Acupressure for Persistent Fatigue in Systemic Lupus Erythematosus Patients
Phase: NA
Conditions: Fatigue, Lupus Erythematosus, Systemic, Pain, Chronic, Quality of Life, Sleep
Sponsor: Suzanna Zick

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Acupressure for Persistent Fatigue in Systemic Lupus Erythematosus  
 
 
UM IRBMED #: HUM00127631 
 
NCT# 03200548 
 
Current protocol submission and version number: Version 10, Approved 11/2/2020 
 
 
 
 
 
 

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1.0 BACKGROUND AND SIGNIFICANCE 
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by involvement of 
multiple organs with a female to male ratio of 12:1 with the highest incidence reported in women of child 
bearing age (15-44 years).1 In general, advances in diagnosis and management have led to significant 
improvements in outcomes.2  However fatigue remains a challenging and prevalent issue for SLE patients. 
1.1 Fatigue in lupus 
SLE patients consider fatigue to be one of the most pervasive and disabling aspects of their disease.  As many 
as 85% report significant levels of fatigue3, a prevalence far in excess of that observed in the general 
population and most other chronic disorders. Moreover, its impact permeates all aspects of life as reflected by 
fatigue’s strong association with impaired quality of life4 and work disability5.  Despite these profound 
consequences, there is a dearth of accepted therapies and in a meta-analysis of 32 studies in over 9,000 
rheumatoid arthritis patients (who receive similar treatments to SLE and also suffer from significant fatigue) 
who received biological treatments found these medications, while effective for pain and disease activity, 
showed modest and mixed impacts on improving fatigue.6 
The etiology of fatigue is likely to be complex and existing evidence supports a multi-dimensional origin.  
While many SLE patients describe cognitive features of fatigue (e.g. difficulties in concentrating), even more 
complain of physical aspects (e.g. needing to rest more)7,8. Physical fatigue is commonly attributed to 
problems with the skeletal muscle (indeed physical fatigue and muscle fatigue are synonymous terms). In fact, 
by measuring voluntary muscle contraction, others have observed significantly reduced skeletal muscle 
strength in SLE patients compared to healthy controls9 – a difference which could be explained by pathological 
abnormalities within the muscles.  In the past, muscle biopsy studies have identified microscopic 
abnormalities in the majority of patients, ranging from muscle fiber atrophy to lymphocytic vasculitis10. 
1.2 Acupressure 
Self-administered acupressure is one possible safe, self-management technique for which may be effective for 
improving fatigue as well as physical and psychosocial functioning in several chronic disease populations.11-13 
Acupressure, a technique derived from acupuncture, is a component of Traditional Chinese Medicine (TCM) in 
which pressure is applied to specific acupoints on the body using a finger or small device, to treat disease. Our 
prior research demonstrated that acupressure, self-administered by women with breast cancer, significantly 
reduced clinically significant fatigue by approximately one-third in fatigued breast cancer survivors and was 
superior to standard therapies.14  Moreover these self-rated improvements were maintained up to one month 
after treatment was discontinued. 
 
However, impact on other chronic disease populations with fatigue is unknown.  To explore this intervention 
in SLE, we propose to conduct a pilot randomized clinical trial in 72 SLE patients with established fatigue, 
through the following aims. 
2.0 SPECIFIC AIMS 
1. To determine the feasibility of recruiting and conducting acupressure in fatigued persons with lupus 
2. To explore the effect of two distinct acupressure formulas (relaxing and stimulating) plus usual care 
versus sham acupressure plus usual care and usual care alone on severity and impact of chronic fatigue 
(as measured by the Brief Fatigue Inventory) 
a. Hypothesis:  Both relaxing and stimulating acupressure are superior to sham acupressure and 
usual care, but relaxing acupressure is superior to stimulating acupressure 

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3. Secondary: To explore the effect of two distinct acupressure formulas (relaxing and stimulating) plus 
usual care versus sham acupressure plus usual care and to usual care alone on quality of life, sleep and 
pain 
a. Hypothesis:  Both relaxing and stimulating acupressure are superior to sham acupressure and 
usual care, but relaxing acupressure is superior to stimulating acupressure 
 
3.0 PRELIMINARY DATA 
3.1 Study 1: Self-administered for Fatigue in Breast Cancer Survivors 14 
 
A total of 424 survivors of stages 0 to III breast cancer who had 
completed cancer treatments at least 12 months previously were 
screened, and 288 were randomized, with 270 receiving relaxing 
acupressure (n = 94), stimulating acupressure (n = 90), or usual 
care (n = 86). One woman withdrew owing to bruising at the 
acupoints. At week 6 (post-treatment), the percentages of 
participants who achieved normal fatigue levels (Brief Fatigue 
Inventory score <4) were 66.2% (49 of 74) in relaxing acupressure, 
60.9% (42 of 70) in stimulating acupressure, and 31.3% (26 of 84) 
in usual care. At week 10, a total of 56.3% (40 of 71) in relaxing 
acupressure, 60.9% (42 of 69) in stimulating acupressure, and 
30.1% (25 of 83) in usual care continued to have normal fatigue 
(see Figure 1). At neither time point were the 2 acupressure 
groups significantly different. Relaxing acupressure, but not 
stimulating acupressure, showed significant improvements in 
sleep quality compared with usual care at week 6, but not at week 
10. Only relaxing acupressure significantly improved quality 
of life vs usual care at weeks 6 and 10. 
 
Both acupressure arms significantly reduced persistent 
fatigue compared with usual care, but only relaxing acupressure had significant effects on sleep quality and 
quality of life. Relaxing acupressure offers a possible low-cost option for managing symptoms. 
 
3.2 Study 2: Acupressure Modulates Sleepiness in the Classroom 15 
We conducted a single-blind randomized crossover study to determine whether self-administered 
acupressure has a significant effect on sleepiness in a population of healthy student participants in a 
prolonged lecture situation. Our study utilized 2 active acupressure treatments with hypothesized opposing 
effects, a relaxation treatment and a stimulation treatment, in a crossover design in which all participants 
received both treatments on different days.  The study population consisted of thirty-nine subjects enrolled at 
the University of Michigan School of Public Health course on clinical research design and statistical analysis. 
Methods:  Acupressure regimens promoting mental stimulation or relaxation were utilized in a 
crossover design with subjects randomized to either Sequence I (day 1 stimulation – day 2 relaxation – day 3 
relaxation) or Sequence II (day 1 relaxation – day 2 stimulation – day 3 stimulation).  Each regimen was taught 
to all study participants by 2 members of the class who were previously trained in acupressure.  Each regimen 
Figure 1. Effect of Two Types of Acupressure on 
Fatigue (Grey area represents normal fatigue levels <4 
on BFI) 

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consisted of a 15-minute self-administered session of acupressure at either 5 stimulatory or 5 relaxation 
points (3 minutes each).  The stimulatory point formula consisted of Si Shen Chong and bilateral – Large 
Intestine 4 (LI 4), Stomach 36 (St 36), Kidney 1 (K 1), and Urinary Bladder 10 (UB 10).  All points were 
stimulated using either the thumb or forefingers to massage in both clockwise and counterclockwise 
directions.  The primary outcome was the difference between afternoon and morning scores on the Stanford 
Sleepiness Scale (SSS) (afternoon score – morning score).16 The SSS was administered 2 hours prior to and 3 
hours after each acupressure regimen.  The 3 hour endpoint was chosen because this was the end of the class 
period where students were most likely to be fatigued.  Data were analyzed using the PROC MIXED procedure 
of SAS (version 8.2). This model incorporated the fixed effects of sequence (I or II), period (day 1, 2, or 3), 
treatment (relaxation or stimulation), and other covariates, as well as the random effects of subject within 
sequence. 
Results:  A mixed model regression analysis using the 
change in SSS as the dependent variable was performed and 
the following variables were retained from the model: 
treatment (p=0.019), day (p=0.004), AM caffeine (p=0.083), 
hours of overnight sleep (p=0.042), and AM upsetting event 
(p=0.071).  No significant carry over effects between days or 
treatments were detected.  The least squares means for the 
stimulation and relaxation acupressure treatments were 
0.570 and 1.127, respectively, with a significant difference in 
change in alertness scores between the 2 acupressure 
treatments.  The mean difference between morning and 
afternoon SSS scores are presented by treatment, sequence, 
and day in Figure 2 above.  Participants in the relaxation 
acupressure group took more naps (p=0.048) during day 1.  Stimulating acupressure yielded a 0.56-point 
greater difference in score on the SSS, corresponding to less fatigue, compared to the relaxing acupressure 
treatment (p = 0.019). Day of study (p = 0.004) and hours of overnight sleep (p = 0.042) also significantly 
affected the change in SSS scores. Incorporating participants' beliefs as to which treatment they received did 
not significantly alter the observed treatment effect. 
4.0 METHODS 
We propose to perform a randomized, single-blind parallel clinical trial.  This will be parallel design with four 
arms (relaxing acupressure plus usual care, stimulating acupressure plus usual care, sham acupressure plus 
usual care and usual care alone) for persistent fatigue in SLE. The study will be approximately 12 weeks in 
duration: Screening (up to 30 days in duration) consists of a phone call evaluation for study eligibility; 
Treatment (active treatment phase; 6 weeks in duration) will consist of random assignment to self-
administered acupressure regiment plus usual care or usual care only daily for 6 weeks (outcomes will include 
fatigue, sleep, QOL, pain); and Post-treatment follow-up (4 weeks in duration) to evaluate the persistence of 
effects following 4 weeks of no treatment. We will allow up to +/- 2 weeks difference for study visits and the 
interim phone call in order to accommodate schedules.  
 
4.1 Participants and Recruitment 
Patients will be recruited from multiple University of Michigan Rheumatology Clinics including the Brighton 
Health Center and the Taubman Clinics at the University of Michigan Hospital. Both General Rheumatology 
and Lupus Specialty Clinics will be available for recruitment.  Participants in other studies who have granted 
permission to be contacted about other research protocols (eg, MILES program or the Michigan Lupus Cohort), 

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will also be recruited. Lastly, we will recruit from the UMHealthResearch.org website and from the 
surrounding community through the use of fliers.  
 
4.2 Eligibility Criteria. 
4.2.1 Participant Characterization 
Eligible participants will be patients with SLE, classified according to the 1997 American College of 
Rheumatology (ACR) criteria, attending General Rheumatology and Lupus Specialty Clinics at the University of 
Michigan.  Participants will undergo a full clinical assessment including collection of core measures such as 
disease damage (SLAQ), disease activity (SELENA SLEDAI), organ involvement, disease duration, medication 
use, serological status and co-morbidities. Furthermore, information of factors which may be associated with 
the reporting of fatigue will be collected. Eligible participants that are not a part of the U of M health system 
will be determined by completing a connective tissue disease screening questionnaire (CSQ), if scoring positive 
on the CSQ these participants will be asked to complete a medical records release form. Once the study team 
receives the medical records they will conduct a medical record review to ensure the ACR criteria for SLE has 
been met.  Additional eligibility criteria are listed in Table 2.0. During screening, identification of an untreated 
mood disorder or suicidal ideations will exclude the participant from the study. The study team will provide a 
list of resources for those with an untreated mood disorder and will follow study protocol for dealing with 
severe depression and suicidal ideations.  
Table 2.0 Eligibility Criteria 
Inclusion Criteria 
Exclusion Criteria 
✓ Women aged 18 years and older 
✓ Report chronic (>3months) clinically 
relevant fatigue, defined as a score of ≥4 
on the Brief Fatigue Inventory (BFI) 
✓ Have inactive disease, defined as SELENA 
SLEDAI ≤ 4, AND/OR no addition or 
increase in dose of corticosteroids, 
immunosuppressive agents, or 
antimalarial medications or hospitalization 
in the last 30 days 
✓ Have no commonly recognized medical 
explanations for fatigue (a history of 
cancer in the previous 5 years –except for 
certain low risk cancer, unstable thyroid 
disease, moderate to severe chronic 
kidney disease, moderate to severe 
anemia) 
✓ Baseline glucocorticoid dose equivalent of 
≤10mg prednisone. 
✓ No other planned intervention for fatigue 
other than current stable medication 
regimen 
 Pregnant or breast feeding 
 Have a diagnosis of untreated mood disorder, e.g., 
bipolar or major depressive disorder  
 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 
 Acupuncture or acupressure receipt in past year 
 
 
 

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4.3 Randomization and Stratification.  
Our randomization scheme will be created by our study statistician. Eligible patients will be randomized into 
one of four groups: once daily relaxing acupressure, once daily stimulating acupressure, once daily sham 
acupressure or usual care in a 1:1:1:1 ratio for a total of 72 participants with 18 randomized into each group.  
4.4 Blinding.  
The three acupressure formulas (relaxing, stimulating and sham) will be labeled acupressure set “A”, set “B”, 
and set “C”.  Acupressure educators, outcome assessors, study participants, and study investigators (who will 
not interact with any of the study participants) will be blinded as to acupressure allocation. Only after data 
analysis is completed will the randomization code be unblinded.  Those randomized to usual care will know 
that they are not receiving acupressure. 
4.5 Intervention Methods.  
We will teach participants to perform acupressure on themselves, i.e., self-administered acupressure. The 
participants will be taught by acupressure educators who are study staff, and who will be trained by the study 
co-PI Richard Harris, a professional acupuncture practitioner.  Training will include basic philosophy of TCM 
and acupressure, demonstration of acupressure points (relaxing, stimulating or sham points).  He will 
designate the three sets of points as set “A”, set “B”, or set “C” so educators will be blinded as to which sets of 
points are the true versus the sham treatment. He will also ask the educators to demonstrate the correct 
location, pressure and stimulation techniques.   
4.5.1 Testing Fidelity of the Intervention in Acupressure Educators 
Dr. Harris will test the acupressure educators after their first two participants and thereafter once every three 
months. He will also ask them to identify each acupoint for both interventions, apply the correct amount of 
pressure and stimulation on a point on himself; and ask them how long to stimulate each point, and how often 
points should be stimulated. Incorrect answers will be addressed and corrected.  Further, acupressure 
educators can request additional clarification and instruction at any time. Acupressure educators achieved a 
92% fidelity score in our previous study.17 
4.5.2 Teaching Participants the Acupoints 
From our previous study18 participants can be taught to perform their acupoints within 15 minutes.  
Acupressure educators will meet with each participant separately and demonstrate the location of each 
acupoint on themselves and on the participants. Participants will be given an illustration of acupoints along 
with a written description of where the points are located.  At the end of the session participants will be 
tested to determine their acupressure fidelity by demonstrating the location of all their acupoints to the 
educator and appropriate adjustments will be made.  Acupressure educators also demonstrate on the 
participant the appropriate level of pressure to apply and the correct motion.  Participants are asked to 
stimulate points on the educator until it is determined that they are using the correct pressure.  Participants 
may return at any time to be retrained or ask clarifying questions.   

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4.5.3 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 3.0). Each of the 9 
acupoints will be stimulated for 1 minute per point giving 
a total treatment time of 9 minutes daily. The relaxing 
acupoints are:  
▪ Point 1: Yin tang (Unilaterally) 
▪ Point 2: Anmian (EX17) (Bilaterally) 
▪ Point 3: Heart 7 (HT7) (Bilaterally) 
▪ Point 4: Spleen 6 (SP6) (Bilaterally) 
▪ Point 5: Liver 3 (LV3) (Bilaterally) 
 
4.5.3.1 Justification for the Choice of Relaxing Acupressure Points. The “True Acupressure” points were chosen 
based on a TCM theory for treating insomnia, that these specific acupoints are commonly used for insomnia in 
clinical trials,19  that previous studies using these 5 specific acupressure points found better results than other 
commonly used acupressure points for inducing sleepiness18 15, and mechanistic studies indicating effects on 
sleep for the 4 of the 5 acupoints: HT-7; SP-6; LV-3; and anmian, which have demonstrated effects on sleep-
related neurotransmitter systems and HPA axis activity in basic, human and animal studies.20-30 
4.5.4 Stimulating Acupressure 
Stimulating acupoints were chosen to increase daytime activity. There are 6 
acupoints with 4 of the acupoints performed on both the left and the right 
sides of the body giving a total of 10 points to stimulate.  
Each of the 10 acupoints will be stimulated for 1 minute per 
point giving a total treatment time of 10 minutes done once 
daily.  The acupoints are:  
▪ Point1: Si Shen Chong (Unilaterally) 
▪ Point2: Conception Vessel 6 (CV6) 
▪ Point 3: Large Intestine 4 (LI4) (Bilaterally) 
▪ Point 4: Stomach 36 (ST36) (Bilaterally) 
▪ Point 5: Spleen 6 (SP6) (Bilaterally) 
▪ Point 6: Kidney 3 (K3) (Bilaterally)  
 
4.5.4.1 Justification for the Choice of Stimulating Acupressure Points Acupoints were chosen by consensus of 4 
acupressure practitioners and based on a previous study design in students with sleep disturbances as well as 
TCM theory for treating insomnia and fatigue.15,31 Practitioners had all been in practice for at least 2 years 
actively seeing patients.  They also had been trained as and received one of more of the following degrees; a 
Naturopathic Doctorate (ND), masters in TCM or Oriental Medicine and a license of acupuncture (L.Ac.) or a 
diploma in acupuncture (Dipl. Ac.).  Practitioners were asked to choose a set of relaxing and stimulating 
acupressure points based on a Western diagnosis of fatigue that could be reasonably reached by participants, 
Figure 3.0 Relaxing 
Acupressure 
Figure 4.0 Stimulating 
Acupressure 

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i.e., not the middle of the back, and not so many points that it would take an excessive amount of time to 
complete a treatment. 
 
 
4.5.5 Sham Acupressure 
Sham acupoints were chosen by Dr. Harris in locations where no 
known acupoints exists. There are 5 acupoints with 4 of the 
acupoints being performed bilaterally (Figure 5.0). None of these 
points are on meridians nor are they near actual points (at least 
one inch away from meridians).  They were chosen to be in the 
same general body quadrant as the true points. Each of the 9 
acupoints will be stimulated for 1 minute per point giving a total 
treatment time of 9 minutes daily. The sham acupoints are:  
▪ Pressure Point #1 (Unilaterally) 
▪ Pressure Point #2 (Bilaterally)  
▪ Pressure Point #3 (Bilaterally) 
▪ Pressure Point #4 (Bilaterally)  
▪ Pressure Point #5 (Bilaterally) 
4.5.6 Usual Care (UC) 
Participants will be asked to continue following their healthcare providers’ instruction for chronic SLE 
management.  We anticipate that most women will be treated per the American College of Rheumatology 
clinical guidelines. Participants will be asked to continue any current treatment and not to start or stop 
treatments including acupuncture/acupressure over the course of the study. All treatments for pain will be 
recorded. 
 
4.6 Study Schedule and Contacts 
  
SCREENING 
TREATMENT PHASE 
FOLLOW-UP 
  
-2 to 0  
(+/- 2 
weeks) 
0 
(+/- 2 weeks) 
1-6  
2  
(+/- 2 weeks) 
6 
(+/- 2 weeks) 
10 
(+/- 2 weeks) 
Participant 
Interaction 
#0 
Participant 
Interaction #1    
Baseline 
Daily           
(Days 1 to 42) 
Participant 
Interaction #2 
Phone Call 
Participant 
Interaction #3  
Post-Treatment 
Participant 
Interaction #4        
Follow-up Call/Visit 
Informed Consent 
 
x 
 
 
 
 
Comorbidities  
x 
 
 
 
 
 
Medication and Health History  
 
x 
 
 
 
 
Sociodemographics 
x 
 
 
 
 
 
Concomitant Medications 
 
x 
 
 
x 
x 
Lupus Activity (SLAQ)1 
x 
x 
 
 
x 
x 
BFI1 
x 
x 
 
x 
x 
x 
CSQ1 
x 
 
 
 
 
 
ARPHI1 
x 
 
 
 
 
 
PHQ9 1 
x 
 
 
 
 
 
Promis Fatigue 8 Item 
 
x 
 
 
x 
x 
RAND SF-361 
 
x 
 
 
x 
x 
PSQI1 
 
x 
 
 
x 
x 
Week
Activity 
Figure 5.0 Sham 
Acupressure 
Figure 5.0 Sham Acupressure 

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IPAQ 
 
x 
 
 
 
x 
GAD71 
 
x 
 
 
x 
x 
PANAS1 
 
x 
 
 
x 
x 
SWLS1 
 
x 
 
 
x 
x 
Fibromyalgia Survey Criteria 
 
x 
 
 
x 
x 
Perform Acupressure 
 
 
x 
 
x 
 
Assess Treatment Fidelity  
 
x 
 
 
x 
 
Assess Blinding 
 
 
 
 
x 
 
Adverse Events 
 
 
 
x 
x 
x 
Adherence to Acupressure 
 
 
x 
x 
x 
 
BPI1 
 
x 
 
 
x 
x 
Logbook 
 
 
x 
 
 
 
1. SLAQ = Systemic Lupus Activity Questionnaire; CSQ – Connective Tissue Screening Questionnaire; ARPHI –Authorization for Protected 
Health Information; BFI = Brief Fatigue Inventory; PHQ9 = Patient Health Questionnaire 9-Item; PSQI = Pittsburgh Sleep Quality Index; IPAQ= 
International Physical Activity Questionnaire; GAD7 = Generalized Anxiety Disorder 7-Item; PANAS = Positive and Negative Affect Schedule; 
SWLS = Satisfaction With Life Scale; BPI = Brief Pain Inventory. 
4.7 Study Visits 
4.7.1 Screening- Participant Interaction #0 (to determine eligibility) 
A screening phone call will be made to evaluate participant interest and eligibility including, comorbidities and 
ability to maintain a stable lifestyle over the course of the study. Sociodemographic and participant contact 
information will be collected. Fatigue will be assessed using the Brief Fatigue Inventory (BFI) and baseline 
depression and lupus disease activity status with the Patient Health Questionnaire 9 (PHQ-9) and the Systemic 
Lupus Activity Questionnaire (SLAQ). If a potential participant is not a part of the U of M health system they 
will complete the Connective Tissue Screening Questionnaire (CSQ) and will be sent an Authorization for 
Release of Protected Health Information form to complete and give to their health care provider. 
4.7.2 Randomization/Baseline- Participant Interaction #1 (Week 0, +/- 2 weeks) 
Written informed consent will be obtained at the beginning of the study visit. Medication and health history, 
concomitant medications, lupus disease activity and urine pregnancy test results will be collected if applicable.  
Participants will complete BFI, SLAQ, PROMIS Fatigue Short Form 8 (PROMIS Fatigue 8), RAND SF-36, Pittsburg 
Sleep Quality Index (PSQI), the Brief Pain Inventory (BPI), Generalized Anxiety Disorder 7 (GAD7), The 
Satisfaction With Life Scale (SWLS), Fibromyalgia Survey Criteria (FM Survey Criteria), International Physical 
Activity Questionnaire (IPAQ) and The Positive and Negative Affect Schedule (PANAS).  Participants will be 
instructed in how to perform their acupressure and told to start their acupressure on the following day. 
Participants will complete the Acupressure Fidelity test after the acupressure instruction has been completed. 
A study logbook will be dispensed, to document conduct of acupressure and the time of day. The post-
treatment visit will be scheduled for exactly six weeks from the start day and the follow-up visit for four weeks 
post termination of treatment.  
4.7.3 Interim phone call- Participant Interaction #2 (within 2 weeks, +/- 2 weeks) 
A phone call by study team will be conducted to assess adherence, AEs, BFI or to otherwise answer questions. 
 
4.7.4 Post-Treatment- Participant Interaction #3 (Week 6, +/- 2 weeks) 
Participants return to study site or we will conduct the interaction via BlueJeans or Skype.  BFI, SLAQ, PROMIS 
Fatigue 8, RAND SF-36, PSQI, BPI, GAD7, SWLS, FM Survey Criteria, and PANAS will be conducted.  Any adverse 
events or change in medication will be collected.  Treatment fidelity and blinding will be assessed; study 

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logbooks will be collected and participants will be asked to stop performing acupressure. If participants choose 
to conduct the visit using BlueJeans or Skype they will email or mail their logbooks in and pressure will be 
assessed by observing nail blanching as an indicator of correct pressure. 
 
4.7.5 Follow-up- Participant Interaction #4(4-weeks Post Acupressure; Week 10, +/- 2 weeks) 
Participants return to study site or we will conduct the interaction via BlueJeans or Skype. BFI, SLAQ, PROMIS 
Fatigue 8, RAND SF-36, PSQI, BPI, GAD7, SWLS, FM Survey Criteria, IPAQ and PANAS will be administered. Any 
adverse events will be collected. All participants will have the option of being taught what study investigators 
consider to be the most effective acupressure technique.  
4.8 Assessment Measures.  
4.81. Disease Activity 
Systemic Lupus Activity Questionnaire (SLAQ):32 is a self-administered tool developed for screening and 
epidemiologic studies; it is not intended for clinical management or in place of physical examination.  The 
SLAQ is based on items from a physician-scored activity index (SLAM) that are suitable for self-report.  It 
includes 24 symptoms questions and a single numerical rating scale asking the patient to rate their disease 
activity over the past three months, based on their most active day during that time.  While the SLAQ 
correlates well with physician tools, as with any measure that does not include laboratory measures, it will not 
detect abnormalities in laboratory findings among asymptomatic patients. 
4.8.2 Fatigue (primary measure) 
Brief Fatigue Inventory (BFI) consists of 9 items that are rated on a 0-10 rating scale where 0 represents “no 
fatigue or does not interfere” and 10 refers to “bad fatigue or completely interferes with activity/work.” The 
BFI has been validated in disease groups including rheumatologic populations.33 
4.8.3 Fatigue (secondary measure) 
The PROMIS Fatigue-Short Form 834,35 consists of 8 items that assess the impact and experience of fatigue in 
the past week. It uses a 5-point Likert-like scale with response options that range from “Not at all” to “Very 
much.” A raw score is calculated by summing scores across items then a conversion table is used to calculate 
T-scores with higher scores indicating greater fatigue. 
4.8.4 Health-Related Quality of Life 
The Rand SF-36 is a reliable and valid self-report questionnaire consisting of 36 items aggregated to score 8 
subscales related to physical and mental health.36   Subscales include Physical Functioning, Role Physical, 
Bodily Pain, General Health, Vitality, Social Function, Role Emotional and Mental Health.  The subscale scores 
are normalized for a mean of 50 with a standard deviation of 10 where higher scores indicate better health.36 
4.8.5 Pain 
The Brief Pain Inventory (BPI) is a 15-item self-report measure that has been validated for use in a wide variety 
of pain states.37  The BPI assesses for the presence of pain, pain intensity (i.e., worst, least, average, current) 
and functional interference from pain.  Broad validation of this measure in the context of assessing chronic 
pain in FM has been reviewed.38 

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4.8.6 Sleep 
Pittsburgh Sleep Quality Index (PSQI) is a widely used, valid and reliable measure of global sleep quality and 
sleep-related symptoms.39 The 19-items yield 7 component-scores that reflect common sleep problems such 
as subjective sleep quality, sleep disturbance and use of sleep medication. The components are summed to 
yield a global score (0 to 21) with poorer sleep quality associated with a higher score. 
4.8.7 Depression 
Patient Health Questionnaire 9-item (PHQ-9): The PHQ-9 is a 9-item multipurpose instrument that has utility 
for screening, diagnosing, monitoring, and measuring the severity of depression. Diagnostic validity has been 
assessed in studies of primary care and obstetrical clinics.   Scores ≥10 have a sensitivity of 88% and a 
specificity of 88% for major depression. Scores of 5, 10, 15, and 20 have been associated with “mild” 
“moderate”, “moderately severe,” and “severe” classifications of depression.40 
4.8.8 Anxiety 
Generalized Anxiety Disorder 7-item (GAD-7). The GAD-7 is a 7-item measure of anxiety. It has good reliability, 
criterion, construct, and factorial validity. It has a sensitivity of 89% and specificity of 82% for generalized 
anxiety disorder. It can be completed in several minutes and administered longitudinally.41 
4.8.9 Subjective Well-Being Scores 
Theory and research suggest that subjective well-being has at least three components: positive affective 
appraisal, negative affective appraisal, and life satisfaction.42,43 Composite scores for well-being will be 
calculated using scores obtained on the measures below. For each case, negative affect will be subtracted 
from positive affect and life satisfaction score will be added to that for a single global well-being score. Well-
being scores derived in this manner have been shown to be sensitive to change.43 
Well-Being – Affect:  Positive and Negative Affect Schedule (PANAS). The PANAS consists of two mood 
scales with 10-items each rated on a 5-point scale for assessing positive (e.g., inspired, strong) and 
negative affect (e.g., guilty, scared).44 Each scale has a range of 10-50 with higher scores indicating 
greater levels of affect. Both scales are internally consistent, uncorrelated, and stable over a 2-month 
time period; good convergent and discriminant validity have been demonstrated.44,45 
Well-Being – Life Satisfaction: Satisfaction with Life Scale (SWLS). The SWLS is a global measure of life 
satisfaction consisting of 5 items rated on a 7-point scale.46 The SWLS is a reliable and valid measure of 
life satisfaction showing large correlations with reports by family/friends of the person's life 
satisfaction, number of memories of satisfying experiences and other similar scales.42,46,47 
 
4.8.10 Fibromyalgia Survey Criteria 
The regional distribution of pain can help differentiate pain due to peripheral damage or inflammation (e.g., a 
few discrete regions) vs that seen in centrally-mediated syndromes such as fibromyalgia.  A modified version 
of the Wolfe Regional Pain Scale48 will be used that queries for the existence of pain in 19 bodily regions, using 
a checklist allowing for efficient scoring, along with the Wolfe Symptom Inventory (SI); a "fibromyalgianess" 
score can thus be calculated.  The presence or absence of comorbid fibromyalgia (thought to occur in at least 
~20% of SLE patients) is the largest predictor of pain, fatigue, and function in SLE49; across various rheumatic 

12 
 
diseases, SI scores are associated with greater severity of disease (including mortality) and sociodemographic 
disadvantage.50  
4.8.11 Physical Activity 
The International Physical Activity Questionnaire (IPAQ) assesses self-reported physical activity at 0 and 10 
weeks via a validated 7-day recall measure in which time and frequency spent performing activities of 
different intensities are recorded and tallied51,52. 
4.8.12 Connective Tissue Screening Questionnaire (CSQ) 
The Connective Tissue Screening Questionnaire (CSQ) is a validated self-report tool used to help identify 
connective tissue diseases (CTD) including SLE.53 The CSQ is reproducible, sensitive, and “moderately specific 
instrument for screening subjects with potential” CTD and is used as a first step in identifying subjects with 
SLE. 53  
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 
(http://med.umich.edu/irbmed/ae_orio/ae_report_standard.htm). 
 
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 
Serious - within 7 days  
   

13 
 
during a study visit,  bruising at the site 
of acupressure treatment) 
 
Non-Serious - with scheduled 
continuation review 
Death while on study  
With scheduled continuation review 
Loss of job or insurability due to breach 
or revelation of research records or 
participation. 
Within 7 days of notification 
Non-Reportable Events 
• Pregnancy, or birth-related complications  
• 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  
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 

14 
 
• 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 
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 

15 
 
• 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.  Participants will 
be asked to refrain from starting or stopping any new medications or supplements for the entire duration of 
the study. 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 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 will be terminated for an individual when a participant completes the full study, as defined as 
completing the week 10 visit (follow-up 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. 
7.2.2 Lost to follow-up 

16 
 
Several 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. 
7.2.3 New illness or Medication 
Participants, who are diagnosed with a new chronic illness, start a new prescribed chronic medication (taking 
medication continuously for longer than 10 days) or have an increase in medication dose during the study 
period, will be withdrawn from the study and replaced by another participant.  Participants who experience an 
acute illness (less than 2 weeks) e.g., a cold or receive acute medications will have these documented but will 
remain in the study.  
7.2.4 Death 
Participants who die while on study will be replaced by another new patient.  
8.0 DATA MANAGEMENT 
8.1 Case Report Form Set 
The CRF, a set of forms for each participant, provides a record of data generated according to protocol.  These 
forms are to be completed on an ongoing basis during the study.  The research chart is the source of 
verification of data.  During the study, CRFs will be monitored for completeness, accuracy, legibility and 
attention to detail.  The CRFs will be retained for review.   
8.2 Data Entry, Data Management and Quality Control 
Hard copies of the data are kept in folders in the project coordinators’ office, where it will be available for the 
project coordinators to evaluate whenever overall protocol assessment is wanted or needed.  The coded list of 
participants on the study is maintained in a locked cabinet by the PIs.  Confidentiality will be maintained and 
information kept on each participant will be made available only to the project coordinator and identified 
investigators. 
8.3 Additional Reporting Requirements 
8.3.1 Protocol revisions and amendments 
• The IRBMED must be notified of proposed protocol amendments to assess impact on trial 
safety and management of regulatory submission. 
• A full copy of the amended protocol must be submitted to the IRBMED for review and approval 
prior to initiating the amended protocol. 
• The revised or amended protocol document must be accompanied by a cover sheet detailing 
the protocol changes, rationale for change, impact on other areas of the protocol, and specific 
reference to the changed protocol sections. 
• The protocol shall be clearly marked with the protocol version number or amendment number 
• All protocol amendments must be approved by the IRBMED prior to activation. 
9.0 STATISTICAL METHODS 

17 
 
Baseline sociodemographic and clinical characteristics will be analyzed by treatment groups, using means and 
standard deviations (SD), counts and percentages as appropriate. Comparisons between groups on baseline 
characteristics will be tested using an independent sample t-test for continuous measures or Pearson’s Chi-
square, for categorical variables.  In all analyses, a p-value of ≤ 0.05 was considered statistically significant. All 
tests will be two-sided. 
9.1 Primary and Secondary Aims 
To investigate the change through time both within and between groups for fatigue (BFI), we will use linear 
mixed models (LMM). An advantage of LMM is that it acts as essentially an intent-to-treat (ITT) analysis as it 
uses all available data at each time point.  For each LMM, a random subject intercept will be included to 
account for subject clustering; visit, group, and the interaction term (visit by group), will also be included as 
fixed effects. The models for BFI will be controlled for the fixed effects of any baseline variable such as age or 
lupus disease activity that is significantly different at baseline. Normality of the residuals derived from the 
LMM will be assessed using the Shapiro–Wilk test and q-q plots.  For non-normal results a Box-Cox 
transformation will be utilized. The same methods will be employed to investigate secondary outcomes of 
interest pain (BPI severity sub-scale), sleep (PSQI global score) and quality of life (RAND SF-36). 
9.1.2 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 patient 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. 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. The multiple imputation 
method uses the assumption that the missing-ness conforms to a missing at random pattern which allows 
missing-ness in a variable X to depend on other covariates but does not allow it to depend on X itself. All 
analyses will be carried out in the statistical software SAS version 9.2.  
9.2 Sample Size Justification  
Power is computed via simulation using LMM with a group, week, group by week interaction, and a random 
subject effect. Mean BFI values at week 6 are taken to be 4, 3, 2 at the end-treatment point for usual care, 
stimulating acupressure, and relaxing acupressure. The between-subject variance is assumed to be 4 at all 
time-points; whereas the variance of the random subject component was also 4 with an intra-class correlation 
of 0.5.31  For this configuration, power for detecting group differences is > 0.80 and power for detecting a 
significant week by group interaction is 0.62 with a sample size of 15 per treatment arm and 5% level of 

18 
 
significance.  We assume a 16 to 17% drop-out rate based on previous studies and thus plan to recruit 18 per 
arm to ensure that 15 participants complete the entire 10-weeks of the study. 
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 to the IRB for approval prior to implementation. 
10.2 Informed Consent 
All potential candidates for the study will be given a 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, he/she will be 
asked to sign the informed consent document. 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.  

19 
 
 
10.3.2 Study-specific DSMP 
The PI will review study progress weekly with study staff, and problems with or pertaining to study subjects 
will be communicated immediately.  The entire research team will meet monthly to review progress and any 
problems encountered. The PI will be notified when an AE occurs and will determine the attribution and 
relatedness of each adverse event. All AE must be given to the PI within 48 hours if involving a death or life 
threatening event, or within one week, if serious (not-life threatening/death) or non-serious. 
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.  
 
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