Optimization of Spinal Manipulation Therapy (SMT) Protocols
Phase: PHASE2
Conditions: Low Back Pain
Sponsor: University of Utah

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Clinical Intervention Study 
Protocol 
 

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TABLE OF CONTENTS 
Page 
Clinical Intervention Study Protocol .......................................................................................... 1 
TABLE OF CONTENTS ............................................................................................................. 2 
Optimization of Spinal Manipulative Therapy (SMT) Protocols .................................... 5 
TOOL REVISION HISTORY: ................................................................................................... 6 
STUDY TEAM ROSTER........................................................................................................... 7 
PARTICIPATING STUDY SITES ............................................................................................ 7 
PRÉCIS ....................................................................................................................................... 8 
1. STUDY OBJECTIVES ............................................................................................................. 9 
1.1 
Primary Objectives .......................................................................................................... 9 
1.2 
Secondary Objectives ...................................................................................................... 9 
2. BACKGROUND AND RATIONALE .................................................................................... 9 
2.1 
Background on Condition, Disease, or Other Primary Study Focus .............................. 9 
2.2 
Study Rationale ............................................................................................................... 9 
3. STUDY DESIGN ..................................................................................................................... 10 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .............................................. 11 
4.1 
Inclusion Criteria .......................................................................................................... 11 
4.2 
Exclusion Criteria ......................................................................................................... 11 
4.3 
Study Enrollment Procedures ....................................................................................... 11 
5. STUDY INTERVENTIONS .................................................................................................. 12 
5.1 
Interventions, Administration, and Duration ................................................................ 12 
 5.1.1  Spinal Manipulative Therapy………………………………………………………... 13 
5.1.2  Multifidus Exercises…………………………………………………………………. 13 
5.1.3  Mobilizing Exercises………………………………………………………………… 14 
5.2 
Concomitant Interventions ............................................................................................ 13 
5.2.1 
Allowed Interventions ............................................................................................... 13 
5.2.2   Prohibited Interventions ............................................................................................. 14 
5.4 
Adherence Assessment ................................................................................................. 14 
6. STUDY PROCEDURES ........................................................................................................ 14 
6.1 
Schedule of Evaluations ................................................................................................ 14 

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6.2 
Description of Evaluations ............................................................................................ 15 
6.2.1 
Screening Evaluation ................................................................................................ 15 
6.2.2 
Enrollment, Baseline, and/or Randomization ........................................................... 15 
6.2.3 
Blinding..................................................................................................................... 17 
6.2.4 
Followup Visits ......................................................................................................... 17 
6.2.5 
Completion/Final Evaluation .................................................................................... 18 
7. SAFETY ASSESSMENTS ..................................................................................................... 18 
7.1 
Specification of Safety Parameters ............................................................................... 18 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 18 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 19 
7.4 
Reporting Procedures .................................................................................................... 19 
7.5 
Followup for Adverse Events ....................................................................................... 19 
7.6 
Safety Monitoring ......................................................................................................... 20 
8. INTERVENTION DISCONTINUATION............................................................................ 20 
9. STATISTICAL CONSIDERATIONS .................................................................................. 21 
9.1 
General Design Issues ................................................................................................... 21 
9.2 
Sample Size and Randomization .................................................................................. 22 
9.2.1  Treatment Assignment Procedures ............................................................................. 22 
9.3  
Definition of Populations .............................................................................................. 23 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 23 
9.5 
Outcomes ...................................................................................................................... 23 
9.5.1 
Primary and Secondary Outcomes ............................................................................ 23 
9.6 
Data Analyses ............................................................................................................... 24 
10. DATA COLLECTION AND QUALITY ASSURANCE .................................................. 24 
10.1 
Data Collection Forms .................................................................................................. 26 
10.2 
Data Management ......................................................................................................... 26 
10.3 
Quality Assurance ......................................................................................................... 26 
10.3.1 
Training ................................................................................................................. 26 
10.3.2 
Monitoring .......................................................................................................... 268 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................... 27 
11.1 
Institutional Review Board (IRB) Review .................................................................... 27 
11.2 
Informed Consent Forms .............................................................................................. 27 

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11.3 
Participant Confidentiality ............................................................................................ 27 
11.4 
Study Discontinuation ................................................................................................... 28 
APPENDICES 
 
 
I. Informed Consent Forms 
II. Case Report Forms (adverse events, serious adverse events, informed consent 
checklist, study completion form, randomization and enrollment, study visit checklist, 
eligibility screening checklist (from REDcap)) 
 

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Optimization of Spinal Manipulative Therapy 
(SMT) Protocols 
 
Study Chairman or Principal Investigator:   
Julie M. Fritz, PhD, PT, FAPTA, Distinguished Professor, Department of 
Physical Therapy, University of Utah 
 
Supported By: 
The National Center for Complementary and Integrative Health  
Grant Number:  1UH3AT009293-01 
Clinicaltrials.gov Identifier: NCT02868034 
 

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Tool Revision History: 
Version Number: 1.0 
Version Date: September 26, 2016 
Summary of Revisions Made: Original Version 
 
Version Number 1.1 
Version Date: November 9, 2016 
Summary of Revisions Made:  Section 10.3.1 – added clarification that 4 clinicians will be trained to 
provide study-related treatments at the University of Utah, 2 clinicians 
at the University of Alberta 
 
Version Number 1.2 
Version Date:  January 3, 2017 
Summary of Revisions Made:   Section 5.3 – Refined definition of “adherence” for per-protocol analyses 
as requiring 80% attendance at scheduled sessions. Also clarified that 
attendance at <80% of scheduled sessions will be considered a 
protocol deviation. 
Section 6.1 The Schedule of Evaluations Table was updated to specify 
the Oswestry and individual self-report questionnaires at appropriate 
time points. 
Section 6.2.2.1 – changed allowed time between eligibility confirmation 
and enrollment from 72 hours to 1 week as specified in Section 6.2.1 
and the IRB documents. 
Section 6.2.3 - Spelling error was corrected. Clarification of language 
in this section to specify that a research staff member who becomes 
unblinded to a participant’s randomization assignment is disallowed 
from future evaluations of that participant only, and not all future 
participants. 
Section 6.2.2.3 was updated to reflect the randomization procedures 
that have been put in place using the REDCap system. 
Appendix 2 updated to include the Study Visit Checklist 
Version Number 1.3 
Version Date:  July 26, 2017 
Summary of Revisions Made:   Section 6.1 was updated to more precisely reflect the evaluations 
completed at the initial screening and baseline assessments.  
Section 6.2.1 was updated to reflect a recently approved IRB 
amendment. Participants may complete the Oswestry Disability survey 
prior to their baseline visit to screen out those who are ineligible due to 
their Oswestry score, to reduce the burden on potential participants 
and researchers of having a baseline assessment only to find out they 
are ineligible. 
Version Number 1.4 
Version Date:  January 3, 2018 
Summary of Revisions Made:   Section 5.2.1 was updated to correct a typographical error.  
Section 6.1 was updated to clarify when the Oswestry and Global Rating 
of Change surveys, spinal stiffness and multifidus assessments and 
demographics are collected. 
Version Number 1.5 
Version Date May 23 2018 
Summary of Revisions Made: 
Sample Size and Population (page 9), Section 3 and Section 9.2 were 
updated to reflect an increased sample size. 

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STUDY TEAM ROSTER  
 
Dr. Julie Fritz, PhD, PT, FAPTA 
Distinguished Professor 
Department of Physical Therapy 
University of Utah 
520 Wakara Way 
Salt Lake City, UT, 84108 
Ph: 801-581-7505, Fax: 801-585-5629 
Email: julie.fritz@hsc.utah.edu 
Role: PI 
 
Dr. Greg Kawchuk, PhD, DC 
Professor 
Rehabilitation Medicine 
University of Alberta 
Ph: 780-492-6891 
Email: greg.kawchuk@ualberta.ca 
Role: Co-Investigator 
 
 
PARTICIPATING STUDY SITES 
1. University of Utah, Principal Investigator: 
Dr. Julie Fritz, PhD, PT, FAPTA 
520 Wakara Way 
Salt Lake City, UT, 84108 
Ph: 801-581-7505 
Email: julie.fritz@hsc.utah.edu 
 
2. University of Alberta, Principal Investigator: 
Dr. Greg Kawchuk, PhD, DC 
3-44 Corbett Hall 
Edmonton, AB, Canada T6G 2R3 
Ph: 780-492-6891 
Email: greg.kawchuk@ualberta.ca 
Dr. Tom Greene, PhD 
Professor  
Population Health Sciences Department 
University of Utah 
Ph: 801-585-3812 
Email: tom.green@has.utah.edu 
Role: Co-Investigator, Bio-Statistician 
Amy Rogers 
Clinical Research Coordinator 
University of Utah 
Ph: 801-585-5961 
Email:  amy.rogers@hsc.utah.edu 
Role: Study Coordinator 
 
Elizabeth Lane, PT, OCS, CSCS, FAAOMPT 
Research Assistant 
University of Utah 
Ph: 801-585-5961 
Email:  ELIZABETH.LANE@hsc.utah.edu 
Role: Research Assistant 
 
Jason Sharpe, DPT 
Research Assistant 
University of Utah 
Ph: 801-585-5961 
Email:  jason.sharpe@utah.edu 
Role: Research Assistant 
Molly McFadden, MS 
Department of Internal Medicine – 
Epidemiology 
University of Utah 
Ph:  801-585-3812 
Role: Statistician 
 
Doug Santillo, DPT 
Research Assistant 
University of Utah 
Ph: 801-585-5961 
Email:  douglas.santillo@gmail.com 
Role: Research Assistant 

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PRÉCIS  
Study Title  
Optimization of Spinal Manipulative Therapy (SMT) Protocols 
Objectives  
Primary Aims 
I. Identify SMT protocol components and interactions that independently predict SMT 
mechanistic outcomes (spinal stiffness and multifidus activation). We hypothesize that one 
or more combination of components will be identified that optimize improvement in SMT 
mechanisms.   
II. Identify SMT protocol components and interactions that independently predict SMT patient-
centered outcomes (function, pain). We hypothesize that one or more combination of 
components will be identified that optimize improvement in patient-centered outcomes. 
Secondary Aims 
I. Explore the moderating effect of responder status after 2 SMT sessions. We hypothesize 
that responder status after 2 sessions will moderate mechanistic and patient-centered 
outcomes.  
II. Define optimized SMT protocol(s) based on combined results of the primary and 
secondary aims. Optimized protocols will be considered as the combination of 
components that maximize improvement in patient-centered outcomes at 3 months while 
also improving SMT mechanisms to the greatest extent. 
Design and Outcomes   
This subject will recruit adults with non-specific low back pain (LBP). We will provide 2 
sessions of SMT to all subjects. We will then assess responder status and randomize 
subjects stratified by responder status to a treatment group for an additional 3 weeks using 
a factorial design to evaluate different combinations of intervention components (muscle 
activation exercise, spinal mobilizing exercise, additional SMT) that influence pathways 
shown to modulate the effects of SMT. Outcomes will include spinal stiffness and muscle 
activation measures as well as patient-reported outcomes assessed at baseline, and after 
1 week, 4 weeks and 3 months. 
Interventions and Duration  
All subjects will receive 2 sessions of SMT provided in the first week of participation. 
Subjects are then randomly assigned to receive an additional 3 weeks of treatment involving 
different combinations of exercise and/or additional SMT, or to receive no additional 
treatment. The final follow-up is conducted 3 months after enrollment. Therefore the total 
time for a subject to be “on study” is 3 months. 
 
 Outline of research design (LM = lumbar multifidus) 
50% Oswestry 
improvement? 
Treatment Phase I (1 week) 
Session Treatment 
Measures 
1 
SMT 
Indentation/RUSI pre- and 
post-SMT 
2 
SMT  
Indentation/RUSI pre- and 
post-SMT 
3 
none 
Indentation/RUSI and 
Clinical Assessment 
YES  
Responder 
NO 
Non-responder 
R 
Treatment Phase II (3 weeks) 
1 No additional treatment 
2 6 sessions SMT 
3 6 sessions LM activation ex 
4 6 sessions mobilizing ex. 
5 6 session LM activation + mobilizing ex 
6 6 session SMT + mobilizing ex. 
7 6 session SMT + LM activation ex. 
8 6 session SMT + LM activation + mobilizing ex.
 
 

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Sample Size and Population  
We will recruit a total of 316 subjects age 18-60 with non-specific LBP and an Oswestry 
Disability score of at least 20%. Following Phase I treatment, subjects will be randomized in 
equal proportions to one of 8 possible treatment combinations in Phase II. Randomization 
will be stratified by responder status (yes/no) during Phase I.     
 
1. STUDY OBJECTIVES 
1.1 
Primary Objectives 
I. Identify SMT protocol components and interactions that independently predict SMT mechanistic 
outcomes (spinal stiffness and multifidus activation). We hypothesize that one or more 
combination of components will be identified that optimize improvement in SMT mechanisms.   
II. Identify SMT protocol components and interactions that independently predict SMT patient-
centered outcomes (function, pain). We hypothesize that one or more combination of 
components will be identified that optimize improvement in patient-centered outcomes. 
1.2 
Secondary Objectives 
I. Explore the moderating effect of responder status after 2 SMT sessions. We hypothesize that 
responder status after 2 sessions will moderate mechanistic and patient-centered outcomes.  
II. Define optimized SMT protocol(s) based on combined results of the primary and secondary 
aims. Optimized protocols will be considered as the combination of components that maximize 
improvement in patient-centered outcomes at 3 months while also improving SMT mechanisms 
to the greatest extent. 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Low back pain (LBP) is a major public health problem. An estimated 60-80% of individuals will 
experience an episode during their lifetime, and prevalence rates have been increasing in the 
past decade. Considering the prevalence of LBP, it is not surprising that the condition imposes 
significant economic burden on individuals, the healthcare delivery system, and society. Total 
annual direct healthcare costs in the U.S. for LBP were estimated at $90 billion in 1998, with an 
inflation-adjusted rate of 65% over the next 7 years, a rate much higher than overall health care 
costs. LBP is the most common symptom for which complementary and alternative medicine 
(CAM) is sought. In 2007, 18% of adult CAM users in the U.S. were seeking care for LBP, more 
than double the next most common condition. The most common CAM intervention sought by 
those with LBP is spinal manipulative therapy (SMT). Several professions use SMT, although it is 
most often provided by chiropractors. Surveys in the U.S. suggest about half of those with chronic 
LBP have sought chiropractic care, and LBP the reason for at least 40% of chiropractic visits. The 
Institute of Medicine identifies LBP as a top 15 priority condition, calling for the development of 
innovative, evidence-based management strategies. In light of the prevalence of LBP and the 
frequency of SMT use for the condition, optimizing SMT protocols for LBP has important public 
health implications.  
2.2 
Study Rationale 
Successful optimization of SMT treatment requires understanding the mechanisms underlying the 
effects of SMT among patients who are SMT-responders. Past research has identified numerous 
biologic phenomena that accompany SMT without relating these phenomena to the presence or 
absence of clinical benefit. In contrast, our research team has worked for more than 10 years to 

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develop and validate a model explaining the mechanisms that underlie the clinical effects of SMT. 
Specifically, our work supports the common clinical observation that SMT is not a broad-spectrum 
therapy, but one that preferentially benefits some individuals with LBP (SMT-responders) but not 
others (non-responders). This work has culminated in the development of a validated model that 
has identified specific biomechanical signals (changes in spinal stiffness and lumbar multifidus  
muscle activation) that relate to favorable clinical response (improved function). The clinically 
important signals we have identified (stiffness and muscle activation) are modifiable with 
interventions other than SMT; thus SMT protocols may be optimized through the use of co-
interventions that modulate these signals. Our team has also developed safe, valid and reliable 
procedures to measure these signals, and have demonstrated successful application of both SMT 
treatment and signal measurement procedures in clinical populations.  
Our goal in this proposal is to optimize SMT treatment protocols for LBP. Our optimization strategy 
will evaluate SMT combined with other treatments known to modulate the same signals that 
underlie the clinical effects of SMT (spinal stiffness and muscle activation) using both mechanistic 
(stiffness, lumbar multifidus activation) and patient-centered (function and pain) outcomes. We 
have grounded our body of work in this area within the Multiphase Optimization Strategy (MOST) 
framework; which provides an efficient multi-step research strategy for optimizing multi-
component interventions. In this project we will use innovative methodology to efficiently evaluate 
the effects of various individual treatment components towards an overall effect; identifying which 
components are contributing to the target outcomes and which, if any, may be discarded. Results 
of this project will provide optimized SMT protocols that will be ready for application in future 
randomized controlled trials examining the efficacy and effectiveness of SMT.   
3. STUDY DESIGN 
We will use a factorial design examining 3 intervention components (additional SMT, mobilizing 
and multifidus activating exercise) provided in 8 different combinations following provision of 2 
SMT treatment sessions as in our prior work. We will recruit 316 subjects with non-specific LBP 
with the goal of enrolling 280 subjects after all eligibility screening are complete. All subjects will 
receive the 2-session SMT protocol used in our prior studies. At the third session subjects will be 
categorized as SMT responders or non-responders based on our previously-validated threshold 
of 50% improvement on the Oswestry (ODQ). Randomization to subsequent treatment will be 
stratified based on responder status. This will allow us to examine the moderating effects of early 
clinical response. In our prior studies 35%-45% of individuals with LBP are responders to SMT 
after 2 sessions. What is unknown is the persistence of the improvement observed in early 
responders and whether or not persistence can be augmented through additional SMT and/or co-
interventions working on the same causal pathways as SMT. Likewise, it is unknown from our 
prior work if early non-responders can be converted to responders with additional SMT and/or co-
interventions. Therefore, we will randomly assign subjects to receive 6 additional sessions (or no 
additional treatment) provided over 3 weeks with varied combinations of additional SMT and 
exercise co-interventions. We chose 6 additional sessions based on work related to SMT dose-
response reporting only modest difference in clinical outcomes in subjects receiving 9-12 sessions 
relative to 3-6 SMT sessions without co-interventions. Outcomes including assessments of 
  Outline of research design (LM = lumbar multifidus) 
50% Oswestry 
improvement? 
Treatment Phase I (1 week) 
Session Treatment 
Measures 
1 
SMT 
Indentation/RUSI pre- and 
post-SMT 
2 
SMT  
Indentation/RUSI pre- and 
post-SMT 
3 
none 
Indentation/RUSI and 
Clinical Assessment 
YES  
Responder 
NO 
Non-responder 
R 
Treatment Phase II (3 weeks) 
1 No additional treatment 
2 6 sessions SMT 
3 6 sessions LM activation ex 
4 6 sessions mobilizing ex. 
5 6 session LM activation + mobilizing ex 
6 6 session SMT + mobilizing ex. 
7 6 session SMT + LM activation ex. 
8 6 session SMT + LM activation + mobilizing ex.
 
 

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mechanisms and patient-centered outcomes will be examined at baseline and after 1 week (end 
of phase I), 4 weeks (primary outcome - end of phase II), and after 3 months (long-term outcome).  
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
Subjects in this study must satisfy all of the following eligibility criteria: 
I. Pain between the 12th rib and buttocks with or without symptoms into one or both legs, 
which, in the opinion of the examiner, originate from the lumbar region. 
II. Age 18 - 60 years 
III. Oswestry disability score > 20% 
4.2 
Exclusion Criteria 
Any subject meeting any of the following exclusion criteria at baseline will be excluded from 
participation. 
I. No prior surgery to the lumbosacral spine 
II. Not currently pregnant 
III. Not currently receiving mind-body or exercise treatment for LBP from a healthcare provider 
(e.g., chiropractic, physical therapy, massage therapy, etc.) 
IV. No neurogenic signs including any of the following: positive ipsi- or contra-lateral straight 
leg raise test (symptoms reproduced <450); reflex, sensory, or strength deficit in a pattern 
consistent with lumbar nerve root compression 
V. No “red flags” of a potentially serious condition including cauda equina syndrome, major or 
rapidly progressing neurological deficit, fracture, cancer, infection or systemic disease 
4.3 
Study Enrollment Procedures  
Participants will be enrolled at two sites: the University of Utah and University of Alberta. At the 
University of Utah we will work within the University of Utah Health Care (UUHC) family practice 
and physiatry providers to encourage direct referral of interested individuals consulting for LBP 
into the study. We will also develop IRB-approved recruitment materials to be integrated into our 
EPIC electronic health record, allowing providers to print and provide the information to 
potentially-interested individuals. We will also work with the Center for Clinical and Translational 
Science (CCTS) Bioinformatics Core to use the UUHC electronic data warehouse (EDW) to 
identify patients with specific characteristics based on demographic information and ICD-10 
codes. These individuals are informed of the study by mail with information on procedures to opt-
in or out of the study by contacting research personnel. For this project we will identify patients 
with a family practice visit with an ICD-10 code related to non-specific LBP (M54.5, M54.9, 
M51.36) between the ages of 18-60 with no record of surgery in the EDW. We will also recruit 
individuals with LBP who are not seeking care with flyers and ads in the community. 
At the University of Alberta we will recruit from clinics that have been used successfully in the 
past. These include general practice, physical therapy and chiropractic clinics within the main 
campus community. University of Alberta already has IRB-approved recruitment materials that 
have been used in these clinics previously and can be further distributed to potential participants 
through various approved electronic distribution services. We will also work with the various 
professional associations to identify patients with specific characteristics using established 
communication strategies (e.g. patient newsletters and social media postings). As is the case in 
Utah, potential participants informed by these means will contact research personnel directly to 
establish eligibility and will align with ICD-10 code related to non-specific LBP (M54.5, M54.9, 
M51.36) between the ages of 18-60 with no record of surgery.  

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Individuals interested in participation will meet the site study coordinator to insure eligibility. 
Reasons for non-enrollment will be tracked. Eligible subjects choosing to participate will sign an 
informed consent document approved by the University of Utah or Alberta IRB, after which 
baseline examination procedures and completion of all eligibility assessments will be performed 
by a Research Assistant who will remain blinded to the subject’s treatment group assignment 
throughout the study. Following baseline examination, all subjects will begin phase I treatment. 
All assessment and treatment sessions will be conducted at the Patient Wellness Center at the 
University of Utah and in the Rehabilitation Robotics Sandbox at the University of Alberta. 
Treatment will be provided by clinicians licensed to provide SMT (DC or PT) and trained in study-
related procedures.   
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
5.1.1  Spinal Manipulative Therapy 
The same SMT procedure will be used in phases I and II. Our past work has found equivalent 
outcomes regardless of SMT technique, thus we will standardize our technique consistent with 
our past work. This SMT technique has been applied successfully at both performance sites. All 
SMT sessions will begin with a brief assessment followed by SMT. The subject is supine. The 
clinician stands opposite the side to be manipulated and side-bends the subject away from the 
clinician. The side to be manipulated is the side the subject identifies as more painful. If the subject 
cannot identify a more painful side the clinician selects a side. The subject interlocks their fingers 
behind the head. The clinician rotates the subject, and delivers a high-velocity, low-amplitude 
(HVLA) thrust to the anterior superior iliac spine in a posterior/inferior direction. The clinician notes 
if a cavitation (ie, a “pop”) occurred. If it does, SMT treatment is complete. If no cavitation occurs, 
the subject is repositioned and SMT is performed again. If no cavitation occurs on the second 
attempt, the clinician will manipulate the opposite side. A maximum of 2 attempts per side is 
permitted. If no cavitation is noted by that time, SMT treatment is complete. The number of SMT 
attempts will be recorded by the clinician.  Our previous research found no difference in outcome 
between this SMT procedure and a side-posture HVLA technique. We will permit substitution with 
side-posture HVLA if the preferred technique is not possible due to subject preference or comfort. 
In prior research we found the supine and side-posture HVLA techniques well-tolerated with no 
adverse events.  
5.1.2  Multifidus Exercises 
Subjects randomized to receive multifidus exercises will begin with isometric multifidus 
contractions in different positions with clinician feedback and exercises to isometrically co-
contract the multifidus and deep abdominal muscles. These exercises have been shown to be 
effective for activating the multifidus. Subjects will also perform lumbar extensor strengthening 
exercises shown to produce 20%-50% of multifidus maximum voluntary contraction. This dose is 
adequate to enhance multifidus activation, without imposing high loads that may exacerbate LBP. 
Subjects will continue to perform isometric exercises throughout treatment. We have applied 
these exercises in prior research with no adverse events. 
Activity 
Description 
Initial Dose 
     Goals for Progression 
Preferential, isometric 
multifidus activation  
exercises 
1. Isolated multifidus contraction while 
prone, seated, standing 
2. Isolated co-contraction of multifidus and 
deep abdominals in sitting, standing 
5 repetitions, 10 sec. hold with 
normal breathing (each 
exercise)  
progress toward 10 
repetitions, 10 sec. hold, 
perform 2-3x daily 
General lumbar 
extensor and multifidus 
activation exercises  
 
1. Quadruped single arm raises 
10 lifts, 5 sec. hold each arm 
progress towards 20 lifts, add 
arm+leg lift 
2. Side-support exercise 
10 repetitions 5 sec. hold each 
side 
progress towards 20 
repetitions 

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Activity 
Description 
Initial Dose 
     Goals for Progression 
(subjects prescribed no 
more than 2 exercises 
at a time) 
3. Bridging while hook-lying 
10 repetitions, 5 sec. hold 
  progress towards 20 
repetitions 
4. Prone single leg lift 
10 lifts, 5 sec. hold each leg 
progress towards 20 lifts, 
add arm+leg lift 
5.  Prone trunk lift 
10 lifts, 5 sec. hold 
progress towards 20 lifts 
Table.  Multifidus activation exercise protocol
 
5.1.3  Mobilizing Exercises 
Subjects randomized to receive mobilizing exercises during phase II will be instructed in a 
program of repeated movements progressing into end-ranges of spinal flexion and/or extension 
based on principles described by McKenzie, and shown in past studies to reduce spinal stiffness. 
Subjects will be instructed in mid-range exercises and will be further assessed for a directional 
preference. A directional preference is present if movement in a particular direction decreases 
LBP intensity or causes symptoms to centralize towards the midline. Directional preference can 
be determined reliably and if present, matching the direction of mobilizing exercise to the 
directional preference improves outcomes. If a subject has a directional preference he or she will 
be prescribed exercises specifically in that direction along with mid-range exercise.  Otherwise 
the subject will be assigned exercises moving into either flexion or extension based on the 
clinician’s discretion.  Subjects will perform their prescribed exercises following SMT at treatment 
sessions and will be instructed to perform the exercises daily on other days. We have applied 
these exercises in prior research with no adverse events. 
Activity 
Description 
Initial Dose 
    Goals for Progression 
Mid-range spinal 
mobility exercises 
1. Supine pelvic tilts to promote lumbar 
flexion/extension 
2. Quadruped rocking into lumbar 
flexion/extension  
3. Supine to side lying rotational mobilizations 
4. Sitting rotational mobilizations 
5. Flexion/Extension  
10-20 repetitions each 
direction performed daily  
(each exercise) 
Full, pain-free ROM, 
progress to 40 repetitions 
throughout the day 
Exercises specifically 
into  spinal flexion 
 
1. Supine pelvic tilt 
2. Quadruped rocking into lumbar flexion 
3. Double knee-to-chest while supine 
4. Standing flexion 
5. Seated flexion 
6. Self mobilization into flexion 
10-20 repetitions performed 
daily (prescribe 2 exercises) 
Full, pain-free ROM, 
progress to 40 repetitions 
throughout the day 
Exercises specifically 
into  spinal extension 
1. Supine pelvic tilt 
2. Quadruped rocking into lumbar flexion 
3. Supported on elbows while prone 30 sec 
4. Prone press-ups to extended elbows  
5. Prone press-ups to extended elbows with 
exhale  
6. Extension while standing 
7. Extension in standing with self over pressure 
10-20 repetitions performed 
daily (prescribe 2 exercises) 
Full, pain-free ROM, 
progress to 40 repetitions 
throughout the day 
Table. Stiffness exercise protocol
5.2 
Concomitant Interventions  
5.2.1 Allowed Interventions 
Interventions permitted during the study period include use of medication to control LBP 
symptoms (NSAIDs, muscle relaxants, etc.) The use of various medications will be recorded at 
the baseline examination. Visits to health care providers for LBP are allowed during the study 
period (e.g., physician visits) as long as no interventional procedures are received (e.g., spinal 
manipulation, massage, exercise therapy, etc.) 

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5.2.2   Prohibited Interventions 
Prohibited interventions during the study period include any mind-body or other interventional 
procedures including spinal manipulation, massage, exercise therapy, acupuncture, spinal 
injections, surgical procedures, etc. If any prohibited events occur these will be recorded as off-
protocol events. Subjects will continue to participate in study-related treatments and assessments 
unless the off-protocol intervention changes the risk-benefit profile for the subject. 
5.3 
Adherence Assessment  
Treatment adherence will be assessed based on attendance at scheduled treatment sessions 
and compliance with treatment protocols during treatment sessions. Once enrolled, a participant 
will have forms in REDCap for each scheduled treatment session according to the participant’s 
randomized group assignment. Treatment session forms will permit an evaluation of the number 
of scheduled sessions attended by each participant. For sessions that are attended, the treating 
clinician will information on the interventions provided and any reasons for non-adherence to 
protocols. The site study coordinator will monitor the forms at least monthly and discuss instances 
of non-adherence with the clinician. All off-protocol events will be recorded, such as the use of 
use of modalities (heat, cold, ultrasound, etc.), or application of manual therapy or exercise 
procedures not outlined in the protocol. For purposes of the data analysis per-protocol analyses 
we will define “adherence” as occurring when at least 80% of scheduled treatment sessions are 
attended. Attendance at <80% of scheduled sessions will be considered a protocol deviation.  
6. STUDY PROCEDURES  
6.1 
Schedule of Evaluations 
Assessment 
Screening 
Assessment 
(Day -7 - 0) 
Baseline 
Assessment,  
Visit 1 ( Day 0) 
TX Visits 1-2 
(Days 0-7) 
1 Week 
Follow-Up 
(Day 7-10) 
TX Visits 3-8 
(Days 8 – 35) 
4 Week 
Follow-Up  
(Day 29-42) 
3 Month 
Follow-Up  
(Day 83-97) 
Informed Consent Form   
 
X 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical History  
 
X 
 
 
 
 
 
Physical Examination 
 
X 
 
X 
 
X 
X 
Enrollment 
 
X 
 
 
 
 
 
Self-Report Questionnaires 
Oswestry Disability Index 
X* 
X* 
 
X 
 
X 
X 
Numeric Pain Rating 
 
X 
 
X 
 
X 
X 
Psychological Covariates 
(FABQ, PSESF, PCSF) 
 
X 
 
X 
 
X 
X 
Global Rating of Change 
 
 
 
 
 
X 
X 
Spinal Stiffness Assessment 
 
 
X  
X 
 
X 
X 
Multifidus Assessment 
 
 
X 
X 
 
X 
X 
Adverse Events/Side Effects 
 
 
 
X 
 
X 
 
Randomization 
 
 
 
X 
 
 
 
Treatment Session Form  
 
 
X 
 
X 
 
 
*Oswestry is to be administered once between screening and baseline, or twice if needed at clinician discretion or if > 7 days 
has passed since first Oswestry completed. 

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6.2 
Description of Evaluations  
6.2.1 
Screening Evaluation 
Individuals who contact the site Study Coordinator will be provided information about the 
study. The Study Coordinator will confirm that the individual is between age 18-60 and is not 
receiving other interventional or mind-body procedures for their LBP. If the individual is 
interested in learning more about the project a baseline assessment will be scheduled to 
obtain informed consent, insure all eligibility criteria are met and schedule a full assessment 
to begin the study either at that time or within 7 days of the screening evaluation. Before the 
scheduled baseline assessment, the participant may complete the Oswestry Disability survey 
to determine if their score is ≥ 20%. If the Oswestry score is < 20%, the participant will be 
notified that they are ineligible for the study and the assessment cancelled. 
6.2.1.1   Consenting Procedure 
Interested individuals who are scheduled for a baseline assessment will begin the 
assessment by providing written informed consent using a form approved by the site 
institutional review board. The consenting process will be conducted by a research 
assistant who is trained by the Principal Investigator at the site and has completed 
Biomedical Research Training for Human Subjects research through the Collaborative 
Institutional Training Institute (CITI) which includes modules on human subjects research 
ethics and regulations related to informed consent. A copy of the signed informed consent 
document will be retained by the researchers. A single consent form will be used for the 
project. The research assistant consenting the participant will sign an Informed Consent 
Form (ICF) checklist which will be retained by the researchers. 
6.2.1.2  Screening 
Once informed consent is obtained the following screening procedures will be completed 
within 72 hours to insure eligibility: 
 Confirm age on the date of consent is between 18 – 60 years old. 
 Confirm that the participant is not aware that she is pregnant. 
 Confirm that the participant is not currently receiving other interventions for their LBP. 
 Confirm that the participant is experiencing LBP defined as pain between the 12th ribs 
and buttock with or without symptoms that extend into the buttock(s) or leg(s). without 
“red flags” suggesting a possible non-musculoskeletal cause (recent trauma, 
unexplained weight loss, night pain, systemtic illness) 
 Participant completes the Oswestry disability index to insure the score is > 20% 
 Research assistant conducts the physical examination to insure no signs of neurologic 
deficit are present (positive ipsi- or contra-lateral straight leg raise test (symptoms 
reproduced <450); reflex, sensory, or strength deficit in a pattern consistent with 
lumbar nerve root compression) 
6.2.2 
Enrollment, Baseline, and/or Randomization 
6.2.2.1  Enrollment 
This study uses a single informed consent document for both screening and treatment 
purposes. Thus the enrollment date is the date on which the consent document was signed 
and eligibility was confirmed. We anticipate that screening will be completed on the same 
day for the majority of participants because of the relatively simple and quick screening 
procedures required. At the latest screening will be completed within 7 days.  
6.2.2.2  Baseline Assessments 
Assessments involve collection of both mechanistic and self-report outcomes. Self-report 

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measures will be collected via REDCap (Research Electronic Data Capture), an NIH-
supported, browser-based, software solution that allows researchers to create secure 
online forms for data capture, management and analysis. At each assessment participants 
will input data directly into REDCap. If a participant is unable to directly input data using a 
computer paper forms will be available with data uploaded at a later time.  
The following assessments are collected at baseline: 
 Demographic data will include age, sex, race/ethnicity, employment status and general 
medical and LBP history. Current medication use for LBP will be recorded. This information 
will be used for descriptive purposes and possible covariates in analyses. 
 Physical examination will include spinal and hip range of motion and segmental mobility 
assessed with manually-applied posterior-anterior force. 
 Oswestry Disability Index (OSW): a self-reported LBP-specific measure of function 
assessed on a 0-100 scale, with lower numbers indicating better function.  
 Numeric Pain Rating Scale: a self-reported 0-10 rating of pain intensity ranging from ‘0’ no 
pain, and ‘10’ worst imaginable pain. 
 Psychosocial Covariate Measures: will include Fear Avoidance Beliefs Questionnaire will 
be used to measure patients’ beliefs about how physical activity and work may affect their 
LBP and perceived risk for re-injury. The Pain Catastrophizing and Pain Self-Efficacy short 
forms will be used to measure the extent to which people catastrophize in response to pain 
and their degree of confidence in the ability to function with pain respectively. These 
variables may serve as covariates in the analyses to control for psychosocial risk factors. 
 Spinal Stiffness Measures: are obtained with a mechanically-assisted indentation device 
consisting of a motorized probe in an external frame. The probe contains a compressive-
tension load cell. Displacement of the probe is measured by a linear variable differential 
transformer. Stiffness is assessed with the subject prone. The indentation probe is 
positioned over the L3 spinous process. Indentation involves advancement of the probe 
from 5 N pre-load to 60 N final load maintained for 1 second. Three trials are performed 
with mean values used for analysis. Indentation data are used to calculate global stiffness 
(GS) (N) as the slope of the force displacement curve and terminal stiffness (TS) (N/mm) 
as the peak applied force and resultant displacement of underlying tissue.  
 Lumbar Multifidus Activation Measures: are obtained with brightness-mode ultrasound 
images. The subject is prone with neck in neutral and arms overhead at about 1200 of 
shoulder abduction. Ultrasound transducer is placed just lateral to the spinal midline and 
angled medially until a parasagittal view of the multifidus at the L4-L5 and L5-S1 levels is 
obtained. Images are acquired at each level with the multifidus at rest and during 
submaximal contraction elicited by lifting the contralateral arm 2 inches while holding a 
weight proportional to body weight. Three images in each state are acquired and averaged. 
Muscle activation is calculated as change in thickness at rest and submaximal contraction. 
6.2.2.3   Randomization 
Following baseline assessment all participants will receive 2 SMT treatment sessions in 
the next week. Randomization to additional treatment will be done at the 1-week 
assessment. A randomization schedule will be developed prior to enrollment by co-
investigator Dr. Greene, Director of the Study Design and Biostatistics Center (SDBC) in 
the CCTS at the University of Utah. Blocked randomization with block sizes of 4 or 6 will 
be used. Randomization will be stratified based on site (Utah or Alberta) and responder 
status after 2 SMT sessions (based on re-assessment of the OSW) to balance these 
variables. At the 1-week assessment the study coordinator or research assistant will look 
up the participant in the study database and open the Responder & Randomization Status  
 

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form in REDCap. This form will display the Oswestry score from the baseline assessment 
and the calculation of score change. The percent change between baseline and 1-week 
scores determines responder status (>50% improvement = “responder”; <50% 
improvement= “non-responder”). Once the responder status is entered the study staff will 
select the randomize button on the screen to trigger study assignment based on the 
allocation table provided by the biostatistician, provided all of eligibility criteria are met and 
the participant has been assigned to one of the two study sites. If any of these criteria are 
not valid a warning message will be displayed indicating the criteria issue(s) and the 
randomization will not be completed. 
6.2.3  Blinding 
Participants cannot be blinded to study treatments. Randomization assignment will not be 
revealed until baseline examination, the first 2 SMT sessions, and the OSW assessment are 
complete to reduce potential bias by either the subject or research assistant. Follow-up 
assessments will be performed by a research assistant who will be blind to participants’ 
treatment assignments. Participants will be reminded by the research assistant not to discuss 
aspects of their treatment during assessments. If a research assistant becomes unblinded 
during the course of a participant’s study participation, he or she will not be allowed to conduct 
additional follow-up assessments for that participant. The research assistant may participate 
in assessments for other participants for whom blinding has not been compromised. Instances 
of unblinding during an assessment will be recorded as an unexpected event.   
Clinicians providing treatment cannot be blinded. The use of standardized protocols for all 
treatments and clinician-compliance audits throughout the project will minimize potential bias 
related to differential treatment application.  
6.2.4 Follow-up Visits 
 Treatment Visits 1 and 2 (completed within the 7 days following day 0): 
o Spine stiffness and multifidus activation assessments pre- and post-SMT treatment 
o Treatment Session Form 
 1-Week Assessment (completed from Day 7 – Day 12): 
o Physical examination 
o Self-report questionnaires 
o Spine stiffness measures 
o Multifidus activation measures 
o Side effects questionnaire 
 Treatment Visits 3 - 8 (completed from Day 8 – Day 35, no more than 2 sessions/week): 
o Treatment Session Form 
 4-Week Assessment (completed from Day 29 – Day 42, 3 weeks after 1-Wk assessment): 
o Physical examination 
o Self-report questionnaires 
o Spine stiffness measures 
o Multifidus activation measures 
o Side effects questionnaire 

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6.2.5 
Completion/Final Evaluation 
The final evaluation occurs 3 months after Baseline (from Day 83 – Day 97). The following 
assessments are performed at the final evaluation. If a participant wishes to terminate the study 
early, this is also the list of assessments we will attempt to complete at termination. Early 
termination will only be done at a participant’s request or if a participant’s risk-to-benefit ratio 
is substantially altered due to a change in status. 
o Physical examination 
o Self-report questionnaires 
o Spine stiffness measures 
o Multifidus activation measures 
7. SAFETY ASSESSMENTS  
Expected adverse events based on our prior experience and literature reports that may occur 
with the study interventions and assessments include the following: 
o Increased back or spine pain intensity 
o Muscle soreness 
o Muscle spasms 
o Psychological distress 
7.1 Specification of Safety Parameters 
Safety parameters intended to reduce risks for adverse events include having licensed clinicians 
specifically trained in the study procedures carry out all treatments. The spinal stiffness 
measurement procedure may be stopped at any time by the participant using a hand held switch. 
The potential risk of psychological distress from answering self-report questions about the impact 
of the individual’s LBP on various aspects of his or her life will be minimized by telling participants 
that they are not required to answer any questions that are distressing. 
7.2 Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
The risk profile of the interventions in this study is minimal. Treatment procedures in the study are 
standard procedures used in everyday clinical practice and the measurement procedures have 
been applied by this research team in several preliminary studies.1,2 The use of manipulation for 
patients with acute LBP is supported by clinical practice guidelines in the United States3 and 
elsewhere, and is not associated with a high risk of serious side effects.4 Ultrasound measurement 
procedures are similar to those used during pregnancy, using low intensity ultrasound waves 
spread over a large area which causes very minimal heating that is mostly undetectable to the 
subject. The spinal stiffness measurement procedure uses a 60 N force to assess spinal stiffness. 
We have tested several hundred subjects with this procedure with no adverse events.2 
1.   Fritz JM, Magel JS, McFadden M, et al. Early Physical Therapy vs Usual Care in Patients With 
Recent-Onset Low Back Pain: A Randomized Clinical Trial. JAMA. 2015;314(14):1459-67.  
2.   Wong AY, Parent EC, Dhillon SS, Prasad N, Kawchuk GN. Do participants with low back pain 
who respond to spinal manipulative therapy differ biomechanically from nonresponders, 
untreated controls or asymptomatic controls? Spine. 2015;40(17):1329-37. 
3.   Chou R, Huffman LH; American Pain Society; American College of Physicians. Non-
pharmacologic therapies for acute and chronic low back pain: a review of the evidence for an 
American Pain Society/American College of Physicians clinical practice guideline. Ann Intern 
Med. 2007;147(7):492-504.  

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4. Furlan AD, Yazdi F, Tsertsvadze A, et al. A systematic review and meta-analysis of efficacy, 
cost-effectiveness, and safety of selected complementary and alternative medicine for neck and 
low-back pain. Evid Based Complement Alternat Med.2012:953139. 
7.3 
Adverse Events and Serious Adverse Events  
Adverse events will solicited at each assessment (1 week, 4 weeks, 3 months). If an adverse 
event is identified unsolicited during a treatment session or other contact with research personnel, 
the event will be recorded and reported as outlined below. 
 Definitions  
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject during participation in the 
clinical study or with use of the experimental agent being studied. An adverse finding can include 
a sign, symptom, abnormal assessment (laboratory test value, vital signs, electrocardiogram 
finding, etc.), or any combination of these regardless of relationship to participation in the study. 
Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to subjects or others to include, in general, any incident, experience, or outcome that meets 
all of the following criteria: 
 Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the subject population being 
studied; 
 Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
 Results in death 
 Is life-threatening (places subject at immediate risk of death from the event as it occurred) 
 Results in inpatient hospitalization or prolongation of existing hospitalization 
 Results in a persistent or significant disability or incapacity 
 Results in a congenital anomaly or birth defect   
7.4 
Reporting Procedures 
The site PI at the University of Alberta must immediately report to the University of Utah PI any 
serious adverse event, whether or not considered study related, and must include an assessment 
of whether there is a reasonable possibility that the study caused the event within 72 hours of PI 
awareness of the event. The site PI for the University of Alberta must also report any unanticipated 
problems within the same timeframe. The Site PI must also report any other adverse events within 
7 days of PI awareness. Participating centers must submit all reports to their local IRB other 
entities using the following timeline:   
 Unanticipated problems that are serious adverse events will be reported to the IRB, DSM 
committee and NCCIH within 3 days of the investigator becoming aware of the event.  

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 Other unanticipated problem will be reported to the IRB, DSM committee, and NCCIH 
within 7 days of the investigator becoming aware of the problem.  
Should an unanticipated problem need to be reported to the IRB it will be reported to the IRB of 
both the University of Utah and University of Alberta. A record of all reportable unanticipated 
problems will be maintained at the coordinating site and reported during annual DSM reports. In 
addition, researchers will record at each study visit the occurrence of any other adverse events 
(e.g., visiting the emergency room or medical provider for pain exacerbation, etc.) A report of all 
adverse events will be maintained by each site and reported annually on the DSM report.  
Characteristics of an Adverse Event 
Relationship to Study Intervention 
To assess relationship of an event to study intervention, the following guidelines are used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
Expectedness of SAEs 
The Study PI and investigators will be responsible for determining whether an SAE is 
expected or unexpected.  An adverse event will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the intervention.   
Severity of Event 
The following scale will be used to grade adverse events: 
1. Mild: no intervention required; no impact on activities of daily living (ADL) 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact on 
ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical 
attention, needs major assistance with ADL 
7.5 
Followup for Adverse Events 
All adverse events will be followed for outcome information until resolution or stabilization. 
7.6 
Safety Monitoring  
The scope and the purpose of this study qualifies as a Phase III clinical trial, therefore a data 
and safety monitoring (DSM) board will be established based on the NIH guidelines and NCCIH 
input, and commensurate with the level of risk, size, and complexity of this study.   
 
Composition of the DSM: The DSM Board will be composed of three individuals with expertise 
in disciplines relevant to the conduct of this study who are not involved in the study, and have 
no conflict of interest or economic interest in the results of the study. 
 

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Frequency and Character of DSM Meetings: Because this study involves procedures with 
minimal risk, we propose to conduct DSM meetings via conference call on an annual basis. 
Each DSM meeting will begin with an open session that will be attended by all trial Investigators, 
Study Coordinators and representatives from the NCCIH Program Office. Open session will 
review study procedures, plans for data and safety monitoring, recruitment and retention, 
gender and minority inclusion, protocol adherence, data management, the occurrence of any 
adverse events. The open session will be followed by a closed session that will be attended by 
only the DSMB members and NCCIH representatives. The closed session will be used to 
discuss data to which the other Investigators must remain blinded.  
 
Content of DSMB Meeting Reports: DSM report from each meeting will review the topics 
discussed at the meeting with respect to study procedures, accrual and retention, data 
management, etc. The DSM report will include a recommendation concerning continuation of 
the study. Each DSM report will provide a tally of all adverse events in each of the categories 
listed above in all treatment groups.  Blinding of adverse event results will be maintained and 
will be broken only if the DSMB indicates a need to un-blind groups for serious safety reasons. 
DSMB reports will be submitted to the Principal Investigator, the NCCIH Program Office, and 
the University of Utah ad University of Alberta Institutional Review Boards. 
8.   INTERVENTION DISCONTINUATION  
The investigators will only discontinue a participant’s intervention if the risk-benefit ratio 
for that participant changes substantially such that they would no longer meet the 
project’s eligibility criteria. Examples include development of signs consistent with 
neurologic deficits or presentation of “red flag” symptoms. These circumstances will be 
identified by research personnel during study visits for treatment or assessments. If a 
participant is discontinued, we will continue to collect the self-report outcomes only. 
9.  STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
This study uses a factorial design examining 3 intervention components (additional SMT, 
mobilizing and multifidus activating exercise) provided in 8 different combinations following 
provision of 2 SMT treatment sessions. All participants will receive 2 SMT sessions. At the third 
session participants will be categorized as responders or non-responders based on a threshold 
of 50% improvement on the OSW. Randomization to subsequent treatment is stratified by 
responder status. We will randomly assign participants to receive 6 additional sessions (or no 
additional treatment) over 3 weeks with varied combinations of additional SMT and exercise co-
interventions. It is important to distinguish the factorial design from an 8-arm trial. The factorial 
approach evaluates the main effects of the 3 additional intervention components (additional 
SMT, mobilizing and multifidus activating exercise) and interactions among components. It does 
not compare 8 distinct treatment arms and thus is more efficient with a smaller sample size 
relative to an 8-arm randomized trial. 
Our primary hypothesis is that one or more combination of treatment components will optimize 
improvement in SMT mechanistic effects (reduction in spinal stiffness and improvement in 
multifidus activation) as well as improvement in patient-centered outcomes (LBP-related 
disability and pain intensity). Our secondary hypothesis is that responder status after 2 sessions 
will moderate the mechanistic and patient-centered outcomes. Our work and the work of others 
has demonstrated that these mechanistic and patient-reported outcomes are valid and can be 
collected reliably.  

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9.2 
Sample Size and Randomization 
Based on our past trials, we project 95% retention at 4-weeks. We estimated standard deviations 
of each outcome based on patients in a similar project with analogous eligibility criteria, and 
conservatively estimated pre-post correlations to be 4%-7% smaller than the values in this study. 
Assuming a sample size of 316, of which 280 meet all eligibility criteria and 92% of enrolled 
participants are retained to 4 weeks, the table below displays minimum detectable effect sizes for 
a) main effects of each protocol component, b) pairwise interactions between components, c) 
comparison of mean outcome between two levels of one component at a fixed level of another 
component, d) main effects of the 3 components in subgroup analyses involving half the 
participants, and e) pairwise interactions between 2 components in subgroup analyses with half 
the participants. This sample size provides at least 80% power to detect the MCID or hypothesized 
effect sizes for the main effects of each component for all outcomes, and for analyses of main 
effects in subgroups and conditional comparisons for each outcome except global stiffness. 
Power is more limited for secondary aims, such as pairwise interactions within subgroups.  
 
 
Assumptions for Outcome Measures in Project  
Global Stiffness 
(N) 
Multifidus Activation 
(mm) 
Oswestry 
Numeric Pain Rating 
Assumption 
 
 
 
 
Mean (SD) 
5.55 (1.60) 
2.60 (0.124) 
24.3 (14.9) 
5.06 (2.12) 
Pre-post score correlation  
0.80 
0.70 
0.70 
0.45 
MCID or hypothesized 
effect size from past work 
0.40 
0.074 
6.0 
2.0 
Type of effect 
Detectable Effect Size 
  Main effect 
0.37 
0.034 
4.12 
0.76 
  Pairwise interaction  
0.74 
0.064 
8.24 
1.53 
  Conditional comparison  
0.53 
0.045 
5.83 
1.08 
  Main effect in 50% of subjects 
0.53 
0.045 
5.83 
1.08 
  Interaction in 50% of subjects 
1.05 
0.091 
11.65 
2.16 
Table.  Assumptions and detectable effect sizes informing sample size for the project. 
 
Because the analyses of the longitudinal models will be based on restricted maximum likelihood 
estimation, statistical inferences will remain valid so long as missing data follow a missing at 
random structure, and based on our past work we expect little missing data at the 4 week 
assessment. Thus we do not believe missing data will lead to substantial bias in our primary 
evaluation of protocol components. However, we will compare subject characteristics between 
subgroups with missing and nonmissing data at 4 weeks and if substantial deviations are 
detected, or the rate of missing data is greater than expected, multiple imputation will be applied 
using comprehensive imputation models which include auxiliary variables to account for additional 
predictors of missingness and/or the values of the outcome variables. 
 
9.2.1   Treatment Assignment Procedures 
A randomization schedule will be developed prior to enrollment by Dr. Greene, Director of the 
Study Design and Biostatistics Center at the University of Utah. Blocked randomization with block 
sizes of 4 or 6 will be used. Randomization will be stratified based on site (Utah or Alberta) and 
responder status after 2 SMT sessions to balance these variables. Sequentially-numbered, 
sealed envelopes will be prepared containing treatment group assignments. The randomization 
envelope will be opened by the site Study Coordinator after completion of all baseline procedures 
and the 2 SMT sessions. 
Subjects cannot be blinded to study treatments. Because our purpose is to optimize protocols, 
not to evaluate the SMT efficacy, we will not use placebos or attempt to balance clinician time. 
Randomization assignment will not be revealed until baseline examination, the first 2 SMT  

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sessions, and the OSW assessment are complete to reduce potential bias by either the subject 
or research assistant. Follow-up assessments will be performed by a Research Assistant who will 
be blind to subjects’ treatment assignments. Clinicians providing treatment cannot be blinded. 
The use of standardized protocols for all treatments and clinician-compliance audits throughout 
the project will minimize potential bias related to differential treatment application. The PI at each 
site will be able to break the blinding if necessary for participant safety considerations. 
9.3  
Definition of Populations 
Intention-to-treat principles will be used with all participants analyzed in their randomized group 
regardless of compliance. We will compare compliance between groups and “per-protocol” 
secondary analyses may be considered if non-compliance is high or disproportionate between 
groups. A compliant treatment episode will be defined as receiving at least 80% of study sessions 
based on randomized group. 
9.4 
Interim Analyses and Stopping Rules 
Because of the minimal risk of the procedures in this study we have not proposed any stopping 
rules. We have not defined any procedures for interim analyses to avoid the risk of inflating Type 
I error. We will monitor the occurrence of adverse events throughout the study. If the number of 
serious adverse events warrants, we will suspend enrollment and review the safety of the study 
procedures under the direction of the DSM board and NCCIH representatives. 
9.5 
Outcomes  
Outcome measure for the primary and secondary hypotheses of the study are outlined below. 
These outcomes will not require any adjudication. 
9.5.1 Primary and Secondary Outcomes   
The outcomes used to address the primary and secondary hypotheses of this project are each 
collected at baseline, 1-week, 4-week and 3-month assessments.   
Oswestry Disability Questionnaire (OSW): The OSW is a LBP-specific measure of function for 
patients with LBP assessed on a 0-100 scale, with lower numbers indicating better function. Our 
past research has found the ODQ to have high test-retest reliability (ICC = 0.90), good construct 
validity, and responsiveness to change for patients with LBP, with a minimum clinically important 
difference (MCID) of 6 points.  
Numeric Pain Rating Scale (NPRS): A 0-10 NPRS (‘0’ no pain, and ‘10’ worst imaginable pain) 
will be used to assess LBP intensity.  The NPRS has excellent test-retest reliability. Our previous 
research has found the NPRS to be responsive to change with an MCID of 2 points for acute LBP.  
Spinal Stiffness: Spine stiffness will be assessed with a mechanically-assisted indentation device 
developed by Dr. Kawchuk and used in our previous research. The device consists of a motorized 
indentation probe supported by an external frame. The probe contains a compressive-tension 
load cell (Entran, Fairfield, NJ) connected in-series with the probe. Displacement of the probe is 
measured by a linear variable differential transformer (Honeywell International Inc., Morristown, 
NJ) attached between the probe and its external housing. Signals from the load cell and 
transformer are collected by customized LABview software (National Instruments, Austin, TX) at 
a collection rate of 200 Hz. 
Spinal stiffness is assessed with the subject prone on a table with arms at the side and a neutral 
neck position.  The examiner manually identifies and marks the L3 spinous process, and positions 
the indentation probe over it.  The subject is instructed to inhale and exhale comfortably, and hold 
their breath at the end of exhalation during indentation, which lasts about 5 seconds. Indentation 
involves advancement of the probe from a 5 N pre-load to 60 N final load maintained for 1 second, 
then the probe raises automatically. Three indentation trials are performed with mean values used 

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for analysis. Indentation data (force and displacement) are used to calculate stiffness variables. 
Global stiffness (GS) (N) is calculated as the slope of the force displacement curve between 5 - 
60 N, representing stiffness of underlying tissues during indentation. Terminal stiffness (TS) 
(N/mm) represents peak applied force and resultant displacement of underlying tissues. We have 
found excellent within- and between-day reliability of stiffness measures made with this device 
(ICC = 0.98-0.99). A safety switch is provided to the subject and assessor that raises the 
indentation probe immediately if pressed, providing additional safety features.  
Lumbar Multifidus Muscle Activation: Multifidus activation will be measured with brightness-mode 
ultrasound images using a 60mm, 2-5 MHz curvilinear array. We have previously reported 
excellent intra- and inter-rater reliability for these measurs. The subject is prone with neck in 
neutral and arms overhead at about 1200 of shoulder abduction. The ultrasound transducer is 
placed just lateral to the spinal midline and angled medially until a parasagittal view of the 
multifidus at the L4-L5 and L5-S1 levels is obtained.  Images are acquired at each level with the 
multifidus at rest and during submaximal contraction elicited by the subject lifting the contralateral 
arm about 2 inches while holding a weight proportional to body weight. Images are acquired at 
the end of exhalation to minimize effects of respiration. Three images in each state are acquired 
and averaged. Images are stored and measured offline by a blinded rater using NIH (Bethesda, 
MD) Image J software (V1.38t). Offline multifidus thickness measures are obtained from 
determining the distance between the posterior-most aspect of the facet joint inferiorly and the 
plane between the multifidus and thoracolumbar fascia superior. Activation is calculated as the 
change in thickness from rest to submaximal contraction (Thicknesscontract–Thicknessrest) / 
Thicknessrest). Research has shown these measures of multifidus activation have good concurrent 
validity compared to EMG activity of the muscle.  
9.6 
Data Analyses  
Primary Aim 1: Spine stiffness and multifidus activation will be co-primary outcomes for evaluating 
effects of SMT protocol components on SMT mechanisms. The effect of intervention components 
(A additional SMT; B multifidus activation; C mobilizing exercises) on each outcome will be 
evaluated using linear mixed models to relate mean levels of each outcome at 1-, 4-weeks and 
3-months to indicator variables to represent the main effects of each interventions (A, B, C) as 
well as each pairwise interaction between the interventions (A x B, A x C, B x C) and the 3-way 
interaction (A x B x C). 1-week assessment, which occurs just before randomization, will serve as 
the baseline for these analyses and the model will be assumed equal between the randomized 
groups. This model, sometimes referred to as a constrained longitudinal model, leads to 
adjustment for baseline levels as in analysis of covariance (ANCOVA), which has been shown to 
remove conditional bias in treatment group comparisons due to chance imbalances and improve 
statistical power over unadjusted comparisons. An unstructured covariance matrix will be used to 
account for correlation of serially measured outcome scores in the same subject. By using an 
unstructured covariance matrix, the model will constitute a special case of a general linear mixed 
model which avoids imposing specific assumptions concerning distribution of random effects. This 
modelling approach is recommended in randomized trials when the number of follow-up outcome 
assessments is small. Restricted maximum likelihood estimation will be used for estimation of 
parameters and their associated standard errors.  
Linear mixed effects analysis will provide estimates and CIs for the following quantities for each 
outcome at both 4-week and 3-month assessments: a) Main effects evaluating effects of each of 
the 3 interventions while averaging over the levels of the other 2 interventions. b) Three pairwise 
interactions evaluating if the effect of an intervention differs between levels of another  
interventions, while averaging over levels of the 3rd intervention. Pairwise interactions will inform 
whether the effects of each intervention pair are additive, synergistic or antagonistic. c) 3-way 
interaction evaluating if each pairwise interaction differs depending on the 3rd intervention. 

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Adjusted means with CIs will be provided for each treatment combination. Interaction plots will be 
used to depict significant interactions and linear contrasts constructed to evaluate the effect of 
each intervention conditional on the presence or absence of the other intervention. To account 
for 2 primary outcomes, each of the hypothesis tests noted above will be performed with 2-sided 
α=0.025 and confidence intervals will be constructed using a confidence coefficient of 0.975. The 
indicated comparisons at 4-weeks will be given primary emphasis in evaluating the effects of each 
intervention. Comparisons at 3-months will evaluate persistence of effects following intervention.  
Primary Aim #2: The OSW and NPRS will be co-primary outcomes for evaluating the effects of 
the 3 SMT protocol components on patient centered outcomes. The same analytic approach 
described above will be used. To account for 2 outcomes, we will again apply a 2-sided α=0.05 
and 97.5% CIs for statistical inference. 
Secondary Aim #1: It is unknown how early SMT response may affect response to additional 
intervention. We will examine this question by evaluating responder status after 1 week as a 
possible effect moderator by adding a main effect for responder status and interaction terms 
between responder status and the indicator variables for treatments (and treatment combinations) 
which are retrained in the final simplified models for the different outcomes developed using the 
BIC criteria for each of the co-primary outcomes for the primary aims 1 and 2. Statistically 
significant interactions between responder status and main effect and/or interaction terms 
between treatment intervention components will be interpreted as suggesting effect moderation. 
Recognizing that tests for interactions have limited statistical power, we will also fit the simplified 
models developed in Aims 1 and 2 separately under the presence and absence of each factor 
(dichotomizing using a median split for continuous factors), and graphically display the estimated 
treatment effects at both levels of responder status. Recognizing the potential for lower statistical 
power, the results of Secondary Aim #1 will be interpreted as exploratory.   
Secondary Aim #2: In order to assess which intervention component combinations provide 
optimal outcomes, we will first simplify the fully saturated factorial analysis of variance model by 
comparing the Bayes Information Criterion (BIC) among all possible models including different 
combinations of main effects, pairwise interactions and the 3-way interaction which satisfy the 
hierarchical consistency constraint that the main effects corresponding to each term in a pairwise 
interaction are retained in models with pairwise interactions, and all component main effects and 
pairwise interactions are retained when considering the 3-way interaction. This will result in a 
more parsimonious model to increase statistical power. Then, using the simplified model, for each 
outcome we will use a simulation approach to derive simultaneous 97.5% CIs for all comparisons 
of estimated mean outcome under each possible treatment combinations (No further treatment, 
A, B, C, A x B, A x C, B x C, A x B x C). After ordering the treatment combinations in accordance with 
the observed mean outcome, the simultaneous CIs will be used to identify which combinations 
are statistically indistinguishable from the optimum treatment, thus identifying a set of candidate 
options for the best combination of treatments. This process will be applied for both mechanistic 
and patient-centered outcomes. We anticipate that more than one combination will be considered 
optimal for different outcomes, and that the combinations that are optimal will differ for different 
outcome measures. Our interpretation of optimized protocols will give preference to longer term 
outcomes (ie, 3-month scores) and patient-centered outcomes. We will also consider an 
application of the robust modelling approach to derive a model for the optimum combination of 
components as a multivariate function which jointly incorporates each the potential effect 
modification of week 1 responder status in the same model. This approach will estimate the 
combination of components providing the optimum expected outcome for each participant based 
on their responder status after 1 week.  

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10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
Participant-reported measures will be collected via REDCap (Research Electronic Data Capture), 
an NIH-supported, browser-based, software solution that allows researchers to create secure 
online forms for data capture, management and analysis. At each assessment participants will 
input data directly into REDCap. If a participant is unable to directly input data, paper forms will 
be available with data uploaded at a later time. Self-report data will be downloaded from REDCap 
and integrated with mechanistic and physical examination data by the SDBC at the University of 
Utah. A research assistant blinded to the participant’s randomly-assigned treatment group will 
conduct the assessments to avoid bias. Confidentiality of participant’s records will be protected 
by storing all electronic information on encrypted, password-protected computers. 
The database for this study will be kept on a server supplied by the University of Utah Health 
Sciences Center (UUHSC). The UUHSC utilizes technology from Hitachi Data Systems called the 
Universal Storage Platform for providing a virtualized storage area network. This network is 
maintained on a server by the University of Utah Health Sciences Information Technology 
Support. All programming for the analyses will also be stored on the same server and coordinated 
through the University of Utah SDBC. 
Source documents not stored electronically will be maintained in locked cabinets within the 
personal offices of the PI and study coordinator at each site.  
10.2 Data Management  
Each subject enrolled in the study will receive a site-specific unique Patient Identifier that will be 
generated prior to beginning the study. Once a subject provides informed consent to participate 
in the study, the Study Coordinator will create a new Patient Profile in REDCap. The Patient 
Profile will be identified by the unique Patient Identifier, and will not contain the patient’s name, 
Social Security number, or any other type of Personal Health Information data that could be used 
to identify the individual patient. The link between the Patient Identifier and the subject’s Personal 
Health Information will be maintained by the Investigators, and will be available only to the Study 
Coordinators and Investigators. After the Patient Profile is created, the subject will be able to input 
all self-report data directly into REDCap using a computer or laptop using a web-based interface. 
All data entered by the subject into REDCap is identified only by the unique Patient Identifier. For 
participants who are unable to complete online data forms, paper forms will be provided. 
 
All self-report subject data will be collected using the REDCap data collection platform. Additional 
subject information (e.g., informed consent documents, demographic and physical examination 
forms completed by the Research Assistant) will be entered into REDCap by the Study 
Coordinator or Research Assistant as appropriate. The University of Utah Study Design and 
Biostatistics Center (SDBC) at the University of Utah Center for Clinical and Translational Science 
(CCTS) will download study data monthly once enrollment begins. This information will not include 
any patient identifying information.  
10.3 Quality Assurance  
10.3.1 
Training 
Project investigators will conduct training sessions for all research assistants and clinicians who 
will provide interventions. The University of Utah will train 4 clinicians in the provision of study-
related treatments. The University of Alberta will train 2 clinicians. Training will consist of written  
instructions for the performance of study-related techniques and hands-on practice. Both 
investigators are experienced in training clinicians to successfully perform treatment procedures, 
and researcher personnel in collection of human subjects data.  All personnel will be trained for 
their role in the project before enrollment begins. During the first 3 months of the study, prior to 

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beginning data collection, a detailed Study Protocol will be compiled under the supervision of the 
Dr. Fritz with input from all investigators. The Protocol will be approved by the DSM prior to 
recruitment. All study personnel will review and familiarize themselves with the Study Protocol in 
detail prior to participation. 
The Principal Investigators will conduct training sessions based on the Study Protocol for 
clinicians and research personnel during the first 3 months of the study. All research staff and 
clinicians will receive instruction in administrative aspects of the study (informed consent, subject 
recruitment, data and safety monitoring and subject confidentiality issues, etc.). Clinicians will 
receive additional training in all study-related treatment procedures previously described. Training 
goals will be accomplished by providing theoretical and practical information related to this project 
and the procedures employed. Management strategies based on group assignment will be 
highlighted with case examples. All clinicians and research personnel must complete training 
before participating in any study-related procedures. A training log will record successful 
completion of training activities. 
10.3.2 
Monitoring 
All protocol deviations and adverse events will be recorded at both sites as previously outlined. 
Deviations or adverse events will be reported in a timely manner to the PI and to the IRBs of the 
participating institutions as required. Annually, a report will be compiled for review by the DSM 
and NCCIH representatives. The DSM may request more frequent reviews if necessary. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent documents from each study site (Appendix I) and any 
subsequent modifications will be reviewed and approved by the IRB or ethics committee 
responsible for oversight of the study.  
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. For participants who cannot consent 
for themselves, such as those with a legal guardian (e.g., person with power of attorney), this 
individual must sign the consent form. The consent form describes the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy will be given to each 
participant or legal guardian and this fact will be documented in the participant’s study record.  
11.3 Participant Confidentiality  
Participant confidentiality will be protected in the data collection process. All personnel involved 
with the research at both sites responsible for collecting and handling the data will have completed 
the Collaborative Institutional Training Institute (CITI) modules for Human Subjects Research and 
Responsible Conduct of Research. Approval has been obtained by the respective Institutional 
Review Boards. Consent forms that identify the patient by name will be stored in a locked cabinet 
by the site Investigator. All data are assigned a unique identifier (not containing PHI) to identify 
each participant. Participants will be instructed not to identify themselves by name on any 
instrument. The data file linking names and code numbers will be accessible only to the site PI or 
Coordinator, and data will be entered into study databases by this unique identifier. If data are 
used in scholarly presentations or journal articles, the investigators will protect the anonymity of  
 
individual participants and will report only aggregate data where appropriate. No audio or video 
taping will be conducted as part of this study. Information will not be released without written 
permission of the participant, except as necessary for monitoring by IRBs, NCCIH, and the OHRP. 

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11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NCCIH, the OHRP, or other 
government agencies as part of their duties to ensure that research participants are protected. 

 
 
 
 
 
 
 
 
 
 
APPENDIX I 
 
Informed Consent Documents