Fibromyalgia Activity Study With Transcutaneous Electrical Nerve Stimulation
Phase: NA
Conditions: Fibromyalgia
Sponsor: Kathleen Sluka

1 
 
 
 
STUDY 
PROTOCOL 
August 2011 
Revised: 
 October 2011 
 June 2012 
July 2013 
June 2014 
September 2014 
December 2014 
July 2015 
September 2015 
February 2016 
 
 

2 
 
 
Study Rationale 
 
The American College of Rheumatology (ACR) classifies fibromyalgia as a clinical syndrome 
defined by chronic widespread muscular pain and tenderness [65]. The cause of fibromyalgia is 
unknown, but people with fibromyalgia show sensitization of central nervous system pain 
pathways, measured by lower pain thresholds, enhanced temporal summation, and reduced 
diffuse noxious inhibitory controls (DNIC)[27;53;56]. Pain associated with fibromyalgia interferes 
with daily function, work, and social activities resulting in a decreased quality of life [3]. In addition 
people with fibromyalgia have a significant amount fatigue and a fear of movement [8]. These two 
associated factors further contribute to the reduction in physical function and quality of life (see 
Figure 1). Thus, one of the main treatments for patients with fibromyalgia must focus on pain relief 
to allow the person to function more independently both at home and at work. The reduction in pain 
would reduce fatigue and fear of movement that ultimately results in increased physical function 
and quality of life. Transcutaneous electrical nerve stimulation (TENS) is a modality used by health 
professionals that delivers electrical stimulation through the skin for pain control. Basic science 
studies, from the PIs laboratory, show that TENS activates descending inhibitory pathways from 
the midbrain and brainstem to inhibit excitability of nociceptive neurons in the spinal cord [10; 25; 
34; 51]. Thus, is the ideal intervention to control pain in people with fibromyalgia since it reduces 
central excitability and increases inhibition. 
 
Although TENS is effective for several pain conditions such as osteoarthritis, chronic 
musculoskeletal pain, and postoperative pain [6;22;41], its effectiveness in treatment of people with 
fibromyalgia is virtually unknown. Furthermore, there is a general thought among clinicians that 
since fibromyalgia pain is widespread, TENS would be ineffective in this population. To initially test 
if TENS was effective in decreasing the pain associated with fibromyalgia we performed a 
preliminary study examining the effectiveness of a single treatment with high frequency TENS. The 
group receiving active TENS showed a reduction in resting pain and pain during movement 
compared with placebo. There were also improvements in measures of function in the active TENS 
group with a greater increase in distance walked in the 6 minute walk test (by 221 feet) as 
compared to a decrease in distance (-100 feet) for placebo. TENS also increased pressure pain 
thresholds (by 20%) during DNIC when compared to virtually no change for placebo TENS (1%). 
Thus, TENS may decrease pain associated with fibromyalgia by increasing central inhibition and 
decreasing central excitability. This decrease in pain is expected to increase function and improve 
quality of life. 
 
 

3 
 
 
Figure 1: Conceptual Model for TENS effects 
 
Hypothesis 
 
We hypothesize that application of Transcutaneous Electrical Nerve Stimulation (TENS) to patients 
with fibromyalgia will reduce resting and movement-related pain and reduce central excitability by 
restoring diffuse noxious inhibitory controls (DNIC), and that this decrease in pain and/or central 
excitability will reduce fatigue and fear of movement, thereby improving function and quality of life 
(see Figure 1). 
 
Aims 
 
Aim #1: The primary aim of the study is to test the effectiveness of repeated TENS use on  
movement-related pain in people with fibromyalgia with random assignment to three treatments:  
standard care, placebo TENS and active  
Aim #2: A secondary aim will test if pain reduction by TENs results in a concomitant decrease in 
fatigue and fear of movement, and an increase in function and quality of life.  Outcome measures 
will include physical function by directly assessing daily activity with an accelerometer, as well as 
performing specific functional tasks 
Aim #3: To determine if active TENS alters pain processing in women with fibromyalgia and if 
improvement in clinical symptoms correlates with normalization of pain processing physiology. We 
will evaluate change in these physiologic parameters in responders versus non-responders as 
assessed clinically. 
 
Aim #4: To determine if PROMIS is a useful instrument for assessing outcome for fibromyalgia by 
comparing to the revised version of the fibromyalgia impact questionnaire (FIQ-R).  
 
 
Healthy Control Aims: 
 
Aims: 
 
    Physically active women with fibromyalgia will have a similar phenotype (pain thresholds and     
    conditioned pain modulation) and cytokine profile to physical active women without pain;   
    conversely sedentary women with fibromyalgia will have a similar phenotype and cytokine release  
    profile to sedentary women without pain.  
 
 
   Aim #5 will perform quantitative sensory testing to profile excitability and central inhibition in  
   individuals with fibromyalgia and healthy controls; both sedentary and physically active individuals  
   will be recruited in each cohort.  
 
 
   Aim #6 will examine for cytokine release profiles in immune cells (monocytes) from the sedentary   
   and physically active individuals with and without fibromyalgia. 
 
 

4 
 
 
Study Synopsis 
 
 
Protocol Title 
Fibromyalgia Activity Study with TENS (Transcutaneous Electrical Nerve 
Stimulation) 
Protocol 
Number 
 
Name of 
Sponsor 
Funded by NIH NIAMS 
Performed at University of Iowa, Vanderbilt University 
Investigational 
Product 
TENS (Transcutaneous Electrical Nerve Stimulation) 
TENS is a non-pharmacological agent which delivers electrical stimulation by 
a battery operated device via electrodes placed on the skin.  TENS is 
considered to be a safe, inexpensive and non-invasive modality used to treat 
a variety of acute and chronic pain conditions.   
Phase of 
Development 
Phase II Clinical Trial 
Purpose of 
Study 
The primary aim of the study is to test the effect of the long-term use of TENS 
on movement-related pain as measured by a numeric rating scale (NRS) 
during six minute walk test (6MWT) in women with fibromyalgia with random 
assignment to three treatments: standard care (No TENS), placebo TENS and 
active TENS. 
Indication 
Women with Fibromyalgia, ages 18-70 
Number of 
Centers 
The study will be conducted at 2 study sites:  University of Iowa and the 
Vanderbilt University 
Study Duration 
5 years 
Objectives 
Aim #1: The primary aim of the study is to test the effectiveness of 
repeated TENS use on  movement-related pain in people with fibromyalgia 
with random assignment to three treatments:  standard care, placebo TENS 
and active  
Aim #2: A secondary aim will test if pain reduction by TENs results in a 
concomitant decrease in fatigue and fear of movement, and an increase in 
function and quality of life.  Outcome measures will include physical 
function by directly assessing daily activity with an accelerometer, as well 
as performing specific functional tasks  
Aim #3: To determine if active TENS alters pain processing in women with 
fibromyalgia and if improvement in clinical symptoms correlates with 
normalization of pain processing physiology. We will evaluate change in 
these physiologic parameters in responders versus non-responders as 
assessed clinically. 
Aim #4: To determine if PROMIS is a useful instrument for assessing 
outcome for fibromyalgia by comparing to the revised version of the 
fibromyalgia impact questionnaire (FIQ-R).  
 
Study Design 
This is a phase II randomized, double-blind, placebo controlled multi-center 
clinical trial. The initial phase of the study will randomly allocate subjects to 
receive active TENS, placebo TENS or standard care (No TENS). After 
participating in the 1 month random assignment, all subjects will receive active 
TENS for 1 month. The subjects will make 4 visits to the clinic. 

5 
 
 
Subject 
Population 
Females with fibromyalgia. 
Inclusion 
Criteria 
 Participants will be 18 to 70 years of age 
 Women may participate in the study 
 Diagnosis of Fibromyalgia by 1990 ACR criteria 
 History of cervical or lumbar pain with fibromyalgia (this is expected in 
all patients since axial pain is required for diagnosis) 
 Current stable treatment regimen for the last 4 weeks and projected 
stable treatment regimen for the next 2 months.  
 English speaking 
Exclusion 
Criteria 
 Current or history of cardiovascular, pulmonary, neurological, 
endocrine, or renal disease that would preclude the involvement in the 
study. 
 TENS use in the last 5 years 
 Pacemaker 
 Uncontrolled blood pressure or diabetes 
 Neuropathic pain condition 
 Systemic autoimmune disorder (Lupus, PMR, RA, Psoriatic arthritis) 
 Spinal fusion – cervical or lumbar 
 Metal implants in the spine 
 Severe skin allergy to adhesive  
 Allergy to nickel 
 Pain less than 4 
 Pregnancy 
 Epilepsy 
 Change in or new drug or treatment program within the last month or in 
the next 2months, i.e. must have a stable treatment plan 
 Unstable medical or psychiatric condition which in the opinion of the 
investigator could compromise the subject’s welfare or confound the 
study results 
Planned 
Sample Size 
Final sample size of 264 subjects divided into 88 subjects per group. We will 
recruit 316 subjects based on a 20% projected attrition. 
Randomization 
Patients will be randomly allocated on the second visit after a re-assessment 
of eligibility. We will use a permuted block schedule, stratified by site. The 
randomization schedule will be implemented using SAS v9.2 PROC PLAN, 
creating blocks of size 6 for each of the strata factors. 
Study  Device 
Dosage and 
Administration 
FDA Summary of Empi Select TENS Unit: TENS is a non-pharmacological 
agent which delivers electrical stimulation by a battery operated device via 
electrodes placed on the skin. TENS is considered to be a safe, inexpensive 
and non-invasive modality used to treat a variety of acute and chronic pain 
conditions. 
 
510(k) Summary for 300 PV Complete Electrotherapy Systems 
1. Manufacturer 
Empi 
599 Cardigan Road 
St. Paul, Minnesota 55126-4099 

6 
 
Contact Person: John Bum 
Telephone: (651) 415-9000 
Date Prepared: April 2, 2002 
2. Device Name 
Proprietary Name: 300 PV Complete Electrotherapy System 
Common/Usual Name: Electrical Muscle and Nerve Stimulator 
Classification Names: Powered Muscle Stimulator, Transcutaneous 
Nerve Stimulator, interferential Current Stimulator, External 
Neuromuscular Functional Stimulator 
3.  TENS Parameters: Active and Placebo Units 
 TENS Frequency – 10 to100 Hz, SMP mode  
 TENS Pulse Width -  200 µs  
 TENS Intensity -  Maximal tolerable intensity 
 Duration: 2 h per day during activity.  The 2 h may be broken into 
smaller segments of time with a minimum of 30 minutes. 
 Administration - Daily 
 TENS Location:  TENS electrode on the skin will be a 4 x 7 butterfly 
electrode to the cervical and lumbar region.   
 Placebo TENS Unit - The placebo TENS unit will deliver current for 45s 
ramping to 0 in the last 15s.  
Study 
Summary 
This is a phase II randomized, double-blind, placebo controlled multi-center 
clinical trial involving a device, TENS, to assess the efficacy of TENS on pain 
with movement over a 1 month period in subjects with fibromyalgia.  After 
participating in the 1 month random assignment, all subjects will receive active 
TENS for 1 month. Subjects will receive a phone call weekly from the study 
coordinator regarding progress. 
 Screening:  Telephone screen for eligibility for the study  
 Assessor – performs baseline and all testing except TENS allocation 
and TENS home instruction.  The assessor is blinded to TENS 
treatment. 
 TENS Allocator – performs TENS allocation, home instructions and 
questions regarding TENS 
Demographic 
and Outcome 
Measures 
 Consent 
 Health History/Demographic 
 Vital Signs 
 Confirmation of ACR 1990 Criteria for FM/Tender Point Exam  
 2010 ACR Criteria 
 NRS Rest Pain, Rest Fatigue, Movement Pain, Movement Fatigue 
 BPI 
 PROMIS 
 FIQR 
 SF-36 
 MAF 
 TSK 
 IPAQ 
 PSQI 
 PSEQ 
 PCS 

7 
 
 Global Impression of Change 
 Accelerometry (Actigraph 
 6MWT 
 STS 
 FR 
 PPT 
 CPM 
 TENS 
Criteria for 
Evaluation 
Primary Efficacy Endpoint: 
 Pain with movement (NRS) during 6MWT 
Secondary Efficacy Endpoints: 
 Health History/Demographics 
 Vital Signs 
 Confirmation of ACR 1990 Criteria for FM/Tender Point Exam  
 2010 ACR Criteria 
 NRS Rest Pain, Rest Fatigue, Movement Pain, Movement Fatigue 
 BPI 
 PROMIS 
 FIQR 
 SF-36 
 MAF 
 TSK 
 IPAQ 
 PSQI 
 PSEQ 
 PCS 
 Global Impression of Change 
 Accelerometry 
 6MWT 
 STS 
 FR 
 PPT 
 CPM 
 TENS 
 Blinding 
Statistical 
Methods 
 Continuous variables will be summarized with descriptive statistics (n, 
mean, standard deviation, standard error, median, first and third 
quartiles, and minimum and maximum).  
 Categorical variables will be described with counts and percentages. 
The endpoints (VAS, BPI, PPT,CPM, and 6MWT, STS, FR and 
accelerometry measures) will be treated as continuous variables as 
well as scores from questionnaires (FIQR, SF-36, MAF, and TSK, 
PROMIS).  
 Changes from initial measurement to one month after randomization 
will be calculated for each of these endpoints. Changes in outcomes 
and percent changes in outcomes will be treated as continuous 
variables and will be summarized with descriptive statistics. Outcomes 
will be summarized by visit, as change from initial measurement, and percent 

8 
 
change from initial measurement.  Continuous endpoints may also be 
categorized into discrete variables when appropriate. Shift tables may 
be utilized to investigate shifts in outcome categories from baseline to 
one month after randomization. SAS v9.2 or higher will be used for all 
analyses and a significance level of 0.05 will be used for all statistical tests. In 
the case that endpoints are found to be non-normal, appropriate 
transformations will be employed and non-parametric tests may be used 
  
Statistical 
Methods Aim 
#1- #4 
Aim #1: The primary endpoint of Aim #1 is the change (visit 3- visit 2) in pain 
scores during movement. In order to evaluate the effectiveness of long-term 
use of TENS (Aim 1), the primary analysis will be the comparison of change in 
pain (with movement for those randomized to either active TENS, placebo 
TENS, or standard of care). The comparison of the change (visit 3 – visit 2) in 
pain for the three groups will be made using linear mixed model analysis for 
repeated measures with treatment group, time (visit2 and visit3), and 
treatment group*time interaction as the fixed effects. The test for the treatment 
group*time interaction effect corresponds to the test comparing mean change 
among the groups. Post-hoc pairwise comparison of mean change between 
groups will performed by test of mean contrasts estimated from the fitted 
linear mixed model with p-values adjusted using Bonferonni’s method to 
account for the number of tests performed (i.e. 3 tests for all pairwise 
comparisons). It is expected that the randomization will lessen the need for 
covariate-adjusted analyses. However, in the event that adjusted analyses are 
necessary, a secondary comparison of the change in endpoints for the three 
groups will be made by expanding the linear mixed model to include 
covariates. Potential confounders include age, race, ethnicity, educational 
attainment, marital status, TENS dose/intensity, change in opioid status, 
medication intake and use of rescue medications. 
 
 
While every effort will be made to follow-up with patients, preliminary data 
suggests that approximately 10% of the patients will not return for follow-up. 
The ITT analysis will be performed using all available data for all randomized 
participants. In the presence of missing data, under the assumption of missing 
at random (MAR), linear mixed model analysis which can handle incompletely 
observed subjects and uses a likelihood estimation method will provide correct 
likelihoods and lead to valid estimates (ref1).  However, since the data under 
analysis cannot distinguish if data is MAR or it it is missing not at random 
(MNAR), sensitivity analysis will also be performed using pattern mixture 
models. Multiple imputations will be used for sensitivity analysis by imputing 
from a non-random pattern mixture model (ref2).  
Furthermore, based on previous work, it is expected that approximately 5% of 
subjects randomized to active TENS may not receive a full dose of active 
TENS because they did not achieve the adequate intensity dose. In the 
primary ITT analysis, these patients will be included as randomized. However, 
as an additional analysis a modified ITT (mITT) analysis will be conducted. 
This analysis will utilize an ITT principle in terms of randomization but will be 
limited to those who achieved at least one adequate intensity dose.  
 
(ref1)  Molenberghs G. and Kenward MG (2007) Missing Data in Clinical 
Studies. John Wiley & Sons Ltd, West Sussex, England. 

9 
 
 
(ref2)  Carpenter J and Kenward MG (2013) Multiple Imputation and its 
Application. John Wiley & Sons Ltd, West Sussex, England. 
 
Aim #2: The primary endpoint of Aim #2 is the change (visit 3 – visit 1) in fear 
of movement scores. Secondary endpoints for this aim include changes in 
function, fatigue, resting pain, function, use of rescue analgesic medications, 
and quality of life. Additionally physical function measures will be determined 
using accelerometer data and data obtained during a course of specific 
functional tasks. Rescue analgesic medications will be recorded as number 
and dose of medications, indicators for increases or decreases in frequency or 
dose, and any utilization. Comparisons between the randomized groups for 
these outcomes will be performed as described in Aim 1. Additional analyses, 
using the change in fatigue, fear of movement, function, quality of life and 
resting pain measures as dependent variables in linear regression models, 
associations between these outcomes and changes in pain values will be 
investigated.  
 
Aim #3: The primary endpoints of Aim #3 are the change (visit 3 – visit 2) in 
PPT and DNIC/CPM for those who complete one month of active TENS. After 
one month of active TENS, participants will be clinically evaluated and 
classified as responders or non-responders using recently published criteria 
for fibromyalgia subjects [7]. Comparisons of these physiologic parameters will 
be made in responders versus non-responders as described in Aim 1. Since 
responder status is not randomized, it is expected that that the linear mixed 
model will also include covariates such as change in opioid status, medication 
intake, and TENS use. Multiple variable logistic regression (with associated 
odds ratio estimates and ROC curves) will also be utilized to investigate 
factors related to being a responder or not.  
 
Aim #4: The primary endpoints of Aim #4 are the FIQR and SF-36 prior to 
randomization. PROMIS modules (also obtained prior to randomization) for 
depression, fatigue, pain behavior, pain interference, physical function, 
satisfaction with social roles, and satisfaction with discretionary social 
activities will be summarized and compared to validated FM instruments 
(FIQR and SF-36).  Scores from each of the PROMIS modules will be 
compared to corresponding FIQR and SF-36 domains (see Table 1) by 
estimating Pearson correlation coefficients and testing for nonzero correlation. 
Multiple linear regression may also be used to investigate this relationship 
while controlling for potential confounding variables. Finally, FIQR, PROMIS, 
and SF-36 will be obtained at four different time points during this study (pre-
treatment, randomized phase, and non-randomized active TENS). Summaries 
will include values at pre-treatment, changes from pre-treatment and percent 
changes. In addition to changes observed in the randomized phase, linear 
mixed models may also be utilized where treatment status (pre-treatment, 
randomized treatment, and non-randomized active TENS) is treated as a time-
varying covariate to estimate the impact of changes in treatment status on 
these outcomes.   
 
As an exploratory analysis, further investigation of changes in pain, responder 

10 
 
status, and relationships between endpoints will be conducted for data 
collected during the non-randomized phase and will include those with an 
additional month of active TENS (originally randomized to active TENS) as 
well as those with a single month of active TENS (originally randomized to 
placebo TENS and no treatment control). Finally, exploratory examinations of 
the relationships between changes in pain, sensory, and quality of life 
measures may utilize multivariate methods (e.g. partial least squares and 
principal component analysis) and classification and regression trees. 
 
 
Safety 
Measures 
 
 
Physical Exam 
Vital Signs 
Clinical signs and symptoms 
Adverse Event analysis 
Increased pain with testing follow-up:  Participants who experience an 
increase in testing will be contacted the day after testing about the status of 
the increase in pain (Added 12/2014) 
Safety analysis 
 
 
Schedule of Visits and Evaluations.  
 
The subjects will attend four visits for the FAST study.  Each session will last 2-4hours for testing.  
Testing measures will include health history/demographics questionnaire, pain measures, 
multidimensional questionnaires, functional assessments and quantitative sensory testing.  Home 
activities will include accelerometry, medication logs, TENS unit. 
 
A general outline of measures and visits is given in Table 1, the order of testing is given in Table 2, 
and a list of equipment, forms, and measures is given in Table 3.  
 
Subjects are considered enrolled after consent and meeting eligibility criteria on Visit 1. They will be 
randomized to treatment on Visit 2 and they will be re-reviewed for eligibility criteria.  
 
It is expected that Visit 1 will take no more than 1h, Visit 2 will take 2-3 hours, Visit 3 will take 3-4 
hours, and Visit 4 will take 2-3 hours.  
 
Table 1:  Schedule of tests and measures 
Measurement 
Instrument 
Visit 
(V)  
Construct and 
General 
Information 
 
Reliability 
Validity-
Cronbach’s-
Alpha (α) 
Reference 
Pain and Fatigue 
NRS 
V1 
V2 
V3 
V4 
Self report of pain 
and fatigue 
intensity on 0-10 
vertical scale; 
ICC=0.71-
0.99 
0.71-0.78 
51, 52 

11 
 
Pain and fatigue 
intensity at rest 
and movement 
Multidimensional 
Questionnaires 
BPI 
 
V2 
V3 
V4 
Pain intensity and 
pain interference 
with activities; 
15 questions 
r=0.57 
 
0.85-0.88 
53 
HH/Demo 
V1 
Demographic; 
Review of past 
medical history 
NA 
NA 
NA 
FIQR 
V1 
V2 
V3 
V4 
Disease specific 
questionnaire;21 
questions 
r=0.88 
0.69-0.88 
54 
GIC 
V3 
V4 
Perception of 
change 
r=0.87 
ICC=0.9 
55 
IPAQ  
V2 
V3 
V4 
Self report  of 
activity level 
among adults; 
Short form 
Spearman’
s ρ = 0.80 
Spearman’s 
ρ = 0.78 
56 
MAF  
V2 
V3 
V4 
Fatigue 
questionnaire; 16 
questions; 4 
dimensions of 
fatigue 
0.93 
r=0.62- 0.84 
57 
PCS 
V2 
V3 
V4 
Pain 
Catastrophizing 
scale; 13 items 
pain 
Total 
Cronbach’s  
alpha 0.95 
0.42 
58 
PSEQ 
V2 
V3 
V4 
Pain Self 
Efficacy; 10 
items; confidence 
in performing 
activities with 
chronic pain 
r=0.73 
0.67 - 0.84 
59 
PROMIS 
V2 
V3 
V4 
Quality of Life; 
NIH patient 
reported outcome 
measurement 
system 
NA 
NA 
NA 
PSQI 
V2 
V3 
V4 
Pittsburgh Sleep 
quality index; 19 
items sleep 
disturbance and 
sleep habits 
0.80 
R= 0.07 to 
0.80 
60 
SF-36 
V2 
V3 
V4 
General Quality 
of Life; 36 items 
r=0.85 
0.97 
61 
TSK 
V2 
V3 
V4 
Fear of pain with 
movement; 17 
items 
r=0.64-.99 
r=0.70-0.81 
62-64 
Function 
6MWT 
V2 
V3 
V4 
Function; Walk 
test for 
endurance 
ICC[2,1]=0.
95-0.97 
r=-/63-0.79 
26 
FTSTS 
V2 
V3 
V4 
Function; 
Measure of leg 
strength 
ICC 1 
1>0.95 
r=0.59-0.88 
LBP r=0.46-
0.76 Control 
65, 66 

12 
 
 
 
 
Table 3:  
List of 
equipment, 
form per 
test and 
measure 
 
 
FR 
V2 
V3 
V4 
Function; 
Measure of 
balance 
r=0.95 
r=0.7 
27, 67 
 
Actigraph: 
Actisleep+ 
Week 
Before 
V2 
V3 
V4 
Function:  Activity 
and Sleep 
Accelerometer 
worn on wrist 
NA 
NA 
NA 
Quantitative 
Sensory Testing 
PPT 
V2 
V3 
V4 
Deep mechanical 
hyperalgesia; 
Pressure Pain 
Thresholds 
r=0.79-0.94 
ICC = 0.85-
0.99 
Test-
retest=0.70
-0.94 
Significant 
differences 
between 
healthy and 
RA subjects 
(p<0.05) 
68-72 
CPM 
(DNIC) 
V2 
V3 
V4 
Central Inhibition 
Face validity as the same test in 
animals activates descending inhibitory 
pathways 

13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

14 
 
Table 3:  List of equipment, form per test and measure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Area 
Form 
Visit 
Equipment: 
Clipboards, Pens, Computer/Form 
 
 
 
 
 
Screening Log 
Pre Visit 
Computer/Form 
Surveys 
Consent 
1 
Computer/Form 
 
Health History/Demographic 
1 
Computer/Form 
 
Diagnostic Confirmation 
1 
Computer/Form 
 
Eligibility Confirmation 
1, 2 
Computer/Form 
 
FIQR 
1,2,3,4 
Computer/Form 
 
MAF 
2,3,4 
Computer/Form 
 
TSK 
2,3,4 
Computer/Form 
 
Medication 
1,2,3,4 
Computer/Form 
 
SF-36 
2,3,4 
Computer/Form 
 
PROMIS 
 2,3,4 
Computer/Form 
 
IPAQ 
2 
Computer/Form 
 
PSQLI 
2 
Computer/Form 
 
PSEQ 
2 
Computer/Form 
 
PCS 
2 
Computer/Form 
 
Blinding Question  
Researcher and Subject 
3 
Computer/Form 
 
Global Impression of Change 
3, 4 
Computer/Form 
Pain 
NRS 
1,2,3,4 Previsit 2,3,4 
Computer/Form 
 
BPI 
2,3,4 
Computer/Form 
Fatigue 
NRS, BORG CR10 
1,2,3,4 
Computer/Form 
QST 
PPT (C,L, Ant Tib) 
2,3,4 
Algometer, Form, Marker, Alcohol swab 
 
CPM 
2,3,4 
Bucket, thermometer, Water, Ice, Towel, 
Form 
Function 
6MWT 
2,3,4 
Timer, Form, Distance Measurement,  
Pulse Oximeter, BP Cuff, 
Sphygmometer 
 
FTSTS 
2,3,4 
Timer, Form, Chair with arms 
 
Functional Reach 
2, 3,4 
Yardstick, Form 
 
Accelerometry 
1,3,4 
Actigraph, home  tracking, initialization 
& instruction sheet 
TENS 
TENS Trial 
1 
TENS, Electrodes, Batteries, Lead 
 
TENS Treatment at Visit 
2,3,4 
TENS, Lead wires, Electrodes, 
Batteries, Participant Handbook 
Handbooks 
Participant 
Assessor 
1,2,3,4 
Handbook 

15 
 
 
 
Data Analysis Plan 
Aim 
Visit 
(V) 
Measures 
Statistical Plan 
General 
Considerations 
V1 
V2 
V3 
V4 
All outcome 
measures: Pain NRS 
rest and movement, 
Fatigue NRS rest 
and movement, BPI, 
PPT, 6MWT, FTSTS, 
FR, CPM, 
Accelerometry 
FIQR, SF-36, TSK, 
GIC, PROMIS, MAF,  
 
Descriptive Statistics 
 
n, mean, standard deviation, standard 
error, median, first and third quartiles, 
minimum, maximum 
 
Outcomes summarized by visit 
 
Changes from visit to baseline; shift tables 
may be used to investigate shifts from visit 
1 to visit 3 
 
 
 
If variables not normally distributed, , non-
parametric tests will be used 
Aim #1 
 
 
 
 
 
V3-V2 
 
 
 
 
 
Pain NRS with 
movement (6MWT 
and FTSTS) for the 
treatment groups: 
active TENS, 
placebo TENS or 
standard care 
 
 
 
 
Linear mixed model analysis (LMM) for 
repeated measures with treatment group, 
time (V3-V2) and treatment group*time 
interaction as fixed effects.  
 
Post-hoc pair wise comparison of mean 
change between all three treatment groups  
 
p-values adjusted using Bonferroni method 
to account for the number of tests 
 
 
Potential confounders include BMI, age, 
race, ethnicity, educational attainment, 
marital status, TENS dose/intensity, 
change in opioid status, medication intake, 
rescue medications; If there are 
differences between potential 
confounders, we will include covariates 
Aim #1  
 
Intention to 
Treat (ITT) 
 
V3-V2 
 
 
 
 
 
Pain NRS with 
movement (6MWT 
and FTSTS) for the 
treatment groups: 
active TENS, 
placebo TENS or 
standard care 
 
 
 
 
Intention to treat (ITT) analyses using all 
available data for all randomized 
participants will be used 
 
If there are missing data, missing at 
random (MAR) LMM will be used. 
Sensitivity analysis will be performed using 
pattern mixture models since data cannot 
be determined if it is MAR or missing not 
at random (MNAR). Multiple imputation will 
be used for sensitivity analysis by imputing 
from a non-random pattern mixture model 
 
Modified ITT (mITT) will be conducted to 
account for subjects who did not achieve 
adequate dose (based on previous work, 
5% of subjects randomized to active TENS 

16 
 
are expected to not achieve adequate 
dose).  This will be limited to those who 
achieved at least one adequate intensity 
dose 73, 74. 
Aim #2 
V3-V2 
Primary: Fear of 
movement scores.  
Secondary:  changes 
in function, fatigue, 
resting pain, use of 
rescue medications, 
accelerometry and 
quality of life 
questionnaires. 
 
Comparison between the randomized 
groups will be performed as described in 
Aim #1.   
 
Additional analysis using the change in 
fatigue, fear of movement, function, resting 
pain measures and quality of life as 
dependent variable in linear regression 
models, associations between these 
outcomes and changes in pain values will 
be investigated. 
Aim #3 
V3-V2 
Change in PPT, 
CPM for those who 
complete one month 
of active TENS. 
 
 
Classification of participants who complete 
one month of active TENS as responders 
or non-responders using published criteria 
50 
 
Linear regression models will assess for 
factors that predict responders and non-
responders to treatment using data 
obtained prior to the intervention.  
Aim #4 
V2 
V3 
V4 
Prior to 
randomization: 
FIQR and SF-36.   
PROMIS modules for 
comparison to FIQR 
and SF-36. 
 
Pearson correlation and testing for 
nonzero correlation between PROMIS 
modules ( and corresponding domains of 
the FIQR and SF-36. 
 
Multiple linear regression may also be 
sued to investigate this relationship while 
controlling for potential confounding 
variables. 
 
FIQR, PROMIS and SF-36 will be obtained 
at 3 time points  and summarizes as 
values, changes from pre-treatment and 
percent changes, changes observed in the 
randomized phase.  Time points are (1) 
V2: pre-treatment; (2) V3 randomized 
phase and (3) V4 non-randomized active 
TENS. 
 
Linear  models may be used where 
treatment status ((1) V2: pre-treatment; (2) 
V3: randomized phase and (3) V4: non-
randomized active TENS) is treated as a 
time-varying covariate to estimate the 
impact of changes in treatment status. 
Exploratory 
Analysis 
 
Changes in pain 
Responder status 
Relationships 
between endpoints 
Relationships 
between changes in 
pain, sensory and 
quality of life 
measures 
 
Further investigation during non-
randomized phase, two months of active 
TENS (initially randomized to active TENS 
and those with a single month of active 
TENS (initially randomized to placebo 
TENS or standard care) 
 
Multivariate methods (e.g. partial least 
squares and principal component analysis 
and classification and regression trees. 

17 
 
 
 
 
 
Table 
3:  List 
of 
equip
ment, 
form 
per 
test 
and 
measu
re 
 
 
Area 
Form 
Visit 
Equipment: 
Clipboards, Pens, Computer/Form 
 
 
 
 
 
Screening Log 
Pre Visit 
Computer/Form 
Surveys 
Consent 
1 
Computer/Form 
 
Health History/Demographic 
1 
Computer/Form 
 
Diagnostic Confirmation 
1 
Computer/Form 
 
Eligibility Confirmation 
1, 2 
Computer/Form 
 
FIQR 
1,2,3,4 
Computer/Form 
 
MAF 
2,3,4 
Computer/Form 
 
TSK 
2,3,4 
Computer/Form 
 
Medication 
1,2,3,4 
Computer/Form 
 
SF-36 
2,3,4 
Computer/Form 
 
PROMIS 
 2,3,4 
Computer/Form 
 
IPAQ 
2 
Computer/Form 
 
PSQLI 
2 
Computer/Form 
 
PSEQ 
2 
Computer/Form 
 
PCS 
2 
Computer/Form 
 
Blinding Question  
Researcher and Subject 
3 
Computer/Form 
 
Global Impression of Change 
3, 4 
Computer/Form 
Pain 
NRS 
1,2,3,4 Previsit 2,3,4 
Computer/Form 
 
BPI 
2,3,4 
Computer/Form 
Fatigue 
NRS, BORG CR10 
1,2,3,4 
Computer/Form 
QST 
PPT (C,L, Ant Tib) 
2,3,4 
Algometer, Form, Marker, Alcohol swab 
 
CPM 
2,3,4 
Bucket, thermometer, Water, Ice, Towel, 
Form 
Function 
6MWT 
2,3,4 
Timer, Form, Distance Measurement,  
Pulse Oximeter, BP Cuff, 
Sphygmometer 
 
FTSTS 
2,3,4 
Timer, Form, Chair with arms 
 
Functional Reach 
2, 3,4 
Yardstick, Form 
 
Accelerometry 
1,3,4 
Actigraph, home  tracking, initialization 
& instruction sheet 
TENS 
TENS Trial 
1 
TENS, Electrodes, Batteries, Lead 
 
TENS Treatment at Visit 
2,3,4 
TENS, Lead wires, Electrodes, 
Batteries, Participant Handbook 
Handbooks 
Participant 
Assessor 
1,2,3,4 
Handbook