Optimizing treatment protocols for spinal manipulative therapy: study protocol for a randomized trial

Optimizing treatment protocols for spinal manipulative therapy: study protocol for a randomized... Background: Low back pain is a common and costly condition. Spinal manipulative therapy (SMT) is a treatment supported in some guidelines, although most clinical trials examining SMT report small effect sizes. Enhancing the effects of SMT requires an understanding of underlying mechanisms and a systematic approach to leverage understanding of mechanisms to create more effective treatment protocols that are scalable in clinical practice. Prior work has identified effects on spinal stiffness and lumbar multifidus activation as possible mechanisms. This project represents a refinement phase study within the context of a multi-phase optimization strategy (MOST) framework. Our goal is to identify an optimized SMT treatment protocol by examining the impact of using co-intervention exercise strategies that are proposed to accentuate SMT mechanisms. The optimized protocol can then be evaluated in confirmation phase clinical trials and implementation studies. Methods: A phased, factorial randomized trial design will be used to evaluate the effects of three intervention components provided in eight combinations on mechanistic (spinal stiffness and multifidus muscle activation) and patient-reported outcomes (pain and disability). All participants will receive two sessions then will be randomly assigned to receive six additional sessions (or no additional treatment) over the next three weeks with factorial combinations of additional SMT and exercise co-interventions (spine mobilizing and multifidus activating). Outcome assessments occur at baseline, and one week, four weeks, and three months after enrollment. Pre-specified analyses will evaluate main effects for treatment components as well as interaction effects. Discussion: Building on preliminary findings identifying possible mechanisms of effects for SMT, this trial represents the next phase in a multiphase strategy towards the ultimate goal of developing an optimized protocol for providing SMT to patients with LBP. If successful, the results of this trial can be tested in future clinical trials in an effort to produce larger treatment benefits and improve patient-centered outcomes for individuals with LBP. Trial registration: ClinicalTrials.gov, NCT02868034. Registered on 16 August 2016. Keywords: Low back pain, Spinal manipulative therapy, Multiphase optimization, Factorial design Background medical condition in the United States, behind only dia- Low back pain (LBP) is a major public health problem [1]. betes and heart disease; and costs have been increasing at An estimated 60–80% of individuals experience an episode the second fastest rate over the past ten years [3]. Despite during their lifetime and LBP is among the most common the resources spent on management, LBP prevalence rates reasons prompting a healthcare visit in the United States have been increasing [4], with rates of opioid prescribing [2]. It is therefore not surprising that LBP imposes signifi- for LBP rising even more rapidly [5]. These circumstances cant economic burden. Low back pain is the third costliest make the development and broad implementation of effect- ive non-pharmacologic treatments an urgent priority [6]. Practice guidelines and systematic reviews identify sev- * Correspondence: julie.fritz@utah.edu eral non-pharmacologic LBP treatments with some evi- College of Health, University of Utah, 520 Wakara Way, Salt Lake City, UT dence of benefit often including spinal manipulative 84108, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fritz et al. Trials (2018) 19:306 Page 2 of 12 therapy (SMT) [7, 8]. While SMT is recommended in to other deep trunk muscles also appeared unrelated to re- many guidelines, effect sizes for SMT are modest for sponsiveness to SMT [33–36]. This body of research re- patient-centered outcomes of pain and disability [9–11], sulted in a model of explaining the mechanisms underlying leading other reviews to conclude the benefits of SMT the clinical benefits of SMT (Fig. 1)that servesas the con- are not clinically meaningful [12, 13]. A partial explan- ceptual basis for this study. ation for these equivocal recommendations is that SMT Uncovering the mechanisms and optimizing the proto- has been provided in clinical trials with highly variable col for providing SMT will help advance its role as a protocols. Some studies have examined SMT as a uni- non-pharmacologic option for patients with LBP. Based modal strategy, while others have used different on our preliminary work and resultant conceptual co-interventions including thermal modalities, soft tissue model, exercises designed specifically to enhance spine techniques, and various forms of exercise [14]. The opti- mobility and lumbar multifidus muscle activation may mal protocol for providing SMT treatment is currently enhance the effects of SMT and optimize clinical out- not established. comes. In addition to co-interventions, the optimal dos- The high degree of variability in clinical protocols may be age of SMT is not established. Research examining partly attributable to the lack of understanding about the dose-response relationships for SMT have examined the mechanisms through which SMT may provide clinical treatment without any co-interventions and have failed benefit [15]. Research has described the clinical presenta- to identify an optimal dose [37, 38]. tion of individuals with LBP who are more likely to respond A traditional approach to evaluating this proposed to SMT including more acute symptoms and absence of multi-component protocol combining SMT with different symptoms extending into the leg(s) [16, 17]. Optimizing types of exercise and varying SMT dose would use a treatment protocols, however, requires an understanding of parallel-group randomized trial design with protocol revi- the underlying reasons why some individuals respond to sions and subsequent randomized trials based on the re- SMT while others do not. If the underlying mechanisms sults [39]. A particular shortcoming of this approach is the through which SMT exerts clinical benefit were under- inability to test the effects of individual components and stood, protocols could be developed to optimize these interactions among components of a multi-component mechanisms through co-interventions designed to impact treatment protocol. Within a multi-component protocol, the same pathways. it is possible that some intervention components actively There is a sizable body of literature documenting various contribute to improved outcomes, while others may be physiologic effects that occur with the application of SMT non-contributory or even detract from beneficial effects. [18]. Until recently, there has been little work to identify The Multiphase Optimization Strategy (MOST) has which, if any, of these effects relate to clinical benefit and been described as an alternative framework for achieving which are unrelated phenomena. Prevailing theories on the the goal of optimizing a multi-component intervention mechanisms of SMT have historically focused on two pri- through a rigorous, multi-phased strategy [40]. From a mary effects resulting from SMT: (1) biomechanical effects MOST perspective, optimization begins with a screening on spinal kinetics and stiffness characteristics [19–21]; and phase during which the most promising treatment com- (2) neuro-physiologic effects on primary afferent neurons ponents are identified and grounded within a theoretical leading to altered motor neuron excitability [18, 22]. Sup- framework. The second phase is used to refine compo- port for these theories comes from studies documenting nent dosage and combinations and explore differences that SMT can alter spinal stiffness [23–27] and that afferent based on moderating effects of participant characteris- stimulation from SMT impacts reflex motor activity and tics. The final phase involves confirmation of the bene- moto-neuron excitability [23, 28–32]. It remains uncertain fits of the optimized intervention typically using a if these effects represented mechanisms of therapeutic randomized trial design [39, 41]. benefit or epiphenomena unrelated to clinical outcomes. We place the current study within the MOST framework We have conducted preliminary work investigating the as a refinement phase project (Fig. 2). Our prior work has role of changes in spinal stiffness and deep trunk muscle identified mechanisms through which SMT may exert an (i.e. transversus abdominus, internal oblique, and lumbar impact on clinical outcomes for patients with LBP. This multifidus) activation [33–35]. These studies have indicated work provides a scientific rationale to select exercise that individuals with LBP who are clinical responders to co-interventions that act along thesamemechanistic path- SMT treatment are characterized by immediate decreases ways as components that may optimize an SMT treatment in spinal stiffness and improvement in activation of program. This study uses a factorial design to permit evalu- the lumbar multifidus muscle sustained over one-week ationof both maineffects ofthree individual treatment follow-up periods. Individuals with LBP who do not benefit components (SMT dose, spine mobilizing exercise, and clinically from SMT did not display this pattern of stiffness lumbar multifidus activating exercises) and interaction ef- and multifidus muscle activation changes [35]and changes fects towards the goal of identifying an optimized SMT Fritz et al. Trials (2018) 19:306 Page 3 of 12 Fig. 1 Conceptual model of underlying mechanisms of SMT based on preliminary research [33] protocol that can be evaluated in future randomized trials. All participants will receive two SMT sessions as phase I The overall goal of this project is therefore to define an op- treatment to allow replication of our conceptual model timized SMT treatment protocol. The primary aim of the (Fig. 1) in a new LBP cohort. This design also permits current study is to evaluate these three SMT treatment examination of the moderating effects of early clinical re- components and their effect on SMT mechanistic out- sponse on longer-term outcomes. In our prior studies 35– comes (spinal stiffness and multifidus muscle activation) 45% of individuals with LBP were responders to the and patient-centered clinical outcomes (disability and pain). two-session SMT protocol [16, 33, 35]. What is unknown Secondary aims will explore the moderating effects of base- is the persistence of the improvement observed in early re- line patient characteristics and early treatment response. sponders and whether persistence can be augmented through additional SMT and/or co-interventions. Likewise, Methods it is unknown if early non-responders can be converted to Study design and rationale responders with additional SMT and/or co-interventions. This project will use a phased, factorial design examining Following the two SMT sessions, we will randomly assign three intervention components (SMT dose, spine mobiliz- participants to receive six additional sessions (or no ing exercise, and multifidus activating exercise) provided in additional treatment) provided over three weeks with fac- eight different combinations following provision of two torial combinations of additional SMT and exercise SMT treatment sessions. The research design is outlined in co-interventions (spine mobilizing and multifidus activat- Fig. 3. To begin, all participants will receive two sessions of ing). We chose six additional sessions (twice weekly for SMT treatment (phase I) after which the one-week three weeks) based on work related to SMT dose-response re-assessment will be conducted. At the one-week assess- reporting only modest difference in clinical outcomes in ment, participants will be randomly assigned to one of eight subjects receiving 9–12 sessions relative to 3–6SMT ses- phase II treatment groups. An aspect of the one-week sions without co-interventions [37, 38]. The factorial de- re-assessment will categorize participants as treatment sign allows evaluation of main effects of each component responders or non-responders based on a previously vali- and interaction effects. dated threshold of 50% reduction in disability [42]. Randomization will be stratified by responder status. Phase II treatment will occur across three weeks followed by four- Study participants and 12-week re-assessments. The CONSORT extension for The eligibility criteria were designed to recruit a sample non-pharmacological interventions (Additional file 1)and of individuals with non-specific LBP without contraindi- the Standard Protocol Items: Recommendations for Inter- cations to SMT or the co-interventions used in the ventional Trials (SPIRIT) Checklist for the implementation study. The criteria are consistent with those from our of study protocols (Additional file 2) were followed in the prior research. Reason(s) for ineligibility will be moni- development of the study and protocol report. tored and recorded so that eligibility and consent rates Fig. 2 Phases of Multiphase Optimization Strategy (MOST) as applied to development of optimized SMT research [40] Fritz et al. Trials (2018) 19:306 Page 4 of 12 Fig. 3 Study design showing three phases and four assessments. Each assessment includes PROs, spinal stiffness, and multifidus activation measures can be determined. Eligibility for participation requires will evaluate persistence of these effects. All assessments each of the following criteria be met: involve physical examination and collection of mechan- istic and patient-reported outcomes (PROs). Relevant Pain between the 12th rib and buttocks with or participant demographic and LBP history variables will without symptoms into one or both legs, which, in be collected at enrollment. Data from study sites will be the opinion of the examiner, originate from the collected and consolidated via REDCap (Research Elec- lumbar region. tronic Data Capture) with appropriate quality checks on Age 18–60 years at the time of enrollment data entry [43] (Fig. 4). Oswestry disability score ≥ 20% No prior surgery to the lumbosacral spine History and physical examination Not currently pregnant History and physical examination will include clinical Not currently receiving mind–body or exercise characteristics associated with an SMT response in prior treatment for LBP from a healthcare provider (e.g. studies including the duration of current LBP symptoms, chiropractic, physical therapy, massage therapy, etc.) presence of any symptoms (pain, numbness, tingling) ex- No neurogenic signs on clinical examination tending below the knee in the past 72 h, and spinal mo- including diminished myotomal strength, muscle bility assessed with manually applied posterior-anterior stretch reflexes or sensation, or positive straight leg force assessed with the subject prone [16]. We will raise sign evaluate multifidus activation using the lift test [44]. No known serious spinal pathology (e.g. spinal Lumbar spine and hip range of motion will be evaluated tumor, fracture, infectious disorder, osteoporosis, or using validated measurement techniques [45]. other bone demineralizing condition) or suspicion of serious pathology based on red flags noted in the Patient-reported outcomes general medical screening. PROs were selected to reflect outcomes that are most meaningful to individuals with LBP and to quantify par- Study measures ticipant’s beliefs and attitudes about LBP. The primary Assessments will be conducted at baseline, after PROs are the Oswestry Disability Questionnaire (ODQ) one week (completion of treatment phase I), four weeks and Numeric Pain Rating Scale (NPRS). The ODQ is a (completion of treatment phase II), and 12 weeks. The LBP-specific measure of function for patients with LBP one-week examination will permit assessment of change assessed on a 0–100 scale, with lower numbers indicat- in stiffness and activation occurring in the short term ing less LBP-related disability. We will use a 0–10 NPRS using the same time frame as in our validation studies (“0” no pain and “10” worst imaginable pain) to assess and clinical assessment for responder status. The LBP intensity. Both the ODQ and NPRS have high test– four-week examination will evaluate short-term effects retest reliability, good construct validity, and responsive- of different SMT protocols. The three-month assessment ness to change for patients with LBP [46–48]. Fritz et al. Trials (2018) 19:306 Page 5 of 12 STUDY PERIOD Enrolment Allocation Post-allocation Close-out Pre-random TIMEPOINT 1-week Tx. 1 Tx. 2 Tx. 3 Tx. 4 Tx. 5 Tx. 6 3 months allocation ENROLMENT: Eligibility screen X Informed consent Allocation X INTERVENTIONS: Two SMT Sessions No Additional Treatment SMT Mobilizing Exercise Activation Exercise SMT + Mobilizing Exercise SMT+ Activation Exercise Mobilizing+ Activation Exercise SMT+ Mobilizing+ Activation Exercise ASSESSMENTS: Demographics X Medical History Physical Examination XX X X Mechanistic Outcomes XX X X Patient-Reported XX X X Outcomes Side Effects XX Fig. 4 The Vertetrack device positioned over a participant to assess spinal stiffness The ODQ score will be used to determine responder which people catastrophize in response to pain [55]. status as a binary outcome at each follow-up. Based on These variables may serve as covariates in the analyses prior research [42], aparticipant whoseODQ scoreis to control for psychosocial risk factors. improved (i.e. decreased) by at least 50% relative to thebaselineODQ scoreisatreatment responder, Side effects and adverse events while those with < 50% improvement are defined as At the one- and four-week follow-ups, participants will non-responders. The 50% threshold is a more stringent complete a questionnaire about side effects they may definition of treatment responder than a threshold have experienced with study treatment [56]. The ques- corresponding to the minimum clinically important dif- tionnaire asks about commonly described side effects ference which is generally defined as at least 30% im- (muscle spasm, radiating discomfort, etc.) and allows provement from baseline [49]. participants to identify anything they perceive as an ad- We will assess pain catastrophizing and fear-avoidance verse symptom resulting from treatment. For each side beliefs about LBP because these constructs have been effect identified, participants indicate the time of onset found to predict chronicity and mediate treatment ef- relative to their last treatment session (< 1 h, 1–24 h, fects among patients with LBP [50–53]. The Fear Avoid- or > 24 h), the severity (light, mild, moderate, or severe), ance Beliefs Questionnaire (FABQ) [54] will be used to and duration (< 1 h, 1–24 h, or > 24 h) of the symptom. measure patients’ beliefs about how physical activity Other adverse events identified by any member of the (FABQPA) and work (FABQW) may affect their LBP research team will be recorded and reported as appro- and perceived risk for re-injury. The Pain Catastrophiz- priate to institutional review boards and study monitor- ing Scale (PCS) will be used to measure the extent to ing groups. Fritz et al. Trials (2018) 19:306 Page 6 of 12 Mechanistic outcomes obtained from determining the distance between the Mechanistic outcomes will assess the constructs under- posterior-most aspect of the facet joint inferiorly and lying the therapeutic effects of SMT in our conceptual the plane between the multifidus and thoracolumbar model including spinal stiffness and lumbar multifidus fascia superior. Muscle activation is calculated as the muscle activation (Fig. 1). The VerteTrack device will be change in thickness at rest and submaximal contraction used to measure lumbar spine stiffness. In this measure, (Thickness –Thickness ) /Thickness ). Re- contract rest rest the VerteTrack frame and indenter apparatus are posi- search has shown these measures of multifidus activa- tioned over the prone-lying participant. The indenter ap- tion have good concurrent validity compared to EMG paratus consists of a rod suspended within a linear activity of the muscle [58]. bearing to permit near-frictionless vertical translation in conjunction with an indentation roller comprising two Recruitment and allocation circular plastic disks (Fig. 5). Force transfer to the par- Participants will be recruited at two sites: the University ticipant occurs via the rod loaded with mass of increas- of Utah and University of Alberta. At each site, potential ing magnitude applied through the indentation roller. participants will be recruited from individuals seeking The rollers straddle the participant’s spinous processes healthcare within these systems as well as from general to provide a rolling contact point for the application of public advertising. Interested individuals will meet with vertical loads. The indenter houses a sensor to provide a member of the research team and those who provide continuous, real-time quantification of the bulk deform- informed consent will begin phase I treatment with all ation of any spinal region for a given mass over a de- participants receiving two SMT sessions. After comple- fined trajectory. Further details on the VerteTrack device tion of the two treatment sessions, each participant’s re- operations have been published [57]. Force displacement sponder status will be determined at the one-week curves for the lumbar spine are used to calculate ter- follow-up. Randomization to one of eight phase II treat- minal stiffness by dividing the maximum applied force ment groups will occur after the one-week follow-up is by the maximal displacement expressed in N/mm. complete. Blocked randomization with block sizes of Multifidus activation will be measured with four or six will be used. The randomization schedule will brightness-mode ultrasound images using a Sonosite be prepared before participant enrollment in the study MicroMaxx (Sonosite Inc. Bothell, WA, USA) and a by project statisticians. Randomization will be stratified 60-mm, 2–5 MHz curvilinear array. Measures are taken based on site (University of Utah or Alberta) and re- with the participant prone with neck in neutral and arms sponder status after two SMT sessions. overhead at about 120° of shoulder abduction. The ultra- sound transducer is placed just lateral to the spinal mid- Blinding line and angled medially until a parasagittal view of the Participants in this study cannot be blinded to treatment. multifidus at the L -L and L -S levels is obtained. Images Because our purpose is to optimize protocols, not to 4 5 5 1 are acquired at each level with the multifidus at rest and evaluate SMT efficacy, we are not using placebos or at- during submaximal contraction elicited by the participant tempts to balance clinician time. Randomization assign- lifting the contralateral arm about 2 in. while holding a ment will not be revealed until the baseline examination, weight proportional to body weight. This procedure re- the first two SMT sessions, and the one-week follow-up sults in ~ 30% maximum voluntary isometric multifidus are complete to reduce potential bias and maintain blind- contraction. Offline multifidus thickness measures are ing of the participant, clinicians, and researchers to the eventual group assignment. Randomization allocation will be done using RedCap in order to conceal sequence from participants and researchers. The four- and 12-week follow-up assessments will be performed by a researcher blinded to participants’ treatment group. Clinicians pro- viding treatment after randomization cannot be blinded. The use of standard protocols and compliance audits throughout the project will minimize potential bias related to differential treatment application. Treatments Treatments used in this study include SMT, spine mobilizing exercise, and multifidus activating exercise. The same SMT protocol will be used in phase I and II Fig. 5 The preferred SMT technique to be used in this study treatment phases. The exercise treatments will be used Fritz et al. Trials (2018) 19:306 Page 7 of 12 during treatment phase II only. Participants will receive and/or extension based on principles described by all prescribed sessions unless participant requests to dis- McKenzie [61] and shown in past studies to improve continue. Outcome measurements will continue if a par- ROM and reduce spinal stiffness [62, 63]. The basic proto- ticipant discontinues treatment sessions. All treatments col for progression of mobilizing exercises is outlined in will be provided by credentialed providers (either li- Table 1. Participants will be instructed in mid-range exer- censed chiropractors or physical therapists). cises and will be further assessed for a directional prefer- ence. A directional preference is present if movement in a Spinal manipulative therapy particular direction decreases LBP intensity or causes All SMT treatment sessions will be provided using proto- symptoms to centralize towards the midline [64]. If a par- cols applied in our prior work investigating clinical out- ticipant has a directional preference he or she will be pre- comes and mechanisms of effect [16, 33, 35, 59, 60]. All scribed exercises specifically in that direction along with SMT sessions will begin with a brief assessment by the mid-range exercise. Otherwise the participant will be clinician followed by treatment. The preferred SMT tech- assigned exercises moving into either flexion or extension nique is performed with the participant supine. The clin- based on the clinician’s discretion. Participants will per- ician stands opposite the side to be manipulated and form their prescribed exercises following SMT at treat- side-bends the participant. The side to be manipulated is ment sessions and will be instructed to perform the the side identified as more painful. The participant inter- exercises daily on other days. Prescribed exercises and par- locks their fingers behind the head. The clinician rotates ticipant compliance with assigned exercises will be re- the participant and delivers a high-velocity, low-amplitude corded at each session. (HVLA) thrust to the anterior superior ilinferior direc- tion/inferior direction (Fig. 6). The clinician notes if a Multifidus activating exercise cavitation (i.e. a “pop”) occurred and, if noted, the SMT Participants randomized to receive multifidus exercises treatment is complete. If no cavitation occurs, the partici- will begin with isometric multifidus contractions in dif- pant is repositioned and SMT is performed again. If no ferent positions with clinician feedback and exercises to cavitation occurs on the second attempt, the clinician will isometrically co-contract the multifidus and deep ab- manipulate the opposite side. A maximum of two at- dominal muscles. These exercises have been shown to tempts per side is permitted. Our prior research found no be effective for activating the multifidus muscle [65]. difference in outcome between this preferred SMT pro- Participants will also perform lumbar extensor strength- cedure and an alternative side-lying technique [60]. We ening exercises shown to produce 20–50% of multifidus will permit substitution with the side-lying technique maximum voluntary contraction (Table 2)[66, 67]. This based on participant preference or comfort. dose is adequate to enhance multifidus activation, with- out imposing high loads that may exacerbate LBP. Par- Spine mobilizing exercise ticipants will continue to perform isometric exercises Participants randomized to receive mobilizing exercises throughout treatment. Prescribed exercises and partici- during phase II will be instructed in a program of repeated pant compliance with assigned exercises will be recorded movements progressing into end-ranges of spinal flexion at each session. Statistical analysis Our primary hypothesis is that one or more combin- ation of treatment components will optimize improve- ment in SMT mechanistic effects (reduction in spinal stiffness and improvement in multifidus activation) and improvement in patient-centered outcomes (ODQ and NPRS). Our secondary hypothesis is that re- sponder status after two sessions will moderate mech- anistic and patient-centered outcomes. The effects of the treatment 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 one week, four weeks, and three months to indicator variables to repre- sent the main effects (A, B, C), pairwise interactions (A × Fig. 6 Study schedule based on the Standard Protocol Items: B, A × C, B × C), and the three-way interaction (A × B × Recommendations for Interventional Trials (SPIRIT) guidelines C). The one-week assessment, which occurs just before Fritz et al. Trials (2018) 19:306 Page 8 of 12 Table 1 Spine mobilizing exercise protocol Activity Description Initial dose Goals for progression Mid-range spinal � Supine pelvic tilts to promote lumbar flexion/extension 10–20 repetitions each direction Full, pain-free ROM, progress mobility exercises � Quadruped rocking into lumbar flexion/extension performed daily (each exercise) to 40 repetitions throughout � Supine to side lying rotational mobilizations the day � Sitting rotational mobilizations � Flexion/Extension Exercises specifically � Supine pelvic tilt 10–20 repetitions performed Full, pain-free ROM, progress to into spinal flexion � Quadruped rocking into lumbar flexion daily (prescribe 2 exercises) 40 repetitions throughout the day � Double knee-to-chest while supine � Standing flexion � Seated flexion � Self-mobilization into flexion Exercises specifically � Supine pelvic tilt 10–20 repetitions performed Full, pain-free ROM, progress to into spinal extension � Quadruped rocking into lumbar flexion daily (prescribe 2 exercises) 40 repetitions throughout the day � Supported on elbows while prone 30 s � Prone press-ups to extended elbows � Prone press-ups to extended elbows with exhale � Extension while standing � Extension in standing with self over pressure randomization, will serve as the baseline for these ana- additive, synergistic, or antagonistic; and (3) three-way lyses. An unstructured covariance matrix will be used to interaction (A × B × C) evaluating if each pairwise inter- account for correlation of serially measured outcome action differs depending on the third component. To ac- scores. By using an unstructured covariance matrix, the count for co-primary outcomes each of the hypothesis tests model will constitute a special case of a general linear noted above will be performed with two-sided α =0.025 mixed model which avoids imposing specific assumptions and CIs will be constructed using a confidence coefficient concerning distribution of random effects. This modeling of 0.975. The indicated comparisons at four weeks will be approach is recommended in randomized trials when the given primary emphasis in evaluating the effects of each number of assessments is small [68]. treatment component. Comparisons at 12 weeks will evalu- Restricted maximum likelihood estimation will be used ate persistence of effects. for estimation of parameters and associated confidence in- In order to assess which treatment component combi- tervals (CI) [69] for the following quantities for each out- nations optimize outcomes, we will first simplify the come at four- and 12-week assessments: (1) main effects fully saturated factorial analysis of variance model by evaluating effects of each of the three treatment compo- comparing the Bayes Information Criterion (BIC) among nents while averaging over the levels of the other two com- all possible models including different combinations of ponents; (2) three pairwise interactions (A × B, A × C, B × main effects, pairwise interactions, and the three-way C) evaluating if the effect of a component differs between interaction which satisfy the hierarchical consistency levels of one of the other components while averaging over constraint that the main effects corresponding to each the levels of the third component. Pairwise interactions will term in a pairwise interaction are retained in models inform whether the effects of each intervention pair are with pairwise interactions, and all component main Table 2 Multifidus activation exercise protocol Activity Description Initial dose Goals for progression Preferential, isometric multifidus � Isolated multifidus contraction while prone, 5 repetitions, 10-s hold Progress towards 10 repetitions, activation exercises seated, standing with normal breathing 10-s hold, perform 2–3× daily � Isolated co-contraction of multifidus and deep abdominals in sitting, standing General lumbar extensor and � Quadruped single arm raises 10 lifts, 5-s hold each arm Progress towards 20 lifts, add arm multifidus activation exercises + leg lift � Side-support exercise 10 repetitions, 5-s hold Progress towards 20 repetitions each side � Bridging while hook-lying 10 repetitions, 5-s hold Progress towards 20 repetitions � Prone single leg lift 10 lifts, 5-s hold each leg Progress towards 20 lifts, add arm + leg lift � Prone trunk lift 10 lifts, 5-s hold Progress towards 20 lifts Fritz et al. Trials (2018) 19:306 Page 9 of 12 effects and pairwise interactions are retained when con- four weeks, Table 3 displays minimum detectable effect sidering the three-way interaction. This will result in a sizes for: (1) main effects of each components; (2) more parsimonious model to increase statistical power. pairwise interactions between two components; (3) Then, using the simplified model, for each outcome we comparison of mean outcome between two levels of will use a simulation approach [70] to derive simultaneous one component at a fixed level of another component; 97.5% CIs for all comparisons of estimated mean outcome (4) main effects of the three components in subgroup under each possible treatment combinations. After order- analyses involving half the participants; and (5) pairwise ing the treatment combinations in accordance with the interactions between two components in subgroup ana- observed mean outcome, the simultaneous CIs will be lyses with half the participants. Our sample size pro- used to identify which combinations are statistically indis- vides at least 80% power to detect the MCIDs or tinguishable from the optimum treatment, thus identifying hypothesized effect sizes for the main effects of each a set of candidate options for the best combination of component for all four outcomes and for analyses of treatment components. This process will be applied for main effects in subgroups and conditional comparisons both mechanistic and patient-centered outcomes. for each outcome except global stiffness. Power is more We will explore responder status after two SMT ses- limited for secondary aims, such as pairwise interac- sions as a possible effect moderator by adding a main ef- tions within subgroups. fect for responder status and interaction terms between Because the analyses of the longitudinal models will be responder status and the indicator variables for the based on restricted maximum likelihood estimation, stat- treatment components which are retrained in the final istical inferences will remain valid so long as missing simplified models for the different outcomes developed data follow a missing at random structure [69]. We do using the BIC criteria for each of the outcomes for the not believe missing data will lead to substantial bias in primary aims. Statistically significant interactions be- our primary evaluation of protocol components. How- tween responder status and main effect and/or inter- ever, we will compare participant characteristics between action terms between treatment components will be subgroups with missing and non-missing data at interpreted as suggesting effect moderation. Recognizing four weeks and if substantial deviations are detected or that tests for interactions have limited statistical power, the rate of missing data is greater than expected, mul- we will also fit the simplified models developed in the tiple imputation will be applied using comprehensive primary aim separately under the presence and absence imputation models which include auxiliary variables to of each factor (dichotomizing using a median split for account for additional predictors of missingness and/or continuous factors) and graphically display the estimated the values of the outcome variables [71]. treatment effects at both levels of responder status. Rec- ognizing the potential for lower statistical power, the re- Trial and data monitoring sults of this aim will be interpreted as exploratory. Trial supervision includes a steering committee com- posed of the investigators and representatives of the Sample size and missing data funding agency (National Institutes of Health). A separ- We estimated standard deviations and pre-post correla- ate Data Safety and Monitoring Committee comprising tions for each outcome based on our prior work [33]. three external members with expertise in SMT, LBP, and Assuming a sample size of 280 and 92% retention to clinical trials will also provide at least annual review of Table 3 Assumptions and detectable effect sizes informing sample size for the project Assumptions for outcome measures 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 prior 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 0.068 8.24 1.53 Conditional comparison 0.53 0.048 5.83 1.08 Main effect in 50% of participants 0.53 0.045 5.83 1.08 Interaction in 50% of participants 1.05 0.091 11.65 2.16 Fritz et al. Trials (2018) 19:306 Page 10 of 12 study and any safety issues as necessary. Protocol modi- then be examined in future randomized clinical trials in fications will be reported to these bodies and recorded an effort to move beyond modest effect sizes for SMT in trial registry. and ultimately to enhance patient-centered outcomes for patients seeking treatment for LBP. Discussion Moving beyond the modest effect sizes for LBP treatments Additional files including SMT requires evidence informing optimal Additional file 1: 2017 CONSORT checklist of information to include treatment protocols. Optimized protocols can then be when reporting a randomized trial assessing nonpharmacologic tested in clinical trials. The MOST framework provides a treatments (NPTs)*. (DOCX 38 kb) multi-phase strategy to optimize an intervention protocol. Additional file 2: SPIRIT 2013 Checklist: Recommended items to address Based on our prior work, we are examining SMT provided in a clinical trial protocol and related documents*. (DOC 123 kb) in various dosages with exercise co-interventions designed to accentuate SMT’s effects of spinal stiffness and multifidus Abbreviations FABQ: Fear avoidance beliefs questionnaire; LBP: Low back pain; muscle activation. Our factorial design will permit efficient MOST: Multiphase Optimization Strategy; NPRS: Numeric pain rating scale; examination of these treatment components and their inter- ODQ: Oswestry disability questionnaire; PCS: Pain catastrophizing scale; actions on clinical as well as mechanistic outcomes. We will SMT: Spinal manipulative therapy also consider the moderating effect of early response to a Acknowledgements brief (two-session) SMT protocol. This strategy will address The authors acknowledge Ms. Molly McFadden, Dr. Anne Thackeray, Dr. an important clinical question related to the interpretation Jake Magel, Amy Rogers, and Lynne Wong for their assistance in of early response to SMT and the extent to which it should supporting this project. influence subsequent treatment decisions. Funding This project provides innovation in several areas of This project is funded by the National Center for Complimentary and critical importance for future studies of SMT. First, our Integrative Health at the National Institutes of Health (1UH3AT009293–01). The study was supported by the University of Utah Study Design and project will be the first that seeks to optimize SMT Biostatistics Center with funding in part through grant 5UL1TR001067–02 treatment protocols for patients with LBP that is guided (formerly 8UL1TR000105 and UL1RR025764) from the National Center for by a validated model explaining the mechanisms under- Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health. The funder was not involved in lying the therapeutic effects of SMT. The project investi- designing the study or in the writing of this manuscript. gates clinically relevant and potentially scalable SMT protocol components. Our project examines both short- Availability of data and materials The final dataset will include data from approximately 280 participants and and long-term outcomes. Additionally, we are grounding will include self-reported data and variables collected for mechanistic our work in the MOST framework described specifically outcomes. We will make the de-identified data and associated documentation for optimizing multi-component treatment protocols but available to users under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify not previously applied to SMT. any individual participant; (2) a commitment to maintaining the data using Our design comes with several important limitations. appropriate, secure technology; and (3) a commitment to destroying or Randomization to co-interventions will occur after two SMT returning the data after analyses are complete. treatment sessions. In clinical practice, co-interventions Authors’ contributions typically are initiated alongside SMT instead of our phase JF and GK led development of the project, obtained funding, and approach. Repeated spinal stiffness and multifidus contributed to all other aspects of the project. JS, EL, and DS contributed muscle activation measures may influence outcomes in a to the final design and implementation of intervention protocols and recruitment procedures. TG designed the analysis plan for the project. All manner that is also not reflective of clinical practice. Our authors have read and approved the final manuscript. JF and GK will have optimization strategy incorporates only two dosages of access to final dataset. All authors have read and approved this manuscript. SMT (two or eight sessions). Our long-term assessment Ethics approval and consent to participate only extends to three months following enrollment which Ethics approval has been received from the University of Utah (IRB_00092127) may not be adequate for a chronic recurrent condition like and University of Alberta (Pro00067152) Institutional Review Boards. Informed LBP. Our protocol does not permit clinicians or partici- consent will be obtained from all participants in the study. pants to be blinded to intervention groups. Consent for publication This trial has the potential to advance understanding The individuals appearing in Figs. 4 and 5 have agreed to publication of of the underlying mechanisms of SMT for individuals these figures with identifiable information. with LBP and promote the identification of SMT proto- Competing interests cols that can be implemented in clinical trials and prac- The authors declare that they have no competing interests. tice. We are placing this study within a MOST context and our goal for this phase II project is to define an opti- Publisher’sNote mized protocol for providing SMT using a factorial de- Springer Nature remains neutral with regard to jurisdictional claims in sign. The optimized protocol defined in this study can published maps and institutional affiliations. Fritz et al. Trials (2018) 19:306 Page 11 of 12 Author details 19. Colloca CJ, Keller TS. Stiffness and neuromuscular reflex response of the College of Health, University of Utah, 520 Wakara Way, Salt Lake City, UT human spine to to posteroanterior manipulative thrusts in patients with 84108, USA. Department of Physical Therapy & Athletic Training, University low back pain. J Manip Physiol Ther. 2001;24:489–500. of Utah, 520 Wakara Way, Salt Lake City, UT 84108, USA. Department of 20. Triano JJ. Biomechanics of spinal manipulative therapy. Spine J. 2001;1:121–30. Internal Medicine and Director, Population Health Research Study Design 21. Cramer GD, Gregerson DM, Knudsen JT, Hubbard BB, Ustas LM, Cantu JA. The and Biostatistics Center, School of Medicine, University of Utah, 295 Chipeta effects of side-posture positioning and spinal adjusting on the lumbar Z joints: Way, Salt Lake City, UT 84132, USA. Department of Physical Therapy, Faculty a randomized controlled trial with sixty-four subjects. 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Optimizing treatment protocols for spinal manipulative therapy: study protocol for a randomized trial

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Abstract

Background: Low back pain is a common and costly condition. Spinal manipulative therapy (SMT) is a treatment supported in some guidelines, although most clinical trials examining SMT report small effect sizes. Enhancing the effects of SMT requires an understanding of underlying mechanisms and a systematic approach to leverage understanding of mechanisms to create more effective treatment protocols that are scalable in clinical practice. Prior work has identified effects on spinal stiffness and lumbar multifidus activation as possible mechanisms. This project represents a refinement phase study within the context of a multi-phase optimization strategy (MOST) framework. Our goal is to identify an optimized SMT treatment protocol by examining the impact of using co-intervention exercise strategies that are proposed to accentuate SMT mechanisms. The optimized protocol can then be evaluated in confirmation phase clinical trials and implementation studies. Methods: A phased, factorial randomized trial design will be used to evaluate the effects of three intervention components provided in eight combinations on mechanistic (spinal stiffness and multifidus muscle activation) and patient-reported outcomes (pain and disability). All participants will receive two sessions then will be randomly assigned to receive six additional sessions (or no additional treatment) over the next three weeks with factorial combinations of additional SMT and exercise co-interventions (spine mobilizing and multifidus activating). Outcome assessments occur at baseline, and one week, four weeks, and three months after enrollment. Pre-specified analyses will evaluate main effects for treatment components as well as interaction effects. Discussion: Building on preliminary findings identifying possible mechanisms of effects for SMT, this trial represents the next phase in a multiphase strategy towards the ultimate goal of developing an optimized protocol for providing SMT to patients with LBP. If successful, the results of this trial can be tested in future clinical trials in an effort to produce larger treatment benefits and improve patient-centered outcomes for individuals with LBP. Trial registration: ClinicalTrials.gov, NCT02868034. Registered on 16 August 2016. Keywords: Low back pain, Spinal manipulative therapy, Multiphase optimization, Factorial design Background medical condition in the United States, behind only dia- Low back pain (LBP) is a major public health problem [1]. betes and heart disease; and costs have been increasing at An estimated 60–80% of individuals experience an episode the second fastest rate over the past ten years [3]. Despite during their lifetime and LBP is among the most common the resources spent on management, LBP prevalence rates reasons prompting a healthcare visit in the United States have been increasing [4], with rates of opioid prescribing [2]. It is therefore not surprising that LBP imposes signifi- for LBP rising even more rapidly [5]. These circumstances cant economic burden. Low back pain is the third costliest make the development and broad implementation of effect- ive non-pharmacologic treatments an urgent priority [6]. Practice guidelines and systematic reviews identify sev- * Correspondence: julie.fritz@utah.edu eral non-pharmacologic LBP treatments with some evi- College of Health, University of Utah, 520 Wakara Way, Salt Lake City, UT dence of benefit often including spinal manipulative 84108, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fritz et al. Trials (2018) 19:306 Page 2 of 12 therapy (SMT) [7, 8]. While SMT is recommended in to other deep trunk muscles also appeared unrelated to re- many guidelines, effect sizes for SMT are modest for sponsiveness to SMT [33–36]. This body of research re- patient-centered outcomes of pain and disability [9–11], sulted in a model of explaining the mechanisms underlying leading other reviews to conclude the benefits of SMT the clinical benefits of SMT (Fig. 1)that servesas the con- are not clinically meaningful [12, 13]. A partial explan- ceptual basis for this study. ation for these equivocal recommendations is that SMT Uncovering the mechanisms and optimizing the proto- has been provided in clinical trials with highly variable col for providing SMT will help advance its role as a protocols. Some studies have examined SMT as a uni- non-pharmacologic option for patients with LBP. Based modal strategy, while others have used different on our preliminary work and resultant conceptual co-interventions including thermal modalities, soft tissue model, exercises designed specifically to enhance spine techniques, and various forms of exercise [14]. The opti- mobility and lumbar multifidus muscle activation may mal protocol for providing SMT treatment is currently enhance the effects of SMT and optimize clinical out- not established. comes. In addition to co-interventions, the optimal dos- The high degree of variability in clinical protocols may be age of SMT is not established. Research examining partly attributable to the lack of understanding about the dose-response relationships for SMT have examined the mechanisms through which SMT may provide clinical treatment without any co-interventions and have failed benefit [15]. Research has described the clinical presenta- to identify an optimal dose [37, 38]. tion of individuals with LBP who are more likely to respond A traditional approach to evaluating this proposed to SMT including more acute symptoms and absence of multi-component protocol combining SMT with different symptoms extending into the leg(s) [16, 17]. Optimizing types of exercise and varying SMT dose would use a treatment protocols, however, requires an understanding of parallel-group randomized trial design with protocol revi- the underlying reasons why some individuals respond to sions and subsequent randomized trials based on the re- SMT while others do not. If the underlying mechanisms sults [39]. A particular shortcoming of this approach is the through which SMT exerts clinical benefit were under- inability to test the effects of individual components and stood, protocols could be developed to optimize these interactions among components of a multi-component mechanisms through co-interventions designed to impact treatment protocol. Within a multi-component protocol, the same pathways. it is possible that some intervention components actively There is a sizable body of literature documenting various contribute to improved outcomes, while others may be physiologic effects that occur with the application of SMT non-contributory or even detract from beneficial effects. [18]. Until recently, there has been little work to identify The Multiphase Optimization Strategy (MOST) has which, if any, of these effects relate to clinical benefit and been described as an alternative framework for achieving which are unrelated phenomena. Prevailing theories on the the goal of optimizing a multi-component intervention mechanisms of SMT have historically focused on two pri- through a rigorous, multi-phased strategy [40]. From a mary effects resulting from SMT: (1) biomechanical effects MOST perspective, optimization begins with a screening on spinal kinetics and stiffness characteristics [19–21]; and phase during which the most promising treatment com- (2) neuro-physiologic effects on primary afferent neurons ponents are identified and grounded within a theoretical leading to altered motor neuron excitability [18, 22]. Sup- framework. The second phase is used to refine compo- port for these theories comes from studies documenting nent dosage and combinations and explore differences that SMT can alter spinal stiffness [23–27] and that afferent based on moderating effects of participant characteris- stimulation from SMT impacts reflex motor activity and tics. The final phase involves confirmation of the bene- moto-neuron excitability [23, 28–32]. It remains uncertain fits of the optimized intervention typically using a if these effects represented mechanisms of therapeutic randomized trial design [39, 41]. benefit or epiphenomena unrelated to clinical outcomes. We place the current study within the MOST framework We have conducted preliminary work investigating the as a refinement phase project (Fig. 2). Our prior work has role of changes in spinal stiffness and deep trunk muscle identified mechanisms through which SMT may exert an (i.e. transversus abdominus, internal oblique, and lumbar impact on clinical outcomes for patients with LBP. This multifidus) activation [33–35]. These studies have indicated work provides a scientific rationale to select exercise that individuals with LBP who are clinical responders to co-interventions that act along thesamemechanistic path- SMT treatment are characterized by immediate decreases ways as components that may optimize an SMT treatment in spinal stiffness and improvement in activation of program. This study uses a factorial design to permit evalu- the lumbar multifidus muscle sustained over one-week ationof both maineffects ofthree individual treatment follow-up periods. Individuals with LBP who do not benefit components (SMT dose, spine mobilizing exercise, and clinically from SMT did not display this pattern of stiffness lumbar multifidus activating exercises) and interaction ef- and multifidus muscle activation changes [35]and changes fects towards the goal of identifying an optimized SMT Fritz et al. Trials (2018) 19:306 Page 3 of 12 Fig. 1 Conceptual model of underlying mechanisms of SMT based on preliminary research [33] protocol that can be evaluated in future randomized trials. All participants will receive two SMT sessions as phase I The overall goal of this project is therefore to define an op- treatment to allow replication of our conceptual model timized SMT treatment protocol. The primary aim of the (Fig. 1) in a new LBP cohort. This design also permits current study is to evaluate these three SMT treatment examination of the moderating effects of early clinical re- components and their effect on SMT mechanistic out- sponse on longer-term outcomes. In our prior studies 35– comes (spinal stiffness and multifidus muscle activation) 45% of individuals with LBP were responders to the and patient-centered clinical outcomes (disability and pain). two-session SMT protocol [16, 33, 35]. What is unknown Secondary aims will explore the moderating effects of base- is the persistence of the improvement observed in early re- line patient characteristics and early treatment response. sponders and whether persistence can be augmented through additional SMT and/or co-interventions. Likewise, Methods it is unknown if early non-responders can be converted to Study design and rationale responders with additional SMT and/or co-interventions. This project will use a phased, factorial design examining Following the two SMT sessions, we will randomly assign three intervention components (SMT dose, spine mobiliz- participants to receive six additional sessions (or no ing exercise, and multifidus activating exercise) provided in additional treatment) provided over three weeks with fac- eight different combinations following provision of two torial combinations of additional SMT and exercise SMT treatment sessions. The research design is outlined in co-interventions (spine mobilizing and multifidus activat- Fig. 3. To begin, all participants will receive two sessions of ing). We chose six additional sessions (twice weekly for SMT treatment (phase I) after which the one-week three weeks) based on work related to SMT dose-response re-assessment will be conducted. At the one-week assess- reporting only modest difference in clinical outcomes in ment, participants will be randomly assigned to one of eight subjects receiving 9–12 sessions relative to 3–6SMT ses- phase II treatment groups. An aspect of the one-week sions without co-interventions [37, 38]. The factorial de- re-assessment will categorize participants as treatment sign allows evaluation of main effects of each component responders or non-responders based on a previously vali- and interaction effects. dated threshold of 50% reduction in disability [42]. Randomization will be stratified by responder status. Phase II treatment will occur across three weeks followed by four- Study participants and 12-week re-assessments. The CONSORT extension for The eligibility criteria were designed to recruit a sample non-pharmacological interventions (Additional file 1)and of individuals with non-specific LBP without contraindi- the Standard Protocol Items: Recommendations for Inter- cations to SMT or the co-interventions used in the ventional Trials (SPIRIT) Checklist for the implementation study. The criteria are consistent with those from our of study protocols (Additional file 2) were followed in the prior research. Reason(s) for ineligibility will be moni- development of the study and protocol report. tored and recorded so that eligibility and consent rates Fig. 2 Phases of Multiphase Optimization Strategy (MOST) as applied to development of optimized SMT research [40] Fritz et al. Trials (2018) 19:306 Page 4 of 12 Fig. 3 Study design showing three phases and four assessments. Each assessment includes PROs, spinal stiffness, and multifidus activation measures can be determined. Eligibility for participation requires will evaluate persistence of these effects. All assessments each of the following criteria be met: involve physical examination and collection of mechan- istic and patient-reported outcomes (PROs). Relevant Pain between the 12th rib and buttocks with or participant demographic and LBP history variables will without symptoms into one or both legs, which, in be collected at enrollment. Data from study sites will be the opinion of the examiner, originate from the collected and consolidated via REDCap (Research Elec- lumbar region. tronic Data Capture) with appropriate quality checks on Age 18–60 years at the time of enrollment data entry [43] (Fig. 4). Oswestry disability score ≥ 20% No prior surgery to the lumbosacral spine History and physical examination Not currently pregnant History and physical examination will include clinical Not currently receiving mind–body or exercise characteristics associated with an SMT response in prior treatment for LBP from a healthcare provider (e.g. studies including the duration of current LBP symptoms, chiropractic, physical therapy, massage therapy, etc.) presence of any symptoms (pain, numbness, tingling) ex- No neurogenic signs on clinical examination tending below the knee in the past 72 h, and spinal mo- including diminished myotomal strength, muscle bility assessed with manually applied posterior-anterior stretch reflexes or sensation, or positive straight leg force assessed with the subject prone [16]. We will raise sign evaluate multifidus activation using the lift test [44]. No known serious spinal pathology (e.g. spinal Lumbar spine and hip range of motion will be evaluated tumor, fracture, infectious disorder, osteoporosis, or using validated measurement techniques [45]. other bone demineralizing condition) or suspicion of serious pathology based on red flags noted in the Patient-reported outcomes general medical screening. PROs were selected to reflect outcomes that are most meaningful to individuals with LBP and to quantify par- Study measures ticipant’s beliefs and attitudes about LBP. The primary Assessments will be conducted at baseline, after PROs are the Oswestry Disability Questionnaire (ODQ) one week (completion of treatment phase I), four weeks and Numeric Pain Rating Scale (NPRS). The ODQ is a (completion of treatment phase II), and 12 weeks. The LBP-specific measure of function for patients with LBP one-week examination will permit assessment of change assessed on a 0–100 scale, with lower numbers indicat- in stiffness and activation occurring in the short term ing less LBP-related disability. We will use a 0–10 NPRS using the same time frame as in our validation studies (“0” no pain and “10” worst imaginable pain) to assess and clinical assessment for responder status. The LBP intensity. Both the ODQ and NPRS have high test– four-week examination will evaluate short-term effects retest reliability, good construct validity, and responsive- of different SMT protocols. The three-month assessment ness to change for patients with LBP [46–48]. Fritz et al. Trials (2018) 19:306 Page 5 of 12 STUDY PERIOD Enrolment Allocation Post-allocation Close-out Pre-random TIMEPOINT 1-week Tx. 1 Tx. 2 Tx. 3 Tx. 4 Tx. 5 Tx. 6 3 months allocation ENROLMENT: Eligibility screen X Informed consent Allocation X INTERVENTIONS: Two SMT Sessions No Additional Treatment SMT Mobilizing Exercise Activation Exercise SMT + Mobilizing Exercise SMT+ Activation Exercise Mobilizing+ Activation Exercise SMT+ Mobilizing+ Activation Exercise ASSESSMENTS: Demographics X Medical History Physical Examination XX X X Mechanistic Outcomes XX X X Patient-Reported XX X X Outcomes Side Effects XX Fig. 4 The Vertetrack device positioned over a participant to assess spinal stiffness The ODQ score will be used to determine responder which people catastrophize in response to pain [55]. status as a binary outcome at each follow-up. Based on These variables may serve as covariates in the analyses prior research [42], aparticipant whoseODQ scoreis to control for psychosocial risk factors. improved (i.e. decreased) by at least 50% relative to thebaselineODQ scoreisatreatment responder, Side effects and adverse events while those with < 50% improvement are defined as At the one- and four-week follow-ups, participants will non-responders. The 50% threshold is a more stringent complete a questionnaire about side effects they may definition of treatment responder than a threshold have experienced with study treatment [56]. The ques- corresponding to the minimum clinically important dif- tionnaire asks about commonly described side effects ference which is generally defined as at least 30% im- (muscle spasm, radiating discomfort, etc.) and allows provement from baseline [49]. participants to identify anything they perceive as an ad- We will assess pain catastrophizing and fear-avoidance verse symptom resulting from treatment. For each side beliefs about LBP because these constructs have been effect identified, participants indicate the time of onset found to predict chronicity and mediate treatment ef- relative to their last treatment session (< 1 h, 1–24 h, fects among patients with LBP [50–53]. The Fear Avoid- or > 24 h), the severity (light, mild, moderate, or severe), ance Beliefs Questionnaire (FABQ) [54] will be used to and duration (< 1 h, 1–24 h, or > 24 h) of the symptom. measure patients’ beliefs about how physical activity Other adverse events identified by any member of the (FABQPA) and work (FABQW) may affect their LBP research team will be recorded and reported as appro- and perceived risk for re-injury. The Pain Catastrophiz- priate to institutional review boards and study monitor- ing Scale (PCS) will be used to measure the extent to ing groups. Fritz et al. Trials (2018) 19:306 Page 6 of 12 Mechanistic outcomes obtained from determining the distance between the Mechanistic outcomes will assess the constructs under- posterior-most aspect of the facet joint inferiorly and lying the therapeutic effects of SMT in our conceptual the plane between the multifidus and thoracolumbar model including spinal stiffness and lumbar multifidus fascia superior. Muscle activation is calculated as the muscle activation (Fig. 1). The VerteTrack device will be change in thickness at rest and submaximal contraction used to measure lumbar spine stiffness. In this measure, (Thickness –Thickness ) /Thickness ). Re- contract rest rest the VerteTrack frame and indenter apparatus are posi- search has shown these measures of multifidus activa- tioned over the prone-lying participant. The indenter ap- tion have good concurrent validity compared to EMG paratus consists of a rod suspended within a linear activity of the muscle [58]. bearing to permit near-frictionless vertical translation in conjunction with an indentation roller comprising two Recruitment and allocation circular plastic disks (Fig. 5). Force transfer to the par- Participants will be recruited at two sites: the University ticipant occurs via the rod loaded with mass of increas- of Utah and University of Alberta. At each site, potential ing magnitude applied through the indentation roller. participants will be recruited from individuals seeking The rollers straddle the participant’s spinous processes healthcare within these systems as well as from general to provide a rolling contact point for the application of public advertising. Interested individuals will meet with vertical loads. The indenter houses a sensor to provide a member of the research team and those who provide continuous, real-time quantification of the bulk deform- informed consent will begin phase I treatment with all ation of any spinal region for a given mass over a de- participants receiving two SMT sessions. After comple- fined trajectory. Further details on the VerteTrack device tion of the two treatment sessions, each participant’s re- operations have been published [57]. Force displacement sponder status will be determined at the one-week curves for the lumbar spine are used to calculate ter- follow-up. Randomization to one of eight phase II treat- minal stiffness by dividing the maximum applied force ment groups will occur after the one-week follow-up is by the maximal displacement expressed in N/mm. complete. Blocked randomization with block sizes of Multifidus activation will be measured with four or six will be used. The randomization schedule will brightness-mode ultrasound images using a Sonosite be prepared before participant enrollment in the study MicroMaxx (Sonosite Inc. Bothell, WA, USA) and a by project statisticians. Randomization will be stratified 60-mm, 2–5 MHz curvilinear array. Measures are taken based on site (University of Utah or Alberta) and re- with the participant prone with neck in neutral and arms sponder status after two SMT sessions. overhead at about 120° of shoulder abduction. The ultra- sound transducer is placed just lateral to the spinal mid- Blinding line and angled medially until a parasagittal view of the Participants in this study cannot be blinded to treatment. multifidus at the L -L and L -S levels is obtained. Images Because our purpose is to optimize protocols, not to 4 5 5 1 are acquired at each level with the multifidus at rest and evaluate SMT efficacy, we are not using placebos or at- during submaximal contraction elicited by the participant tempts to balance clinician time. Randomization assign- lifting the contralateral arm about 2 in. while holding a ment will not be revealed until the baseline examination, weight proportional to body weight. This procedure re- the first two SMT sessions, and the one-week follow-up sults in ~ 30% maximum voluntary isometric multifidus are complete to reduce potential bias and maintain blind- contraction. Offline multifidus thickness measures are ing of the participant, clinicians, and researchers to the eventual group assignment. Randomization allocation will be done using RedCap in order to conceal sequence from participants and researchers. The four- and 12-week follow-up assessments will be performed by a researcher blinded to participants’ treatment group. Clinicians pro- viding treatment after randomization cannot be blinded. The use of standard protocols and compliance audits throughout the project will minimize potential bias related to differential treatment application. Treatments Treatments used in this study include SMT, spine mobilizing exercise, and multifidus activating exercise. The same SMT protocol will be used in phase I and II Fig. 5 The preferred SMT technique to be used in this study treatment phases. The exercise treatments will be used Fritz et al. Trials (2018) 19:306 Page 7 of 12 during treatment phase II only. Participants will receive and/or extension based on principles described by all prescribed sessions unless participant requests to dis- McKenzie [61] and shown in past studies to improve continue. Outcome measurements will continue if a par- ROM and reduce spinal stiffness [62, 63]. The basic proto- ticipant discontinues treatment sessions. All treatments col for progression of mobilizing exercises is outlined in will be provided by credentialed providers (either li- Table 1. Participants will be instructed in mid-range exer- censed chiropractors or physical therapists). cises and will be further assessed for a directional prefer- ence. A directional preference is present if movement in a Spinal manipulative therapy particular direction decreases LBP intensity or causes All SMT treatment sessions will be provided using proto- symptoms to centralize towards the midline [64]. If a par- cols applied in our prior work investigating clinical out- ticipant has a directional preference he or she will be pre- comes and mechanisms of effect [16, 33, 35, 59, 60]. All scribed exercises specifically in that direction along with SMT sessions will begin with a brief assessment by the mid-range exercise. Otherwise the participant will be clinician followed by treatment. The preferred SMT tech- assigned exercises moving into either flexion or extension nique is performed with the participant supine. The clin- based on the clinician’s discretion. Participants will per- ician stands opposite the side to be manipulated and form their prescribed exercises following SMT at treat- side-bends the participant. The side to be manipulated is ment sessions and will be instructed to perform the the side identified as more painful. The participant inter- exercises daily on other days. Prescribed exercises and par- locks their fingers behind the head. The clinician rotates ticipant compliance with assigned exercises will be re- the participant and delivers a high-velocity, low-amplitude corded at each session. (HVLA) thrust to the anterior superior ilinferior direc- tion/inferior direction (Fig. 6). The clinician notes if a Multifidus activating exercise cavitation (i.e. a “pop”) occurred and, if noted, the SMT Participants randomized to receive multifidus exercises treatment is complete. If no cavitation occurs, the partici- will begin with isometric multifidus contractions in dif- pant is repositioned and SMT is performed again. If no ferent positions with clinician feedback and exercises to cavitation occurs on the second attempt, the clinician will isometrically co-contract the multifidus and deep ab- manipulate the opposite side. A maximum of two at- dominal muscles. These exercises have been shown to tempts per side is permitted. Our prior research found no be effective for activating the multifidus muscle [65]. difference in outcome between this preferred SMT pro- Participants will also perform lumbar extensor strength- cedure and an alternative side-lying technique [60]. We ening exercises shown to produce 20–50% of multifidus will permit substitution with the side-lying technique maximum voluntary contraction (Table 2)[66, 67]. This based on participant preference or comfort. dose is adequate to enhance multifidus activation, with- out imposing high loads that may exacerbate LBP. Par- Spine mobilizing exercise ticipants will continue to perform isometric exercises Participants randomized to receive mobilizing exercises throughout treatment. Prescribed exercises and partici- during phase II will be instructed in a program of repeated pant compliance with assigned exercises will be recorded movements progressing into end-ranges of spinal flexion at each session. Statistical analysis Our primary hypothesis is that one or more combin- ation of treatment components will optimize improve- ment in SMT mechanistic effects (reduction in spinal stiffness and improvement in multifidus activation) and improvement in patient-centered outcomes (ODQ and NPRS). Our secondary hypothesis is that re- sponder status after two sessions will moderate mech- anistic and patient-centered outcomes. The effects of the treatment 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 one week, four weeks, and three months to indicator variables to repre- sent the main effects (A, B, C), pairwise interactions (A × Fig. 6 Study schedule based on the Standard Protocol Items: B, A × C, B × C), and the three-way interaction (A × B × Recommendations for Interventional Trials (SPIRIT) guidelines C). The one-week assessment, which occurs just before Fritz et al. Trials (2018) 19:306 Page 8 of 12 Table 1 Spine mobilizing exercise protocol Activity Description Initial dose Goals for progression Mid-range spinal � Supine pelvic tilts to promote lumbar flexion/extension 10–20 repetitions each direction Full, pain-free ROM, progress mobility exercises � Quadruped rocking into lumbar flexion/extension performed daily (each exercise) to 40 repetitions throughout � Supine to side lying rotational mobilizations the day � Sitting rotational mobilizations � Flexion/Extension Exercises specifically � Supine pelvic tilt 10–20 repetitions performed Full, pain-free ROM, progress to into spinal flexion � Quadruped rocking into lumbar flexion daily (prescribe 2 exercises) 40 repetitions throughout the day � Double knee-to-chest while supine � Standing flexion � Seated flexion � Self-mobilization into flexion Exercises specifically � Supine pelvic tilt 10–20 repetitions performed Full, pain-free ROM, progress to into spinal extension � Quadruped rocking into lumbar flexion daily (prescribe 2 exercises) 40 repetitions throughout the day � Supported on elbows while prone 30 s � Prone press-ups to extended elbows � Prone press-ups to extended elbows with exhale � Extension while standing � Extension in standing with self over pressure randomization, will serve as the baseline for these ana- additive, synergistic, or antagonistic; and (3) three-way lyses. An unstructured covariance matrix will be used to interaction (A × B × C) evaluating if each pairwise inter- account for correlation of serially measured outcome action differs depending on the third component. To ac- scores. By using an unstructured covariance matrix, the count for co-primary outcomes each of the hypothesis tests model will constitute a special case of a general linear noted above will be performed with two-sided α =0.025 mixed model which avoids imposing specific assumptions and CIs will be constructed using a confidence coefficient concerning distribution of random effects. This modeling of 0.975. The indicated comparisons at four weeks will be approach is recommended in randomized trials when the given primary emphasis in evaluating the effects of each number of assessments is small [68]. treatment component. Comparisons at 12 weeks will evalu- Restricted maximum likelihood estimation will be used ate persistence of effects. for estimation of parameters and associated confidence in- In order to assess which treatment component combi- tervals (CI) [69] for the following quantities for each out- nations optimize outcomes, we will first simplify the come at four- and 12-week assessments: (1) main effects fully saturated factorial analysis of variance model by evaluating effects of each of the three treatment compo- comparing the Bayes Information Criterion (BIC) among nents while averaging over the levels of the other two com- all possible models including different combinations of ponents; (2) three pairwise interactions (A × B, A × C, B × main effects, pairwise interactions, and the three-way C) evaluating if the effect of a component differs between interaction which satisfy the hierarchical consistency levels of one of the other components while averaging over constraint that the main effects corresponding to each the levels of the third component. Pairwise interactions will term in a pairwise interaction are retained in models inform whether the effects of each intervention pair are with pairwise interactions, and all component main Table 2 Multifidus activation exercise protocol Activity Description Initial dose Goals for progression Preferential, isometric multifidus � Isolated multifidus contraction while prone, 5 repetitions, 10-s hold Progress towards 10 repetitions, activation exercises seated, standing with normal breathing 10-s hold, perform 2–3× daily � Isolated co-contraction of multifidus and deep abdominals in sitting, standing General lumbar extensor and � Quadruped single arm raises 10 lifts, 5-s hold each arm Progress towards 20 lifts, add arm multifidus activation exercises + leg lift � Side-support exercise 10 repetitions, 5-s hold Progress towards 20 repetitions each side � Bridging while hook-lying 10 repetitions, 5-s hold Progress towards 20 repetitions � Prone single leg lift 10 lifts, 5-s hold each leg Progress towards 20 lifts, add arm + leg lift � Prone trunk lift 10 lifts, 5-s hold Progress towards 20 lifts Fritz et al. Trials (2018) 19:306 Page 9 of 12 effects and pairwise interactions are retained when con- four weeks, Table 3 displays minimum detectable effect sidering the three-way interaction. This will result in a sizes for: (1) main effects of each components; (2) more parsimonious model to increase statistical power. pairwise interactions between two components; (3) Then, using the simplified model, for each outcome we comparison of mean outcome between two levels of will use a simulation approach [70] to derive simultaneous one component at a fixed level of another component; 97.5% CIs for all comparisons of estimated mean outcome (4) main effects of the three components in subgroup under each possible treatment combinations. After order- analyses involving half the participants; and (5) pairwise ing the treatment combinations in accordance with the interactions between two components in subgroup ana- observed mean outcome, the simultaneous CIs will be lyses with half the participants. Our sample size pro- used to identify which combinations are statistically indis- vides at least 80% power to detect the MCIDs or tinguishable from the optimum treatment, thus identifying hypothesized effect sizes for the main effects of each a set of candidate options for the best combination of component for all four outcomes and for analyses of treatment components. This process will be applied for main effects in subgroups and conditional comparisons both mechanistic and patient-centered outcomes. for each outcome except global stiffness. Power is more We will explore responder status after two SMT ses- limited for secondary aims, such as pairwise interac- sions as a possible effect moderator by adding a main ef- tions within subgroups. fect for responder status and interaction terms between Because the analyses of the longitudinal models will be responder status and the indicator variables for the based on restricted maximum likelihood estimation, stat- treatment components which are retrained in the final istical inferences will remain valid so long as missing simplified models for the different outcomes developed data follow a missing at random structure [69]. We do using the BIC criteria for each of the outcomes for the not believe missing data will lead to substantial bias in primary aims. Statistically significant interactions be- our primary evaluation of protocol components. How- tween responder status and main effect and/or inter- ever, we will compare participant characteristics between action terms between treatment components will be subgroups with missing and non-missing data at interpreted as suggesting effect moderation. Recognizing four weeks and if substantial deviations are detected or that tests for interactions have limited statistical power, the rate of missing data is greater than expected, mul- we will also fit the simplified models developed in the tiple imputation will be applied using comprehensive primary aim separately under the presence and absence imputation models which include auxiliary variables to of each factor (dichotomizing using a median split for account for additional predictors of missingness and/or continuous factors) and graphically display the estimated the values of the outcome variables [71]. treatment effects at both levels of responder status. Rec- ognizing the potential for lower statistical power, the re- Trial and data monitoring sults of this aim will be interpreted as exploratory. Trial supervision includes a steering committee com- posed of the investigators and representatives of the Sample size and missing data funding agency (National Institutes of Health). A separ- We estimated standard deviations and pre-post correla- ate Data Safety and Monitoring Committee comprising tions for each outcome based on our prior work [33]. three external members with expertise in SMT, LBP, and Assuming a sample size of 280 and 92% retention to clinical trials will also provide at least annual review of Table 3 Assumptions and detectable effect sizes informing sample size for the project Assumptions for outcome measures 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 prior 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 0.068 8.24 1.53 Conditional comparison 0.53 0.048 5.83 1.08 Main effect in 50% of participants 0.53 0.045 5.83 1.08 Interaction in 50% of participants 1.05 0.091 11.65 2.16 Fritz et al. Trials (2018) 19:306 Page 10 of 12 study and any safety issues as necessary. Protocol modi- then be examined in future randomized clinical trials in fications will be reported to these bodies and recorded an effort to move beyond modest effect sizes for SMT in trial registry. and ultimately to enhance patient-centered outcomes for patients seeking treatment for LBP. Discussion Moving beyond the modest effect sizes for LBP treatments Additional files including SMT requires evidence informing optimal Additional file 1: 2017 CONSORT checklist of information to include treatment protocols. Optimized protocols can then be when reporting a randomized trial assessing nonpharmacologic tested in clinical trials. The MOST framework provides a treatments (NPTs)*. (DOCX 38 kb) multi-phase strategy to optimize an intervention protocol. Additional file 2: SPIRIT 2013 Checklist: Recommended items to address Based on our prior work, we are examining SMT provided in a clinical trial protocol and related documents*. (DOC 123 kb) in various dosages with exercise co-interventions designed to accentuate SMT’s effects of spinal stiffness and multifidus Abbreviations FABQ: Fear avoidance beliefs questionnaire; LBP: Low back pain; muscle activation. Our factorial design will permit efficient MOST: Multiphase Optimization Strategy; NPRS: Numeric pain rating scale; examination of these treatment components and their inter- ODQ: Oswestry disability questionnaire; PCS: Pain catastrophizing scale; actions on clinical as well as mechanistic outcomes. We will SMT: Spinal manipulative therapy also consider the moderating effect of early response to a Acknowledgements brief (two-session) SMT protocol. This strategy will address The authors acknowledge Ms. Molly McFadden, Dr. Anne Thackeray, Dr. an important clinical question related to the interpretation Jake Magel, Amy Rogers, and Lynne Wong for their assistance in of early response to SMT and the extent to which it should supporting this project. influence subsequent treatment decisions. Funding This project provides innovation in several areas of This project is funded by the National Center for Complimentary and critical importance for future studies of SMT. First, our Integrative Health at the National Institutes of Health (1UH3AT009293–01). The study was supported by the University of Utah Study Design and project will be the first that seeks to optimize SMT Biostatistics Center with funding in part through grant 5UL1TR001067–02 treatment protocols for patients with LBP that is guided (formerly 8UL1TR000105 and UL1RR025764) from the National Center for by a validated model explaining the mechanisms under- Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health. The funder was not involved in lying the therapeutic effects of SMT. The project investi- designing the study or in the writing of this manuscript. gates clinically relevant and potentially scalable SMT protocol components. Our project examines both short- Availability of data and materials The final dataset will include data from approximately 280 participants and and long-term outcomes. Additionally, we are grounding will include self-reported data and variables collected for mechanistic our work in the MOST framework described specifically outcomes. We will make the de-identified data and associated documentation for optimizing multi-component treatment protocols but available to users under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify not previously applied to SMT. any individual participant; (2) a commitment to maintaining the data using Our design comes with several important limitations. appropriate, secure technology; and (3) a commitment to destroying or Randomization to co-interventions will occur after two SMT returning the data after analyses are complete. treatment sessions. In clinical practice, co-interventions Authors’ contributions typically are initiated alongside SMT instead of our phase JF and GK led development of the project, obtained funding, and approach. Repeated spinal stiffness and multifidus contributed to all other aspects of the project. JS, EL, and DS contributed muscle activation measures may influence outcomes in a to the final design and implementation of intervention protocols and recruitment procedures. TG designed the analysis plan for the project. All manner that is also not reflective of clinical practice. Our authors have read and approved the final manuscript. JF and GK will have optimization strategy incorporates only two dosages of access to final dataset. All authors have read and approved this manuscript. SMT (two or eight sessions). Our long-term assessment Ethics approval and consent to participate only extends to three months following enrollment which Ethics approval has been received from the University of Utah (IRB_00092127) may not be adequate for a chronic recurrent condition like and University of Alberta (Pro00067152) Institutional Review Boards. Informed LBP. Our protocol does not permit clinicians or partici- consent will be obtained from all participants in the study. pants to be blinded to intervention groups. Consent for publication This trial has the potential to advance understanding The individuals appearing in Figs. 4 and 5 have agreed to publication of of the underlying mechanisms of SMT for individuals these figures with identifiable information. with LBP and promote the identification of SMT proto- Competing interests cols that can be implemented in clinical trials and prac- The authors declare that they have no competing interests. tice. We are placing this study within a MOST context and our goal for this phase II project is to define an opti- Publisher’sNote mized protocol for providing SMT using a factorial de- Springer Nature remains neutral with regard to jurisdictional claims in sign. The optimized protocol defined in this study can published maps and institutional affiliations. Fritz et al. Trials (2018) 19:306 Page 11 of 12 Author details 19. Colloca CJ, Keller TS. Stiffness and neuromuscular reflex response of the College of Health, University of Utah, 520 Wakara Way, Salt Lake City, UT human spine to to posteroanterior manipulative thrusts in patients with 84108, USA. Department of Physical Therapy & Athletic Training, University low back pain. J Manip Physiol Ther. 2001;24:489–500. of Utah, 520 Wakara Way, Salt Lake City, UT 84108, USA. Department of 20. Triano JJ. Biomechanics of spinal manipulative therapy. Spine J. 2001;1:121–30. Internal Medicine and Director, Population Health Research Study Design 21. Cramer GD, Gregerson DM, Knudsen JT, Hubbard BB, Ustas LM, Cantu JA. The and Biostatistics Center, School of Medicine, University of Utah, 295 Chipeta effects of side-posture positioning and spinal adjusting on the lumbar Z joints: Way, Salt Lake City, UT 84132, USA. Department of Physical Therapy, Faculty a randomized controlled trial with sixty-four subjects. 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