Cool Down With EMBr: Enhancing Menopausal Hot Flash Symptom Reduction After Breast Cancer
Phase: NA
Conditions: Breast Carcinoma, Breast Ductal Carcinoma In Situ, Breast Lobular Carcinoma In Situ, Hot Flashes
Sponsor: Ohio State University Comprehensive Cancer Center

 
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Local Protocol #: OSU-19152 
 
 
ClinicalTrials.gov Identifier:  
 
TITLE: Cool down with EMBr: Enhancing Menopausal Hot Flash Symptom Reduction after 
Breast Cancer 
 
 
 
 
Principal Investigator: 
 
Sagar Sardesai, MBBS MPH 
Division of Medical Oncology 
The Ohio State University Wexner Medical Center 
B450 Starling Loving Hall 
320 W 10th Avenue 
Columbus, OH 43210 
Tel: 614-293-6401 
Email: Sagar.Sardesai@osumc.edu 
 
 
Co-Investigators:  
 
 
 
 
 
 
 
 
 
Bhuvaneswari Ramaswamy, MD, MRCP 
 
 
 
 
 
 
Division of Medical Oncology 
The Ohio State University Wexner Medical Center 
B406 Starling Loving Hall 
320 W 10th Ave 
Columbus, OH 43210  
 
 
 
Tel: 614-293-6401 
Email: Bhuvaneswari.Ramaswamy@osumc.edu  
 
Robert Wesolowski, MD 
Division of Medical Oncology 
The Ohio State University Wexner Medical Center 
B401 Starling Loving Hall 
320 W 10th Ave 
Columbus, OH 43210  
Tel: 614-366-8541 
Email: Robert.Wesolowski@osumc.edu  
  
Daniel Stover, MD 
Division of Medical Oncology 
The Ohio State University Wexner Medical Center 
512 Biomedical Research Tower 
460 W. 12th Avenue 
Columbus, OH 43210 
Tel: 614-685-6700 
Email: Daniel.Stover@osumc.edu 
 

 
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Nicole Williams, MD 
Division of Medical Oncology 
The Ohio State University Wexner Medical Center 
B405 Starling Loving Hall 
320 W. 10th Avenue 
Columbus, OH 43210  
Tel: 614-293-3316 
Email: Nicole.Williams@osumc.edu 
 
Matthew Cherian, MBBS 
Division of Medical Oncology 
The Ohio State University Wexner Medical Center 
Email: Matthew.Cherian@osumc.edu 
 
   
Statistician:                           Patrick Schnell, PhD 
  College of Public Health 
  226 Cunz Hall 
  1841 Neil Ave. 
  Columbus, OH 43210 
  Tel: (614) 292-5274 
  Fax (614) 247-1846 
  Email: Schnell.31@osu.edu  
 
 
Company:  
 
 
Embr Labs, Inc. 
 
 
 
 
24 Roland St STE 102, Boston, MA 02129-1250 
 
Pamela Peeke, MD, MPH 
Chief Medical Officer, Embr Labs 
Pam@embrlabs.com 
301-407-0467 
 
 
 
 
 
Matthew Smith  
 
 
 
 
Chief Scientific Officer 
 
 
 
 
Matt@embrlabs.com 
 
 
 
 
 
Sonja Billes, PhD 
Senior Scientific Advisor, Embr Labs 
Sonja@embrlabs.com 
503-896-0563 
 
Interventions(s): EMBr Wave 
 
 
Protocol Type: 
Version #6.0 / Version Date: 3/14/2023 
IRB Approved  
 

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Table of Contents 
 
TRIAL SUMMARY & SCHEMA ............................................................................................................... 4 
1.1 TRIAL DESIGN .................................................................................................................................................... 4 
1.2 STUDY SCHEMA .................................................................................................................................................. 5 
2.0 TRIAL OBJECTIVES ......................................................................................................................................... 5 
1.1 
PRIMARY OBJECTIVE ........................................................................... ERROR! BOOKMARK NOT DEFINED. 
1.2 
SECONDARY OBJECTIVES .................................................................... ERROR! BOOKMARK NOT DEFINED. 
3.0 BACKGROUND .................................................................................................................................................. 6 
3.1 BOTHERSOME HOT FLASHES .............................................................................................................................. 6 
3.2 EMBR WAVE DEVICE ........................................................................................................................................ 6 
3.3 RATIONALE AND FEASIBILITY ............................................................................................................................ 7 
4.0 METHODOLOGY .............................................................................................................................................. 7 
4.1 ENTRY CRITERIA ................................................................................................................................................ 7 
4.1.1 Inclusion Criteria ................................................................................................................................................ 7 
4.2. STUDY LOCATION AND SAMPLE ........................................................................................................................ 8 
4.3 REGISTRATION .................................................................................................................................................... 8 
4.4 HOT FLASH ASSESSMENTS ................................................................................................................................. 8 
4.5 STUDY INTERVENTION ...................................................................................................................................... 10 
4.6 CLINICAL ASSESSMENT .................................................................................................................................... 10 
4.7 DURATION OF THERAPY ................................................................................................................................... 10 
4.8 DURATION OF FOLLOW UP ................................................................................................................................ 11 
4.9 CRITERIA FOR REMOVAL FROM STUDY ............................................................................................................ 11 
4.10 ADHERENCE ................................................................................................................................................... 11 
5.0 POTENTIAL TOXICITY, DOSE MODIFICATIONS, AND MANAGEMENT ........................................ 11 
7.0 TREATMENT PLAN ........................................................................................................................................ 12 
7.1 TREATMENT PLAN AND OVERVIEW .................................................................................................................. 12 
IN ADDITION, PATIENTS WILL RECORD THEIR DAILY HOTFLASH SCORE DAILY IN THEIR JOURNALS. ........................ 13 
9.0 ADVERSE EVENT REPORTING ................................................................................................................... 13 
9.1 ATTRIBUTION OF THE ADVERSE EVENTS .......................................................................................................... 13 
9.2 DOCUMENTATION ............................................................................................................................................. 13 
9.3 REPORTING ....................................................................................................................................................... 14 
 
CRITERIA FOR RESPONSE ASSESSMENT ........................................................................................ 14 
10.1 MEASUREMENT OF EFFECT ............................................................................................................................. 14 
 
DATA REPORTING / REGULATORY REQUIREMENTS ................................................................. 14 
11.1 ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................................. 14 
11.2 INSTITUTIONAL REVIEW BOARD ..................................................................................................................... 14 
11.3 INFORMED CONSENT ...................................................................................................................................... 14 
11.4 PATIENT CONFIDENTIALITY ............................................................................................................................ 15 
11.5 PUBLICATION AND RESEARCH FINDINGS ........................................................................................................ 15 
11.6 COMPLIANCE MONITORING ............................................................................................................................ 15 
11.7 DATA SAFETY MONITORING ........................................................................................................................... 15 
11.8 RESPONSIBILITY FOR DATA SUBMISSION ........................................................................................................ 15 
11.9 DATA AND RECORDS ...................................................................................................................................... 15 
11.10 SAFETY AND MONITORING ........................................................................................................................... 15 
 ......................................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
3.12 
DOCUMENTATION ..................................................................................................................................... 15 
11.13 REPORTING ................................................................................................................................................... 16 
12.0 STATISTICAL CONSIDERATIONS ........................................................................................................... 17 
12.1 STATISTICAL DATA ANALYSIS AND STUDY DESIGN ....................................................................................... 17 
13.0 REFERENCES ............................................................................................................................................... 199 
 
 
 
 
 

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 TRIAL SUMMARY & SCHEMA 
 
Abbreviated Title 
Embr Wave Study 
Trial Phase 
Feasibility 
Clinical Indication 
Patients with a breast cancer history experiencing 
bothersome hot flashes   
Trial Type 
Feasibility Pilot Trial 
Type of control 
Non-placebo controlled 
Route of “administration” 
Wrist, non-invasive wearable thermoelectric 
system 
Trial Blinding 
no 
Treatment Groups  
Two-arm, cross-over, non-placebo controlled 
trial 
Number of trial subjects 
50  
Estimated enrollment 
period 
12 months 
Estimated duration of trial 
Patients will not be followed after study 
termination  
 
Duration of Participation 
Approximately 8 weeks 
 
 
 
1.1 Trial Design 
This study is a randomized, crossover, non-placebo controlled trial of 50 patients with 
history of breast cancer and bothersome hot flashes.  We propose to have 25 patients 
per arm in a two-arm study randomized to Embr Wave device vs no device or other 
treatment for bothersome hot flashes with a 1-month crossover. The study has enrolled 
23 participants with no active subjects in follow up as of 01/05/2022. The current 
amendment version dated  1/5/2022 includes the following changes a) update the study 
intervention to recently launched Embr Wave Generation 2 device and b) enroll an 
additional 10 participants so that approximately 50% of the study population will use 
the Generation 2 device. This increases initial planned sample size of n=40 by an 
additional 10 subjects to n=50.  Study design shown below in Figure 1.  
 

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1.2 Study Schema  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0 TRIAL OBJECTIVES 
This study will evaluate the preliminary efficacy of the EMBr Wave wrist device in managing 
the symptoms of  hot flashes in patients with a history of breast cancer who have been 
experiencing hot flashes for at least 30 days prior to study entry. This study is based on 
published data that this device can improve thermal comfort by producing varying temperature 
pulses to counter uncomfortable sensations of heat or coolness.   
 
1.1 Primary Objective 
(1) To evaluate the feasibility of using EMBr Wave technology in women with a 
history of breast cancer who are experiencing bothersome hot flashes. 
1.2 Secondary Objectives  
(1) To evaluate the preliminary efficacy of EMBr Wave in reducing hot flash 
severity and frequency in women with a history of breast cancer. 
(2) To identify in what ways EMBr Wave has the greatest potential efficacy, 
such as reduction in hot flash severity, frequency, duration, sense of control, 
or self-esteem. 
(3) To estimate effect sizes to inform power calculations for a future Phase III 
trial 
 
 
 
 
 
Figure 1: Study schema 
50 randomized patients: Symptomatic 
hot flashes with a history of breast 
cancer 
Group A: 
EMBr Wave 
N=25 
Crossover @ 4 weeks 
Group B: 
No treatment 
N=25 
Group A: 
No treatment 
N=20 
Group B: 
EMBr Wave 
N=20

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3.0 BACKGROUND 
 
3.1 Bothersome Hot Flashes  
At menopause, roughly 75% of women report bothersome hot flashes.1 While the gold standard 
for hot flash relief is Hormone Replacement Therapy (HRT), this treatment is contraindicated 
for women with a history of, or active, breast cancer. Simultaneously, due to the negative impact 
of chemotherapeutics on remaining endogenous estradiol levels, and/or the induction an earlier 
menopause, breast cancer survivors often report more severe hot flash compared to women 
without breast cancer, negatively affecting their quality of life (QOL).2 
 
3.2 EMBr Wave Device 
While there are non-hormonal medical options to treat hot flash for breast cancer survivors, this 
study is investigating the use of a personalized cooling mechanism for hot flash relief. The 
EMBr Wave device has not previously been tested in clinical studies in breast cancer, but shows 
novel and promising hot flash relief for this unique population, possibly allowing for hot flash 
reduction without the use of an oral medication. The EMBr Wave   device (both Generation 1 
and 2) works by delivering heating or cooling pulses through the wirst bracelet. Because of the 
wrist’s sensitivity to temperature, these pulses can be used to promote overall comfort despite 
other uncomfortable temperature senstions affecting the entire body. Users simply press either 
the cooling or heating button depending on which sensation they desire. The Generation 2 Embr 
Wave device has the same functionality as the Generation 1 device, but with an improved 
smaller design. A graphical design of the devices is showin in Figure 2. 
 
 
 

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3.3 Rationale and Feasibility 
There are multiple side effects associated with breast cancer treatments, which are unable to be 
treated with traditional hot flash symptom management due to the contraindication of HRT in 
women who have been diagnosed with breast cancer. Safe and affordable strategies that may aid 
in the management of debilitating hot flashes are therefore needed. The overall objectives of this 
pilot trial are to evaluate a promising non-invasive intervention for treatment of hot flashes via 
EMBr Wave. If data from this pilot evaluation suggest that Embr Wave is beneficial, then more 
formal studies, with larger patient numbers, will be considered. Our goal is to leverage these 
results to secure additional funding, from grants or commercial partners, to support larger pilots 
and/or the development of new prototype devices.  
 
4.0 METHODOLOGY 
 
 4.1 Entry Criteria 
4.1.1 Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Age ≥ 18 years. 
2. Women with history of breast cancer, DCIS, or LCIS (currently 
without evidence of malignant disease)  
3. Bothersome hot flashes (defined by their occurrence of ≥ 28 times 
per week and of sufficient severityto prompt the patient to seek 
therapeutic intervention). Mean severity in a day should be >=4/10 
on log scale of 0(none at all)-10(extremely).  
4. Presence of hot flashes for >30 days prior to study entry 
5. Ability to complete questionnaire(s) by themselves or with assistance. 
6. Willingness to wear EMBr Wave device during the study period 
Figure 2: EMBr Wave Generation 1 Device 
(top) and Embr Wave Generation 2 Device 
(bottom) 

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7. Willingness to use the EMBr Wave mobile application 
8. Have a working smartphone that can download the EMBr Wave mobile 
application (iPhone 6 or more recent generation, Android 8.0 or more recent 
generation) 
9. ECOG Performance Status (PS) = 0, 1 
10. Ability to provide informed written consent. 
11. Life expectancy ≥6 months 
 
                   4.1.2 Exclusion Criteria 
 
Any of the following current (≤4 weeks prior) or planned therapies: 
1. Antineoplastic chemotherapy (anti-HER2 agents allowed) 
2. Androgens 
3. Systemic estrogens. Local vaginal estrogen preparations are allowed, but 
need to have been initiated for vulvo-vaginal atrophy at least 28 days prior, 
and must not be expected to stop or change the dose or frequency of the 
medication during the study period.  
4. Progestogens 
5. Tamoxifen, raloxifene and aromatase inhibitors are allowed, and must 
not be expected to stop the medication during the study period 
6. SSRIs/SNRIs, when being used for hot flash management or other 
indications such as depression, is allowed, assuming the dose will remain 
unchanged for the study duration 
7. Gabapentin/pregabalin, is allowed, assuming the dose will remain 
unchanged for the study duration 
8. Clonidine 
9. Prior use of EMBr Wave. 
10. Nickel allergy 
11. Pregnant or nursing women since the safety of device has not been 
established in this population 
 
 
4.2. Study Location and Sample 
This study will be open for accrual at the Stefanie Spielman Comprehensive Breast Center 
and James Cancer Hospital. This trial will be conducted under the auspices of The Ohio State 
University. Testing will take place in clinics of the Stefanie Spielman Comprehensive Breast 
Center or done so virtually via phone and/or video calls. Patient eligibility will be determined 
according to the eligibility criteria listed. The study will enroll up to approximately 50 
patients.  
 
4.3 Registration and Randomization 
Subjects who have given informed consent will be registered by the research coordinator and 
given a study number. Subjects will then be randomized via block randomization with random 
block sizes by the study coordinator following a randomization schedule produced by the 
statistician. Randomization will not be stratified. 
 
4.4 Hot Flash Assessments 
 
This pilot trial will be conducted to get an initial reading as to the potential benefit of EMBr 
Wave for diminishing distress caused by hot flashes.  We do not expect that this instrument will 

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actually decrease the number of hot flashes.  However, it might decrease hot flash severity and 
decrease the interference of hot flashes on patients’ lives.  The main instrument to determine the 
amount that hot flashes are interfering with patients’ lives is by using a validated instrument 
called the Hot Flash-Related Daily Interference Scale (HFRDIS).3  
 
Additionally, we will follow daily hot flash numbers and severities.  The hot flash number and 
severity will be measured by the Daily Hot Flash Score,4 which is a composite entity of both 
frequency and severity of hot flashes. The Daily Hot Flash Score is computed by the grade of 
severity multiplying the frequency of the same grade hot flashes according to the hot flash 
diary over a 24 hour period. 
 
The OCEAN survey will also be administered to the participant to complete at baseline. This 
survey assesses the participant’s personal connectedness that they have with their body and to 
the world around them. This survey gives perspective to the information obtained from the 
participant while they are using the EMBr Wave.  
 
Patients will also be given instructions on how to sync their EMBr Wave with the EMBr Wave 
mobile application once a day, which will allow us to collect usage data from the devices. This 
will be used to further understand technology adoption over the 4 weeks that patients are using 
EMBr Wave during study participation.  
 
We will also evaluate patient satisfaction with device use at the end of treatment using a 10-
point Likert scale and through answering several Likert-type questions related to perceived 
device efficacy. These items will include assessment of the ways EMBr Wave had the greatest 
potential efficacy, such as reduction in hot flash severity, frequency, duration, sense of control, 
or self-esteem, as well as device usage. 
 
The HFRDIS, Daily Hot Flash Score, and OCEAN survey will be administered on paper or 
virtually via RedCap survey distribution at baseline. Participants will be given paper Daily Hot 
Flash Score sheets for their own use. For study data collection, electronic surveys will be sent 
by email via Research Electronic Data Capture (REDCap) for daily and weekly hot flash 
assessments and the post-treatment satisfaction and efficacy questionnaires.  Survey reminder 
emails and phone calls from study team will be sent to participants for incomplete HFRDIS 
surveys and satisfaction and efficacy assessments. If a participant initiated the daily surveys on 
paper prior to the study team using electronic data collection, she will continue using paper 
assessments for the duration of the study. If assessments are incomplete at end of intervention, 
the study coordinator will utilize paper forms to collect assessments, as appropriate. 
 
Virtual enrollment will be presented as an option to eligible participants. In this option, calls 
(phone and/or video) will be done between the research coordinator and participant to discuss 
the study; screen for eligibility; discuss the informed consent and how to sign it; orient the 
patient to the device and associated smart phone application; and discuss how to return the 
device at the conclusion of the device usage. The informed consent document will be sent to the 
participant to sign via email or mail to obtain a pen signature after the participant has verbally 
agreed to participate in the study during the call. In addition to either receiving the signed 
informed consent form via email or mail, the participant will also be able to email the full 
picture of their signed informed consent form to the study coordinator’s email and this will 
serve as a third option of informed consent documentation. After the consent document is 
signed, randomization will be done and the research coordinator will then inform the patient the 

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next steps depending upon their group assignment. When it is time for the participant to wear 
the device, it will be mailed to them via a secure and reliable address. An orientation call will be 
conducted when the device is received and will be worn starting the day of their designated 
month. The device will be returned at the end of this said month. For the orientation call, the 
participants will be sent an instructional packet to reference and discuss. These participants that 
enroll virtually will also complete the surveys electronically via RedCap. The EMBr device will 
be mailed in safe and secure packaging for transit. 
The OSUCCC Recruitment, Intervention and Survey Shared Resource (RISSR) will be utilized 
to administer electronic data collection for assessments. REDCap (Research Electronic Data 
Capture) provides a secure, web-based application that is flexible enough to be used for a 
variety of types of research, provides an intuitive interface for users to enter data and has real 
time validation rules (with automated data type and range checks) at the time of entry. Data are 
maintained behind the OSUMC firewall, and REDCap is 21 CRF Part 11 capable. It offers easy 
data manipulation with audit trails and ad hoc reporting functionality for reporting, monitoring 
and querying patient records, and an automated export mechanism to common statistical 
packages (SPSS, SAS, Stata, R/S-Plus). 
 
 
4.5 Study Intervention 
EMBr Wave devices will be worn by study participants during the daytme and nighttime 
during the treatment periods of the trial. Participants will be asked to use the device as 
needed during the daytime and nighttime for management of hot flashes and night sweats. 
Participants will be asked to complete the hot flash assessments described above. Because 
hot flashes are transient and the EMBr Wave device is not expected to modify the 
underlying condition, a carry-over effect is unlikely in the crossover design. Due to the 
unlikeliness of carry-over and to avoid unnecessarily increasing patient burden, we will not 
use a wash-out period. 
 
4.6 Clinical Assessment 
Participants will be evaluated for hot flashes prior to initiation of the study. For participants 
enrolled to the study, the study team will abstract from the electronic medical record: 
clinical characteristics (cancer type, stage, receptor status), treatment history (surgery, 
radiation therapy, chemotherapy, endocrine therapy) and associated dates, and medications 
that affect or treat hot flashes. Chart abstraction will include the use of antidepressant 
medications since these drugs may have an effect on hot flashes. 
 
 
4.7 Duration of Therapy  
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Loss of device greater than one time 
 

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4.8 Duration of Follow up 
Patients will not be followed after eight weeks. Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event.  
 
4.9 Criteria for Removal from Study 
The following criteria will be used for removal of patients from the study: (1) patient withdraws 
their participation; (2) patient has a disease progression or dies (whichever occurs first); (3) the 
study is terminated by the Principal Investigator; The reason for study removal and the date the 
patient is removed must be documented in the Case Report Form. 
 
4.10 Adherence 
Because of the limited anticipated adverse effects from the device and the ease of wearing the 
device, we anticipate excellent adherence. Devise usage will be electronically tracked 
through the study. Lost devices will be replaced once and if recurred, will be removed from 
study. 
 
 
 
5.0 POTENTIAL TOXICITY, DOSE MODIFICATIONS, AND MANAGEMENT 
 
Because EMBr Wave is a superficial, non-invasive device, we expect to see very little or no 
toxicities at all that are seen in its chronic use. Regardless, we will monitor for them. The 
severity of adverse reactions is categorized from grade 1 to grade 5 in increasing severity.  
 
Table 4. General descriptors for the toxicity grades, ranged from mild to 
fatal. 
Grade 1 
Mild – the adverse reaction does not interfere in a significant 
manner with the subject’s normal functioning level. It may be an 
annoyance. 
Grade 2 
Moderate – the adverse reaction produces some impairment of 
functioning but is not hazardous to health. It is uncomfortable 
and/or an embarrassment 
Grade 3 
Severe – the adverse reaction produces significant impairment of 
functioning or incapacitation and is a definite hazard to the 
subject’s health 
Grade 4 
Severe – adverse reactions that include or lead to either a) a life-
threatening event, though acute and without permanent effect, b) 
prolonged inability to resume usual life pattern, or c) impairment 
of ability to adequately deal with future medical problems 
Grade 5 
Death related to AE 
 
Toxicity will be monitored during study visits and telephone calls using the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE) of the 
National Cancer Institute will be used: 

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(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_5x7.pdf). Grade 3, 4 and 5 toxicities that are related to the study will be reported as 
adverse events.  
 
Patients with Grade 3-4 adverse reactions that are related to the study will be removed from the 
study.  
 
7.0 TREATMENT PLAN 
 
7.1 Treatment Plan and Overview 
Eligible patients will be approached by study personnel in the clinics at Stefanie Spielman 
Comprehensive Breast Center, the James Cancer Hospital, and the Center for Women’s 
Health at the Ohio State University Wexner Medical Center. The person obtaining informed 
consent will tell the patient that 1) participation is voluntary, 2) participation or non-
participation will not affect their usual care and management, and 3) patient confidentiality 
will be maintained in the event that the results of the study are published. The potential 
toxicities associated with EMBr Wave will be explained fully to the patient. Patients will be 
provided with a consent form to review, and all questions will be answered. After the signed 
informed consent has been obtained, a study identification number will be assigned to the 
patient for use on all data collection forms and samples. Medications and supplements will be 
reviewed with participants. Research team members may periodically call participants on the 
phone to remind them to complete the study surveys and to see if the participants are having 
any problems with the watch. 
 
7.2 Study Calendar 
Informed consent, randomization 
 
Group A 
Group B 
Day 0 
• Receive EMBr Wave 
• EMBr Wave orientation 
with introduction to 
device and mobile 
application 
• HFRDIS questionnaire 
• Daily Hot Flash Score 
• OCEAN psychographic 
survey 
 
• HFRDIS questionnaire 
• Daily Hot Flash Score 
• OCEAN psychographic 
survey 
Days 1–28 
• Daily Hot Flash Score 
• Device usage assessment 
• Daily Hot Flash Score 
Days 7, 14, 21, 28 
• HFRDIS questionnaire 
• HFRDIS questionnaire 
Day 28 
• Return EMBr Wave 
• Patient satisfaction / 
perceived efficacy 
assessment 
• Receive EMBr Wave 
• EMBr Wave orientation 
with introduction to device 
and mobile application 
Days 29–56 
• Daily Hot Flash Score 
• Daily Hot Flash Score 
• Device usage assessment 
Days 35, 42, 49, 56 
• HFRDIS questionnaire 
• HFRDIS questionnaire 
Day 56 
 
• Return EMBr Wave 

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• Patient satisfaction / 
perceived efficacy 
assessment 
 
In addition, patients will record their Daily Hot Flash Score daily in their journals. 
 
9.0 ADVERSE EVENT REPORTING 
 
Adverse event: Any unfavorable and unintended sign (including abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the medical treatment or procedure; also an 
“unanticipated problem” of any nature (e.g., psychological or social harm) (designated as 
unrelated, definitely related, probably related, or possibly related; see below) 
 
Serious adverse event: Any adverse event that is fatal or life threatening, is permanently 
disabling, requires inpatient hospitalization or prolongs hospitalization, or results in a congenital 
anomaly or birth defect. 
 
Life-threatening event: Any adverse event in which the subject is at immediate risk of death 
from the reaction as it occurs; does not include a reaction that, if it were to occur in a more 
serious form, might cause death 
 
Unexpected event: Any adverse event that is not identified in nature, severity, or frequency in 
the investigator brochure, study protocol, consent form, or IND application; or the event was 
more serious than anticipated.  
 
9.1 Attribution of the Adverse Events 
 
Definite:  AE is CLEARLY RELATED to the study treatment.  
Probable: AE is LIKELY RELATED to the study treatment. 
Possible: AE MAY BE RELATED to the study treatment.  
Unlikely: AE is DOUBTFULLY RELATED to the study treatment. 
Unrelated: AE is CLEARLY NOT related to the study treatment 
 
9.2 Documentation  
CTCAE version 5.0 will be utilized for AE reporting. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
For expedited reporting purposes only: 
 
• AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
All adverse events must be documented in detail within the medical record. The patient will be 
observed and monitored carefully until the condition resolves, stabilizes, or its cause is 
identified. All adverse events, including laboratory abnormalities, will be followed up according 
to good medical practices. Information to be recorded includes the following: 

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1. Specific type of reaction. 
2. Duration of reaction. 
3. Severity/grade of reaction according to the NCI Common Terminology Criteria for 
Adverse Events v5.0 (CTCAE). 
4. Suspected cause of the reaction (i.e. possibly or probably related to one of the 
following: study intervention, progression of disease, concurrent medications, 
concurrent illness, or other factors). 
5. Patient’s response to medical interventions. 
 
9.3 Reporting  
Since it is difficult to discern which AEs may impact gait and balance testing, all AEs will be 
collected, not just neuropathy symptoms. Although unlikely, some unrelated symptoms may 
impact gait and balance and may also be indirectly related to neuropathy symptoms (e.g. 
cytopenias and fatigue may impact balance and gait).  
 
 CRITERIA FOR RESPONSE ASSESSMENT  
 
     
All patients will be considered evaluable. Participants with only baseline measures will be 
considered as drop-outs. 
 
10.1 Measurement of Effect 
We will evaluate effect of EMBr Wave by PRO, primarily HFRDIS. We will also include 
satisfaction/perceived efficacy questions measuring ratings on a 10-point Likert scale with 10 
being most satisfied or most effective. 
 
  DATA REPORTING / REGULATORY REQUIREMENTS 
 
11.1 Ethical and Regulatory Considerations 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice guidelines, 
and all applicable regulatory requirements. 
 
11.2 Institutional Review Board 
The Principal Investigator will have obtained written approval to conduct the study from The 
Ohio State University IRB and the Clinical Scientific Review Committee of the James Cancer 
Hospital and Solove Research Institute. All amendments must be approved by the Institutional 
Review Board of The Ohio State University prior to implementation. 
 
11.3 Informed Consent 
All potential candidates for the study will be given a copy to read of the consent form for the 
study. The Principal Investigator and/or designee will explain all aspects of the study in lay 
language and answer all the candidate’s questions regarding the study. If the candidate desires to 
participate in the study, he or she will be asked to sign the Informed Consent. The study agent 
will not be released to a subject without a signed Informed Consent. Elements of informed 
consent include explanations of 1) the purpose of the trial, 2) what the study entails, 3) alternate 
treatments, 4) expenses and inconveniences to be incurred, 5) discomfort and risks to the 
subject, 6) whether she will receive payment for participation in the study, 7) contact person to 
call in the event of an emergency, 8) subject rights as a result of illness or injury from trial 

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participation, 9) subjects right to withdraw from the trial at any time without prejudice, 10) 
confidentiality of trial participation. 
 
11.4 Patient Confidentiality  
The information obtained during the conduct of this study is considered confidential and will 
not be released without the written permission of the subject, except as necessary for regulatory 
agencies. Signed consent forms, data sheets, and laboratory notebooks will be kept in locked 
cabinets in Clinical Trials Office at Stefanie Spielman Breast Center. 
 
11.5 Publication and Research Findings 
Publications of the research findings will present data in a format that will not reveal the identity 
of the participants. 
 
11.6 Compliance Monitoring 
In accordance with IRB guidelines, the study program will be reviewed by the IRB every 12 
months or less. Deviations from the protocol must be documented in the medical record and 
reported immediately to the PI. Deviations that meet the criteria for Immediate Event Reporting 
(http://orrp.osu.edu/irb/event/index.cfm) such as those that increase risks to subjects and/or 
compromise scientific integrity will be reported immediately to the IRB. 
 
11.7 Data Safety Monitoring 
The data and safety monitoring plan will involve the continuous evaluation of safety, data 
quality and data timeliness. Investigators will conduct continuous review of data and patient 
safety at their regular Disease Group meetings (at least monthly) and the discussion will be 
documented in the minutes. The PI of the trial will review toxicities and responses of the trial 
where applicable at these disease center meetings and determine if the risk/benefit ratio of the 
trial changes. Frequency and severity of adverse events will be reviewed by the PI and 
compared to what is known about the agent/device from other sources; including published 
literature, scientific meetings and discussions with the sponsors, to determine if the trial should 
be terminated before completion. Serious adverse events and responses will also be reviewed by 
the OSUCCC Data and Safety Monitoring Committee (DSMC). The PI will also submit a 
progress report biannually that will be reviewed by the committee per the DSMC plan. All 
reportable Serious Adverse Events (SAE) will also be reported to the IRB of record as per the 
policies of the IRB. 
 
11.8 Responsibility for Data Submission  
Data are to be submitted via OnCore on a real-time basis, but no less than once every 2 weeks. 
 
11.9 Data and Records 
Primary source documents will include forms routinely used at the Stefanie Spielman 
Comprehensive Breast Center, namely the Breast Patient Information Form, clinic and office 
notes as well as laboratory and radiology reports, including documentation found in the 
electronic medical record (EPIC). 
 
11.10 Safety and Monitoring 
Adverse events will be monitored by self-reporting of signs and symptoms.  
 
 
11.12 Documentation  

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All adverse events must be documented in detail within the medical record. The patient will be 
observed and monitored carefully until the condition resolves, stabilizes, or its cause is 
identified. All adverse events, including laboratory abnormalities, will be followed up according 
to good medical practices. Information to be recorded includes the following: 
1. Specific type of reaction.  
2. Duration of reaction. 
3. Severity/grade of reaction according to the NCI Common Terminology Criteria for 
4. Adverse Events 5.0 (CTCAE). 
5. Suspected cause of the reaction (i.e. possibly or probably related to one of the following: 
study treatment, progression of disease, concurrent medications, concurrent illness, or 
other factors).  
6. Changes made in the administration of the study drugs and other actions taken to 
alleviate the clinical event.  
7. Patient’s response to medical interventions. 
 
11.13 Reporting  
According to FDA regulations (21 CFR 312.32), IND safety reports shall address “any adverse 
experience associated with the use of a drug that is both serious and unexpected.” The IRB will 
be notified of any adverse event fulfilling the following criteria: 
 
1. The adverse event is SERIOUS (as defined above), 
OR 
2. The adverse event is not serious, but is UNEXPECTED and its association with the 
study drug, device, or research-related procedure is either DEFINITELY, 
PROBABLY, or POSSIBLY RELATED, or UNKNOWN (as defined above). 
 
Federal policy [45 CFR 46.116(b)(5)] also requires that investigators inform subjects of any 
important new information that might affect their willingness to continue participating in the 
research. When an adverse event necessitates changes to the consent/assent form(s) and/or 
protocol, or that notification is given to currently or previously enrolled subjects, an amendment 
request will be submitted in conjunction with the adverse event report. The IRB will make a 
determination whether any new findings, new knowledge, or adverse effects should be 
communicated to subjects. 
 
In accordance with IRB guidelines, serious adverse events will be reported within 10 days of the 
investigator’s or research staff members’ learning of the event to The Ohio State University 
Institutional Review Board. OSU IRB Event Reports should be submitted through BuckIRB at: 
http:/orrp.osu.edu/irb/buck-IRB/. Events resulting in temporary or permanent interruption of 
study activities by the investigator or sponsor to avoid potential harm to subjects should be 
reported within 48 hours whenever possible. 
 
All events that may represent unanticipated problems involving risks to subjects or others will 
be promptly reported (as described above), regardless of whether they occur during or after the 
study, or involve a subject who has withdrawn from or completed study participation. If changes 
to the research or consent process are proposed as a result of the event or if additional 
information will be provided to current and/or past participants, an amendment request will also 
be submitted for IRB review. 
 
Related events involving risk but not meeting the prompt reporting requirements will be 

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reported to the IRB in summary form at the time of continuing review. 
 
12.0 STATISTICAL CONSIDERATIONS 
 
12.1 Statistical Data Analysis and Study Design 
 
Feasibility will be evaluated primarily with respect to device usage, and secondarily with 
respect to patient satisfaction. Device usage will be evaluated by the number of minutes and 
sessions per 24-hour day per participant. The mean patient satisfaction scores for each Likert-
type question and proportion of reporting satisfaction scores at or above 7 will be estimated in 
the entire sample and compared between sequence groups at the 5% significance level (two-
sided). 
Preliminary efficacy will be evaluated with respect to the Hot Flash-Related Daily Interference 
Scale (HFRDIS), hot flash number and severity (as a daily hot flash score; DHFS), and patient 
perception of efficacy (10-point Likert scale items). HFRDIS measurements will be evaluated at 
the end of each week on the study, and DHFS will be used as recorded in the daily hot flash 
journal.  Repeated measurements will be modeled as repeated outcomes in a linear mixed effects 
model with fixed effects for treatment, period, and treatment-by-period interaction, and random 
effects for subjects and for subject-by-treatment interactions to account for correlated 
measurements within the same subject. The period variable will be represented in the sum-to-
zero coding so that the target of inference will be the fixed main effect of treatment, tested at the 
5% significance level (two-sided). Thus the treatment effect will be interpreted as time-averaged 
and estimated using information from the mixed model. Patient perception of efficacy will be 
evaluated at the end of the device period and estimated in the entire sample and compared 
between sequence groups. 
All analyses will proceed on an intent-to-treat basis. When observations of preliminary efficacy 
endpoints are missing, the rest of that patient’s observations may still be used in the mixed 
effects model. To assess the potential impact of informative loss to follow-up, we will compare 
patients who leave the study or cease reporting endpoints to those who provide data for the full 
study duration. Patients will be compared on the basis of baseline variables and available 
longitudinal measurements. The pattern of loss to follow-up will be reported via CONSORT 
chart. Potential impact on estimates will be assessed via multiple imputation. For the purpose of 
evaluating compliance, patients who leave the study will be recorded as not wearing the device 
after leaving the study, ensuring that all patients are evaluable.  
As an exploratory analysis, individual components of the HFRDIS will be analyzed using the 
same model as the total HFRDIS. As sensitivity analyses, the preliminary efficacy analyses will 
be repeated allowing for temporal correlation of measures, and including as covariates any 
baseline variables with large imbalances.  
Our feasibility target is that at least 75% of all patients meet the compliance criteria described 
above. The minimum number of the 38 enrolled patients meeting the compliance criteria to 
achieve this threshold is 23 (77%), in which case the 95% Jeffreys interval lower bound is 60% 
(thus we can rule out population compliance rates below 60%) (Figure 3, left). We expect the 
population compliance rate to be at least 85%, in which case we have at least 93% probability of 

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achieving the compliance target (Figure 3, right). With a population compliance rate of 80%, we 
have a 76% probability of achieving the compliance target. 
 
 
Power to detect a treatment effect with respect to HFRDIS and DHFS measures via the mixed 
model depend on the size of the average treatment effect relative to the within-subject standard 
deviation (i.e., Cohen’s d via the SD of the error term in the mixed model) and the standard 
deviation of the random within-subject treatment effects. Figure 4 displays study power for 
different combinations of these factors, estimated via simulation of 1000 datasets per scenario. 
For instance, if the within-subject SD and individual treatment effect SD are equal, we have 
80% power to detect an average treatment effect of 0.7 (Cohen’s d). 
Figure 3: Left: Jeffreys intervals (95% equal tail probability credible intervals from a Beta(0.5, 0.5) prior) corresponding to various 
sample proportions with 30 patients. Right: Probability of achieving target compliance rate for various population rates. 

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Data from this study will be used to design future definitive intervention studies to evaluate the 
efficacy of this intervention in larger randomized studies.  
 
 
13.0 REFERENCES 
 
1. 
Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between 
vasomotor symptoms and race/ethnicity across the menopausal transition: study of 
women's health across the nation. Am J Public Health. 2006;96(7):1226-1235. 
2. 
Faubion SS, Loprinzi CL, Ruddy KJ. Management of Hormone Deprivation Symptoms 
After Cancer. Mayo Clin Proc. 2016;91(8):1133-1146. 
3. 
Carpenter JS. The Hot Flash Related Daily Interference Scale: a tool for assessing the 
impact of hot flashes on quality of life following breast cancer. J Pain Symptom 
Manage. 2001;22(6):979-989. 
4. 
Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. 
Methodologic lessons learned from hot flash studies. J Clin Oncol. 2001;19(23):4280-
4290. 
 
 
Figure 4: “Indiv. Trt. Eff. SD” is the standard deviation of the individual treatment effects (random slopes in mixed model) and 
“Within subj. SD” is the within-subject standard deviation during each period (error term in mixed model). Variability of the random 
intercepts has minimal effect on power.