Pilot Evaluation of Wrist Cooling Devices on the Severity of Hot Flashes for Women and Men Who Suffer From Moderate and or Severe Hot Flashes
Phase: NA
Conditions: Hot Flashes
Sponsor: Boston University

Double Blind Randomized Controlled Crossover Pilot Evaluation of Wrist Cooling Devices on the 
Severity of Hot Flashes for Women and Men Who Suffer from Moderate and or Severe Hot 
Flashes 
 
 Version number 1.8 and January 23, 2024 
 
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Double Blind Randomized Controlled Crossover Pilot Evaluation of Wrist Cooling Devices on 
the Severity of Hot Flashes for Women and Men Who Suffer from Moderate and or Severe 
Hot Flashes 
 
Protocol Version Number: 1.8 
Protocol Version Date: 01/23/2024 
ClinicalTrials.gov number: NCT05595213 
H-43277 
Funding Mechanism: Internally funded. Devices supplied by manufacturer. 
 
Principal Investigator: Michael F. Holick 
 
Phone: 617-358-6139 
 
 
E-mail: mfholick@bu.edu 
 
Statistical Analysis Plan -page 22 
CONFIDENTIAL 
 
This document is confidential and the property of Boston University. No part of it may be transmitted, 
reproduced, published, or used by other persons without prior written authorization from the 
institution. © 2022 Trustees of Boston University. All rights reserved. 
 
 
Summary of Changes: 
The table should summarize changes of IRB-approved versions of the protocol, including a description of 
the change and rationale.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.8 
1/23/2024 
To expand recruitment by 
advertising on social media. 
We will be able to expand the 
pool of subjects thereby have 
to ability to complete the 
recruitment more efficiently. 
1.6 
10/24/2023 
To expand recruitment by enrolling 
subjects who meet the inclusion 
criteria locally or virtually. 
We will be able to expand the 
pool of subjects thereby have 
to ability to complete the 
recruitment more efficiently. 
1.5 
8/1/2023 
Revised protocol and consent form 
to be the same as the approved 
consent form regarding blinding.  
Responding to IRB stipulation.  
1.4 
06/05/2023 
To expand recruitments by including 
all women and men who meet the 
We now will be able to include 
subjects with the most common 

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inclusion criteria of having at least 2 
moderate or severe hot flashes daily 
for the past 2 months. There will no 
longer be a requirement for the 
women and men to be on hormone 
deprivation therapy. 
causes of hot flashes i.e., post-
menopausal women and 
women who have surgically 
induced menopause.  
 
 

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Severity of Hot Flashes for Women and Men Who Suffer from Moderate and or Severe Hot 
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TABLE OF CONTENTS 
1 List of Abbreviations ......................................................................................................................... 5 
2 Protocol Summary ............................................................................................................................ 5 
3 Background/Rationale & Purpose ................................................................................................ 8 
 
3.1 Background Information ........................................................................................ 8 
 
3.2 Rationale and Purpose .......................................................................................... 8 
4 Objectives ............................................................................................................................................ 9 
 
4.1 Study Objectives .................................................................................................... 9 
 
4.2 Study Outcome Measures .................................................................................... 9 
 
4.2.1 Primary Outcome Measures ............................................................... 9 
 
4.2.2 Secondary Outcome Measures ......................................................... 9 
 
4.2.3 Exploratory Outcome Measures ........................................................ 9 
5 Study Design ...................................................................................................................................... 9 
6 Potential Risks and Benefits .......................................................................................................... 9 
 
6.1 Risks ........................................................................................................................ 9 
 
6.2 Potential Benefits ................................................................................................. 10 
 
6.3 Analysis of Risks in Relation to Benefits .......................................................... 10 
7 Study Subject Selection ................................................................................................................ 10 
 
7.1 Subject Inclusion Criteria .................................................................................... 10 
 
7.2 Subject Exclusion Criteria ................................................................................... 10 
8 Study Intervention ........................................................................................................................... 11 
9 Recruitment and Retention Procedures ................................................................................... 11 
 
9.1.1 Recruitment Procedures .................................................................... 14 
 
9.1.2 Retention Procedures ........................................................................ 15 
10 Screening Procedures ................................................................................................................... 15 
11 Consent Procedures ...................................................................................................................... 16 
12 Study Procedures ........................................................................................................................... 17 
13 Assessment of Safety and Data Safety Monitoring Plan (DSMP) ................................... 19 
 
13.1 Definitions for Safety Assessment .................................................................. 19 
 
13.2 Safety Review ..................................................................................................... 20 
 
13.2.1 Multi-Site Safety Monitoring ........................................................... 20 
 
13.3 Reporting Plans .................................................................................................. 20 
 
13.4 Stopping Rules ................................................................................................... 21 
14 Data Handling and Record Keeping.......................................................................................... 21 
 
14.1 Confidentiality ..................................................................................................... 21 
 
14.2 Study Documentation, Source Data................................................................ 21 
 
14.3 Study Records Retention .................................................................................. 22 
15 Statistical Plan ................................................................................................................................. 22 

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15.1 Study Hypotheses .............................................................................................. 22 
 
15.2 Sample Size Determination .............................................................................. 22 
15.3 Statistical Methods ................................................................................. 22 
16 Ethics/Protection of Human Subjects ....................................................................................... 22 
17 Literature References .................................................................................................................... 23 
18 Appendix ............................................................................................................................................ 24 

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1 
List of Abbreviations 
None 
 
2 
Protocol Summary 
Title: 
Double Blind Randomized Controlled Crossover Pilot Evaluation of 
Wrist Cooling Devices on the Severity of Hot Flashes for Women 
and Men Who Suffer from Moderate and or Severe Hot Flashes 
Population: 
Thirty adult women and men experiencing at least 2 hot flashes a 
day for at least the past 2 months that are either moderate and/or 
severe in intensity.  
Intervention: 
 Wrist cooling devices placed on the wrist. 
Objectives: 
To determine the effect of two wrist cooling devices on symptom 
control of hot flashes in adult women and men experiencing at least 
2 hot flashes daily for at least the past 2 months that are of 
moderate and/or severe in intensity. 
 
Design/Methodology: 
This pilot randomized double blind controlled crossover study aims 
to determine the impact of two wrist cooling devices on symptom 
control of hot flashes in adult women and men experiencing hot 
flashes. We will recruit 30 adults experiencing bothersome moderate 
and/or severe hot flashes at least twice a day for at least the past 2 
months. We plan to conduct the study at BUSM, locally or virtually. 
Subjects who will be seen at BUSM or locally;  
1. If the potential subject passes the pre-screen and agrees to 
participate, he/she will be invited to participate in the clinical 
trial. The subjects who meet the inclusion criteria to participate 
in the study and who wish to be consented by the PI will meet 
with the subject in person and follow the consenting procedure 
as outlined in the protocol. The subjects who were given the 
consent form will have an opportunity to read it and ask 
questions of the PI or study personnel. The potential subjects will 
be given up to 30 minutes to decide if they want to participate. 
The PI will then ask them to sign the consent form. Once the 
signed consent form is obtained, it will be signed by the PI who 
reviewed the consent form with the subject and put into their 

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file. After the PI signed the consent form, the consent form will 
be copied, and the copy will be given to the subject. 
2. The subjects who are seen and after completing consenting 
process will receive the two devices and diaries and will be 
contacted as outlined in the approved protocol.  
3. The subjects will return the devices and diaries to the PI or 
study personnel as outlined in the protocol. They will also have 
the option to receive the commercially available device after 
completion the study as outlined in the protocol. 
Subjects who will be seen virtually: 
1. If the potential subject passes the pre-screen and agrees to 
participate, he/she will be invited to participate in the clinical 
trial. The subject who meets the inclusion criteria to participate 
in the study and who wish to be consented virtually the PI will 
meet with the subject by zoom to follow the consenting 
procedure as outlined in the protocol. The subject will be 
provided the consent form by email. The subject will have an 
opportunity to read it and ask questions of the PI or study 
personnel. The potential subject will be given up to 30 minutes 
to decide if they want to participate. The PI will obtain a verbal 
consent by asking the subject do they agree with the consent 
form? If they agree, the PI or study personnel will document the 
subject’s consent agreement, and this will be noted in the 
subject’s study file. The date and time will be recorded. You will 
receive the signed consent form documenting your verbal 
acceptance by email. 
2. After obtaining verbal consent, the subject will be randomized as 
outlined in the approved protocol. The subjects who were 
consented by zoom and who had provided their verbal consent 
to the PI or study personal will then receive the devices and 
diaries by United Parcel Service (UPS), United States Parcel 
Service (USPS) or by Federal Express (FEDEX) that will have a 
tracking number and signature request documenting that 
subject received the devices and diaries.  
3. The subject who will be participating virtually will be required to 
return the devices and diaries to the PI or study personnel by 

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using the UPS, USPS, FEDEX return box that will have a return 
address, tracking number and signature request documenting 
that subject received the devices and diaries. The return box will 
have an account number to pay for the return of the devices and 
diaries. Once the devices and diaries have been received by 
either the PI or study personnel, the subject will have the option 
to be sent the commercially available device. 
The participants will be randomly assigned to wear one of the two 
wrist cooling devices that have an identical appearance during weeks 
3 and 4 of the study and then use the other device during weeks 5 
and 6 of the study.  The devices will be attached to the wrist with the 
white plate placed on the interior side of the wrist. When activated, 
one device will turn on a cooling fan with the white plate being active 
and cooling the skin for up to 5 minutes, and the other device will 
turn on a cooling fan only for up to 5 minutes without the white plate 
being active to cool the skin. We will try to recruit 50% men and 50% 
women.  
We will use a 3-category diary for hot flash symptom monitoring 
(assessed as mild, moderate, and severe). This study will take at least 
6 weeks and up to 8 weeks requiring the participants to see a study 
team member either in person or virtually at the beginning and end 
of the study. The participants will receive three phone calls/ zoom 
calls during the study to remind them of when to use each device. 
The participant will be instructed that for the first 2 weeks that he 
/she will document as soon as possible in the Hot Flash Diary his/her 
daily each experience with hot flash and record the severity of each 
hot flash in the diary without using any device. They will then be 
instructed at the beginning of week 3 to use the device that they 
were randomly assigned to use. They can wear the device 24/7, i.e., 
all the time or they can place it on their wrist when they begin to 
experience a hot flash. They will be asked to fill in their Hot Flash and 
Device Use Diary as soon as possible after the hot flash the severity 
of each of their hot flashes that they experienced throughout the day 
and night.  They will also be instructed at the time that they are 
documenting in the diary the severity of the hot flash as to whether 
or not they used the device while having the hot flash in the same 

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diary. They will continue this activity for 2 weeks and then be 
instructed to use the second randomly assigned device at the 
beginning of week 5.  They will use this device during weeks 5 and 6 
of the study documenting as soon as possible in their diary the 
severity of each hot flash and whether or not they used the device 
during the hot flash.  
They will be instructed after the 6 weeks to have either an in person 
return visit or a virtual return visit. Those subjects who are 
participating at BUSM or locally will be given the diaries and the 
devices to the study personnel. Those subjects who are participating 
in the study virtually will be asked to return the diaries and devices 
by FEDEX, UPS or USPS.  During the last visit subjects who are 
participating in the study at BUSM or locally will have the option to 
receive the commercially available wrist cooling device as 
compensation. Those subjects who are participating in the study 
virtually will have the option to be sent the commercially available 
wrist cooling device as compensation by FEDEX, UPS or USPS.  
Total Study Duration: 
1 year 
Subject Participation Duration: At least 6 weeks and up to 8 weeks 
 
3 
Background/Rationale & Purpose 
 
 
3.1 
Background Information 
A hot flash is a sudden, temporary onset of body warmth, flushing, and sweating (often associated with 
menopause).  This symptom is associated with women and men who suffer from moderate and or 
severe hot flashes. 
 
3.2 
Rationale and Purpose  
There have been numerous studies with nonhormonal pharmaceutical interventions including 
antidepressants, gabapentin and black cohosh with minimum demonstrable benefit to reduce severity 
and duration of hot flashes.  Other techniques including electrical stimulation with acupuncture 
provided some short-term relief (1-3).  
Temperature management therapy has been proposed to be an alternative method to control hot 
flashes. However, there has been no previous data on the efficacy of a wrist cooling device on hot flash 
symptom control. We aim to conduct a pilot double-blind randomized crossover study to evaluate the 

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effectiveness of 2 wrist cooling devices on the severity of hot flashes.  This study will be conducted in 
women and men who experience at least 2 hot flashes daily for the past 2 months that are either 
moderate or severe in intensity.   
 
4 
Objectives 
 
4.1 
Study Objective 
 
To determine the effect of using a wrist cooling device with an active cooling fan and active cooling 
porcelain plate versus a wrist cooling device with an active cooling fan and an inactive cooling porcelain 
plate on the severity of hot flashes occurring in adult women and men who experience daily at least 2 
moderate and/or severe hot flashes for at least the past 2 months.  
 
4.2 
Study Outcome Measures 
 
4.2.1 Primary Outcome Measures 
 
Daily severity (mild, moderate, and severe) of hot flashes that the participant records in their diary.  
 
4.2.2 Secondary Outcome Measures 
 
Daily use of whether they did or did not use the wrist cooling device during their hot flash that will be 
recorded in their diary during the last 4 weeks of the study.  
 
4.2.3 Exploratory Outcome Measures 
 
There is no exploratory outcome in this study. 
 
5 
Study Design 
This pilot randomized double blind crossover study aims to determine the impact of two wrist cooling 
devices on symptom control of hot flashes in adult women and men experiencing moderate and/or severe 
hot flashes for at least the past 2 months. 
 
6 
Potential Risks and Benefits 
 
6.1 
Risks 
 

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The most common risks of the wrist cooling device in this study include a reaction that impairs blood flow 
to the hand and could make it worse for disorders such as Raynaud's phenomenal which is why people 
with Raynaud’s and similar conditions should not take the part in the study.  The participant may also 
experience the coolness as being uncomfortable.   
To minimize the risk of adverse events, we will exclude subjects with any history of cold sensitivity to the 
wrist or hand. In addition, the participant may find the attachment of the device around the wrist to be 
uncomfortable. We will exclude subjects with a history of experiencing discomfort when placing anything 
such as a wristwatch on their wrist.  
To mitigate discomfort for the device that when activated results in white plate cooling the skin 
underneath it to a temperature of 47°F we will instruct the participant to press the square button and the 
temperature will almost immediately increase to 60°F.  If it is still uncomfortable the participant has the 
option of pressing the button again to further increase the temperature to 77°F. They have the other 
option to shut it off by holding the button down for 2 seconds. The device can also be removed 
immediately from the wrist which is attached by a Velcro connection that can be easily opened.  To 
mitigate any discomfort for the device that when activated turns on the cooling fan only they will be 
instructed to press the square button for 2 seconds which will set off the device or they can immediately 
remove the device from their wrist. 
 
6.2 
Potential Benefits 
There may be a direct benefit to the participant by the device reducing the severity of their hot flashes. 
However, the likelihood and degree of the benefit is currently unknown given lack of prior clinical data to 
support the use of this device.  
 
6.3 
Analysis of Risks in Relation to Benefits 
The risk associated with the device is discomfort and Raynaud phenomenon, which will be minimized by 
excluding participants with a history of these conditions. We expect that the possible benefit from the 
device in reducing the severity of hot flashes that the participant experienced. 
 
7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
a. Experiencing at least 2 hot flashes per day that are either moderate and/or severe in intensity 
for at least the past 2 months.  

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• 
Moderate hot flash: sensation of heat with sweating/dampness but able to continue 
activity with only brief fanning needed 
• 
Severe hot flash: sensation of intense heat with sweating and causing disruption of 
current activity 
b. English speaking and English writing ability 
 
c. Must be 21 years old age or older  
 
 
7.2 
Subject Exclusion Criteria: 
 
An adult who meets any of the following criteria will be excluded from participation in this study: 
1. Temperature sensitivity due to cooling associated with an autoimmune or vascular disorder, 
such as Raynaud's phenomena, peripheral arterial disease or for any other reasons. 
2. Any wrist skin sensitivity that is known to cause discomfort when any type of device such as a 
wristwatch is placed on the wrist. 
3. Any lack of sensitivity to coolness on the wrists or hands 
4. Current use of pharmaceuticals or devices to treat hot flashes. 
5. Unable to understand and speak English and unable to write English 
 
8 
Study Intervention: 
 
The subject will be randomized using the computer-generated randomization chart that will be produced 
by Dr. Charoenngam. Dr. Charoenngam will not be involved in any of the studies activities associated with 
interacting with this subject. The subject will be randomized in this double blinded randomized crossover 
study to use assigned device the depending upon their randomization during weeks 3 and 4 followed by 
using the other assigned device during weeks 5 and 6.  For example, if the subject was randomized to use  
the device in box B for weeks 3 and 4 then they will be instructed to use the assigned device that in the 
box A for weeks 5 and 6 of the study.  The wrist cooling device. The randomization chart will be given to 
Dr. Alexandrian whose only activity is to keep the chart until the study is unblinded.  
 
Wrist cooling device with a cooling porcelain plate 
• 
The name of the device is Kulkuf 
• 
Device size is 11.25 inches long and is 2.5 inches in width 
• 
Device model is Kulkuf wrist cooling device. One of the devices when turned on will have the fan 
and wrist cooling porcelain plate activated while the other device that is identical in appearance 
will have the fan working when turned on and the cooling porcelain plate inactivated. 

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• 
The device contains a mini heat pump attached to a Velcro open sleeve that can be wrapped 
around and attached to the wrist (Figure 1). 
• 
The device that when turned on results in the cooling fan and cooling porcelain plate to be 
activated has 3 settings when the square bottom is depressed. When first depressed the device 
is immediately turned on and generates a cool temperature of 47°F. When the square bottom is 
depressed a second time the temperature increases to 60°F. When the square button is pressed 
a third time the temperature increases 77°F. When the square bottom is held down for two 
seconds the device will stop operating. The device automatically shuts off after 5 minutes. 
• 
The device that when turned on results in the cooling fan being turned on will have the heat pump 
deactivated and therefore the white cooling porcelain plate will not cool the skin.   
• 
The device will be used whenever a hot flash occurs during weeks 3, 4, 5 and 6 of the study.   
• 
Dhama USA is the manufacturer of the device. 
• 
The devices will be stored in the locked cabinet in Dr. Holick’s office. 
• 
The devices will be supplied at no cost to the subject. 
 
Wrist cooling device.  On the left panel of figure 1 is the front and back of the device that has the cooling 
porcelain plate (white square).  The device is wrapped around the wrist with the cooling porcelain plate 
on the inside of the wrist (figure 1 right panel). The device will be provided to the subject with the removal 
of the A or B label (Figure 2).  The cooling devices in both boxes are identical in appearance.  The subject 
will place the device on their wrist using the Velcro attachment.  Briefly, when activated by pushing the 
square button the cooling fan in both devices is activated. One of the devices when activated will also 
have the cooling porcelain plate almost immediately begin to cool to a temperature of 47°F while the 
other control device will not activate the cooling porcelain plate. If the cooling temperature is 
uncomfortable the participant will have an opportunity to press the button again and the temperature 
will increase to 60°F.  If this remains uncomfortable the participant can press the button a third time and 
the temperature will rise to 77°F.  For the device that has the fan turned on only the participant can press 
the square button for 2 seconds to turn it off if for some reason it becomes uncomfortable.  The alternative 
for both devices if uncomfortable the device can be easily removed from the wrist. 
The devices will be supplied by the company at no cost and will be stored in Dr. Holick’s laboratory.  

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Figure 1: Wrist cooling device.  On the left is the front of the device and on the right is the back 
of the device that has the cooling porcelain plate.  The device is wrapped around the wrist with 
the cooling porcelain plate on the inside of the wrist. 
 

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Figure 2: Boxes labeled A and B will be randomized and after the randomization the A and B labels 
will be removed on the front of the box. The following language "CAUTION - Investigational 
Device. Limited by Federal (or United States) law to investigational use" to comply with the 
abbreviated IDE requirements under §812.5 for labeling a nonsignificant risk device.  
 
9 
Recruitment and Retention Procedures: 
 
9.1.1 Recruitment Procedures 
Physicians including oncologists, urologists, endocrinologists, gynecologists, general medicine 
practitioners, physician assistants, nurse practitioners and other health care professionals at Boston 
University Medical Campus who see patients who complain of hot flashes, will be contacted by phone or 
email informing them of the study. For those physicians and health care professionals who are interested 
in having their patients be aware of this study we will provide copies of a BU Communications/IRB 
approved flyer explaining the study. They will be provided with a flyer as a hard copy either as a 8x10 flyer 
or 4x4 flyer that can be placed in their pocket for easy distribution.  Alternatively, they will be provided a 
PDF of the BU communications/IRB approved flyer. The doctor or healthcare professional will have the 

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option to provide to Dr. Holick prospective patients who meet the exclusion and inclusion criteria their 
contact phone number or instruct the patient to call him directly. The patient may call Dr Holick as a result 
of seeing the flyer. We will advertise for this study at the Boston University Medical campus via study 
flyer, on the BU communications sites and on social media. We would like to expand our recruitment 
capability by including subjects who have contacted Dr. Holick about their interest in participating in the 
study as a result of seeing the study posted on the ClinicalTrials.gov or hearing about the study from a 
physician, family member or friend. These interested subjects will be recruited virtually by zoom or meet 
Dr. Holick or a study personnel locally outside of the Boston University Medical Campus. Only after they 
meet all of the requirements in the protocol including the inclusion and exclusion criteria will they be 
enrolled in the study either locally or virtually. 
 
9.1.2 Retention Procedures 
 
The subject will be contacted by study personnel via telephone or zoom call 1-3 days before the expected 
date he/she will use the device during weeks 3 and 4 of the study and then a telephone or zoom call 1-3 
days before the expected date when the participant will use the other randomly assigned device during 
weeks 5 and 6. The subject will be contacted during week 6 of the study before the study end date to 
remind them to come back and return the diaries and devices at their scheduled visit that was provided 
to them during their first visit. Those subjects who are participating in the study virtually will be contacted 
during week 6 of the study before the study end date to remind them to return the diaries and devices by 
FEDEX, UPS or USPS. 
 
10 Screening Procedures 
 
Once subjects have responded to the study flyer, ClinicalTrial.gov or word of mouth, they will be screened 
over the phone or by zoom to determine eligibility using brief screening agreement and pre-screening 
questionnaire. During the preliminary screening call, the subject will be asked about their medical history 
and inclusion/exclusion criteria. Completion of the preliminary anonymous screening for the potentially 
eligible participants will be documented in the study binder. The information to be retained in the study 
binder include study ID and answers to the pre-screening questionnaire. For the individuals with screening 
failure, no information will be retained. Once the subjects are determined to be eligible, they will be 
scheduled for their first visit to our clinical research space in the Vitamin D, Skin, and Bone Research 
Laboratory, located at 85 E Newton St, M-1013 Boston, MA 02118 (BUSM), locally or virtually. The PI will 
consent the subjects either in person or virtually by zoom.  
  
The eligibility data will be stored in Dr. Holick’s offices under lock and key. The door to Dr.Holick's lab is 
accessed by those who have ID access to the lab. Electronic information will be stored on a departmental 

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server ("Y"drive) which is password protected. Paper records will be stored in a locked room for which 
only study staff will have access to. Master list will be stored on the Y-drive and will not be stored with 
study data. All other electronic data will be on the Y-drive which is password protected. Paper master list 
will be stored and locked in M1013; only study staff and study coordinator have access to this room. For 
individuals with screening failure, data including answers to the screening question, contact information 
and identifiable information will not be retained and will be destroyed on the day of the pre-screening 
process. 
 
11 Consent Procedures  
 
All interested potential subjects, will undergo a prescreening questionnaire to determine eligibility. If the 
potential subjects passes the pre-screen, he/she will be invited to participate in the clinical trial.  
Subjects who will be seen at BUSM or locally;  
▪ 
If the potential subject passes the pre-screen and agrees to participate, he/she will be invited to 
participate in the clinical trial. The subjects who meet the inclusion criteria to participate in the study 
and who wish to be consented locally the PI will meet with the subject in person and follow the 
consenting procedure as outlined in the protocol. The subjects who were given the consent form in-
person will have an opportunity to read it and ask questions of the PI or study personnel. The potential 
subjects will be given up to 30 minutes to decide if they want to participate. The PI will then ask them 
to sign the consent form. The subject who signs the consent form in person and will give the signed 
consent form to the PI or study personal. Once the signed consent form is obtained, it will be signed 
by the PI who reviewed the consent form with the subject and put into their file. After the PI signed 
the consent form, the consent form will be copied, and the copy will be given to the subject. 
▪ 
The subjects who are seen and after completing consenting process will receive the two devices and 
diaries and will be contacted as outlined in the approved protocol.  
▪ 
The subjects will return the devices and diaries to the PI or study personnel as outlined in the protocol. 
They will have an option to receive the commercially available device after completion the study as 
outlined in the protocol. 
Subjects who will be seen virtually: 
▪ 
If the potential subject passes the pre-screen and agrees to participate, he/she will be invited to 
participate in the clinical trial. The subject who meets the inclusion criteria to participate in the study 
and who wish to be consented virtually the PI will meet with the subject by zoom to follow the 
consenting procedure as outlined in the protocol. The subject will be provided the consent form by 
email. The subject will have an opportunity to read it and ask questions of the PI or study personnel. 
The potential subject will be given up to 30 minutes to decide if they want to participate. The PI will 

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obtain a verbal consent by asking the subject do they agree with the consent form? If they agree, the 
PI or study personnel will document the subject’s consent agreement, and this will be noted in the 
subject’s study file. The date and time will be recorded.  
▪ 
After obtaining verbal consent, the subject will be randomized as outlined in the approved protocol. 
The subjects who were consented by zoom and who had provided their verbal consent to the PI or 
study personal will then receive the devices and diaries by United Parcel Service (UPS), United States 
Parcel Service (USPS) or by Federal Express (FEDEX) that will have a tracking number and signature 
request documenting that subject received the devices and diaries.  
▪ 
The subject will be required to return the devices and diaries to the PI or study personnel by using the 
UPS, USPS, FEDEX return box that will be given to them. The return box will have an account number 
to pay for the return of the devices and diaries. The box will also contain a return address and have a 
tracking number. Once the devices and diaries have been received by either the PI or study personnel, 
the subject will have the option to be sent the commercially available device. 
 
12 Study Procedures 
See the Appendix for the schedule of events.  
 
During the screening process, potential participants will be asked with prescreening questionnaire to 
determine eligibility. Once they are determined to be eligible, they will be invited to participate in the 
study.  
 
This study will take at least 6 weeks and up to 8 weeks. In the first visit in person or virtually this is expected 
to last up to 1 hour, the participant will be given a consent form and have an opportunity to read it. The 
study personnel or PI will review the information on the consent form and conduct consent discussion. 
The subject will have an opportunity to ask questions of the PI or study personnel before signing it in 
person or providing verbal consent virtually.  After signing the consent form or giving verbal consent, it 
will be signed by the PI or study personnel and printed out and put into their file. A copy of the fully signed 
consent form for subjects who have been seen personally by the PI or study personal will be provided a 
copy of the signed consent form either in person or by email. The subjects who were consented verbally 
will receive by email the consent form signed by PI or study personnel with documentation of the time 
and date that the verbal consent was obtained. Once consenting is complete, the subjects who are seen 
in person will be given the diaries and the two devices. Those subjects who have completed the consenting 
process will receive the diaries and two devices by FEDEX, UPS or USPS. The participant will be shown how 
to attach the devices to their wrist and then shown how to activate the devices and control the 
temperature and to shut it off either in person or virtually. Written instructions will also be provided to 
the participant for their reference (see the attachment).  

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The participant will be instructed that for the first 2 weeks that he/she will document in the diary labeled 
as Hot Flash diary each hot flash rating it as severe, moderate, or minimal without using the device. Study 
personnel will contact the participant by phone or zoom call 1-3 days before the expected date to start 
using the device that they were randomly assigned to use. During this call, they will be instructed at the 
beginning of week 3 to open up one of the two boxes (depending on which arm they are randomized into) 
that they were given during the first visit and begin using it. The device will be in the box with labeled 
instructions. They will be instructed that they can wear the device 24/7 i.e. all the time or they can place 
it on their wrist when they begin to experiencing a hot flash.  The study personnel will also explain that 
during weeks 3 and 4 they will now be using the diary labeled as Hot Flash and Device Use.  The study 
personnel will go over how to use this diary and how to record the severity of their hot flash and document 
whether or not they used the device.  
If you are not available to use the device at the beginning of week 3, you will be allowed to keep 
documenting the severity of the hot flashes without using the device for another 2 weeks +3 days. You 
will be contacted by phone or zoom call again 1 – 3 days prior to the date you expect to start using the 
device. 
At the end of week 4, they will be contacted again by the study personnel to stop using the current device 
and change to the second one that they were randomly assigned to use. They will continue to use the 
device and document the same information during weeks 5 and 6 of the study.  Subjects who were seen 
in person will be instructed to return and see the PI or one of the study personnel after completing the 
activity and give the diaries and the devices to the PI or study personnel. Those subjects who are 
participating in the study virtually will be instructed to return and see the PI or one of the study personnel 
by zoom after completing the activity and return the diaries and the devices to the PI or study personnel 
by FEDEX, UPS or USPS. They will be asked questions about the use of the devices. During this in person 
or virtual visit, all participants will have the option to receive the commercially available wrist cooling 
device (valued at $199), as compensation either in person or by FEDEX, UPS or USPS. 
 
In summary, there will be a total of two in-person visits for BUSM and local subjects and no in person visit 
for those are participating virtually 1.) During the first visit the subject will undergo consent process and 
randomization. Those subjects participating at BUSM or locally will receive the two devices and the  
diaries. Those subjects participating virtually will receive the two devices and diaries by FEDEX, UPS or 
USPS. They will be instructed how to use the diaries and the devices at the appropriate time. 2.) During 
the return visit at the end of the study the subject will be asked questions about the use of devices, and 
they will return the diaries and the devices either in person or by FEDEX, UPS or USPS. They will have the 
option to receive the commercially available cooling device as compensation for their participation in this 
study. There will be 3 telephone or zoom call visits including 1-3 days before the subject is 
scheduled/expected to use the assigned device during weeks 3 and 4 of the study and then a Zoom call 
our phone call 1-3 days before the subject is scheduled/expected to use the other device during weeks 5 

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and 6 of the study. There may be multiple follow-ups calls if the subject is unable to start using the device 
on the indicated day. During week 6 before the end of the study they will get a reminder call to come back 
to return the diaries and the devices. The subjects in the virtual study will be reminded to send back the 
diaries and devices. 
 
This is a double blinded crossover study; the devices will be in boxes that will be labeled as A or B. Only 
one co-investigator (Dr. Alexanian), who will not be communicating with the subjects will possess the 
information as to which one (A or B) of the labeled boxes that have a wrist cooling device that when 
turned on activates the fan and cooling porcelain plate or a wrist cooling device that when turned on only 
activates the fan.  We will unblind the labels at the completion of the study for data analysis.  
 
13 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
13.1 Definitions for Safety Assessment 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered related 
to the subject’s participation in the research. 
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the 
event as it occurred.  
 

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Unanticipated Problem is defined as an event, experience or outcome that meets all three of 
the following criteria:  
• 
is unexpected; AND 
• 
is related or possibly related to participation in the research; AND 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
Possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
• 
the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol–related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as product labeling and 
package inserts; or 
• 
the expected natural progression of any underlying disease, disorder, or condition of the subject(s) 
experiencing the adverse event and the subject’s predisposing risk factor profile for the adverse 
event. 
 
Unanticipated adverse device effect means any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
 
13.2 Safety Review 
 
Both the risks listed in Section 4.1 and unknown risks will be monitored as follows: the participants will be 
given written and verbal instruction during the consenting process and at each telephone/zoom call will 
be asked if they have experienced any adverse effects. The subject will also have the opportunity to 
contact the study personnel or PI if they experience any adverse effects or significant discomfort from 
coolness among others.  
 
13.2.1 Multi-Site Safety Monitoring 
This is not a multi-site study. 
 
13.3 Reporting Plans 
    

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The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, safety 
monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB in accordance with IRB policies: 
 
• 
Unanticipated Problems will be reported to the BMC/BU Medical Campus IRB within 7 days of the 
investigator learning of the event. 
• 
Adverse Events (including Serious Adverse Events) will be reported in summary at the time of 
continuing review, along with a statement that the pattern of adverse events, in total, does not 
suggest that the research places subjects or others at a greater risk of harm than was previously 
known. 
 
13.4 Stopping Rules 
 
The study has no pre-defined stopping rules since that devices are considered to be nonsignificant risk 
devices. 
 
14 Data Handling and Record Keeping 
 
14.1 Confidentiality 
 
Subjects are assigned a code after consent and enrolled in the study. All coded records containing subject 
information will be stored in Dr. Holick’s offices under lock and key. Data will be kept in the Dr. Holick lab 
(M-1011). The door to the Vitamin D lab is accessed by those who have ID access to the lab. The data will 
be coded and after 7 years will be deidentified and kept indefinitely. Electronic information will be stored 
on a departmental server (“Y”drive), which is password protected. Paper records will be stored in a locked 
room for which only study staff will have access to. Master list will be stored on the Y drive and will not 
be stored with study data. All other electronic data will also be stored on the Y-drive which is password 
protected. Paper master list will be stored and locked in M1013; only study staff and study coordinator 
have access to this room. All locations where data will be kept are inaccessible to the public. Data will be 
available only to study personnel. Data will be kept in a locked room. Study code will be used for all study 
data that is collected. The study coordinator and study staff will keep the subject list on a secure network 
drive, which is password accessible only. 
 
To maintain confidentiality for the zoom calls the zoom call will only be made at Boston University School 
of Medicine that is password protected or by zoom on a laptop computer that is connected to the VPN of 
Boston University School of Medicine.   
 
14.2 Study Documentation, Source Data 
 

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Data generated by the methods described in the protocol will be recorded. Data may be transcribed 
legibly for each subject or directly inputted into an electronic system or any combination thereof. 
 
14.3 Study Records Retention 
 
Study records will be retained for at least seven years after completion of the study. Documentation of 
informed consent of subjects will be retained for at least seven years after the study is closed, unless the 
IRB waived the requirement for informed consent or documentation of informed consent. Such records 
may be preserved in hardcopy, electronic or other media forms and must be accessible for inspection and 
copying by authorized individuals.  
 
15 Statistical Plan 
 
15.1 Study Hypotheses 
 
We hypothesize that the wrist cooling device with a cooling porcelain plate more effective than the wrist 
cooling device with a fan only in reducing the severity of the hot flash.    
 
15.2 Sample Size Determination 
Reviewing the different types of treatment for hot flashes showed that the mean number of hot flashes 
per week decreased by 30%, 58%, 71% and 85% by Yoga poses, Citalopram, pregabalin and Gabapentin 
respectively. Also, hot flashes were reduced by 15-20% in the group receiving placebo.  
We want to consider the sample size of a balanced, cross-over design and the within mean square error 
from the ANOVA table will be used to analyze crossover design.   
We need 11 participants in each group to detect a 40% difference (average 60% reduction in severity in 
the treatment group and 20% reduction in severity in the placebo group) with 80% power using two-sided 
significance level of 0.05.  
Therefore, with the expected 25% drop-out rate, we will recruit a total of 30 participants (15 per arm). 
15.3 Statistical Methods 
 
The ANOVA table for crossover design will be used for statistical analysis.  
 
16 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional policies 
(which are based in federal regulations, guidance, and ICH Good Clinical Practice guidelines). 
 

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This protocol and any amendments will be submitted to the Boston Medical Center and Boston University 
Medical Campus IRB for formal approval of the study conduct. The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator.  
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. The consent 
form will be submitted with the protocol for review and approval by the IRB. The consent of a subject, 
using the IRB-approved consent form, must be obtained before that subject is submitted to any study 
procedure. Consent will be documented as required by the IRB.   
 
We will conduct a blinding index evaluation at the end of the study. This will be accomplished by 
standardized questionnaire that will be used to ask the subject about the use of the devices. The 
participants will be asked if they believe that they were assigned to the (i) control or (ii) treatment groups, 
or (iii) if they are uncertain of their assignment (the “don’t know” response).  
 
We will use a minor modified questionnaire published by  
Williams SL, Ferrigno L, Maraini G, Rosmini F, Sperduto RD. A post-trial survey to assess the impact of 
dissemination of results and unmasking on participants in a 13-year randomised controlled trial on age-
related cataract. Trials. 2011 Jun 14; 12:148. doi: 10.1186/1745-6215-12-148. PMID: 21672204; PMCID: 
PMC3136405. 
 
 
17 Literature References 
1. 
Schrock NM et. al. pilot study to determine the effects of dronabinol on hot flash relief 
in breast cancer patients.  Journal of Clinical Oncology, 22 (14): 8189, 2004. 
2. 
Mao JJ et al.  Electro Acupuncture versus gabapentin for hot flashes among breast 
cancer survivors: A randomized placebo-controlled trial.  Journal of Clinical Oncology.  33 (31): 
3615-3620; 2015 
3. 
De Boer H. et al. Luteinizing hormone-releasing hormone and postmenopausal flushing.  
New England Journal of Medicine.  361: 1218-1219, 2009. 
4. 
Guttuso T.  Review of hot flashes diaries. Maturitas 71: 213-216; 2012 
 
 
 

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18 Appendix 
 
Schedule of Events 
 
 
Baseline 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 7 
In-Person/ Virtually 
At home 
In-Person/ 
Virtually 
Consent + HIPAA 
Authorization 
X 
 
 
 
 
 
 
 
Eligibility 
Confirmation 
X 
 
 
 
 
 
 
 
Receive Hot Flash 
Diaries and receive 
instruction how to 
use them 
 
                     X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receive Two 
Devices 
and receive 
instruction how to 
use them  
X 
 
 
 
 
 
 
 
Use of Hot Flash 
Diary 
 
 
 
 
X 
X 
 
 
 
     
 
 
 
 
 
 
 
Use of Hot Flash 
and Device A Diary  
 
 
 
X 
 
X 
 
 
 
 
Use of Hot Flash 
and Device B Diary 
 
 
 
 
 
 
X 
 
X 
 
 
Telephone/zoom 
call 
 
 
X 
 
X 
 
X 
 

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Intervention – 
Wear the first 
device 
 
 
 
X 
X 
 
 
 
Intervention – 
Wear the second 
device  
 
 
 
 
 
X 
X 
 
You will either 
return to see Dr. 
Holick or one of his 
assistants to return 
the devices and the 
diaries or send the 
devices and diaries 
to Dr. Holick or one 
of his assistants by 
FEDEX, UPS, USPS. 
You will then have 
the option to 
receive the 
commercially 
available wrist 
cooling device. You 
will also be asked 
questions about the 
use of the devices. 
 
 
 
 
 
 
 
 
 
 
       X 
 
Note: The subject will be allowed to monitor hot flash symptom without using the device for up to 4 
weeks +3 days.