. 
 
5.7.2  An AE is any untoward medical occurrence in a subject during participation in the clinical study 
or with use of the experimental device being studied. An adverse finding can include a sign, 
symptom, abnormal assessment (laboratory test value, vital signs, electrocardiogram finding, 
etc.), or any combination of these. 
 
5.7.2.1 Only AEs that are possibly, probably, or definitely related to the study intervention will  
be recorded in this study. 
 
5.7.3 The MedWatch form found at http://www.fda.gov/Safety/MedWatch/default.htm will be used for 
reporting any AEs or SAEs that are possibly, probably, or definitely related to the study 
intervention.   
 
5.7.4 The NCI Common Terminology Criteria for Adverse Events version 4.0 will be utilized to 
describe and grade any AEs or SAEs that are possibly, probably, or definitely related to the study 
intervention. 
Rev 
5/23/13 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          14 

 
5.7.5 SAEs and AEs at HOACNY, RPCI, and RGH-LCC will be reported according to the following 
guidelines: 
 
 
5.7.5.1 SAEs that are that are possibly, probably, or definitely related to the study intervention 
must be reported to the URCC by phone (585 275-9962 or 585 276-3559) within 24 
hours of learning of the event with a written report to follow within 5 calendar days.   
 
5.7.5.2 Any AE that is possibly, probably, or definitely related to the study intervention must 
be reported to the URCC within 10 calendar days. 
 
5.7.5.3 SAEs and AEs should be reported to the local IRB as per their requirements. 
 
 
5.7.5.4    SAE and AE reports should be submitted to the URCC in one of the following ways: 
 
• 
Mail: 
 
Joseph A. Roscoe, Ph.D. 
Department of Radiation Oncology 
 
University of Rochester Medical Center 
265 Crittenden Blvd 
 
CU 420658 
 
Rochester, NY  14642-0658 
• 
Fax: 585-461-5601. 
• 
Email: joseph_roscoe@urmc.rochester.edu 
 
5.7.6 All MedWatch forms received by the URCC will be reviewed upon receipt by Drs. Roscoe, 
Shayne, and/or Morrow to confirm toxicity, grade, expectedness, relatedness, sequelae, follow- 
up required, risk to current or future subjects, and for possible expedited reporting. 
 
  
5.7.7 Expedited reporting:  Any SAE that is possibly, probably, or definitely related to the study 
intervention will be reported within 15 calendar days to the NCCAM Program Officer and within 
10 calendar days to the DSMC, the RSRB, and study investigators at HOACNY, RPCI, and 
RGH-LCC.  The DSMC Chair will determine whether further action is required, and when 
patient safety is of concern, an interim meeting may be called.   
 
5.7.7.1 In addition, SAEs that are that are possibly, probably, or definitely related to the study 
intervention AND are also either life threatening or result in death will also be reported 
within 24 hours via phone to the University of Rochester Research Subjects Review 
Board and within 7 calendar days to the NCCAM Program Officer.   
 
5.8  Clinical Trials Data Safety Monitoring Committee (DSMC):  The DSMC provides oversight of study 
progress and safety by review of accrual and events at regularly scheduled meetings.  Based on the size, 
risk, and complexity of this study, the URCC Protocol Review Committee has scheduled this study for 
annual review.  The PI will submit annual progress reports of these data to the DSMC for review.  The 
report will include the number of patients enrolled, withdrawals, and all SAEs and AEs that are possibly, 
probably, or definitely related to the study intervention.  The PI maintains a database of all adverse 
events that are at least possibly related with description of event, toxicity, expectedness, grade, 
attribution, and information regarding treatment required complications, or sequelae.  The adverse event 
summary sheet, including any SAEs previously reported, will be reviewed by the DSMC at the annual 
meeting.    
 
Rev 
5/23/13 
 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          15 

 
5.8.1 Reports regarding the study from the Clinical Trials Data Safety Monitoring Committee at the 
University of Rochester Cancer Center will be sent to RGH-LCC, RPCI, HOACNY and NCCAM.  
 
5.9 
Fidelity of the Intervention:  To ensure the fidelity of the intervention, all study packets and all of the 
intervention elements (i.e., the acupressure bands, the two versions of the MP3, and the two versions of 
the handout) will be created at the URCC in an identical fashion.  These packets will be appropriately 
coded for randomization purposes and distributed to the study sites as needed.  In addition, we will 
provide the research coordinators with a script on how to present the study and the intervention materials 
to patients.  A checklist to document that key elements of the script were followed for each patient 
accrued will be signed by the research coordinators and kept as a study document.  Finally, the research 
coordinator from the URCC will make three site visits to each study location during each year of the 
study—as well as an additional visit to each site to set up the study—to assure uniformity across 
treatment sites and over time. 
 
------------------------------- 
6.0  Treatment Evaluation 
------------------------------- 
Measures: 
 
6.1 
The On-Study Data questionnaire is used to record demographic and clinical information and patient’s 
history of nausea from various causes.  It also includes questions concerning the information sources for 
expectations concerning nausea and expected acupressure band efficacy.   
 
6.2 
The measure of patients' expectations for side effects is based on a questionnaire used previously by our 
group,7,35 as well as by others.36,37  Expectations of developing specific side effects (e.g., nausea, 
vomiting) are assessed on separate 5-point Likert-scales that are anchored at one end by 1 = "I am 
certain I WILL NOT have this" and at the other end by 5 = "I am certain I WILL have this."  Questions 
concerning the expected efficacy of the acupressure wrist bands and whether this expectation was 
changed by the information materials have been added to the post-intervention version of the 
questionnaire.   
 
6.3 
Nausea and emesis will be measured by a patient report diary developed by Burish38 and Carey39 and 
completed by patients over a five-day period.  Each day is divided into four segments (morning, 
afternoon, evening, night) in which patients report the severity of nausea and number of vomiting 
episodes for each period of the day (20 total reporting times for each five-day period).  Severity of 
nausea is assessed on a 7-point rating scale, anchored at one end by 1 = "Not at all nauseated" and at the 
other end by 7 = "Extremely nauseated."  Vomiting episodes will be recorded for the same time intervals 
as part of the five-day diary for later exploratory analyses.  We have used this scale in previous 
studies,7,13,40 so we will be able to compare current findings with results of our previous research.  
 
6.4 
Logs will be used to assess use of the wristbands, MP3s, antiemetic medications, and concomitant 
therapies for nausea, as well as the effect of the intervention on patients’ levels of apprehension 
regarding treatment-related side effects, their sense of control over side effects, and the perceived 
credibility of the intervention.   
 
6.5 
Health-Related Quality of Life will be assessed using the Functional Assessment of Cancer Therapy 
Scale – General (FACT–G).  The FACT–G is a 28-item scale developed specifically for use in cancer 
clinical trials.41  It was developed by Cella and his group through extensive interviews with patients 
experiencing symptoms of cancer and with oncology professionals and has been validated in a series of 
studies of 542 cancer patients.  It has shown very good test-retest reliability as well as validity.42,43  
Along with a total score representing HRQL, there are psychometrically validated subscales of physical, 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          16 

functional, social, and cognitive-emotional status.  It has become one of the most commonly used 
measures in oncology, and we have used this scale in our previous studies.  
 
6.6 
Demographic and treatment information will be abstracted from patients’ charts or obtained from 
patients in a brief interview.   
 
 
6.6.1 Data on white blood cell counts (i.e., lymphocytes, monocytes, neutrophils, basophils, and 
eosinophils) from CBC blood work done within a week of patients’ first chemotherapy and/or 
within a week of patients’ second chemotherapy will be abstracted from patients’ charts.  We 
note that a CBC is not required for the study and will not be paid for by study funds.  We are 
collecting this data, if it is available, for exploratory analyses to see whether there is an effect of 
the relaxation MP3 on cell counts. 
 
 
-------------------------------------- 
7.0  Statistical Considerations 
------------------------------------- 
 
7.1 
Data Handling and Statistical Considerations: 
 
7.1.1 Data will be entered on scannable forms (Teleform) and electronically sent to an Access 
Database.  After scanning, data is audited visually for errors.  R, SPSS, and SAS statistical 
packages will be used for the analyses.  Every effort will be made to encourage and facilitate 
patients' completion of questionnaires.   
 
7.1.2 Unless otherwise stated, all statistical tests will be performed at the two-tailed 5% level of 
significance.  Likewise, 95% confidence intervals will be constructed to quantify uncertainty of 
effect estimates.  Data will be analyzed on an "intent-to-treat" basis; participant data will be 
included in the treatment group to which the participant was randomized, regardless of any 
subsequent changes to the treatment.  No interim analyses of efficacy data from the trial are 
planned.  
  
7.1.3 Assumptions and Outliers:  The assumptions underlying all statistical analyses will be 
thoroughly checked using appropriate graphical and numerical methods.44,45  In the case of 
serious violations of the assumptions, appropriate nonparametric methods or transformations will 
be attempted.46,47  Outlying data are a potential concern in the collection of data on nausea 
severity in a diary format, such as we propose.  This concern did not materialize in a study we 
concluded that assessed nausea severity in 96 breast cancer patients.48  Patients completed the 
same 5-day nausea diary as in the study proposed herein.  No patients were considered outliers in 
this prior dataset.  For the present study, we will consider observations that are more than 3 
standard deviations above or below the mean as outlying, where the mean and standard deviation 
are calculated based on data without the observation under consideration.  Should any be present, 
we will carefully check the data and make corrections if necessary.  If no errors are found, we 
will conduct analyses both with and without the outlying data and report both results. 
 
7.2 
Calculation of the Primary Outcome Variable, Handling of Missing Data, and ITT:   
 
7.2.1 The primary outcome variable will be Peak Nausea (measured on a 7-point scale anchored by “Not 
at all Nauseated” and “Extremely Nauseated”) defined as the highest nausea rating across the 20 nausea 
assessment points (i.e., four measuring points on each of the five days).  If scored outcomes are missing, 
we will evaluate if they are missing at random (MAR) with respect to treatment arm and key prognostic 
variables.  Under the MAR assumption, we will use multiple imputation to assess significance and 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          17 

uncertainty of the key analysis parameters.49  In the unlikely event we suspect the missing values are not 
missing at random (MNAR), we will use selection and pattern-mixture models to assess the sensitivity 
of the results to missing data.49   
 
7.2.2 All analyses evaluating the interventions will follow the Intent to Treat (ITT) principle, and all 
subjects will be included in the analysis regardless of compliance or outlier status.  Separate analyses 
will be performed after removing noncompliant subjects.  These analyses will be considered exploratory 
and the results will be treated with caution; we note that the power will be reduced because of the 
smaller sample size. 
 
7.3 
Potential Covariates to be Added to the Statistical Analyses Below:  Variables that may be related to 
nausea report, (i.e., age, doxorubicin-based chemotherapy or not, susceptibility to motion sickness or 
not, morning sickness or not, ethnicity, race, educational level, receiving trastuzumab or not, receiving 
palonosetron or not, receiving a first generation 5HT-3 on Day 1 only or not, baseline FACT-G scores, 
receiving dexamethasone on Day 2 or not, receiving dexamethasone on Day 3 or not, and receiving 
optional aprepitant or fosaprepitant as part of antiemetic regimens 3 or 4 or not) will be tested as 
potentially meaningful covariates to the analyses below by using ANCOVA.  Only covariates testing at 
P < 0.05 will be left in the final model.   
 
 
7.4 
Primary Analysis:  The Primary Aim to determine whether acupressure bands provided with efficacy-
enhancing supplementary material are more effective in controlling chemotherapy-induced nausea than 
acupressure bands provided with neutral supplementary material will be examined using ANCOVA with 
Peak Nausea after the first chemotherapy as the response, Arm (Arms 2 and 3) as the factor and 
expectancy of acupressure bands as the covariate (in addition to any covariates identified as stated 
above).  
 
7.5 
Secondary Analysis:  Study Arm 1 and Study Arm 3 will be compared to determine whether 
acupressure bands combined with a relaxation MP3 and supplementary material are a helpful adjunct to 
standard antiemetics in controlling nausea.  The analysis will be the same as the one used in the primary 
analysis with Arms 1 and 3 as the factor. 
 
7.6 
Additional Analyses: The following will be interpreted very cautiously.  It is our intention to use them 
solely to support findings from the Primary and Secondary analyses and to generate information to be 
used in the design of further randomized controlled investigations.  
  
7.6.1  ANCOVA analyses the same as those used for the primary and secondary aims will be used with 
Average Nausea and HRQL as the responses.   
 
7.6.2.  Analyses will be conducted to see if the intervention positively affects patients’ pre-
randomization expectations of developing nausea (EXPN) using ANOVA with EXPN as the response 
and Arm as the factor.  Using only the Arms 2 and 3 subjects (i.e. those that received acupressure bands) 
an ANOVA will be conducted with pre-randomization expectations of how effective the acupressure 
bands (EXPAB) as the response, and Arm (2 vs 3) as the factor.  
 
7.6.3  Analyses will be conducted to see how patients’ pre-randomization expectations of developing 
nausea (EXPN) as well as their pre-randomization expectations of how effective the acupressure bands 
(EXPAB) will be in controlling nausea mediate the effect of the interventions on Peak Nausea.  
Specifically, we will fit a linear model with Peak Nausea as the response, and Arm, EXPN, EXPAB, 
Arm*EXPN, Arm*EXPAB as the factors.  The two-way interactions will be used to assess how the 
expectancies moderate the effect of the interventions.   
 
Rev 
2/5/13 
and 
3/19/14  
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          18 

7.6.4  The effects of the intervention following patients’ second chemotherapy on Peak and Average 
nausea, and HRQOL will be examined in the same manner as the primary and secondary analyses, also 
including Peak Nausea after the first chemotherapy (PN1) and Arm*PN1 as additional factors to assess 
how PN1 affects Peak Nausea and the effect of the interventions after the second treatment.    
 
7.6.5  We will use a linear mixed model to assess the growth/persistence of the intervention effects over 
the first and second chemotherapy.  Peak nausea from both times will be the response.  Arm (all three 
arms for this analysis), Cycle (1 or 2), and expectancy (in addition to any covariates identified) will be 
the fixed effects.  Subject and within-subject will be the random effects.  REML estimation will be used, 
and F-Tests will be used to test significance.50 We will test whether the intervention effect is stable over 
the course of the two interventions (i.e. the effects at each assessment are the same) using the 
appropriate contrast test.  
  
7.6.6  Interactions in any of the above models will be retained only if there are statistically significant at 
the 0.05 level.   
 
7.7 
Sample Size:  The Primary Aim is to evaluate whether a difference exists between Study Arm 2 and 
Study Arm 3 in Peak Nausea.  Using the data from our multicenter study of delayed nausea in breast 
cancer patients conducted by the URCC CCOP, the SD of peak nausea was 1.89.  Conservatively 
assuming a correlation of 0.5 between baseline and post-intervention, a sample size of 64 subjects per 
arm will have 80% power to detect a difference between the arms of 0.82, using ANCOVA with a 0.05 
two-sided significance level.  Based upon these figures and assuming approximately 24 patients (11%) 
fail to provide evaluable information, our accrual target will be 72 patients per group or 216 total 
patients.  Based upon our R21 study, we anticipate being able to recruit 72 patients at the Rochester, 
N.Y. site.  This is approximately one patient every 4 weeks during the 54-month recruitment period.  We 
also anticipate a total recruitment of 72 patients each at HOACNY and RPCI.   
 
 
7.7.1  The total accrual target has been increased from 216 to 252  i.e., 84 patients per group, with the 
additional 36 subjects coming from RGH-LCC. 
 
-------------------------------- 
8.0  Records To Be Kept 
------------------------------- 
 
8.1 
Completed questionnaires from RPCI, HOACNY, and RGH-LCC will be photocopied with originals 
sent immediately by mail to Rochester and copies placed in the patients’ study folders at HOACNY, 
RPCI, and RGH-LCC.  The Case Summary should accompany ALL data submissions. Once forms 
arrive in Rochester, they will be scanned and audited for missing or out-of-range data.  Queries for 
missing or out-of-range data will be relayed to the study coordinator in the three off-site locations to be 
rectified.   
 
8.2 
All completed forms should be sent to: 
 
 
 
Tsige Temanu 
Department of Radiation Oncology 
University of Rochester Medical Center 
265 Crittenden Blvd. 
CU 420658 
Rochester, NY  14642-0658 
 
Rev 
1/9/15 
Comment [PDR1]: Usually, this section would 
also be updated to justify and better reflect any 
revisions to the targeted sample size(s). 
Alternative Approaches for Nausea Control version 01/09/2015 
 
 
          19 

8.3 
Personnel from Rochester will also conduct a yearly site audit of HOACNY, RPCI, and RGH-LCC 
using the procedures already in place for our CCOP site audits.  The auditors will review source 
documentation on randomly selected patients. 
 
8.4 
All questionnaires will be kept confidential, locked in the private office of the research coordinator and 
identified only by ID numbers.  
 
 
 
Schedule Of Data Collection  
Measure 
 
Prior to 
randomization 
(pre-
randomization) 
After intervention 
materials are 
provided to patient 
but prior to 
chemotherapy 
(post-
randomization) 
After first 
chemotherapy 
After second 
chemotherapy 
On Study Data 
X 
 
 
 
Expectation Questionnaire 
(pre- randomization) 
X 
 
 
 
Expectation Questionnaire 
(post- randomization) 
 
X 
 
 
5-Day Patient Report Diary 
 
 
X 
X 
FACT-G (HRQL) 
X 
 
X 
X 
Medication Log 
 
 
X 
X 
Wristband Log  
(with feedback) 
 
 
X 
X 
MP3 Log 
(with feedback) 
 
 
X 
X 
Data on white blood counts if 
available 
 
 
X 
X 
 
 
        -------------------------------------------------- 
9.0  Patient Consent and Peer Judgment 
---------------------------------------------------      
 
9.1 
All investigational, FDA, NCI, State, Federal, and Institutional regulations concerning informed consent 
and peer judgment will be fulfilled.  
 
--------------------- 
10.0 References  
---------------------   
 
 1.  Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H. The role of expectancies in the placebo effect 
and their use in the delivery of health care: A systematic review.  Health Technology Assessment 
(Rockville, Md) 1999;3:1-96. 
 2.  Colagiuri B, Roscoe JA, Morrow GR, Atkins JN, Giguere JK, Colman LK. How do patient expectancies, 
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