Acupressure for Fatigue in Ovarian Cancer Survivors
Phase: NA
Conditions: Fatigue, Ovarian Cancer
Sponsor: University of Michigan Rogel Cancer Center

UMCC 2018.130    
Acupressure for Fatigue in Ovarian Cancer Survivors 
   NCT03763838 
 

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Acupressure for Fatigue in Ovarian Cancer Survivors 
Principal Investigator: 
Suzanna M. Zick, ND, 
MPH 24 Frank Lloyd 
Wright Drive 
P.O. Box 375 Lobby M 
Ann Arbor, MI 48105 
Ph: 734-998-9553 
Fax 734-998-6900 
Co-Investigators: 
Richard E Harris, PhD 
24 Frank Lloyd Wright Drive 
P.O. Box 375 Lobby M 
Ann Arbor, MI 48105 
Ph: 734-998-6996 
Fax 734-998-6900 
Ananda Sen, PhD 
Family Medicine 
1018 Fuller Street 
Ann Arbor, MI 48109-1213 
Ph: 734-763-4263 
Ph: 734-998-7120 
Celeste Leigh Pearce, PhD 
School of Public Health, Epidemiology 
1415 Washington Heights 
Ann Arbor, MI 48109-2029 
Ph: 734-764-3835 
Project Manager: 
Sara Snyder, MBA 
 UM IRBMED #00143509: 
Current protocol submission and version number: Version 26 1/23/2025 
Date of previous submission and version numbers: Version 25 7/13/2023 
UMCC 2018.130 

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Contents 
1.0 BACKGROUND AND SIGNIFICANCE ......................................................................................................................... 5 
Risk Assessment ................................................................................................................................................................ 8 
Benefit Assessment ........................................................................................................................................................... 9 
HYPOTHESES AND OBJECTIVES ................................................................................................................................ 9 
2.0 SPECIFIC AIMS ............................................................................................................................................................... 9 
3.0 
METHODS .................................................................................................................................................................... 9 
3.1 Participants ................................................................................................................................................................. 10 
Recruitment ....................................................................................................................................................................... 10 
3.2 Randomization and Stratification. ............................................................................................................................. 11 
3.3 Intervention. ................................................................................................................................................................ 11 
3.4 Blinding. ....................................................................................................................................................................... 12 
4.0 
Design Considerations .............................................................................................................................................. 12 
4.1 Study Measures ......................................................................................................................................................... 13 
5.0 
REPORTING ADVERSE EVENTS ......................................................................................................................... 18 
5.1 Definition ..................................................................................................................................................................... 18 
5.2 Assessment of Relationship of AE to Treatment ................................................................................................... 18 
5.3 Study Specific Adverse Event Reporting Plan ....................................................................................................... 18 
5.4 Follow-up of AEs ........................................................................................................................................................ 19 
5.5 AE Reporting and Data Elements ........................................................................................................................... 19 
5.6 Severity of AEs ........................................................................................................................................................... 19 
6.0 
CONCOMITANT MEDICATION, EXERCISE, DIET AND SMOKING ................................................................ 20 
6.1 Limitations on Medication, Exercise, Diet and Smoking ...................................................................................... 20 
6.2 Documentation of Medication.................................................................................................................................... 20 
7.0 
OFF-STUDY CRITERIA ........................................................................................................................................... 20 
7.1 Study Termination ...................................................................................................................................................... 20 
7.2 Premature Removal of a Participant ....................................................................................................................... 20 
7.2.1 Personal reason ..................................................................................................................................................... 20 
7.2.2 Lost to follow-up ................................................................................................................................................... 20 
7.2.3 New illness ............................................................................................................................................................ 20 
7.2.4 Death .................................................................................................................................................................... 21 
8.0 DATA MANAGEMENT.................................................................................................................................................... 21 
9.0 STATISTICAL METHODS ............................................................................................................................................ 22 
10.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................................... 24 
10.1 
Institutional Review Board (IRB) Approval ..................................................................................................... 24 
10.2 
Informed Consent............................................................................................................................................... 24 
10.3 
Data and Safety Monitoring .............................................................................................................................. 24 
10.3.1 Guidelines ............................................................................................................................................................. 24 
10.3.2 Study-Specific DSMP ............................................................................................................................................. 24 

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10.4 Record Retention ..................................................................................................................................................... 25 
11.0 REFERENCES ............................................................................................................................................................. 26 
 

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1.0 BACKGROUND AND SIGNIFICANCE 
Fatigue and Ovarian Cancer. Women diagnosed with ovarian carcinoma (cancer) report multiple quality of life 
challenges, including persistent fatigue and sleep disturbances.1-3 Persistent fatigue is a commonly reported 
symptom in these women, with as many as 30 to 60% of ovarian cancer survivors continuing to report significant 
fatigue even several years after the end of treatment.1,4-7 In ovarian cancer, persistent fatigue has been linked to 
higher levels of chronic pain,6,8 lower quality of life,9,10 and reduced participation in other self-care activities such 
as physical activity.11,12 Interestingly, risk factors for fatigue post cancer treatment does not appear to be 
associated with type of cancer, cancer treatment, stage of diagnosis or histopathology of the cancer, but instead 
with other host factors such as presence of depression or level of physical activity.8,13 While the etiology of 
persistent fatigue in cancer survivors is unknown, recent research in female cancer survivors suggests that 
cancer related fatigue may involve pathology within the brain, and thus treatments that target the brain may have 
promise for treating fatigue.14,15 Despite the challenges caused by persistent fatigue, there have been very limited 
attempts to identify self-care-focused interventions, which could improve fatigue, sleep, and quality of life among 
ovarian cancer survivors. We are proposing to carry out a randomized, controlled trial comparing self- 
administered acupressure to sham acupressure and no treatment to determine if this is an intervention that 
survivors can use to address their fatigue. 
 
Acupressure and Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. A plot of mean weekly fatigue scores 
for relaxing acupressure (red circles), High 
Intensity Stimulating Acupressure (closed black 
circles), and Low Intensity Stimulating (open 
circles) across study weeks 
Self-administered acupressure is one possible safe, self- 
management technique for improving persistent fatigue as 
well as physical and psychosocial functioning in ovarian 
cancer 
survivors 
with 
chronic 
cancer-related 
fatigue. 
Acupressure, a technique derived from acupuncture, is a 
component of Traditional Chinese Medicine in which pressure 
is applied to specific acupoints on the body using a finger or 
small device to address health issues. Acupressure has 
shown promise for treating fatigue in cancer patients and 
survivors, although these have been small studies with 
numerous methodological flaws including inclusion of 
multimodal treatment approaches, patients currently receiving 
or recently completing cancer treatment, and no examination 
of carry-over effect of acupressure.16-20 We performed a pilot 
intervention of relaxing and stimulating self-acupressure in 
fatigued adult cancer survivors, of which 14% had been 
diagnosed with ovarian cancer.21 In this study, participants were 
randomized to one of three groups: 1. relaxing acupressure 
(n=14); 2. High intensity stimulating acupressure (n=15); or 
1. low intensity stimulating acupressure (n=14). Participants 
performed acupressure for 12 weeks between 3 to 14 times per 
week depending on group. Fatigue was measured with the Brief Fatigue Inventory on a weekly basis. The 
change in the Brief Fatigue Inventory was significantly different across groups, with self-administered relaxing 
acupressure engendering greater reductions in fatigue when compared to acupressure. Deviation acupressure 
2.2±1.6, low p=0.027). In a either high or low intensity stimulating (See Figures 1 and 2; mean ± standard 
reduction in Brief Fatigue Inventory: relaxing 4.0±1.5, high intensity stimulating acupressure intensity 
stimulating acupressure 2.7±2.2; linear regression model with change in Brief Fatigue Inventory as the dependent 
variable, the group difference remained significant after adjusting for age, cancer type, cancer stage, and cancer 
treatments (p=0.013). Across groups, these reductions in fatigue were on the order of 45% to 70%, which are 
clinically relevant and could represent significant improvements in quality of life for cancer survivors.21,22 
Acupressure was effective in reducing fatigue in other cancer survivors, including women with ovarian 
cancer. 

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As a demonstration that a larger study is feasible, we recently 
completed a randomized clinical trial in 288 fatigued breast cancer 
survivors (stage 0 to III), which demonstrated that self-administered 
acupressure was an effective intervention for persistent fatigue.22 
Survivors were randomized to one of two different types of self- 
acupressure (relaxing acupressure or stimulating acupressure) or usual 
care. After 6 weeks of daily treatment, both acupressure arms had 
significantly reduced fatigue compared to usual care and this effect 
persisted for one-month post-treatment (Figure 3). The mean percentage 
fatigue reductions at 6 weeks were 34%, 27%, and −1% in relaxing 
acupressure,  stimulating  acupressure,  and  usual  care, 
Figure 2. Scatter plot of individual participant BFI 
change scores (week 12— week 0) indicate greater 
reductions for relaxing acupressure (red circles), 
High Intensity Stimulating Acupressure (closed 
black circles), and Low Intensity Stimulating 
(open circles). 
respectively. Moreover, over 60% of women in the treatment 
arms achieved normal fatigue levels compared to only 31% in the 
usual care arm. Relaxing acupressure also significantly improved 
sleep quality and improved quality of life when compared to the 
usual care arm.22 Further, acupressure worked equally well 
despite stage or histopathology of the cancer. Women were able 
to perform the self-acupressure with a high level of fidelity, i.e. the 
accuracy with which the acupressure treatment was performed by participants including correct location of 
acupoints, amount of pressure, duration and frequency of treatments (95% out of 100% on their fidelity ratings), 
and adherence (performed 73% of all acupressure sessions on average).22,23 These data indicate that 
acupressure was effective in reducing fatigue in female cancer 
survivors, and importantly, survivors can be recruited through the Michigan Cancer Registry and a large 
randomized, controlled study completed. However, no study has examined using a mobile app to teach 
female cancer survivors to self-administer acupressure — an important innovation to help increase 
implementation and accessibility for cancer survivors. 
 
 
Figure 3. 
Fatigue by Week and Group Assignment. The 
Brief Fatigue Inventory consists of 9 items, each 
measuring fatigue on a scale of 0 to 10, and the 
score is calculated from the mean of completed 
items. Scores of 4 or higher indicate clinically 
relevant fatigue. The shaded area represents 
nonclinical or normal levels of fatigue. 

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Self-Administered Acupressure 
 
An advantage of self-acupressure is that once a person 
learns the technique they are free to control the frequency 
and dose of the intervention. Since the intervention can be 
easily learned (generally in less than 15 minutes),24 we 
reasoned that an online or mobile application (app) could 
increase its utilization. In a recent pilot survey of cancer 
patients with fatigue, use of technology such as a computer 
program or smartphone app was the most popular 
response for learning acupressure. Consequently, we 
developed a mobile app in association with focus groups 
consisting of cancer survivors (six focus groups consisting 
each of eight to ten women) and the University of Michigan 
3D Media Laboratory. The acupressure app is called 
MeTime Acupressure (Figure 4). One concern with some 
 
Figure 4. Sample MeTime Acupressure Screen 
 
 
app-based interventions are that the company that initially develops the app may cease to make it available or 
support it. Our app was developed at the University of Michigan by the Principal Investigator and thus there 
is no chance it will not be available in the future. Importantly, further refinements of the app can be done in an 
iterative manner. 
 
Focus group participants also asked for a device to accompany the app in order to learn and apply an 
accurate amount of pressure to each acupoint (the hardest skill to 
learn for participants and one they expressed as being of high 
importance).23 They also wanted a device that was comfortable to 
use and could minimize any strain in the hand or fingers from 
applying the acupressure. To achieve this goal, we partnered with 
Arbor Medical Innovations (AMI), a Michigan-based technology 
company to translate their expertise in hand held devices, which 
provide precise amounts of pressure to create the “AcuWand” 
device (see Figure 5). The AcuWand is a digital force gauge for 
the controlled delivery of pressure to discrete acupressure points 
throughout the body. The AcuWand applies forces from 0-100N, 
at 100ms intervals, to match the typical 
delivery of acupressure stimulation and gives feedback through visual and audio cues letting participants know 
when “too much” or “too little” pressure is being applied. It also incorporates an ergonomic handle so the user 
can easily grasp the device and apply pressure through a sprung probe with a soft rubber tip. The AcuWand was 
designed in collaboration with users and can objectively and comfortably enable ovarian cancer survivors 
to deliver an adequate amount of pressure to each acupressure point – a critical aspect for performing 
reliable and efficacious acupressure treatment. 
Figure 5. AcuWand Prototype 

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Mechanism of Action of Relaxing Acupressure. 
 
It is important to have a “biological rationale” for 
how stimulating certain areas of the body with a 
somatic stimulus, such as a finger applying 
pressure, could actually reduce fatigue any more 
so than beyond a simple placebo. For instance, a 
lack of a mechanism could impede the acceptance 
of, recommendation, and adoption of acupressure 
by medical professionals. While currently the 
underlying 
mechanisms 
explaining 
how 
acupressure improves fatigue and alleviates sleep 
disruption are unclear, recent research by our 
group and others provide important clues to 
systemic and central nervous system processes. A 
recent review by Zhao25 suggested that fatigue and 
sleep effects of acupressure are mediated by a 
number 
of 
neurotransmitters 
including 
norepinephrine, melatonin, gamma-aminobutyric 
acid, and β-endorphin. Animal studies also indicate 
down-regulation of the hypothalamic–pituitary– 
adrenal axis, which reduces plasma corticosterone 
and adrenocorticotropin hormone levels.26 A 
heterogeneous and large number of acupoints and 
methods of stimulating, e.g., needle insertion, 
electrical acupuncture, moxibustion, acupressure 
etc., were examined for their mechanistic effects. In 
general, 
the 
type 
of 
stimulation 
appears 
unimportant, while the acupoint location appears to 
have 
some 
impact 
on 
affecting 
these 
neuroendocrinological changes.25 
 
 
 
Figure 6. Differential changes in connectivity to the default mode 
network (DMN) following different acupressure treatments. (A) 
An independent component analysis of resting state functional 
MRI data shows increased connectivity between the to the superior 
colliculus (SC)/periaqueductal gray and the DMN following 
relaxation acupressure but not stimulating acupressure. Increased 
connectivity between the DMN and the thalamus (pulvinar) was 
observed following stimulating but not relaxing acupressure. (B) 
Scatter plots showing changes in DMN connectivity by 
acupressure treatment (stimulation: open circles, relaxation: black 
circles). Connectivity patterns are mutually exclusive: increases in 
SC-DMN connectivity are accompanied by decreases in pulvinar- 
DMN connectivity for relaxation acupressure, while the converse 
Given the importance of acupoint location it is germane to know that four out of the five acupoints we 
propose using in the relaxing acupressure formula are commonly used for insomnia in clinical trials:25 heart 7; 
spleen 6; liver 3; and Animan, and have demonstrated effects on sleep-related neurotransmitter systems and 
hypothalamic–pituitary–adrenal axis activity in basic, human and animal studies.26-36 Our own small-scale study, 
15 which examined the effect of two different types of acupressure--relaxing and stimulating--on fatigue in breast 
cancer survivors using magnetic resonance imaging, also found that the different types of acupressure 
(distinguished only by their acupoint locations) work via different mechanisms within the brain. In particular, we 
found that the relaxing acupressure formula increased the connectivity between the superior colliculus – a 
brainstem region important in humans and primates that regulates sleep and alertness – and the default mode 
network – a network of brain regions that is activated when thinking about one’s internal state. In comparison 
stimulating acupressure decreased this same connection (see Figure 6).15 Moreover, for relaxing (but not 
stimulating) acupressure, these changes were associated with improvements in sleep quality. 
 
Risk Assessment 
The known or expected risks are risk of bruising at points of pressure; there is a very small chance (<1%) of 
having bruises at points of pressure if too much pressure is applied. This bruising should not continue or get 
worse. The researchers will try to minimize the risk of bruising by having the acupressure app demonstrate the 
correct amount of pressure to apply at the start of the study. Additionally, a member of the research team will call 
the particpant at certain times during the study to evaluate their health and safety. During these conversations the 
study coordinator will ask the participant about any bruising. 
 
Risk lowering measures: Study procedures to manage or minimize risks include a vibration feature installed in the 

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AcuWand programming to signify or “warn” participants that minimum pressure has been achieved. 
 
The AcuWand is not FDA approved, nor are we seeking FDA approval for its use. We do not anticipate any 
problems with the device which would cause injury or harm in any way. 
 
 
Benefit Assessment 
Participants may not receive any personal benefits from being in this study. However, it is possible that the 
acupressure treatments could reduce the severity of fatigue they are experiencing. We hope the information 
learned from this study will benefit other ovarian cancer patients. 
 
 
HYPOTHESES AND OBJECTIVES 
We are proposing to evaluate the impact of six weeks of daily self-administered relaxing acupressure on 
fatigue, sleep, and quality of life in persistently fatigued ovarian cancer survivors compared to 6 weeks of daily 
self-administered sham acupressure or no treatment. Survivors who have fatigue starting at or after cancer 
diagnosis, and have ≥4 on the Brief Fatigue Inventory, which is the cutoff for moderate fatigue, will be eligible for 
the study.37 During the study period we will randomize and follow 171 survivors (we anticipate a ~13 % dropout 
with the goal of 150 completers). We hypothesize that persistently fatigued ovarian cancer survivors will 
experience improvements in fatigue, sleep, quality of life, and symptoms commonly associated with persistent 
fatigue from utilizing relaxing as compared to sham acupressure or no treatment. 
 
2.0 SPECIFIC AIMS 
To investigate our hypothesis, we will randomize fatigued ovarian cancer survivors into 6 weeks of daily: 1. 
Relaxing self-acupressure (n=57); 2. Sham self-acupressure (n=57); or 3. No treatment (n=57) followed by 18 
weeks of no acupressure and investigate the following aims: 
 
1. Examine the effect of 6 weeks of daily self-administered relaxing acupressure compared to self-administered 
sham acupressure or no treatment on: 
 
A. Persistent fatigue (Primary aim) -- measured with The Brief Fatigue Inventory; 
 
B. Quality of life (Secondary aim) -- using the Functional Assessment of Chronic Illness Therapy 
Measurement System, specifically the ovarian cancer specific instrument; 
 
C. Sleep Quality (Secondary aim) -- using the Pittsburgh Sleep Quality Index; 
 
D. Symptoms commonly associated with persistent fatigue (Exploratory aim) (sleep disturbance, pain, 
cognitive function, mood, and female sexual function) -- using Patient Reported Outcomes Measurement 
Information System. 
 
2 (Exploratory aim). To investigate the duration of effect self-administered relaxing acupressure as compared 
to self-administered sham acupressure or no treatment during the 18 weeks following the end of acupressure 
treatment (carry-over phase) on persistent fatigue, quality of life, sleep quality, and symptoms commonly 
associated with persistent fatigue (sleep disturbance, pain, cognitive function, mood, and female sexual function) 
using the measurement tools described for the primary aim. 
 
Both acupressure treatments will be delivered via the MeTime Acupressure app in association with the 
AcuWand. 
 
3.0 METHODS 
Study Design. We propose a randomized, controlled clinical trial comparing relaxing acupressure to sham 
acupressure and no treatment for persistent fatigue in ovarian cancer survivors. The study will be 25 weeks in 

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duration: Phase I (screening phase; 7 days in duration/weeks -1 to 0), consisting of telephone screen for study 
eligibility, obtaining informed consent, random assignment to treatment group, and shipment of computer tablet 
and AcuWand, if appropriate; Phase II (active treatment phase; 6 weeks in duration), which will consist of 
performing once daily self-acupressure—sham or relaxing—with the study app and the AcuWand or no treatment 
with outcomes including baseline and 6-week subjective measures of fatigue; sleep quality, pain, female sexual 
function, cognition, and quality of life; Phase III (carry-over phase) is an 18-week follow-up to evaluate fatigue, 
sleep quality, pain, female sexual function, cognition, and quality of life after completion of the acupressure 
treatments with outcomes assessed at 12 and 24 weeks. Our studies have indicated that the effects of self- 
acupressure can persist for 4 weeks after the end of treatment and acupuncture interventions in chronic pain 
populations have seen sustained effects ranging from 6 months to one-year post-intervention.38,39 As such, we 
intend to determine if acupressure has sustained impacts beyond 4 weeks after the end of treatment. All groups 
including the no treatment group will have an equal number of study contacts. 
 
3.1 Participants. 
Table 1 Eligibility Criteria 
 
Inclusion Criteria 
Exclusion Criteria 
✓ women aged 21 years and older 
✓ diagnosis of ovarian cancer, stages I to IV 
✓ have average persistent fatigue defined as ≥ 4 
on the Brief Fatigue Inventory  
✓ fatigue must have started at or after the 
diagnosis of ovarian cancer 
✓ initiated 
all 
primary 
cancer 
treatments 
(surgery, chemotherapy at least 3 weeks 
prior), including maintenance therapies 
✓ undergone any primary debulking surgery at 
least 4 weeks prior 
✓ undergone interval debulking surgery at least 
4 weeks prior if they have had neoadjuvant 
chemotherapy (NACT) 
✓ no other planned interventions for fatigue 
other than current stable medication 
x 
medically unstable 
x 
acupuncture or acupressure receipt in past 
year 
x 
have a diagnosis of untreated mood disorder, 
e.g., bipolar or major depressive disorder 
x 
have a current diagnosis of anemia 
x 
have a current untreated diagnosis of 
hypothyroidism 
x have an initiation, a cessation or change of 
treatment of any chronic medications, dietary 
supplements, behavioral therapy, physical 
therapy etc., or any planned change of 
medications, supplements or therapies during 
the study 
x  have the possibility of becoming pregnant 
x  diagnosis of COVID-19 on or after 3/1/2020 
with fatigue onset following diagnosis 
 
 
Recruitment. 
Participants will be identified through a variety of sources. The Michigan Department of Health and Human 
Services (MDHHS) Michigan Tumor Registry collects information about cancer incidence, stage, and to a limited 
extent, the kinds of treatment that patients receive. These data are reported to the registry from various medical 
facilities. The Michigan Tumor Registry includes cancer case information received from the metropolitan Detroit 
Surveillance, Epidemiology, and End Results (SEER) registry. The Michigan Cancer Surveillance Program, 
which operates the Michigan Tumor Registry, is a member of the North American Association of Central Cancer 
Registries (NAACCR). The registry is certified by NAACCR as meeting all standards for quality, completeness, 
timeliness, and unresolved duplicate records and is estimated to be greater than 95% complete based on 
external audit findings.40,41 We will request Michigan Tumor Registry data for women diagnosed throughout the 
State of Michigan, even if they no longer reside in Michigan. Women will receive an introductory letter from the 
MDHHS describing the study and asking them to contact us if they are interested or if they would like to opt out 
of future mailings. A second letter will be sent to all women who do not respond within two weeks, and a final 
third letter to any non-responders from prior mailings two weeks after the second letter. Interested women from 
the Michigan database send their contact information to the MDHHS, who pass it along to the study team. 
We will also be recruiting from the Los Angeles Cancer Surveillance Program (the Los Angeles SEER) and our 
local University of Michigan Cancer Registry in a similar manner. After approval from the State of California 

10 
 
Cancer Registry IRB, they will provide contact information of potentially eligible women diagnosed with ovarian 
cancer and we will send them the same introductory letter being sent out by the MDHHS, a study flyer, and a 
brochure from the California Cancer Registry. A second letter will be sent to all women from Los Angeles who do 
not respond within two weeks, and a final third letter to any non-responders from prior mailings two weeks after 
the second letter. Interested women from Los Angeles will be able to contact the study team directly. The study 
team then performs a phone screen to determine eligibility with all interested women. We will also contact a 
randomly selected group of women from the LA SEER registry directly via phone and/or text message (SMS). 
 
We will also recruit from the North Carolina Central Cancer Registry (NC CCR) and follow the same process as 
LA SEER; we will receive contact information from the NC CCR for potentially eligible women and continue with 
our 3 communication letters or direct phone call and/or text message (SMS). If we don’t receive any response 
from text messages from women from the NC CCR, we may send up to three letters via mail.   
 
We will utilize the UM Cancer Registry to identify potentially eligible women diagnosed with ovarian cancer and 
will send them the same introductory and consecutive 2nd and 3rd/final recruitment letters. We may utilize 
certified mail for the final recruitment mailing for all participants contacted via mail.  For participants identified 
through the UM Cancer Registry we may choose to contact them via phone or text message (SMS) for 
recruitment. We will also reach out to the leadership at ovarian cancer survivor groups, including, but not limited 
to the Michigan Ovarian Cancer Alliance (MIOCA), Ovarian Cancer Research Alliance (OCRA), Facing Our Risk 
of Cancer Empowered (FORCE), Michigan Oncology Quality Consortium (MOQC), and Ovarian Cancer 
Canada. We will email a study flyer and a short description of the study to the contact person at these at these 
organizations to allow them to distribute this information to their members as they deem appropriate. Interested 
women will again be able to contact the study team, who will perform the same phone screen. 
 
Additionally, we will utilize Michigan Institute for Clinical and Health Research (MICHR) services to provide 
social media advertisement support. MICHR will manage all IRB approved advertising. We may also choose to 
use the images and texts in the MICHR advertisements to advertise through U-M Rogel Cancer Center Social 
Media and Health Communications Core. 
 
We will work with the Michigan Department of Communications to assist us to recruit via paid advertisement on 
website search engines.  
 
We will post the study on researchmatch.org.  Like UMHealthResearch, Research Match is a participant 
recruitment and feasibility analysis tool for researchers at participating institutions, University of Michigan is a 
participating institution. We will post our study information here as well for potential participants to learn more 
and to enroll. 
Social media accounts may be created to help recruit participants and guide them to our study. A detailed 
recruitment portfolio which includes imagery and text can be found in section 8-1.8 of our application. 
We may choose to work with BuildClinical to help accelerate enrollment. BuildClinical is a health technology 
company that enables academic researchers to accelerate their clinical research patient recruitment efforts by 
engaging the exact population needed through digital advertising and ultimately reducing the patient access 
and awareness gaps that exist today. 
We may choose to utilize the DataDirect resource at U-M to help identify potentially eligible participants. 
DataDirect is available for faculty researchers and their study team members to access both discrete variables 
and free-text string data from the electronic medical record (EMR). 
Snowballing: We may choose to email participants who have completed study, and share our flyer and social 
media content with them. If they would like to, they may share our study information to their own personal 
accounts or groups that they may be members of. 
 
3.2 Randomization. 
The biostatistician will provide sealed envelopes for the randomization of all participants. Participants will be 

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randomized to one of the three study arms: Acupressure, Sham acupressure or Control. A random generator for 
block stratified randomization in blocks of 6 participants will be programmed by Dr. Sen, the study statistician. 
Eligible patients will be randomized into one of three groups - relaxing acupressure, sham acupressure, or no 
treatment - in a 1:1:1 ratio for a total of 171 participants with 57 randomized into each group. 
   
We will be delivering our self-acupressure interventions (relaxing and sham) using our modified MeTime 
Acupressure mobile app. We will rename the MeTime Acupressure app to “Study App” and change the icon so 
participants will not be able to locate it in the Apple or Google Play Stores and unblind themselves. In 
association with the 3D Media Lab at the University of Michigan we will create a mobile app for our sham 
acupressure points. The sham and relaxing acupressure apps will be identical in all aspects except for the 
acupoint locations. For women randomized into the “no treatment arm” they will receive the acupressure app 
and AcuWand at the end of their study participation. The acupressure app will be loaded onto computer tablets 
by our computer information technology (IT) support person. Women in the acupressure arms will also receive 
an AcuWand to be used in association with the acupressure app to help women apply the correct amount of 
pressure to acupoints. The women will receive directions within the acupressure app on how to use the 
AcuWand. The AcuWand has been designed to use two lithium-ion long lasting (up to one year with normal 
use) batteries. Participants are asked to return the AcuWand with provided materials at no cost to them in 
order to upload data about frequency, duration and amount of pressure of acupressure applications. Of note: 
no Wi-Fi connection is needed to use the acupressure app and our IT support person will be available to help 
participants who are unfamiliar with or have any issues with their tablet, AcuWand or the app. 
 
Relaxing Acupressure. There are 5 acupoints with 4 of 
the acupoints performed on both the left and right sides of 
the body (total of 9 points to stimulate; see Figure 7). Each 
of the 9 acupoints will be stimulated for 3 minutes per point 

12 
 
 
with the AcuWand giving a total treatment time of 27 
minutes daily. The relaxation acupoints are: 
 
Yin 
tang 
(Unilaterally): 
forehead, 
between 
eyebrows 
 
Anmian (EX17) (Bilaterally): posterior aspect of 
the neck 
 
Heart 7 (HT7) (Bilaterally): palmer surface of the 
hands on the wrist crease 
 
Spleen 6 (SP6) (Right and Left/bilaterally): inside 
of the lower leg 
 
Liver 3 (LV3) (Bilaterally): foot 
The relaxing points were selected based on existing data 
showing their effectiveness for treating fatigue.21,22 
 
Sham Acupressure. Sham acupoints were chosen by Dr. 
Harris in locations where no known acupoints exist. There 
are 5 acupoints with 4 of the acupoints performed on both 
the left and right sides of the body (total of 9 points to stimulate; see Figure 7). None of these points are on 
meridians nor are they near actual points (at least one inch away from meridians and points). They were chosen 
to be in the same general body quadrant as the relaxation points. Each of the 9 acupoints will be stimulated for 
3 minutes per point giving a total treatment time of 27 minutes daily. The sham acupoints are: 
 
Pressure Point #1 (Unilaterally): This point is located on the side of the head, above the right ear. 
 
Pressure Point #2 (Bilaterally): This point is located on the muscle of the upper arm. Located in the middle 
point directly between the crease of the elbow (when arm is flexed) and the shoulder muscle one finger 
width toward the biceps muscle. 
 
Pressure Point #3 (Bilaterally): This point is located on the upper thigh muscle on the lateral side of the 
leg. 
 
Pressure Point #4 (Bilaterally): This point is located on the lower thigh muscle on the lateral side of the 
upper leg. 
 
Pressure Point #5 (Bilaterally): This point is located on the lateral side of the lower leg and is located 
midway between the line connecting the outer ankle bone and the knee. 
 
3.3 Blinding. 
Our IT support person will place the computer tablets—already loaded with either the acupressure app--sham 
or relaxing--or the “no treatment” message and the AcuWands into opaque shipping boxes per our 
randomization code, i.e., a tablet with the sham acupressure app loaded on it would be placed in a shipping 
box labeled with a study ID assigned to the sham arm. The outside of the shipping boxes will be labeled with 
study IDs. This will ensure that only our IT support person will be unblinded, but all study staff and researchers 
will remain blinded until after the completion of data analyses. The IT support person will not be responsible for 
collecting or analyzing any study data. Participants in the “no treatment” arm will not be blinded; however, the 
two self-acupressure arms will be blinded as to which acupressure treatment they have been randomized. The 
MeTime app will be re-named to “Study App” for the study. 
 
4.0 Design Considerations. 
Justification for Sham Acupressure and No Treatment Arms. We chose to add a sham acupressure arm to 
this study so that we had a control arm that could be blinded to participants and study staff. Sham acupressure 
also controls for placebo (non-specific) effects associated with acupressure, and thus will allow us to estimate 
the specific or true effects of the relaxing acupressure treatment. The no treatment arm controls for regression 
to the mean and is an accurate reflection of what the majority of cancer survivors are receiving for their persistent 
fatigue from health care providers—no treatment. 
 
Justification for Acupressure Dose (3 minutes per acupoints) and Duration (6 Weeks). In our original 
Figure 7 

13 
 
acupressure pilot study in adult cancer patients,21 we found that, regardless of treatment arm, the number of 
minutes performing acupressure was significantly correlated with reduction of fatigue or sleepiness. Participants 
(per their study logbooks) who stimulated their points for shorter periods of time, i.e., 1 minute, had less of an 
effect on fatigue and sleepiness compared to those who stimulated their points for 3 minutes. We also 
determined, from pilot work with fatigued cancer patients assigned to self-administered acupressure for 12 
weeks, that change in fatigue improved over 6 weeks and then plateaued, with no further significant 
improvement.21 Finally, our preliminary data from our randomized controlled trial in fatigued breast cancer 
subjects demonstrated improvements in subjective fatigue outcomes at 6 weeks. 22 
 
Justification for 24-Week Follow-up. Our pilot data in fatigued adult breast cancer patients demonstrates that 
our 6-week acupressure intervention has sustained effects on fatigue, sleep and quality of life outcomes up to 4 
weeks after the cessation of the acupressure treatment. Other acupuncture interventions mainly in chronic pain 
populations have seen sustained effects ranging from 6 months to one year post-intervention39,42 and similarly, 
behavioral therapies for fatigue have sustained impacts of from 24 to 26 weeks (6 months).43 For acupressure to 
be a widely used and implemented treatment we would need to observe sustained effects on fatigue reduction of 
the intervention similar to other pain treatments. As such, we are proposing a 24-week post-treatment follow- up 
for this study. 
 
4.1 Study Measures. 
Table 2 lists all study procedures and indicates with an ‘x’ during which visit a particular 
procedure is performed. 

 
Table 2 
 
 
Screening 
phone call 
Baseline 
Week 0 
Treatment Phase 
Weeks 1 - 6 
Follow-up 
Week 6 
(- 2 days/+5 
days)  
Follow-up 
Week 12 
(- 2 days/+5 
days) 
Follow-up 
Week 24 
(- 2 days/+5 
days) 
Phone Screen 
X 
 
 
 
 
 
Screening Survey 
X 
 
 
 
 
 
BFI 
X 
X 
 
X 
X 
X 
PHQ-2 
X 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
Pt. Info & Dem. 
X 
 
 
 
 
 
Concomitant of Medications 
 
X 
 
 
 
 
Diagnosis & Treatment of initial 
cancer 
 
X 
 
 
 
 
FACT-O 
 
X 
 
X 
X 
X 
PSQI 
 
X 
 
X 
X 
X 
PROMIS 
 
X 
 
X 
X 
X 
IPAQ 
 
X 
 
 
 
 
SCQ 
 
X 
 
 
 
 
FSQ 
 
X 
 
 
 
 
MAIA 
 
X 
 
X 
 
 
Daily Logbook 
 
 
X 
 
 
 
Acupressure Fidelity 
 
 
 
X 
 
 
Assessment of blinding 
 
 
 
X 
 
 
AcuWand Comfort 
 
 
 
X 
 
 
Final Evaluation 
 
 
 
 
 
X 

15 
 
Administering Study Assessments. All potential participants will be screened over the phone using a brief 
questionnaire to confirm eligibility for the study. Enrolled participants will then receive an email link to their RedCAP 
study measures at baseline, weeks 0, 6, 12 and 24. All the surveys will be administered at all-time points with the 
exception of descriptive and baseline assessments, which will only be collected at week 0; fidelity, blinding and 
adherence, which will only be asked at week 6; and a final evaluative questionnaire about the participants’ 
perception of the study and the use of the AcuWand device. Adverse events will be collected at all-time points. 
Inspirational reminder emails, texts, or phone calls (as appropriate for a given participant) will be made to 
encourage the highest possible response rate to each round of study assessments. Participants without an email 
account will be assisted in obtaining a free Gmail account and how to access it on their computer tablet by study 
staff. Those participants who do not have access to Wi-Fi will be assisted in finding free Wi-Fi in their community 
(e.g., public library, Starbucks, McDonalds, etc.44 IT study staff will be available to assist participants with any 
questions that may arise. E-mail is required so that study instruments may be accessed through surveys in 
RedCAP. 
 
Screening. All potential participants will be screened over the phone using a basic questionnaire to confirm their 
eligibility. Specifically, an abbreviated form of the Patient Health Questionnaire (PHQ-2) will be used to detect 
untreated depression, and the Brief Fatigue Index (below; BFI) will be used to determine fatigue. These 
measures will be collected before consent and enrollment in to the study and will therefore be kept to the 
absolute minimum to determine eligibility. 
 
Rescreening. Participants may be rescreened at 6 weeks after initial screening if they failed their initial screening 
based on: stable chronic medications and no new planned interventions for their fatigue or cancer. 
 
Fatigue Measure (administered at screening and weeks 0, 6, 12 ,24). Brief Fatigue Inventory (BFI)37 will be 
used to assess the severity and impact of fatigue on daily functioning. The BFI is a scale validated in cancer 
patients with an alpha coefficient exceeding 0.95, which correlates well with other fatigue measures.45 The BFI 
assesses severity and impact of fatigue in cancer patients over the past 24 hours. The instrument consists of 9 
items, each measuring fatigue on a 0-10 scale, and is calculated from the mean of completed items. Scores of ≥4 
indicate clinically- relevant fatigue.37 A three-point change or a drop below 4 is considered a clinically meaningful 
change.46 
 
Sleep Quality (administered weeks 0, 6, 12 ,24). Pittsburgh Sleep Quality Index (PSQI) is widely used 19-item 
questionnaire evaluates sleep disturbance over the past month. It yields a total score and 7 component scores: 
sleep quality; sleep latency; sleep duration; habitual sleep efficiency; sleep disturbances; use of sleep-promoting 
medication; and daytime dysfunction. In women with breast cancer, Cronbach’s alpha for the global PSQI is 
0.80.47 A score >7 in breast cancer patients and thus likely in ovarian cancer patients suggests poor sleep 
quality.48 The scale has adequate psychometrics.49,50 The primary outcome will be the total PSQI score at 
baseline and week 6, although we will conduct exploratory analyses on the PSQI subscales. 
 
Quality of Life (administered weeks 0, 6, 12 ,24). The Functional Assessment of Cancer Therapy Ovarian 
(FACT-O)51 is a multidimensional questionnaire developed and validated for use by ovarian cancer patients; it 
includes the 27-item FACT-General (FACT-G) targeted to general cancer patients and 12 questions specific to 
issues faced by ovarian cancer patients (FACT-O subscale). The FACT-G questionnaire includes the following 
four subscales: physical well-being (PWB; seven items), social well-being (seven items), emotional well-being (six 
items) and functional well-being (FWB; seven items). These subscales can be analyzed separately or aggregated 
to produce a total health related quality of life score. The FACT-G has demonstrated reliability, validity and 
responsiveness to change over time. Two of the FACT-G subscales (PWB and FWB) plus the FACT- O subscale 
are summed to represent the total quality of life score. 
 
Symptoms Associated with Fatigue (administered weeks 0, 6, 12 ,24). We will be using Patient Reported 
Outcomes Measurement Information System (PROMIS) measures. To diminish participant burden, we will be 
using the short form versions of these measures. In a study in head and neck cancer patients a PROMIS battery 
asking about physical function, fatigue, sleep disturbance, depression, negative perceived cognitive function took 
only 6.2 minutes to complete.52 The validity of PROMIS instruments has been assessed in both general and 

16 
 
clinical U.S. sample populations including oncology populations.53-55 PROMIS short forms represent the items of 
the PROMIS item banks constructed to measure the targeted constructs. All of the included PROMIS forms use 
5-point Likert-type response categories to capture intensity, frequency, or duration, described in detail below. Most

17 
 
instruments use a seven-day recall period, with the exception of PROMIS Sexual Function and Satisfaction Profile 
which has a 30-day timeframe. PROMIS instruments are publicly available on the PROMIS Assessment Center 
Library website.56 Following are detailed description of our included measures. 
 
PROMIS Short Form v1.0 - Emotional Distress- Anxiety 7a57 measures “fear, anxious misery, hyperarousal, 
and somatic symptoms related to arousal”. The instrument consists of 7 items that ask respondents about the 
frequency with which they experienced emotions such as fear, stress, and anxiety (“never” to “always”). Scores 
range from 36.3 to 82.7 with higher scores indicating worse anxiety. 
 
PROMIS Short Form v1.0 - Emotional Distress - Depression 8b57 measures “negative mood, decrease in 
positive affect, information processing deficits, negative views of the self, and negative social cognition”57. It 
consists of 8 items in which respondents indicate the frequency with which they have experienced emotions such 
as worthlessness, hopelessness, and sadness (“never” to “always”). Scores range from 35.2 to 82.4 with higher 
scores representing worse depression. 
 
PROMIS Short Form Sexual Function and Satisfaction Profile v1.0 – Female58 - A collection of 11 brief (1- 
3) item short forms assessing interest in sexual activity, orgasm, global satisfaction with sex life, lubrication, and 
vaginal discomfort. The profile is intended for broad use, although almost all of the development work was with 
cancer populations. Scores range from 25.2 to 84.4 with higher scores representing worse sexual function. 
 
PROMIS Short Form v1.0 - Sleep Disturbance 8b59 This is an 8 item measure of perceptions of sleep quality, 
sleep depth, and restoration associated with sleep. Scores range from 28.9 to 76.5 with higher scores representing 
worse sleep disturbance. 
 
PROMIS Short Form v1.0 - Pain Interference 8a60 measures “impact of pain on physical, mental, and social 
activities”. It consists of 8 items measured on a 5-point Likert-type scale (first 5 questions: “not at all” to “very 
much”; final question: “never” to “always”). The questions assess the degree to which pain interferes with 
enjoyment in life, ability to concentrate, day-to-day activities, recreational activities, tasks away from home, and 
socializing with others. The scores range from 41 to 78.3 with higher scores representing worse pain impact. 
 
PROMIS Short Form v2.0 - Cognitive Function 8a61 measures “mental acuity, concentration, verbal and 
nonverbal memory, verbal fluency, and perceived changes in these cognitive functions. The extent to which 
cognitive impairments interfere with daily functioning, whether other people observe cognitive impairments, and 
the impact of cognitive dysfunction on quality of life are also assessed. Scores range from 14.7 to 68.6 with higher 
scores representing worse cognitive function. 
 
Multidemensional Assessment of Interoceptive Awareness (administered weeks 0, 6). The  
Multidimensional Assessment of Interoceptive Awareness (MAIA)80 is a multidimensional questionnaire 
developed as a self-report measure of interoceptive body awareness. The MAIA includes an 8-scale state-trait 
questionnaire with 37 items to measure multiple dimensions of interoception by self-report. Participants score 
each answer on a range from 0 to 5 with total scores being calculated using the included rubric. 
 
Descriptive/Baseline Variables (administered week 0). 
 
Fibromyalgia Symptom Questionnaire (FSQ) consists of an assessment of widespread pain and symptom severity. 
The Widespread Pain Index (WPI) assesses the 19 specific body areas described in the survey criteria with scores 
ranging from 0-19. The second aspect of the criteria will be evaluated using the Symptom Severity (SS) scale (score 
0-12). As per the survey criteria, patients will be classified as fibromyalgia positive (FM+) if their scores were WPI 
≥ 7 and SS ≥ 5 or WPI = 3-6 and SS ≥ 9. The validity of the survey criteria has been established both when compared 
with the 1990 ACR criteria (which included the tender point examination) and the 2010 preliminary diagnostic 
criteria which include physician assessment.78 
 
Concomitant Medications including dose, duration/frequency of use, and reason for use will be recorded. 

18 
 
Sociodemographic Variables will include, but not be limited to: date of birth, race, ethnicity, marital status, 
education, and annual household income. 
 
Cancer Diagnosis and Treatment. We will collect information about cancer treatments and diagnoses. These will 
be cross validated with data from the tumor registry. 
 
Physical Activity. Because physical activity is known to impact the presence and severity of cancer-related fatigue 
and sleep disturbance63,64 we will collect participants’ activity using The International Physical Activity 
Questionnaire (IPAQ). The IPAQ assesses self-reported physical activity via a validated 7-day recall measure in 
which time and frequency spent performing activities of different intensities are recorded and tallied.65,66 
 
Obesity and related comorbid conditions may also increase risk for common adverse cancer treatment effects, 
including fatigue, poor health-related quality of life, and worse functional health67. As such, we will be collecting: 
 
Comorbidities using the Self-Administered Comorbidity Questionnaire (SCQ).68,69 The SCQ is based on Katz’s 
validated self-report adaptation of the Charlson Comorbidity Index to measure the presence and/or history of several 
chronic health conditions. 
 
Body Mass Index (BMI) using a modified version of an e-health anthropometric questionnaire that includes 
questions dealing with self-measurement of current height, weight and has been found to highly correlate with in- 
person height and weight measurements.70 
 
Safety, Fidelity, Blinding and Adherence (administered week 6 except for adverse events and adherence to 
acupressure, which are collected throughout the study). 
 
Adverse Events will be graded according to National Cancer Institute Common Toxicity Criteria version 4.03. 
Testing Participant Fidelity21 We will be assessed using two methods. The first, as detailed in our prior study,23 is 
done by research staff using a Skype face-to-face call (we will install Skype on the computer tablets and assist 
participants in using this program as needed.) Participants will be asked to identify the location, stimulation 
technique, and the amount of pressure (be able to demonstrate correct use of their AcuWand) of their acupoints. 
The number of acupoints correctly located will be recorded as will the adequacy of stimulating the acupoints 
(recorded as “yes” or “no”). The percentage of correct answers 0 to 100% will be calculated, based on circular 
(clockwise or counterclockwise) motion, maintaining contact with skin, and applying pressure such that the nail of 
the applying finger/thumb blanches. The second method will be data download from the AcuWand via Bluetooth 
when the computer tablet is connected to Wi-Fi. The AcuWand will be able to provide data on the duration, 
frequency, and amount of pressure used by participants-it cannot provide data on the location of where participants 
stimulated their points. We employ both methods to ensure that fidelity is measured across all parameters and in 
collect redundant measure in case an AcuWand does not transmit data. 
 
Blinding will be assessed by asking participants, which type of acupressure they thought they were performing. 
 
Adherence to Acupressure will be assessed by asking participants to record if and when they performed 
acupressure, the order in which they performed their acupressure points, and the amounts of achiness and/or 
tenderness they experienced while performing the acupressure on a Visual Analog Scale daily in the study 
logbooks. These will be used in association with data downloaded from the AcuWands. Bi-weekly emails will be 
used to troubleshoot and encourage adherence. 
 
AcuWand Comfort Questionnaire (administered week 6). 
 
Massachusetts General Hospital Acupuncture Sensation Scale (MASS) consists of twelve predefined descriptors 
and one subjective component specified by the subjects in their own words to measure levels of de qi sensations. 

19 
 
De qi is a prerequisite term in Traditional Chinese Medicine (TCM) used to describe sensory stimulation. It has 
historically been thought to be an indicator of appropriate acupuncture or acupressure treatment and thus relates 
to therapeutic effectiveness.79 
Comfort level and ease of use of the AcuWand device will also be assessed. 
 
 
5.0 REPORTING ADVERSE EVENTS 
5.1 Definition 
An adverse event (AE) is any condition which appears or worsens after a participant is enrolled 
in an investigational study. An AE does not necessarily have a causal relationship with the study 
agent. 
 
5.2 Assessment of Relationship of AE to Treatment 
The possibility that the adverse event is related to study treatment will be classified as one of the following: 
not related, unlikely, possible, probable, definite. 
 
5.3 Study Specific Adverse Event Reporting Plan 
All Serious Adverse Events that are deemed related, probably related or possibly related will be reported to the 
IRBMED within 7 days, as per UM IRBMED guidelines 
 
All other non-serious, non-life-threatening adverse events will be reviewed by the PI and reported as per the 
following Study Specific Adverse Event Reporting Plan: 
 
Reportable Events 
Timing of Report to IRBMED 
Unanticipated / unexpected problem 
involving risks to subjects or others 
Serious - within 7 days 
 
 
Non-Serious - with scheduled 
continuation review 
Any physical, social, or psychological 
harm attributable to participation in this 
research study (e.g. an injury occurring 
during a study visit, bruising at the site of 
acupressure treatment) 
Serious - within 7 days 
 
 
 
 
Non-Serious - with scheduled 
continuation review 
Death while on study 
Within 7 days of notification 
 
Loss of job or insurability due to breach 
or revelation of research records or 
participation. 
Within 7 days of notification 
Non-Reportable Events 
 
Hospitalizations and morbidity expected in population (e.g. surgery for 
removal of fibroid tumor) 
 
Other serious or non-serious events deemed not related or unlikely related to 
the research 
 
Serious = an event requiring hospitalization, permanent disability, incarceration, significant familial disruption 
(e.g. separation, divorce), job loss 

20 
 
Non-Serious = an event requiring some medical, psychological, psychiatric or similar attention to resolve. 
Scheduled continuation review = renewal application. 
 
5.4 Follow-up of AEs 
All AEs will be followed according to good medical practices, and documented as such. 
 
5.5 AE Reporting and Data Elements 
All participants will be questioned regarding adverse events during the follow up phone call and final visit. All 
participants will be instructed to contact the study coordinator via phone call or email at any time during the 
study if they have a concern. 
 
All adverse events that occur after the informed consent is signed will be recorded on the adverse event case 
report form (CRF) whether or not related to study intervention. 
 
The following information will be collected for all adverse events: 
 
 
AE reported date 
 
AE Verbatim Term 
 
CTCAE Term (v 4.03) 
 
Event onset date and event ended date 
 
Severity grade 
 
Attribution to study treatment (relatedness) 
 
Whether or not the event was reported as a Serious Adverse Event (SAE) 
 
Action taken with the study intervention 
 
Outcome of the event 
 
Comments 
 
5.6 Severity of AEs 
Severity will be graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03. The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. A copy 
of the CTCAE can be found at [http://ctep.cancer.gov]. 
 
AEs will be assessed according to the CTCAE grade associated with the AE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to their impact on the participant’s ability to perform 
daily activities as follows: 
 
Grade 
Severity 
Description 
1 
Mild 
 
Asymptomatic or mild symptoms 
 
Clinical or diagnostic observations only 
 
Intervention not needed 
 
2 
Moderate 
 
Minimal, local or non-invasive intervention 
indicated 
 
Limiting age-appropriate instrumental activities 
of daily living 

21 
 
3 
Severe 
 
Medically significant but not immediately life- 
threatening 
 
hospitalization or prolongation of hospitalization 
 
Disabling 
 
Limiting self-care activities of daily living 
4 
Life threatening 
 
Life threatening consequences 
 
Urgent intervention needed 
5 
Death 
 
Death related to Adverse Event 
 
 
6.0 CONCOMITANT MEDICATION, EXERCISE, DIET AND SMOKING 
6.1 Limitations on Medication, Exercise, Diet and Smoking 
Concomitant prescribed medications are allowed except as listed in Exclusion Criteria. Acute medication will 
be allowed, defined as taking a medication for < 10 days over the course of a month with the intent to 
discontinue that medication. 
 
Similarly, participants will be asked (once consented) to maintain their customary exercise, dietary and 
smoking habits during the screening, intervention and follow-up phase of the study. Participants will be asked 
to refrain from starting or stopping any new lifestyle modifications for the entire duration of the study. 
 
6.2 Documentation of Medication 
All chronic medications (prescription or OTC used for at least 14 days continuously), dietary supplements 
and/or herbal preparations taken by the participant during the study period will be documented on a CRF with 
information including: 
 
 
Type of medication 
 
Medication dosage/schedule 
 
Purpose for taking the medication, supplements or herbs (if available) 
 
 
7.0 OFF-STUDY CRITERIA 
7.1 Study Termination 
The study participant will be considered off-study when they complete the full study, as defined as completing 
the 24-week visit. 
 
The Principal Investigator can decide to terminate a participant's participation in the study at any time. This 
decision could be based on factors such as unacceptable adverse events or for safety concerns. The reason 
for termination shall be documented in the case report form. 
 
7.2 Premature Removal of a Participant 
7.2.1 Personal reason 
A participant may withdraw from the study at any time; the reason will be documented in patient study records. 
 
7.2.2 Lost to follow-up 
Three attempts must be made by telephone and letter to determine the circumstances for loss to follow-up, 
since such loss may be related to the study intervention. 
 

22 
 
7.2.3 Death 
Participants who die while on study will be replaced by another participant. 
 
7.2.4. Lost to follow-up after enrollment but withdrew before the baseline visit 
Participants who withdraw between enrollment and the baseline visit can be replaced with a new participant 
 
 
8.0 DATA MANAGEMENT 
Study measures will be delivered electronically to participants using RedCAP. RedCAP is a generalized survey 
service supported by the University of Michigan Medical School permitting the creation and distribution of 
surveys, as well as data storage and analysis. RedCAP is user-friendly but can handle complex designs. For 
instance, simple surveys can be produced in minutes. Complex studies, involving randomization and embedded 
and longitudinal data, are also possible. RedCAP is also HIPAA compliant. RedCAP surveys will be accessed 
by the participant through an electronic device, via e-mail link forwarded from the study team, and are separate 
from the acupressure app. Those unable to effectively access and use these instruments will have a study team 
member administer these measures via phone, entered directly into RedCAP. 
 
Statistics Section. 
 
The primary aim of this study is to investigate the differential effects of different modes of acupressure (relaxing 
vs. sham vs. no treatment) on fatigue as measured by the BFI in ovarian cancer survivors at week 6. The BFI, 
which measures the average degree of fatigue, gives a score that ranges between 0 and 10, with higher numbers 
indicating more fatigue. To investigate the difference in BFI between the three study arms, we shall use linear 
mixed-effects regression analysis with BFI as outcome, week as the within-subjects factor with four levels (0, 6, 
12, 24) and group (relaxing acupressure, sham acupressure, no treatment) as the primary between-subjects 
factor. Of interest is the group-by-week interaction (to be included in the model), significance of which will indicate 
differences in extent of decrease between the arms. The covariate cancer stage at diagnosis and the interaction 
term group-by-stage will be added to models. Post-hoc sliced main effect of weeks within each study arm will be 
estimated. A subject random-effect will be used to account for the clustering effect within the four measurements 
on the same subject. Model diagnostics will be carried out to confirm the distributional assumptions and 
appropriate corrective actions (e.g. transformation) will be performed as needed. Models with more flexible 
covariance pattern (e.g. unstructured covariance, heterogeneity across groups) will be explored. An additional 
analysis with a spline version of weeks will be carried out which uses week as a continuous variable allowing one 
to estimate the rate of change in BFI. 
 
A secondary analysis with BFI will also be carried out which investigates the difference in proportion of fatigued 
subjects (BFI ≥ 4) across the three study arms. The analytical framework will be that of a mixed-effects logistic 
regression model with presence of fatigue (BFI ≥ 4 yes/no) being the dichotomous outcome. Apart from group, 
week, and group-by-week interaction as primary covariates, the model will also be adjusted for baseline status 
of severity. Remaining covariates in the model are identical to those in the continuous BFI model. The clustering 
effect due to subject will be accounted for using a generalized estimating equations approach under a 
generalized linear mixed models framework. 
Secondary Aims. Analogous linear mixed-effects regression analyses as described in the primary outcome 
analysis will be employed to investigate our secondary outcomes  at week 6 the Secondary Aim “B”, FACT-O, 
of which we will use two of the Functional Assessment of Cancer Therapy general subscales (PWB and FWB) 
plus the FACT-O subscale summed to represent our quality of life outcome; and Secondary Aim “C”; PSQI, 
which has scores for seven components, namely sleep quality; sleep latency; sleep duration; habitual sleep 
efficiency; sleep disturbances; use of sleep-promoting medication; and daytime dysfunction, all derived from the 
original PSQI. The component scores are summed to obtain a total score, the outcome for the proposed study. 
 
Since PSQI score greater than 5 is considered an indicator of poor sleep quality, we shall also carry out a logistic 
regression analysis with a dichotomous outcome indicating whether PSQI > 5 is satisfied or not. This will compare 
the proportions (longitudinally) of subjects with poor sleep quality across the study arms. The analytical framework 
will be very similar to that for testing equality of proportions of subjects that are fatigued. 

23 
 
 
Exploratory Aims. Analogous linear mixed-effects regression analyses as described in the primary outcome 
analysis will be employed to investigate our exploratory outcomes (all administered on weeks 0, 6, 12, and 24) 
the summation of the PROMIS Short Form questions covering: anxiety, depression, pain interference, sleep 
disturbance, cognitive function, and sexual function and satisfaction profile. 
 
To investigate the duration of effect of self-administered relaxing acupressure as compared to self-administered 
sham acupressure or no treatment during the 18 weeks following the end of acupressure treatment (carry-over 
phase) on persistent fatigue, quality of life, sleep quality, and symptoms commonly associated with persistent 
fatigue (sleep disturbance, pain, cognitive function, mood, and female sexual function) we will break up the 
observation period into two phases. In the first phase BFI and other study measures will be obtained by averaging 
week 0-week 6 measures and will indicate the status until end of the acupressure treatment (treatment-phase). 
The second phase comprises of week 7-week 24 and indicates the washout phase (washout). To investigate the 
difference in BFI and other study measures between the three study arms, we shall use mixed- effects regression 
analysis with average BFI and other study measures in the two phases as outcome, phase as the within-subjects 
factor and group (RA, SA, standard of care) as the primary between-subjects factor. We shall carry out an analysis 
with the phase variables as treatment-phase and washout as the levels. The purpose of investigating the model 
will compare the differences between the treatment and washout period across groups (phase-group interaction). 
 
Handling Missing Data. The linear mixed-effects framework is an intent-to-treat framework in the sense that it 
uses all available data at all time-points. So if there are missing outcome values in any phase due to participant 
dropout, the usual analysis will still be valid. If the proportion of dropouts is substantial (20% or more) in either 
arm, then we shall also perform a weighted analysis with weights equal to the inverse of the probability of dropout. 
On the other hand, missing covariate values for the subject-level information will be imputed using multiple 
imputation methods. All missing values will be imputed using the chained equation method.72 The advantage of 
using this technique is its flexibility in allowing different types of variables (categorical and continuous) to be 
imputed together without requiring any multivariate joint distributional assumption. In this method, the missing 
values are sequentially updated using bootstrap or Markov Chain Monte Carlo based on multiple regression 
models with other variables as covariates. This procedure will be carried out for a number of repetitions or cycles, 
thereby constructing an ‘imputed’ dataset. Ten such ‘imputed’ datasets will be used for the final analysis, a 
number which is considered adequate for most applications. Finally, we shall combine the results from the ten 
regressions with the imputed data using Rubin’s formula.73 
 
 
9.0 STATISTICAL METHODS 
Power Analysis. Our power analysis is based on our primary aim to, “Examine the effect of 6 weeks of daily 
self-administered relaxing acupressure compared to self-administered sham acupressure or no treatment on 
persistent fatigue as measured with The Brief Fatigue Inventory.” Although we will run a larger model for the 
analysis, in the power calculation we focus on the specific components of the model in which we are interested. 
Towards that end, we compute the power via simulation using a mixed effects model with a between-subject 
factor group (3 levels), a within-subject factor week (0, 6, 12, and 24), group-by-time interaction and a random 
subject effect. The mean BFI at baseline is assumed to be 5.5, whereas values at end of treatment were assumed 
to be 4.5, 3.5, and 2, respectively for no treatment, sham acupressure and relaxing acupressure arms. The 
between-subject variance is assumed to be 4 at all time-points whereas the variance of the random subject 
component is taken to be 4 also (yielding an intra-class correlation of 0.5). These assumed values are estimates 
based on our pilot data.21 For this configuration, the power for detecting a significant week-by-group interaction 
is greater than 95% with a sample size of 50 evaluable participants per treatment arm (we anticipate a ~13 % 
drop out with the goal of 150 completers for a total sample size of 171) and a 5% level of significance. Such a 
model is able to detect a post-hoc difference between the relaxing acupressure and each of the other two arms 
with more than 90% power at a reduced 0.01 level of significance in order to protect against Type I error 
probability inflation. In the second phase after the treatment period, it is anticipated that both the no-treatment 
and the sham acupressure arms will experience a bounce 
back close to the baseline level, while the relaxing acupressure arm will maintain its end-of-treatment average. 
Thus, the differences will be more pronounced than those in the active treatment phase, and we will be well 

24 
 
powered to detect the effect size. 
 
We also want to power the study to allow us to observe differences in sleep parameters. The extent of overlap 
between fatigue and sleep disturbances in ovarian cancer survivors is currently unknown. Research indicates 
that anywhere from 55 to 67% of ovarian cancer survivors experience sleep disruptions.7,74 While fatigued women 
are most likely enriched with individuals experiencing sleep disturbances we will conservatively assume that 
roughly 50% of women will have some significant sleep disturbances per treatment arm. As such, with 50 women 
per treatment group we will be overpowered for detecting a difference in fatigue and sufficiently powered to detect 
changes in sleep measures. For example, using the PSQI as a basis for powering differences in sleep quality 
from previous studies the mean PSQI in female cancer survivors ranges from 6.84  0.376 to 7.16 
0.325.47 A 1-point decrease in the PSQI from ~7 to ~6 is considered a clinically significant difference. The mean 
PSQI values at baseline is assumed to be 7 in all arms whereas the means are taken to be 7, 6, and 5 at 6 weeks 
in the no treatment, sham and relaxing acupressure arms, respectively. Assuming an intra-subject correlation of 
0.5, we have powers above 95% to detect differences between any pair of arms at 1% level of significance. 
 
All power calculations are carried out on the basis of 100 simulations in the software PASS 2008 (NCSS, 
Kaysville, Utah 84037, USA). 
 
9.1 Definition of an Evaluable Participant. Evaluable participants must complete both the baseline and week 
6 BFI.  
 
9.2. Post-hoc Power Analysis. Average changes in BFI between baseline and 6 weeks for both true and sham 
acupressure were statistically significant at 5% level, so power was not an issue in detecting these effect sizes. It is 
evident from Table 4 that although it did not reach statistical significance, the difference between true and sham 
acupressure was trending towards that (p = 0.08). It turns out that with the mean of the changes estimated to be 
that obtained in the data (Table 3), in order to detect a difference between the two Acupressure arms with 80% 
power, we would have needed 94 subjects per arm. The calculation is based on a two-sample t-test with a pooled 
standard deviation estimate of 1.7.  
 
Table 3: Mean and standard deviation of changes between baseline and 6 weeks by study arm 
 
N 
Mean 
Std. Deviation 
True Acupressure 
41 
-1.9621 
2.04466 
Sham Acupressure 
45 
-1.2988 
1.63485 
Usual Care 
51 
-.4336 
1.51849 
Total 
137 
-1.1752 
1.82757 
 
Table 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

25 
 
Study Limitations and Challenges. As with any study we anticipate potential barriers. Recruitment may prove 
to be one potential challenge; however, our methods of recruiting breast cancer survivors from the Michigan 
Tumor Registry41 have been effective and we are planning similar methods in this study. We can also recruit 
from the members of the Michigan Ovarian Cancer Science and Innovation Consortium of which Dr. Pearce is a 
member. Attrition from the study may be another challenge. We have had experience in keeping participants in 
fatigue and cancer studies21,22,75 with higher levels of study burden compared to this proposal for at least 3 
months. In our previous studies, which included four in-person visits, twice as many questionnaires, and offered 
no participant incentives such as a free computer 
tablet, our withdrawal rates ranged from 10% to 
20%.21,22 As such, we have planned for a 10% 
withdrawal rate for this proposal given our lower level 
of participant burden and greater study incentives. 
 
We also understand that not all women are 
familiar with or use computers, mobile apps, Wi-Fi or 
email. This may be a particular concern for older 
women who will make up a significant portion of the 
proposed study’s participant pool as ovarian cancer 
rates are highest in women aged 55-64 years with 
the median age at which women are diagnosed 
being 63.76 The most recent PEW statistics on 
internet and technology shows that roughly half of all Americans own tablet computers and this has been swiftly 
rising (see Figure 8). Computer tablet ownership is higher in younger, more educated, white urban adults. Despite 
this, 37% of adults aged 55-65 and 32% 65+ own a tablet.77 To address those women who are unfamiliar or have 
limited familiarity with computer tablets we will provide support from a dedicated research IT personnel Mr. 
Budde. Mr. Budde has extensive experience offering computer support to a wide range of computer users of 
diverse skill sets and sociodemographic backgrounds. We will also supplement Mr. Budde’s support with simple 
written directions geared to a seventh grade level of education. 
 
Conclusion. This proposal aims to investigate a low-cost, evidence-supported intervention for improving fatigue, 
sleep quality and quality of life in ovarian cancer survivors with persistent cancer-related fatigue. This patient- 
centered self-management intervention has the potential to be easily disseminated in healthcare settings and 
Figure 8 

26 
 
directly to the community via a mobile app. It could also be an adjunct to current treatment options for persistent 
cancer-related fatigue. 
 
 
10.0 ETHICAL AND REGULATORY CONSIDERATIONS 
10.1 Institutional Review Board (IRB) Approval 
Prior to initiating the study, the PI must obtain written approval to conduct the study from the appropriate IRB. 
Should changes to study protocol become necessary, protocol amendments will be submitted electronically by 
the PI or designated study staff to the IRB for approval prior to implementation. 
 
10.2 Informed Consent 
All potential candidates for the study will be given an electronic copy of the study informed consent to read. 
The investigator or their designee will explain all aspects of the study in lay language and answer all the 
candidate's questions regarding the study. If the candidate decides to participate in the study, they will be 
asked to sign the informed consent document electronically. Participants who refuse to participate or who 
withdraw from the study will be treated without prejudice. 
 
The informed consent document must be reviewed and approved by the IRB prior to study initiation. Any 
subsequent changes to the informed consent must be approved by the IRB for approval prior to 
implementation. 
 
10.3 Data and Safety Monitoring 
10.3.1 Guidelines 
The purpose of the data and safety monitoring plan is to insure the safety of participants, the validity of data, 
and the appropriate termination of studies for which significant benefits or risks have been uncovered or when 
it appears that the trial cannot be concluded successfully. Risks associated with participation in research must 
be minimized to the extent practical, and the method and degree of monitoring should be commensurate with 
risk. The essential elements of the Data and Safety Monitoring Plan include: 
 
 
Monitoring the progress of trials and the safety of participants 
 
Plans for assuring compliance with requirements regarding the reporting of adverse events (AE) 
 
Plans for assuring data accuracy and protocol compliance. 
 
The known or expected risks associated with this study include: 
 
 
Risk of bruising at points of pressure; there is a very small chance (<1%) of having bruises at points of 
pressure if too much pressure is applied. This bruising should not continue or get worse. To minimize 
the risk of bruising study staff members will demonstrate the correct amount of pressure to apply at the 
start of the study. Additionally, a member of the research team will call participants during the study to 
evaluate their health and safety. During these conversations study team members will ask about any 
bruising. 
 
Risk of breach in confidentiality; there is a possible risk of the loss of confidentiality of participant 
medical information. The study team will try to protect participant privacy and the confidentiality of 
information. 
 
10.3.2 Study-Specific DSMP 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel Cancer Center 
Data and Safety Monitoring Plan. 
 
The study team will meet every six months or more frequently depending on the activity of the protocol. The 

27 
 
discussion will include matters related to the safety of study participants (SAE/UaP reporting), validity and 
integrity of the data, enrollment rate relative to expectations, characteristics of participants, retention of 
participants, adherence to the protocol (potential or real protocol deviations) and data completeness. At these 
regular meetings, the protocol specific Data and Safety Monitoring Report form will be completed and signed 
by the Principal Investigator or by one of the co-investigators. 
Data and Safety Monitoring Reports will be submitted to the University of Michigan Rogel Cancer Center Data 
and Safety Monitoring Committee (DSMC) every six months for independent review. 
10.4 Record Retention 
Clinical records for all participants studied, including CRFs, history and physical findings, laboratory data, and 
results of consultations, will be maintained by the Investigator in a secure storage facility and stored for at least 
five years after the study is closed. 

28 
 
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