Effect of Usual Medical Care Plus Chiropractic Care vs Usual Medical Care Alone on Pain and Disability Among US Service Members With Low Back Pain

Importance It is critically important to evaluate the effect of nonpharmacological treatments on low back pain and associated disability. Objective To determine whether the addition of chiropractic care to usual medical care results in better pain relief and pain-related function when compared with usual medical care alone. Design, Setting, and Participants A 3-site pragmatic comparative effectiveness clinical trial using adaptive allocation was conducted from September 28, 2012, to February 13, 2016, at 2 large military medical centers in major metropolitan areas and 1 smaller hospital at a military training site. Eligible participants were active-duty US service members aged 18 to 50 years with low back pain from a musculoskeletal source. Interventions The intervention period was 6 weeks. Usual medical care included self-care, medications, physical therapy, and pain clinic referral. Chiropractic care included spinal manipulative therapy in the low back and adjacent regions and additional therapeutic procedures such as rehabilitative exercise, cryotherapy, superficial heat, and other manual therapies. Main Outcomes and Measures Coprimary outcomes were low back pain intensity (Numerical Rating Scale; scores ranging from 0 [no low back pain] to 10 [worst possible low back pain]) and disability (Roland Morris Disability Questionnaire; scores ranging from 0-24, with higher scores indicating greater disability) at 6 weeks. Secondary outcomes included perceived improvement, satisfaction (Numerical Rating Scale; scores ranging from 0 [not at all satisfied] to 10 [extremely satisfied]), and medication use. The coprimary outcomes were modeled with linear mixed-effects regression over baseline and weeks 2, 4, 6, and 12. Results Of the 806 screened patients who were recruited through either clinician referrals or self-referrals, 750 were enrolled (250 at each site). The mean (SD) participant age was 30.9 (8.7) years, 175 participants (23.3%) were female, and 243 participants (32.4%) were nonwhite. Statistically significant site × time × group interactions were found in all models. Adjusted mean differences in scores at week 6 were statistically significant in favor of usual medical care plus chiropractic care compared with usual medical care alone overall for low back pain intensity (mean difference, −1.1; 95% CI, −1.4 to −0.7), disability (mean difference, −2.2; 95% CI, −3.1 to −1.2), and satisfaction (mean difference, 2.5; 95% CI, 2.1 to 2.8) as well as at each site. Adjusted odd ratios at week 6 were also statistically significant in favor of usual medical care plus chiropractic care overall for perceived improvement (odds ratio = 0.18; 95% CI, 0.13-0.25) and self-reported pain medication use (odds ratio = 0.73; 95% CI, 0.54-0.97). No serious related adverse events were reported. Conclusions and Relevance Chiropractic care, when added to usual medical care, resulted in moderate short-term improvements in low back pain intensity and disability in active-duty military personnel. This trial provides additional support for the inclusion of chiropractic care as a component of multidisciplinary health care for low back pain, as currently recommended in existing guidelines. However, study limitations illustrate that further research is needed to understand longer-term outcomes as well as how patient heterogeneity and intervention variations affect patient responses to chiropractic care. Trial Registration ClinicalTrials.gov Identifier: NCT01692275


Introduction
The focus of this study is on low back pain (LBP) for several critical reasons. First, LBP is well-recognized as a public health problem in both military and civilian populations. Second, ninety percent of LBP in clinical practice is diagnosed as "idiopathic," because its pathophysiology, diagnosis and treatment are not well understood. 1,2 This pervasiveness, as well as the lack of understanding of the condition, have led to a consensus among experts on the importance of an extensive research agenda focusing on clinically relevant scientific questions about the problem. 3,4 Third, LBP has no cure, or even a "silver bullet" medical approach. Carey et al. (2009) recently conducted a survey to determine health care utilization patterns in patients with chronic LBP. 1 They found high health care utilization in this group, with an average of 21 visits to an average of 2.7 provider types annually. Many of the tests and treatments used did not conform to evidence-based practice. The authors conclude that 1) care utilization for chronic LBP is very high, including high rates of use of advanced imaging, narcotics, and physical treatments; 2) use of evidence-based treatments is low when compared with current best evidence; and 3) many treatments appear to be over-utilized. Fourth, the most recent comprehensive survey of complementary and alternative medicine (CAM) use in the US showed that 17% of those who use CAM treatments, including chiropractic, do so for back pain or problems, making it the most common and costly condition for which chiropractic treatment is sought. 5 Fifth, a cadre of randomized clinical trials (reviewed below) generally shows a positive benefit from chiropractic manipulative therapy (CMT), the cornerstone of chiropractic practice, for LBP. Finally, investigators for this study are able to present pilot data demonstrating the effectiveness of CMT in active duty military personnel for LBP (reviewed below).

Overview of Low Back Pain and the Use of Chiropractic Manipulative Therapy:
LBP is a well-recognized public health problem in the US with estimates of overall prevalence ranging from 12-33% and one year prevalence ranging from 22-65%. 6 Back pain is the 2 nd most frequent reason for physician visits, the 5 th for hospitalizations, and 3 rd for surgery. There is no question it is debilitating to society: in the civilian sector, work-related cases result in over one million lost work days per year and nearly 15 times that many visits to medical doctors. Care and productivity cost estimates in the US are at least $26 billion or more annually. 7,8

Low Back Pain in the Military
Low back pain (LBP) is the most common cause of disability worldwide, but it is even more prevalent in active duty military personnel. A recent study published in Archives of Internal Medicine reported that back pain is most prevalent in soldiers in combat deployments, and it is among the most likely conditions to interrupt combat duty. 9 In fact, more than 50% of all diagnoses resulting in disability discharges from the military across all branches are due to musculoskeletal conditions. 10 . A study by Jones and Hanson (2010) found that payments to veterans amounted to $485 million to newly disabled Army personnel in 1993. 11 Lincoln and colleagues examined the natural history and risk factors that led to disability among US Army personnel. 12 Their study was a retrospective cohort that followed active-duty Army personnel from initial hospitalization for a musculoskeletal-related condition for years 1989-1996 through the development of physical disability up to 1997. To be included in the study, subjects had to have been on active duty at the time of hospitalization, been hospitalized for a musculoskeletal disorder or severe sprain/strain during 1989-1996, and have completed a health risk appraisal during that period. Data were derived from the Total Army Injury and Health Outcomes Database. The outcome of interest, disability, was defined as having been assigned the following status at a medical evaluation board during the study period and up to 1997: • Permanent disability/retirement (disability rating of at least 30% or having 20 years of service) • Severance without benefits (disability rating of less than 30% and having less than 20 years of service) • Temporary disability (similar to permanent disability except for the possibility that the condition will change within the next five years and enable the subject to return fit for duty) The data from this project demonstrated that intervertebral disc degeneration had the highest cumulative disability at 6 and 12 months, and that the five-year cumulative risk of disability was highest for intervertebral disc degeneration, intervertebral disc derangement and non-specific back pain. One surprising finding was that personnel at highest risk included those with 1-4 years of service, similar to the group under study in this project, compared to those with more than 10 years of service. Back conditions were associated with the highest 5-year cumulative risk of disability discharge, making them a critical issue with regard to troop and personnel readiness.
Back pain has been characterized as "The Silent Military Threat," because of its negative impact on mission readiness, and the degree to which it compromises a fit fighting force. For these reasons, military personnel with LBP need a practical and effective treatment that relieves their pain and allows them to return to duty quickly, but also one that preserves function and military readiness, addresses the underlying causes of the episode and protects against re-injury. The DoD/VA clinical practice guidelines (CPG's) for the treatment of LBP offer wide options for care. These include screening for "red flag" indicators of potential surgical or medical urgencies, and first-line treatments including NSAID's and acetaminophen; patient education on the importance of exercise; and monitoring and documentation of clinical course. However, they are generally focused on standardizing minimum care and documentation that can be applied in all practice settings where service members are treated, and less focused on long-term strategies for the minimization of lost duty time and for secondary prevention. The program of research proposed herein is aimed at meeting the needs to establish evidence-based standards of care for acute, sub-acute and chronic LBP, which can be integrated in to the healthcare systems for all active-duty personnel, including combat-deployed troops and Special Operation Forces.

Definition of Chiropractic Manipulative Therapy
Chiropractic manipulative therapy (CMT) is a manual therapy commonly used to treat low back pain and is the cornerstone of chiropractic practice. The procedure in its broadest definition describes the therapeutic application of a load (force) to specific body tissues (usually vertebral joints). CMT can vary in terms of its velocity, amplitude and frequency, as well as anatomical location, choice of levers, and direction of force application. 13,14 In a course of care, the dosage of CMT (e.g. in terms of treatment frequency) can also vary significantly. Numerous procedures are used in practice, but a more detailed and quantitative biomechanical picture of CMT is emerging from studies on the forces applied and the resultant kinetics and kinematics. [14][15][16] CMT can be divided into two broad categories by their force/time profiles: those maneuvers that deliver a high-velocity low amplitude load or impulse "thrust" to body tissues (HVLA-CMT) and those that deliver a low-velocity variable amplitude load (LVVA-CMT). [17][18][19] Velocity refers to the speed with which a load is applied, while amplitude refers to the depth of the thrust into body tissues. HVLA manipulations are called "adjustments" by chiropractors, or "manipulation" by other professionals. Both terms distinguish it from LVVA maneuvers, which most experts label as "mobilization". 14,20 HVLA-CMT procedures are often associated with a cavitation sound or "crack," as synovial joint linings are quickly separated. In contrast, in low-velocity maneuvers, the loads are applied slowly, and the amplitude (depth) of each load may vary depending on the clinical situation. Both forms of CMT are typically used by most doctors of chiropractic and both will be used in this study. biomechanics, the nervous system, chiropractic manipulation therapy and end-organ physiology. The figure is not all inclusive; circulatory and immunological changes in response to CMT have also been suggested. 22,23 The dark black line represents a "black box" of mechanisms by which a disordered motion segment is thought to contribute to a patient's symptomatology in general. The facet joints are thought to become restricted, disturbed or functionally asymmetric due to paraspinal muscle dysfunction, synovial meniscoids or inclusions trapped between articular surfaces of the facet joints, intra-articular or myofascial adhesions and/or distortion of the annulus fibrosus. [24][25][26][27][28][29] Any of these vertebral dysrelationships may produce a biomechanical overload with effects on nerve roots or spinal cord directly or via meningeal traction, or on surrounding paraspinal tissues that secondarily alter their physiology including the signaling properties of mechanically-or chemically-sensitive neurons in the paraspinal tissues. 30 The changes in neural activity are thought to modify neural integration, either by directly affecting reflex activity and/or by affecting central neural integration within motor, nociceptive and autonomic neuronal pools. Pain, discomfort, altered muscle function or autonomic function comprises the signs or symptoms that might cause patients to seek CMT. Mechanical treatment using manipulation, then, theoretically alters the inflow of sensory signals from paraspinal tissues or activity of central neurons either by direct effects on the nervous system or via indirect effects on tissue biomechanics. A goal of CMT is to remove joint restrictions and "restore maximal, pain-free movement of the musculoskeletal system". 22,27,31,32

Randomized Controlled Trials (RCTs) of chiropractic manipulation therapy
The 1975 NINCDS conference on the "Research Status of Spinal Manipulative Therapy" pointed out the lack of any significant research to justify claims made by chiropractors or any other practitioner of CMT. 33 By 1992, at least 45 RCTs of all forms of CMT for the treatment of acute, sub-acute and chronic LBP have been published. 8 Thirty-one favored CMT over the comparison treatments in at least a subgroup of patients, and the rest found no significant differences 8 .
The majority of systematic reviews are in agreement that CMT appears to reduce pain and disability at least some of the time to some degree for a significant proportion of LBP patients. [34][35][36][37] They also agree on the highly variable quality of extant trials and reviews 38,39 , on the inconsistent results, small effect sizes, and large variation in outcomes. 40,41 Part of the problem is attributable to poor trial methodologies, part to poor execution and reporting, and part is probably due to the large variation in CMT treatments that have been studied. Finally, it is suspected that there is large and as yet unidentified heterogeneity in LBP patients. 42 The unexplained inconsistency in RCT results currently obscures the true utility of CMT for LBP patients and contributes to ongoing debate. Current RCT evidence has not ruled out CMT's potential effectiveness for LBP, but the appropriate role of CMT in treating LBP has not been confirmed; thus additional high quality RCTs are required. 11,37,43,44 Successful completion of the study aims outlined in this proposal will not only provide critical information regarding the impact of CMT in military populations; it will also represent the largest multi-site randomized clinical trial conducted to evaluate CMT to date.

Chiropractic manipulation therapy and Chiropractic
CMT delivered by doctors of chiropractic is commonly used by LBP patients. Although CMT is a treatment procedure used by both conventional and CAM professions, chiropractors provide over 90% of CMT in the US. 4 Chiropractors report using some form of CMT on at least 80% of their patients. 45,46 At least 7.5% of the US population seeks care from chiropractors annually, representing approximately 190 million patient visits. 5,47 A national survey of patterns and perceptions of care found that 20% of those reporting back or neck pain sought chiropractic care, while 37% sought conventional care. 48 Surveys suggest that patients are highly satisfied with chiropractic care. 49,50 More than 60% of chiropractic patients report their care as being "very helpful," while 27% report the same for conventional medical care. 48

Comparative Effectiveness Research
This protocol describes a comparative effectiveness trial (CER). The Institute of Medicine definition 51 for Comparative Effectiveness Research (CER) is: "CER is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a clinical condition, or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both individual and population levels." The Agency for Healthcare Research and Quality (AHRQ) states that their Effective Health Care Program purpose is to fund research that provides reliable and practical data that can inform decisions in clinical practice. 52 CER has been identified by several names in the past: pragmatic trials, head-to-head trials and practical clinical trials.
Some writers have contrasted CER (or Practical Clinical Trials -PCTs) trials to explanatory trials 53 , which are hypothesis driven and usually done with the hope of revealing the biological effect of a treatment. In contrast CER or pragmatic trials are done to assist decision makers. Zwarenstein and Treweek (2009) note that there is often a mismatch between the clinical setting in which decisions must be made and the RCTs (explanatory trials to test hypotheses). 54 They note "evidence from an explanatory trial is unlikely to inform a pragmatic question, nor vice versa…". 51 One key feature of CER is a focus on effectiveness rather than efficacy. 55 Efficacy establishes a causal connection between an intervention and a specific outcome. To do this it is necessary to control all biases so that the only thing contributing to the outcome is the specific intervention. This requires that the enrollments in the trial are controlled and random, that the intervention is standardized and controlled (it must be constant and identical across all subjects), that the populations are homogeneous and that the outcome measures are standardized and objective. These trials will have at least two arms, one where the intervention is given and one where a sham treatment or a placebo is given. Individual subjects are randomly allocated to one of the arms. Neither the provider of the therapy nor the patient should know which arm of the trial the patient is in (double blinding).
The problem is that to achieve the kind of controls you need for an efficacy RCT, you end up creating a situation that is very different from the normal way in which the therapy will ultimately be practiced in the real world. The exclusion criteria for the subjects in the trial may be so restrictive that the very subpopulations the provider wants to treat were not even included in the trial. In summary, the evidence from efficacy RCTs may be rigorous but not relevant to the real world of practice. Most methodologists describe pragmatic trials as enrolling all patients to whom health care providers might offer the intervention, allowing clinicians to administer the intervention and co-interventions without restrictions and measuring patient-important outcomes. 56 Maclure (2009) in discussing how to describe pragmatic trials to policy makers, states "pragmatic trials are real-world studies for decision whereas explanatory trials are specialized studies for information." 57 The investigative team has chosen a modified comparative effectiveness approach for the proposed study that combines elements of both efficacy trials and pragmatic trials. We believe that this is the best way to answer questions that will be meaningful to policy makers as they consider the appropriate role for CMT in active duty military populations. Further, our experience in the conduct of clinical trials in military treatment facilities (aka site) has shown us that this type of trial is feasible to conduct in busy clinical practice settings.

Smoking in the Military
Smoking is a known major public health concern in the United States. Recent statistics indicate that 20.6% of American adults, or 46 million people, smoke. 58 Smoking is a proven risk factor for major illnesses, such as lung cancer, chronic obstructive pulmonary disease (COPD), heart attacks, stroke and a host of other related cancers and vascular syndromes. 59 The individual lifelong impacts of smoking include decreased overall quality of life, significant disability that affects work life and productivity, as well as decreased life expectancy. The societal impact in the United States has been estimated as: number of smoking-related deaths per year (450,000); productivity loss due solely to smoking-related premature deaths of workers ($97 billion); and medical costs for smoking-related illness ($96 billion). 58 Smoking in the military is associated with even more disturbing statistics. A 2009 report by the Institute of Medicine reported an overall smoking rate of more than 30% in active duty (AD) personnel. Additional data suggest that as many as two thirds of military personnel deployed use tobacco. The report recommended that the DoD close "the pipeline of new tobacco users entering the military and promote cessation programs to ensure abstinence." Furthermore, it urged the military to "treat tobacco use in the same way as other health-related behaviors, such as alcohol abuse and poor physical fitness." The 2005 DoD Survey of Health-Related Behaviors reported that smoking rates were highest among members of the Army and Marine Corps (38.2% and 36.3%, respectively); smoking was more prevalent among men than women (37.8% v. 35.5% overall, respectively); and that the 18-25 year old segment of the military has higher smoking rates (38.7%) than the 26-55 year-olds (35.7%). 60 The high costs of smoking in the military, reportedly $564 million 61 , are driven higher still when one considers literature indicating that smokers are more likely to fail trainings and PT tests; [62][63][64] indulge in other substance abuse behaviors; and to sustain injuries, particularly musculoskeletal injuries. 65,66 Since the heaviest tobacco use occurs in the same populations that characterize young combat soldiers and Marines, who are more prone to injury, and given the high overall rates of tobacco use in the military, it is appropriate that programs targeting smoking cessation be evaluated in military patients seeking care for LBP.
Research has linked smoking with back pain, identifying it as a risk factor for back pain severity and duration. [67][68][69] Smoking has also been implicated as self-medication for back pain. 70 It therefore comes as no surprise that chiropractors have taken increasing interest in promoting cessation of tobacco use by their patients. 71,72 Gordon et al found that chiropractors in Oregon advise their patients to quit smoking and were interested in learning more about helping their patients quit smoking. 73 The authors subsequently developed and pilot tested a tobacco cessation program tailored for use in private chiropractic practice. Cessation outcomes were positive and the program was found to be promising. 74 It should be noted that no randomized trials have assessed the effect of CMT for smoking cessation. 36 There is no current reason to suspect a direct effect on tobacco cessation. However, CMT might help relieve back pain, which in turn might reduce patients' need to self-medicate with tobacco. A recent study by Gordon et al provides both preliminary data and a smoking cessation program for delivery by doctors of chiropractic, which form the model for the proposed nested study of tobacco cessation. 74 We will attempt to replicate these findings in active duty smokers with LBP.

Summary of Significance
The significance of this study is high. Low back pain (LBP) is a prevalent public health problem in both the military and civilian populations. Currently a clear "gold standard" medical treatment for low back pain does not exist and studies show that evidence-based guidelines are rarely used in general practice. Thus, there is a need to consider innovative treatment options for chronic diseases such as LBP. Our preliminary data suggest that chiropractic manipulative therapy (CMT) in addition to standard medical care may be superior to standard medical care alone in active duty service members. In addition, doctors of chiropractic are well positioned to provide information to support tobacco cessation. The results from this randomized clinical trial, with a nested tobacco (smokers and smokeless tobacco users) cessation intervention will provide critical information regarding the health and mission-support benefits of chiropractic health care delivery for active duty service members in the military.

Specific Aims
The primary objectives of the proposed study described in this clinical protocol are to: 1) assess the effectiveness of chiropractic manipulative therapy (CMT) for pain management and improved function in active duty service members with low back pain that do not require surgery; and 2) to assess the impact of a chiropractic intervention on smoking cessation. This study will focus on active duty service members who are not deployed in theater. The primary hypothesis is that CMT, in addition to conventional medical care, will provide significantly better pain relief and improved functional status in volunteers with LBP than conventional medical care alone. A secondary hypothesis is that education and monitoring of tobacco habits provided during routine chiropractic care visits for LBP will result in a significant decrease in the average number of tobacco use per week among those who selfidentify as a tobacco user at baseline. Please refer to Figure 2 'Chiropractic Trials Logic Model' for a snapshot of the program design. SPECIFIC AIMS A multi-site RCT will be conducted at 3 military sites [Walter Reed National Military Medical Center in Bethesda, MD (n = 250); Naval Hospital in Pensacola, FL (n = 250); Naval Medical Center in San Diego, CA (n = 250)] to accomplish the following two Specific Aims. Specific Aim #1: To evaluate the pain and functional outcomes of CMT plus conventional medical care to those of conventional medical care alone in a total of 750 active duty military personnel ages 18-50 with non-surgical acute, sub-acute or chronic LBP. Specific Aim #2: To measure the impact of a tobacco cessation program delivered by doctors of chiropractic in active duty volunteers receiving CMT for LBP.

Sample and Methodology
To accomplish the specific aims, a multi-site Clinical Comparative Effectiveness Trial designed to rigorously compare the outcomes of CMT and conventional medical care (CMC) to CMC alone. Chiropractic treatment will include chiropractic manipulative therapy (CMT) plus ancillary physiotherapeutic interventions. CMC will be delivered following current standards of medical practice at each site. At each of the three participating sites, active duty military personnel, ages 18-50, who present with acute, sub-acute or chronic low back pain that does not require surgery will be randomized to one of the two treatment groups. Outcome measures include the Numerical Rating Scale for pain, the Roland-Morris Low Back Pain and Disability questionnaire, the Back Pain Functional Scale for assessing function, and the Global Improvement questionnaire for patient perception regarding improvement in function. Patient Expectation and Patient Satisfaction questionnaires will be used to examine volunteer expectations toward care and perceptions of that care. Pharmaceutical use and duty status data will also be collected. The PROMIS-29 will be used to compare the general health component and quality of life of our sample at baseline. As a secondary aim, this clinical trial will include a nested study designed to measure the impact of a tobacco cessation program delivered by a doctor of chiropractic.

OVERVIEW OF TRIAL ORGANIZATION
Responsibility for the conduct of the clinical trial described in this protocol is placed on the Palmer College of Chiropractic, in collaboration with RAND Corporation, the parent institution, and the Samueli Institute (SIIB). Please see the organizational chart in Figure 4.
Dr. Christine Goertz is Co-PI of the grant, with the overall administrative and scientific responsibility for the success of the clinical trial described in this protocol. As Vice Chancellor for Research and Health Policy at Palmer College of Chiropractic Research, reporting directly to the Chancellor, she is in an excellent position to ensure the availability of institutional resources. She will work closely and continuously with the Internal Steering Committee (ISC) and Expert Advisory Committee (EAC) to assure progress, focus, coordination and synergy.

Internal Steering Committee
Dr. Coulter will establish and chair an Internal Steering Committee (ISC) composed of the lead investigators and project managers from RAND, Palmer and Samueli Institute, as well as the site PIs. This committee will provide a wide range of input to manage the multi-centered trial. The primary purpose of the ISC is to share information, monitor progress, raise issues and solve problems and plan for future research. The ISC will make recommendations for policy or protocol additions or changes when necessary. In keeping with a governance structure most conducive to productive research, the ISC will be advised when major decisions regarding the study must be taken. ISC members have the responsibility to communicate and share appropriate decisions with their project staff.
Regular telephone meetings of the ISC will take place on a weekly basis, with RAND, Palmer and Samueli personnel required to attend by teleconference. Agendas will be prepared in advance of each meeting and minutes will be recorded, circulated and kept. These meetings will also be used to confirm the success or make recommendations regarding the more regular communication expected between Co-PIs. Site PIs and PMs will have one-on-one monthly meetings with the PI and lead PM at Palmer.

External Advisory Committee
The External Advisory Committee (EAC) will be the primary advisory body for the clinical trial and will assist the Co-PIs to meet its goals. The EAC will provide written annual reports to the project investigators focused on the following issues: 1) progress of research projects; 2) effectiveness of communication and collaboration between co-investigators; 3) use of resources; 4) changes to the original research plan; 5) the Co-PI's effectiveness; and 6) identified challenges, problems and proposed solutions. The EAC will first meet 3 months after the award date and then will meet yearly after that. The EAC is comprised of six individuals who have all agreed to sit on the Board. These individuals represent leaders in either the research community in LBP, the chiropractic research community or in the military. They include the following individuals: Anthony

Data and Safety Monitoring Committee
The Data and Safety Monitoring Committee (DSMC) is a standing independent committee at the PCCR to provide an independent means of examining objectively accruing controlled trial data for indications of harm (from adverse events from the interventions applied or tested) as well as benefit.
The DSMC will monitor the overall conduct of the RCT described in this protocol. Responsibilities of the DSMC are: 1) to ensure the overall safety of participants in clinical trials conducted by PCCR investigators by protecting participants from avoidable harm and declaring clear benefit when there is proof beyond a reasonable doubt; and 2) to provide DoD and the EAC with advice about the scientific and ethical conduct of clinical trials.
The DSMC will meet at least twice per year either in person or by teleconference. The DSMC will evaluate the adverse event data to protect the safety of study participants. If necessary, DSMC members will make recommendations to the Co-PIs and DoD regarding continuation, termination or other modifications of the trial based on observed adverse events of the treatments under study.
The DSMC is comprised of a biostatistician, medical physician, doctor of chiropractic and epidemiologists/clinical trialists, none of whom are affiliated with Palmer. The team biostatistician will prepare a study report for the DSMC including accrual plots and other enrollment data, data collection forms processing status, baseline characteristics of enrolled participants, follow-up and treatment compliance, protocol violations and all web-based reportable adverse events (see Reporting of Adverse Events) every 6 months.

Institutional Collaboration and Support
Scientific and institutional collaboration and commitment are key attributes to the success of the proposed project. During the planning process of the grant writing, the Co-PIs identified key investigators, core resources and institutions that demonstrated a high level of enthusiasm for developing this application. An ad hoc planning team was composed to consider and reach out to potential DoD partners based on common and complementary scientific interests, expertise, past experience and productivity. Enthusiastic letters of support were included in the original grant application from each Institution and Military site involved in the project. Before the grant was received, each of the partner institutions had already contributed considerable resources to the development of this joint project and each had committed the institution and its resources to successfully carrying out the project.

Publication Committee
The publication committee consists of all investigators and other invited individuals that have contributed scientifically to this study. This committee will meet six months after the onset of primary data collection and will continue meeting once a quarter with potential to bi-weekly toward the end of implementation. They will discuss potential papers, necessary data, projected journal submissions, conference presentations and timelines for each publication project.

Naval Air Station (Pensacola, FL) n = 250
The Naval Air Station (NAS) Pensacola has approximately 11,200 active duty personnel and is the primary training base for all Navy, Marine and Coast Guard aviators and Naval Flight officers. It is also home to the Navy Flight Demonstration Team (Blue Angels), Naval Air Technical Training Center and Training Air Wing 6. Health care is provided at the Naval Hospital Pensacola (NHP), a 108-bed hospital, as well as at the Naval Branch Health Clinic which supports approximately 12,000 active duty personnel ranging in age from 18 to 55 years old. Chiropractic services were established in September 2003 and are offered at the Chiropractic Clinic, which is part of the Sports Medicine and Reconditioning Team (SMART) clinic. The clinic sees approximately 600 new patients, and 3,500 to 4,000 total patient visits a year, all of whom are active duty personnel. Seventy percent of the patients are treated for low back pain. Of these, 30% are treated for acute pain, 50% for sub-acute and 20% for chronic pain. Dr. Greg Lillie is the treating chiropractor at this site.

Walter Reed National Military Medical Center (Bethesda, MD) n = 250
The 500-bed Walter Reed National Military Medical Center (WRNMMC) is the Navy's third largest health care delivery system, providing more than 12,500 ambulatory surgeries and almost 8,000 inpatient admissions each year. It is the designated hospital for Navy and Marine casualties returning to the continental United States from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). In 2006, there were approximately 7,960 hospital admissions, 455,503 visits to hospital clinics and an average daily patient load of 128. Since 2003, WRNMMC has treated more than 1,600 war wounded service members. The chiropractic clinic there is staffed by two chiropractors and additional supportive staff, who provide care for Army (33%), Navy (40%), Marine Corps (11%) and Air Force (15%) personnel based in the Washington, DC area. Navy personnel stationed at Washington Navy Yard, Naval Surface Weapons Centers in Indian Head, and Carderock, MD, the US Naval Academy and Naval Air Station Patuxent River are among the patients served, as are Marines stationed at Quantico and Marine Corps barracks in Washington, DC. Low back pain is the most common condition treated. The doctors of chiropractic at this site are William E. Morgan and Terence Kearney.

Naval Medical Center (San Diego,CA) n = 250
NMCSD sees about 3, 600 to 4,000 active duty patients per year, 20 to 25% of which are new patient exams. Chiropractic services are part of the Physical Therapy Department and are located in the acute care area at both the Naval Air Station and BUDS Medical (SEALs). Patients seeking services come from diffuse locations including medical sick call, acute care area, flight medicine, BUDS medical primary providers, physical therapy and other specialty providers. The chief complaint of chiropractic patients is spinal pain, most often LBP (40%). Approximately 20% of the patient population is special operation forces including Explosive Ordinance Demolition (EOD), Special Boats Units and SEALs, who often suffer LBP, premature disc degeneration, disc herniations and facet arthritis. The treating doctor of chiropractic is David W. Ward and Bart Green.

Recruitment Strategies
The volunteers required for this clinical trial will be recruited primarily through the existing primary care triage system established at each site. Initial recruitment efforts will include efforts by primary contact providers with patients who present with an episode of acute, sub-acute or chronic LBP during routine patient care visits. Other recruitment efforts may include signs and brochures describing the study posted and distributed in the patient care clinic lobbies and review of existing patient records to identify patients with a previous diagnosis of low back pain.
Volunteers will not be compensated for participation in the study. Any recruitment materials will accurately reflect the study and will not advertise "free treatment" or promise a cure or benefit beyond that mentioned in the consent form protocols. In addition, all materials will be approved by local and central DoD/Palmer/RAND IRBs. Materials will not be coercive or offer undue inducements. We do not anticipate recruitment of vulnerable populations for this study.

Enrollment of Women and Ethnic as well as Racial Minorities
The inclusion of women and minorities will be proportional to that found in the active duty military population. General demographics on military populations indicate a 14.8% female distribution. Ethnic/minority distribution is as follows: 17.6% African American, 8.8% Hispanic and 9.2% other (Bray, Olmsted, et al, 2006). All reasonable attempts will be made to include representation from women and ethnic and racial minorities proportional to that found in active duty service members across the US.

Eligibility Criteria
All participants must meet the following inclusion and exclusion criteria. Use of manipulative care for any reason within the past month Unwilling to provide phone and electronic contact information Unable to confirm that they will not be transferred during the active phase of the study: i.e., deployment, receive orders for a distant duty assignment or training site or otherwise be absent from the current military site over the next 8 weeks (active study participation period).
Does not agree to be enrolled regardless of group assignment PTSD Classification

Randomization
A total of 750 active duty (AD) personnel ages 18-50 with acute, sub-acute or chronic LBP will be randomized to one of the two treatment groups. Randomization will be done by using an adaptive computer-generated minimization treatment allocation to balance volunteer characteristics between groups on the baseline factors of sex, age, LBP duration and baseline Numeric Rating Scale (NRS) measurement. The site project manager will access the Treatment Assignment Module in the passwordprotected web database system on a secured computer network and pull down the volunteer ID. The minimization algorithm will run and produce the coded treatment assignment. The treatment group assignment and date, time and study personnel ID will be stored in the SQL database. All study personnel are blinded to the next treatment assignment. The back-up treatment assignment protocol is by predetermined sequentially numbered, opaque envelopes and to be used when the web-based system for randomization is unavailable.

Overview of Data Collection
The Manual of Operating Procedures (MOOP) will be created in Year One and posted on a passwordprotected secure server with a user friendly web interface. The MOOP will include current versions of consent and HIPAA forms, paper back-up of all web data collection forms, and all protocols and procedures that are standardized across and within sites.
Using the model that was successful in conducting our pilot study at Ft Bliss, Palmer will hire site project managers for each data collection site. The site project managers will be trained and supervised by an experienced project manager at the Palmer Center for Chiropractic Research. Site project managers will have the overall day-to-day responsibility for ensuring the completion and accuracy of data collection. The data collection instruments and timing for data collection efforts are indicated in Table 1.

Baseline Visit (BL)
At this baseline visit, the site project manager will explain the handling of data and personal health information as dictated by HIPAA and guide potential participants through the informed consent process. This interview will be held in a room with a closed door to insure volunteer privacy. During the informed consent process, the site project manager will explain the study requirements and provide a study flow chart ( Figure 3) to the potential participant. This discussion will include an explanation of the interview time commitments, examination procedures (which may or may not have already occurred), follow-up assessments, intervention commitments, potential risks of participation, potential benefits of participation, what to do in case of an adverse experience, and the option for discontinuing study participation. In addition, the site project manager will answer any questions the participant may have about chiropractic care and the research study requirements and commitment. The study staff will ensure that volunteers understand and agree to all aspects of participation before proceeding.
Volunteers will have the opportunity to discuss the implications of participating in the study at the baseline visit or at any time thereafter if questions arise. These points include the following: 1. Volunteers who qualify for the study will be randomly assigned to one of two treatment groups. One involves conventional medical care only and the other involves chiropractic care in combination with conventional medical care. 2. All exams (including screening x-rays) and treatments will be provided at no charge to the volunteer. 3. Investigators cannot predict whether the treatments will be effective for each volunteer. However, based on previous evidence and clinical experience, there is a likelihood that volunteers will experience improvement in their LBP condition. 4. Potential study participants must be screened for eligibility, and if they are not eligible for the study they will be told so at that point, and will continue to receive care at the site. 5. Volunteers are expected to meet all scheduled appointments and complete all study questionnaires, interviews and tests. 6. Volunteers are expected not to initiate other types of manual or medical care for their LBP during their involvement in the study and to inform their study clinician if such treatment, or treatment for any other health problem, becomes necessary.
Once informed consent has been obtained, both the participant and site project manager will sign and date the consent form. The participant will receive a copy of the informed consent document. If the participant requests documentation about their participation in the study that does not contain protected health information, they will be given a participant certificate (Appendix F).

Exam
As discussed in recruitment strategies (section 5.1.1.1) there are 2 ways in which a potential participant enters into the study. They can either be recruited directly from their acute or primary care provider within the site clinic system or through recruitment efforts such as signs and brochures.
When military personnel present in the site clinic system, they meet initially with an independent duty corpsman (IDC) (corpsmen with specialized medical training) or other primary care provider (PCP) prior to having care rendered. The PCP or a IDC will be informed in advance that patients seeking care for back pain may be eligible for the trial and will be trained to complete an exam form which assesses study eligibility (Appendix E). When the medical examination is complete and the provider has given the military personnel their recommended conventional medical care treatments, the exam form will be given to the site project manager. S/He will key enter items from the study eligibility form into the secure module during the baseline interview after the informed consent document (ICD) has been signed. If a potential participant does not have their baseline interview completed within 2 weeks of the exam, then a new exam form and interview will need to be completed.
If study participant is recruited through other recruitment efforts, they will first go through the baseline visit and then be given the exam form. The site project manager will assist the potential participant in obtaining an appointment with a primary care provider or an independent duty corpsman who will be able to complete the exam form and provide them with conventional medical care as required in this study. The form will be returned to the site project manager, who will enter the information into the secure web module. After the form has been entered into the system, the participant will know if they meet all eligibility criteria. If so, they will be randomized to a treatment group (per section 5.1.3).

Conventional Medical Care
Conventional medical care may include the following: a focused history and physical examination; limited diagnostic imaging restricted to select volunteers (i.e., for example, those with radiculopathy); education about self-management, including maintaining activity levels as tolerated and local ice/heat application; pharmacologic management with the use of analgesics and anti-inflammatory agents; and additional therapies that may be applied for volunteers not responding to the initial interventions, including physical therapy and referral to a pain clinic.

Chiropractic Care & Conventional Medical Care
Volunteers in the chiropractic care groups will receive the same care listed above in the conventional medical care group, as well as chiropractic manipulative therapy (CMT). CMT will occur from a doctor of chiropractic over a six week period of time. We will set an a priori treatment schedule of up to 2 times per week for six weeks for this study; for a total of up to 12 total visits. It is conceivable that a participant may not medically need this number of visits. Therefore, as with conventional medical care, the treatment plan will be based on the patient's baseline evaluation by the chiropractor, the severity of the patient's condition, and how they respond to treatment. Two times a week was chosen as this frequency is a common treatment schedule seen in general clinical practice and was used in our pilot work at Ft Bliss. A duration of six weeks was chosen over the four weeks used in our pilot because in this study we will be including volunteers with sub-acute and chronic low back pain, which generally requires a longer treatment period. Following numerous discussions with the chiropractic clinicians at the three sites participating in this trial, the investigators have concluded that at some sites it may not be feasible to follow a tightly prescribed treatment schedule. Many of the DoD doctors of chiropractic frequently have waiting times of up to two weeks for a new patient, with a similar wait for additional patient visits.
To address potential differences among sites on this issue, we will take the following steps: 1) each site will have a large enough sample size to detect significant differences between groups; 2) we will carefully track the number of visits each volunteer received and the timing of those visits; 3) investigators at RAND and SIIB will use both quantitative and qualitative methods to evaluate the potential impact that varying treatment schedules has on patient care outcomes. At each treatment visit, the study clinician will determine which of the two most common therapeutic approach(s) to consider with each participant: high-velocity, low-amplitude (HVLA) or low-velocity, variable-amplitude (LVVA). An informal survey of the doctors of chiropractic participating in this study confirmed that these two treatments are most commonly used in active duty service members. Thus, treatment will be limited to these two techniques for the purposes of this study.
The clinician will decide which form of CMT to use based primarily upon the diagnosis and combination of co-morbid or complicating diagnoses. The volunteer's previous response to care (if known), flexibility and mobility, and general condition are also considered. Clinicians then make a second decision regarding the application (location and direction) of CMT. This decision is most often based upon the diagnosis; however, other items are considered such as tenderness, hypertonicity, hypomobility, positions of relief and provocation, imaging findings (e.g., spinal curvatures, degeneration, spondylolisthesis) and other factors individual to the case.
Lastly, the clinician considers what other forms of treatment would benefit the volunteer. Rehabilitation exercises (attended or at-home), passive stretching, neuromobilization techniques, manual muscular therapies (e.g., ischemic compression, friction massage), counseling (proper movement, activities and nutrition), or other modalities such as ultrasound, electrical neuromuscular stimulation (e.g. interferential current), heat, ice, taping and bracing may also be used as adjunctive therapies. 75 The type of CMT and adjunctive therapies used in the study will be carefully tracked throughout the study.
At each chiropractic visit, a treatment form will be completed (Appendix E) by the chiropractor. All forms will follow the data storage collection procedure described in Section 5.2.

Tobacco Cessation
Investigation of a tobacco cessation program delivered by doctors of chiropractic will be imbedded in the LBP trial. Volunteers randomized to the CMT who self-identify as tobacco users (i.e. smokers or smokeless tobacco users) at baseline and agree to participate by signing the informed consent document will receive the program. The tobacco cessation program to be used is based on the "Clinical Practice Guidelines for Treatment of Tobacco Use and Dependence" of Fiore et al. 76,77 These guidelines promote the use of the "5As" of a tobacco cessation intervention to be delivered by health care practitioners. It has been refined for dental and chiropractic practice by Gordon et al (R21 DA021349) and adapted for a large RCT in public dental clinics. 74,78 Volunteers for the LBP trial will be screened to identify tobacco users and level of interest in quitting as in Gordon et al. 74,78 Smokers will be defined as persons who have smoked at least one cigarette, cigar, or pipe in the last 7 days. Smokeless tobacco users will be defined as anyone taking at least one dip or chew in the last 7 days. Willingness to participate in the tobacco cessation component of the study will be documented through written informed consent. Those who wish to participate in the LBP study but not the tobacco cessation program will still be allowed into the LBP study as participation in the nested tobacco cessation study is optional.
Prior to initiation of data collection, study chiropractors will attend a 3-hour webinar training session on delivering the intervention. 74,78 (Handouts and lecture items are in Appendix B.) The webinar will include a PowerPoint presentation to present the tobacco cessation program. Refinements may be made to address study clinic operating procedures. Brief follow-up training sessions will be required every six months The outline for the webinar is: 1) Tobacco Cessation in Chiropractic Setting; 2) Tobacco-Related Health Problems; 2a) Chronic Pain/Musculoskeletal Problems; 2b) Decreased Healing; 2c) Respiratory Problems; 2d) Heart Diseases; 2e) Allergies; 2f) Diabetes; 2g) Macular Degeneration; 3) Helping your Patients Quit Tobacco; 3a) Patient Flow; 3b) Ask about Tobacco Use; 3c) Ask Assessment Questions; 3d) Advise-Relate Findings & Give Direct Advice to Quit; 3e) Arrange Help for Quitting; 4) Assess Readiness to Quit; 5) What about "Hard Core" Users?; 5a) Motivational Interviewing; 5b) Express Empathy; 5c) Promote Patient Autonomy; 5d) Avoid Argumentation; 5e) Roll with Resistance; 5f) Develop Discrepancy; 5g) Support Self-Efficacy; 6) Complete Personal Quit Plan; 6a) Reasons for Quitting; 6b) 5 Step for Quitting: Get Ready, Get Support, Learn New Skills & Behaviors; Get Cessation Treatment; Be Prepared; 7) Quitting Resources; and 8) Follow-Up.
Prior to recruitment at each site, the study chiropractor will complete a baseline tobacco cessation survey and then again 1 year after recruitment has started at their site. (Survey is in Appendix C.)

Tobacco Cessation Intervention
Volunteers in the chiropractic treatment group will receive the "5As" tobacco cessation program as adapted for chiropractic clinics. 74 It is designed to be brief and fit into clinic patient flow. The program will be modified slightly to fit into this randomized trial.

Ask:
The volunteers will be asked about their tobacco use status at each visit by the treating chiropractor. The questions will include the baseline questions from the baseline instrument.

Advise:
The chiropractor will discuss health risks of using tobacco. S/he will emphasize how tobacco affects the volunteers' low back condition and other health problems they may have such as chronic pain, decreased healing, respiratory conditions, and allergies. The chiropractor will then advise the volunteer to quit, and will be direct and non-judgmental, as well as acknowledging the difficulty of quitting.

Assess:
The chiropractor will ask a series of questions about the readiness to quit. These questions will include the "5 Rs" of motivational interviewing: relevance, risks, rewards, roadblocks, and repetition. Reasons for quitting must be made personally relevant. The volunteers must identify risks and rewards for themselves. Personal obstacles will be identified. The chiropractor will express empathy, promote patient autonomy, and support self-efficacy.

Assist:
The chiropractor will assist the volunteer in completing a personal quit plan with quit date. The chiropractor will work with the volunteer on a five-step plan for quitting (get ready, get support and encouragement, learn new skills and behaviors, get cessation treatment, and be prepared for difficulties), disseminate tobacco cessation resources, and make necessary referrals. This discussion will include pharmacotherapy options (prescription and nicotine patches, natural methods (e.g., exercise and relaxation), and web-based quitting programs. All volunteers in the program will be given a volunteer packet with motivational cessation information.
Arrange: Study investigators will arrange follow-up to determine adherence to the program, level of motivation to quit and program success. This information will be gathered at each follow up visit.

Ending Care
Volunteers in either care group may at some time during the six-week period have severe exacerbations that may require referral for surgery or other specialty care. Criteria for ending care may include the presence of any exclusion criteria, worsening pain, or loss of function. The chiropractor will have the responsibility to end care for participants in the CMT plus conventional medical care (CMC) group, while the primary care provider will provide this service to the CMC group. Any volunteer who must change care due to referral will remain in the study and for statistical purposes will be included in his/her original group for analysis. All attempts will be made to obtain outcome measures at all collection points regardless of whether participants change care (intention-to-treat analysis).

Demographics
The following information will be collected at baseline after receipt of written informed consent: Date of birth, gender, ethnicity, race, marital status.

Numerical Rating Scale (NRS) (primary endpoint)
Volunteers will be asked to rate their level of pain on that day on an ordinal 11-box scale (0=no LBP; 10=worst LBP possible) at baseline and at all of the follow-up assessments. The NRS has excellent metric properties, is easy to administer and score, and has received much use in LBP research. 79,80 Pain data will be collected at baseline and at all endpoint visits. The question will capture information pertaining to pain over the last 24 hours.

Figure 6. Follow-up reminders (See Appendix D) E-mail follow-up reminder:
Thank you for your continued participation in the ACT low back pain study. As a reminder we ask that you fill out assessments at week 2, 4, 6, and month 3. It is time for your week xx assessment. Please complete this by XX at https://backtoaction. If you have any questions, please contact me at XX (site manager's contact information). Thank you, Site PM (to be determined) Reminder: Your login is your email address. Text follow-up reminder: Your ACT assessment for week XX is ready to be completed. Please go to www.backtoaction.com and complete by XX. (provide date of one week later) Thank you, Site PM As in previous LPB studies, the volunteer self-report 81 modified 24-item version of the RMDQ will be used to assess LBP-related disability. The RMDQ may be the most common and respected LBP assessment instrument in LBP outcomes research. 82 It is a one-page questionnaire related to LBP disability with documented reliability and validity. 83 It can discriminate between different forms of treatment for back pain, and it is sensitive to clinical change. 81,84,85 The RMDQ has been chosen for a number of clinical trials of LBP treatments for its excellent metric properties, ease of use, patient acceptance, and high face validity. This questionnaire will be administered at baseline and at all endpoint visits.

Bothersomeness of Symptoms
The bothersomeness of symptoms commonly associated with LBP will be measured using an existing measure from the LBP literature. Volunteers will be asked to rate how bothersome various aspects of their LBP have been during the past week, each symptom measured on a 1 to 5 scale (where 1=not at all bothersome and 5=extremely bothersome). A LBP bothersomeness index will be calculated by summing the four symptom ratings (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Bothersomeness questions are practical and have demonstrated good internal consistency, construct validity, and responsiveness to change with time in patients with LBP and sciatica. 86 Bothersomeness will be measured at baseline and at all endpoint visits.

Back Pain Functional Scale (BPFS)
The Back Pain Functional Scale is a 12-question functional status survey designed for use as an individual patient decision-making tool. Each of the 12 questions is answered using a 5-point Likert-type scale and therefore scores for this scale will range from 0-60. 85 In recent studies, the BPFS is showing more improved sensitivity to change than the RMDQ. This scale will be administered at baseline and all endpoint visits.

Patient Expectation
Previous work has shown that patient expectation regarding benefit of care can be a significant nonspecific effect. 87 Two questions regarding patient expectation of benefit from CMT and their general expectation of improvement in 1 month were modified for this study. Patient expectation will be assessed at the baseline visit only.

Patient Satisfaction
A one item patient satisfaction questionnaire was developed based on the work of Cherkin et al. 50 This will be administered at week 2, week 4 and week 6 of care.

Global Improvement Scale
This is a modification of the Visual Analog Scale (VAS) developed to assess degree of improvement over a specified period of time. It will be administered at week 6 and month 3.

Medication Use
Based upon the pilot study conducted at Ft Bliss, volunteers will most likely have been prescribed pain medication by a primary care provider prior to being enrolled in the study. At baseline and at all endpoint visits, we will collect data on the types of medication used and frequency of use.

Duty Status
Volunteers will be asked about their duty status (full, light, limited) at their baseline interview. Change to that status will be questioned at each assessment.

Tobacco Use
Volunteers will be asked about their tobacco use with the questionnaire by Gordon et al. 74,78 The 7-day abstinence will be determined from the point-prevalence of tobacco use: "Have you smoked, even a puff, in the last 7 days?" Prolonged abstinence will be defined as no tobacco use in the prior 6 months. Other variables will include annual quit attempts, number of cigarettes smoked per day, extent of current tobacco use, and current readiness to quit.

Tobacco Dependence
The level of tobacco dependence will be evaluated as in Fagerstrom & Schneider. 88 We will ask how long the volunteer has smoked, how soon after waking the first cigarette is smoked, and if there are strong cravings when going two hours without a cigarette.

Data Analysis
The analysis team will conduct the data analyses using SAS System for Windows (Release 9.2). They will collaborate with the investigators in presenting and interpreting the results. Descriptive statistics of participant baseline characteristics will be presented for each treatment group to assess their comparability as well as the generalizability of the sample. Descriptive statistics of the primary and secondary outcome variables will be presented for each treatment group at baseline, weeks 2, 4, 6 and month 3.
The primary outcome analysis will focus on the changes from baseline to week 6 since this is the length of the chiropractic care group. Similar analyses will be conducted including the 2 week, 4 week and 3 month waves. Outcome measures will be compared between the chiropractic and medical care only groups at baseline to check for imbalances in the randomization.
A difference-of-differences approach will be used to compare changes over time in the chiropractic arm to changes over time in the conventional medical care only arm. This will be implemented as a regression model rather than by literally modeling change scores. Each study participant will contribute an observation for each wave of data collection. The regression models can be ordinary, logistic, ordered logistic or Poisson depending on the distribution of the outcome measure. As an example we present the logistic version of the model that might be used for a simple satisfied vs. not satisfied survey response. . Participant level random effects can be included to control for clustering within participant over time. X can include other patient level covariates to control for imbalance in randomization and differential attrition. It may also be fit for a single outcome type or simultaneously fit across several outcomes to accommodate the correlations between outcomes within participant. Adjusted mean differences and 95% confidence intervals between conventional medical care alone and conventional medical care plus CMT at week 6 will be based on the final models. An intention-to-treat analysis will be used.

Sample Size Pain Sample Size
The study power is primarily driven by the requirement to detect a practically important average difference between treatment and control groups of 2.0 in the RMDQ. A sample size of 250 (100 treatment and 100 medical care after 20% attrition) will produce a power of 80% at the 5% level for a 2sided test for this difference. At this sample size the power to detect a practically important difference of 1.0 for the NRS is 92%. This sample size will also have 80% power for a difference of 4.4 (less than half a population standard deviation) in the BPF scale. For a dichotomous self-reported satisfaction measure the power will be 80% to detect a difference of 20% (e.g. 40% for chiropractic participants vs. 20% for medical care.)

Tobacco Cessation Sample Size
A conservative estimate of the subset of the study population that smokes is 30%. Two measures of tobacco use reduction will be considered, 7 day abstinence and prolonged abstinence. With a sample size of 75 (30 treatment and 30 medical care after 20% attrition), we will have 80% power at the 5% level for a difference in 7 day abstinence of 35% (e.g., 9% vs. 44%). We will have 80% power at the 5% level for a difference in prolonged abstinence of 37% (e.g., 13% vs. 50%). We will have more power for similar comparisons when combining sites. After adjusting for clustering within sites a combined multisite estimate would have 80% power to detect differences of 14% for 7 day abstinence and 16% for prolonged abstinence.

Reporting of Protocol Deviations
All protocol deviations will be tracked and submitted to the Palmer DSMC and reported to study IRBs per respective reporting requirements. It is important to note that any deviation to the protocol that may have an effect on the safety or rights of the volunteer, or the integrity of the study will be promptly reported to the Palmer College of Chiropractic Human Protections Officer within 24 hours of becoming aware of the deviation.
In this study, protocol deviations will be tracked on the web system by all personnel. Necessary information needed to complete the form includes: date of occurrence, participants involved (options include: all, several, one, none), and a notes field for specific details. After submission an automatic email notification will be sent to the lead and site project manager. The site project manager will have primary responsibility for accessing the protocol deviation report and updating the submission with the appropriate category and notes.

Data Management
The Clinical Trial Coordinating Center (CTCC) within the Palmer Center for Chiropractic Research has: 1)developed web-based data collection forms; 2) program web applications to support data and project management; 3)will continue to provide technical support; and 4) execute procedures for data security and data quality control, storage and back-up. The programmer has designed the web applications and database structures based on Palmer Center for Chiropractic Research standards. He has programed the ASP.NET web application elements in C# and Structured Query Language (SQL) using Microsoft Visual Studio 2010 and Microsoft SQL Server Enterprise Manager. Web application modules include patient baseline screening questionnaires and follow-up data collection, patient eligibility checks, random treatment assignment, participant tracking, report generation and follow-up scheduling. Data entry interfaces are programmed with appropriate participant flow restrictions, validation schemes and skip patterns. The CTCC uses a Project/Users Permissions System (PUPS) to control project personnel access to web modules. All data are stored on a secure internal Microsoft SQL Server. The system was developed and tested by data-related CTCC personnel on a development server and then published to the training site for further testing and training by other CTCC personnel. After testing was complete the site was published to the official project site that resides on a production web server secured with Secure Socket Layers (SSL) certified by Thawte Server CA. The servers are all maintained by Information Services, Palmer College of Chiropractic. All project systems are integrated with the Central Patient Database (CPD) and use a PUPS to control project personnel access to web modules. All data are stored on an internal Microsoft SQL Server to which only the Data Core Manager, Data Manager, Web Application Architect and Web Programmer have access via a Microsoft SQL Server Enterprise Manager interface. The CTCC manager will monitor the quality of the web applications and related databases, manage change requests and create documentation, and assisted by the Web Programmer.
All participant questionnaires will be administered via the web. Baseline screening will be performed on the site PM's computer. Follow-up questionnaires can be completed at any computer available to the participant. During the baseline screening, the participant will be asked to create a username/email and password that can be used to provide secure access on follow-up questionnaires. Forgotten passwords will be emailed to their personal email account. In the event of a forgotten username, the participant will be asked to contact their site project manager. During baseline screening, the participant will also be required to provide email and cell phone information. Follow-up contact will be made using email, cell phone voicemail, and/or text messaging.
Web reports detailing when follow-up contacts need to be made with each participant will be made available to the lead and site project managers. The web system is also programmed to send out a reminder email to each participant when study assessment becomes available (date that data collection window opens for that study assessment) as well as when the online assessment is actually due if the participant has not completed the assessment by the due date. Site PMs may also contact study participants by email, text message, and/or phone call for additional reminders if needed. (See Appendix D for details) Data management and quality control of web forms are performed using SQL views, stored procedures and real-time, web-based reports. Automated reports are viewed by the Data Manager and Project Managers to determine if quality improvement actions such as improved documentation, protocol revisions or personnel retraining.
Final project datasets are assembled by transferring data from Microsoft SQL Server to SAS System for Windows (Release 9.1). The Data Core Manager writes and tests SAS programs to create datasets as requested by the investigators and creates the data dictionaries. Database management system copy is used to move data across software applications.

Data and Safety Monitoring Plan.
Participant Safety Monitoring Plan: See Reporting of Adverse Events.

Data Monitoring Plan: Data Collection and Management
Information is collected at every stage of recruitment, treatment allocation, and throughout treatment, so that patient flow can be reported according to the CONsolidated Standards of Reporting Trials (CONSORT) guidelines. 89 Specifically, we collect recruitment source, total number of responses per recruitment source, potential participants' resolution (i.e., ineligible, do not wish to participate, allocated), the number allocated to each treatment group, participant compliance to treatment protocol, the number lost to follow-up, and the number of participants completing the trial. All selfreport questionnaires are web based and password protected. They are stored in a secure database at the CTCC. Site PMs have oversight for all data collection.
The project's web system is password-protected and uses a Microsoft SQL Server database platform to store all data. Study personnel have unique user IDs and passwords restricting access from a Main Menu. All data collected by study personnel are recorded in user-friendly data-entry interfaces. The CTCC data manager creates the data dictionaries and datasets for analysis.
Quality control procedures are utilized to ensure that recruitment is on schedule, treatment allocation is occurring as planned, data collection protocols are being used accurately, data collected through the Computer Assisted Telephone Interview (CATI) and other web interfaces are being stored correctly in the SQL databases, and that the data are being transferred and retrieved properly.

Data Storage
All Informed Consent Documents/HIPAA and all paper data collection forms used will only include unique study ID numbers or participant name, be accessible only by study personnel, and kept in locked filing cabinets. Treatment and Exam forms will be kept in the locked cabinet. After information has been entered into the database, it will be stored in the locked cabinet for up to 7 years after the study has been completed. Computer files with volunteer names will be password protected with restricted access to project staff who will only use this information to recruit volunteers and obtain follow-up data. All analytic data files and tracking databases will be maintained on a secure, password-protected server at the Clinical Trial Coordinating Center (CTCC).

Data Transfer
Electronic data are collected via web forms on a web server secured with Secure Socket Layers (SSL) certified by ipsCS CLASEA1 Certification Authority, www.ipsCS.com. All data are stored on an internal Microsoft SQL Server to which only the CTCC Data Manager and Database Programmer have direct access. All web forms and reports have limited accessibility based on individual project role.
Once data have been verified, cleaned, and de-identified by the Data Core Manager, these data will be a passed for analysis to RAND Corporation via encrypted password-protected file transfer (secured FTP). All RAND research that involves acquisition of private, individual-level data is required to follow the common federal rule for the protection of human subjects of research. These guidelines are spelled out in 45 CFR 46 and in RAND's Multiple Project Assurance of Compliance with the regulations. The Assurance of Compliance is on file with the Department of Health and Human Services and also serves as our assurance of compliance with the regulations of other federal departments and agencies.
It is not possible for all study data to remain anonymous. However, to protect confidentiality, paper data will be kept in locked filing cabinets and will be identifiable only by unique study ID numbers. Computer files will be password protected with access restricted to staff who will use this information only to recruit volunteers or obtain follow-up data. All web based questionnaires and data files are password protected and stored in a secure database at the CTCC.

CTCC Data Security and Confidentiality
The CTCC computer servers are stored in locked, temperature-controlled rooms with the other institutional servers at Palmer College. Back-up tapes of the network drive are produced nightly. Palmer College uses Symantec Backup Exec and FalconStor for server backups. Tapes are handled solely by network staff, primarily by one person. Backup tapes are transported daily to a storage vault in a building designated for this purpose. The vault is used exclusively for backup tape storage and the door requires both a key and combination for access.

Compliance and Co-Interventions
Non-compliance with treatment protocols is a potential confounder of outcomes in clinical trials. Participants are asked on each questionnaire about any co-interventions, including care from providers outside the study and the use of medications or other self-administered treatments. Individual site tracking logs were created to monitor participant's compliance with respect to completing assessments within the allotted time period (see Appendix D). In addition, another log is utilized to ensure data is collected at all study chiropractic treatment visits.

Reporting of Adverse Events AE Collection
For this study an Adverse Event (AE) will be defined as any untoward medical occurrence that may present itself during the conduct of the study and that may or may not have a causal relationship with the study procedures. AEs will be monitored at three levels: 1) self-report AE collected at Week 2, Week 4, and Week 6 assessments or via self-report to the study physician or site PM directly; 2) serious adverse events (SAE) regardless of their attribution reported via Week 2, Week 4, Week 6 or Month 3 assessments or via self-report to the study physician or site PM directly; and 3) Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOs) that are unanticipated, serious, and at least possibly related to the research procedures that do not meet the SAE definition also reported directly to the site PM. Each allocated participant will be given a business card with the PMs' contact information as well as instructions for when it is important to contact the PM. Additionally, contact information for the site PM as well as the PI are listed in the informed consent document.

AE Reporting
Since the majority of AEs will be reported via the participant at the online assessments, a protocol was developed to ensure oversight of this data is being maintained and that AEs meeting site IRB reporting requirements are conveyed to the site PM/PI contemporaneously. A designated study clinician will be assigned to review a live report of AEs reported from the 'Reactions and discomforts' section of the participant online assessment. This portion of the assessment is designed to illicit adverse events during the time period from the last online assessment (see Appendix A). These questions have been added to study assessments at week 2, week 4, and week 6. Additionally, participants are told during the informed consent process about the importance of reporting adverse experiences and instructions for how to report these experiences.
The designated study clinician will convey these events to the site PM for appropriate reporting to IRB.
The study clinician may also ask that the site PM contact the participant if more information is needed regarding a reported adverse experience that could be potentially serious, appear to have no resolution date, or appear to require additional medical follow-up for safety purposes. Our goal is to ensure that we are following up with any event that could appear to affect participant safety and report adverse events per all study IRB reporting guidelines.
We will use the FDA definition of SAE, which is any adverse experience occurring during treatment that results in any of the following outcomes: death, a life-threatening adverse experience, in patient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. The medical monitor is required to review all UPRIRTSOs involving risk to volunteers or others, SAEs, and all volunteer deaths associated with the protocol, and provide an unbiased written report of the event to the USAMRMC Office of Research Protections (ORP), HRPO. At a minimum, the medical monitor will comment on the outcomes of the event or problem, and in the case of a SAE or death, comment on the relationship to participation in the study. The medical monitor will also indicate whether he/she concurs with the details of the report provided by the study investigator. Reports for events determined by either the investigator or medical monitor to be possibly or definitely related to participation, and reports of events resulting in death will be promptly forwarded to the HRPO.
All study protocol violations will be reported to the Palmer DSMC. Protocol violations meeting respective study site's IRB criteria for reporting will also be reported per IRB guidelines.

Qualitative Analysis and Quality Assurance
Site visits will be conducted to ensure the rigor and robustness of the trials. This oversight will provide quality control and feedback to the Palmer Center for Chiropractic Research and to DoD for implementation of future research programs. In addition, because it is a multi-site study in which the intervention will vary from context to context, by using both quantitative and qualitative data, we can systematically describe each context to determine how they are similar and different from each other and to determine to what degree (if any) these similarities and differences might affect the effectiveness of the intervention being studied. Robustness is the confidence that an intervention will perform (within a given range) similarly across different contexts. In this study, programs must be successfully implemented across widely varying military contexts.
The approach to be used is akin to fidelity evaluation and is a practice-level method that serves purposes similar to treatment adherence in clinical studies. Fidelity measurement assesses integrity of initial and on-going implementation (i.e., is the practice model being delivered according to design). How faithfully an intervention is implemented as it was planned affects how well it succeeds and how reliably it can be adapted to other settings.
Fidelity is assessed by a process evaluation tailored to the practice and can involve multiple data sources including questionnaires, administrative records, and qualitative observations. The method to be used will be to interview key informants who have been involved at the site (in this instance WRNMMC) with the chiropractic trials either in the implementation, administration or in the running of the trials. We have identified 7 key informants (potential participants) to be interviewed such as local leadership, providers, and study staff.
Potential participants will be invited to take part in this qualitative portion of the ACT 1 study. Research staff will review the informed consent document with each partipant emphasizing the purpose of the qualitative piece, and potential information to be gained by participating in this study. Research staff will also emphasize that participation in this piece is voluntary and that refusal to participate will not have any implications. The interview will begin after the informed consent document is signed and all participant questions are answered to satisfaction.
Standard probes, such as verification and compare and contrast questions will be used. These questions provide more details about the topic being discussed and usually generate lists of items, short qualitative answers, and close-ended, quantitative data. We will follow well-established procedures for conducting semi-structured interviews.

Quality Assurance
The Clinical Trial Coordinating Center will use their standard Quality Assurance / Quality Control (QA/QC) processes. Their focus will be on the recruitment process and treatment protocols, looking at the application of both the eligibility and exclusion criteria. Initial questions during the site visits will glean information as to whether randomization occurred and was followed. We will also examine the administration of the trials including the management of Informed Consent Documents, HIPAA forms, adverse events and data transfer. Overall we are interested in fidelity to the treatment protocol and identifying challenges to maintaining standardized practice and evaluation methods.
These indicators will be part of the chart review: •

Episodes of Pain
An episode of pain is defined as at least some low back pain requiring you to seek treatment or modify your activity during consecutive weeks (a week or more with no pain separates episodes).
Have you had more than one episode of low back pain?   I avoid heavy jobs around the house because of my back.
Because of my back pain, I am more irritable and bad tempered with people than usual.
Because of my back, I go upstairs more slowly than usual.
I stay in bed most of the time because of my back.

SECTION Reactions and Discomforts
During the past 2 weeks, have you seen a healthcare provider for any reason besides routine care*?
No Yes *Any planned visit to the physician such as preventive care, routine physical exams, or maintenance exams. Please be sure to tell us of any unplanned visit to the doctor or hospital.
If yes, please describe the reason for the visit and any treatment that was provided.

SECTION Reactions and Discomforts
Were you hospitalized during the course of treatment?

No Yes
If yes, please describe*:   *Please be sure to include whether it was an ER visit only or not (and length of visit), hospital admission and discharge dates.

SECTION Reactions and Discomforts
During the past 2 weeks, have you experienced any discomfort and/or an unpleasant reaction that you think could be connected to the treatment you received in this study?

Reaction to medication(s), continued
How long after the treatment did the discomfort/reaction begin?
Less than 30 minutes 30 minutes to 4 hours 4 hours to 24 hours More than 24 hours How long did the discomfort last?
Less than 1 day 1 day -1 week More than 1 week Ongoing Did you have to modify your normal daily activities at home and/or work?
Not at all A little Moderately Could not perform daily activities If you could not perform daily activities, please explain:

Muscle and/or joint soreness
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Muscle and/or joint soreness, continued
Describe the discomfort from your muscle and/or joint soreness:

 
How would you rate the amount of discomfort?

Neck Pain
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Neck pain, continued
Describe the discomfort from your neck pain:

 
How would you rate the amount of discomfort?

Headache
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Headache, continued
Describe the discomfort from your headache:

 
How would you rate the amount of discomfort?

Pain or tingling down the arm/hand or leg/foot
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Pain or tingling down the arm/hand or leg/foot, continued
Describe the discomfort:

 
How would you rate the amount of discomfort?

Mid and upper back
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Mid and upper back, continued
How long after the treatment did the discomfort begin?
Less than 30 minutes 30 minutes to 4 hours 4 hours to 24 hours More than 24 hours How long did the discomfort last?
Less than 1 day 1 day -1 week More than 1 week Ongoing Did you have to modify your normal daily activities at home and/or work?
Not at all A little Moderately Could not perform daily activities If you could not perform daily activities, please explain:

Dizziness
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Dizziness, continued
How long after the treatment did the discomfort begin?
Less than 30 minutes 30 minutes to 4 hours 4 hours to 24 hours More than 24 hours How long did the discomfort last?
Less than 1 day 1 day -1 week More than 1 week Ongoing Did you have to modify your normal daily activities at home and/or work?
Not at all A little Moderately Could not perform daily activities If you could not perform daily activities, please explain:

Broken rib
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Broken rib, continued
Describe the fracture:

 
How long after the treatment did you first suspect a fracture/injury? Less than 30 minutes 30 minutes to 4 hours 4 hours to 24 hours More than 24 hours How long was it until you sought medical treatment for the fracture?
Less than 1 day 1 day -1 week More than 1 week Ongoing

Broken hip
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Broken hip, continued
Describe the fracture:

 
How long after the treatment did you first suspect a fracture/injury? Less than 30 minutes 30 minutes to 4 hours 4 hours to 24 hours More than 24 hours How long was it until you sought medical treatment for the fracture?
Less than 1 day 1 day -1 week More than 1 week Ongoing

Other reaction/discomfort
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Other reaction/discomfort, continued
How long after the treatment did the reaction/discomfort begin?
Less than 30 minutes 30 minutes to 4 hours 4 hours to 24 hours More than 24 hours How long did the reaction/discomfort last?
Less than 1 day 1 day -1 week More than 1 week Ongoing How much did the reaction/discomfort affect your normal daily activities at home and/or work? This list contains sentences that people have used to describe themselves when they have back pain. When you read them, you may find that some stand out because they describe you today. As you read the list, thing of yourself today. When you read a sentence that describes how you feel today, choose YES. If the sentence does not describe you, then choose NO.
Remember, only choose YES if you are sure that the sentence describes you today.

No Yes
I stay home most of the time because of my back.
I change position frequently to try and get my back comfortable.
I walk more slowly than usual because of my back.
Because of my back, I am not doing any jobs that I usually do around the house.
Because of my back, I use a handrail to get upstairs.
Because of my back, I lie down to rest more often.
Because of my back, I have to hold on to something to get out of an easy chair.
Because of my back, I try to get other people to do things for me. This section only appears if the pt stated they were a tobacco user and signed the consent.

SECTION Reactions and Discomforts
Were you hospitalized during the course of treatment?

No Yes
If yes, please describe*:   *Please be sure to include whether it was an ER visit only or not (and length of visit), hospital admission and discharge dates.

Reaction to medication(s)
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Please be sure to include admission and discharge dates.

Reaction to medication(s), continued
How long after the treatment did the discomfort/reaction begin?

Muscle and/or joint soreness
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Muscle and/or joint soreness, continued
How long after the treatment did the discomfort begin?

Neck Pain
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Neck pain, continued
How long after the treatment did the discomfort begin?

Headache
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Headache, continued
How long after the treatment did the discomfort begin?

Mid and upper back
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Mid and upper back, continued
How long after the treatment did the discomfort begin?

Dizziness
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Dizziness, continued
How long after the treatment did the discomfort begin?

Broken rib
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Broken rib, continued
Describe the fracture:

 
How long after the treatment did you first suspect a fracture/injury? Less than 30 minutes 30 minutes to 4 hours 4 hours to 24 hours More than 24 hours How long was it until you sought medical treatment for the fracture?
Less than 1 day 1 day -1 week More than 1 week Ongoing

Broken hip
Please describe the study treatment that you believe is connected to this discomfort/reaction:

 
Were you hospitalized because of this reaction/discomfort?

No Yes
If Yes, please describe*:   *Description should include date of admission and date of discharge.

Thank you for your time!
Your next questionnaire will be available on . You will receive a reminder at that time.
Please take this time to verify your contact information is current. Chantix (varenicline) is a prescription medicine to help adults 18 and over stop smoking. Chantix helps reduce the urge to smoke. Chantix is a non-nicotine pill, that targets nicotine receptors in the brain, attaches to them, and blocks nicotine from reaching them.

Contraindications
Some people have had changes in behavior, hostility, agitation, depressed mood, suicidal thoughts or actions. Persons with a history of depression of other mental health problems.

Instructions
Chew until spicy flavor begins, then flatten and "park" between cheek and gum for maximum absorption. Remove after 1/2 hour. Acidic beverages decrease absorption.

Department of Defense-Low Back Pain Clinical Trial
Advising Patients to Quit Example 1: "I think you should consider quitting smoking now. As your chiropractor, I need you to know that quitting smoking is one of the most important things you can do to protect your health. And quitting may help your back injury to heal more quickly." Example 2: "You've been having on-going problems with back pain. You and I both want your health to improve, so I must advise you that quitting smoking is a crucial part of your treatment."

Assessing Patients' Readiness to Quit
Example 1: "Have you thought about quitting in the next few weeks?" If yes: "Are you ready to make a Personal Quit Plan today?" Example 2: "Have you ever tried to quit before?" If yes: "Would you be willing to work with me to make a Personal Quit Plan to quit again?" If the patient is not ready to quit, consider using motivational interviewing techniques at each visit to increase the patient's readiness to quit over time.

Setting a Quit Date
Example: "It's great that you're ready to quit. Pick a date in the next few weeks to be your 'quit date". I'll give you some materials to take home and we can discuss other ways I can help you quit." Page 2

Dosing and Administration of Over-the-Counter Medications for Tobacco Cessation
Nicotine Patch

Transdermal nicotine patch
Continuous delivery of nicotine provides constant blood levels. Requires 2-3 days to achieve maximal serum levels.

Purpose and Rationale
Data collected are patient-centered outcomes that have been conveniently designed for the participant to complete on any device that has internet. We have created a protocol for the site PM to monitor and assist participants by reminding them when their study assessments are due. Participants are asked to provide email address and phone contact information at the time of consent for this purpose.

Methods for Participant Contact Email
The web system is designed to automatically send the participant an email on the first day that the assessment is available for completion and on the due date if the assessment has not been completed. The respective site PM are copied on all of these emails. Additional emails may be sent by the site PM as needed to remind participant that the respective assessment is due.

Text Message/Phone Contact
The site PM may also utilize text messaging and/or phone contact as needed to remind participant that assessment is available. The site PM will track methods used for each participant at each assessment.

E-mail (-3/-7 days before date due)
Thank you for your continued participation in the ACT Low Back Pain study. As a reminder, we ask that you fill out assessments at week 2, 4, 6, and month 3. It is time for your {week/month} XX assessment. Please complete this assessment by XX/XX/XXXX at https://www.backtoaction.org If you have any questions, please contact me at XX@palmer.edu (site PM's contact information).
Thank you, Site PM https://www.backtoaction.org Reminder, your login is your email address.

E-mail (Due Date-Day 0)
It has been exactly XX weeks since your enrollment into the ACT study. This means that your {week/month} XX assessment needs to be completed. Please complete this assessment by XX/XX/XXXX at https://www.backtoaction.org. If you have any questions, please contact me at XX@palmer.edu (site PM's contact information).
Thank you, Site PM https://www.backtoaction.org Reminder, your login is your email address.

Personal Call/Text/Voicemail Message from Site PM (as needed)
Thank you for your continued participation in the ACT study.
As a reminder, your ACT assessment for {week/month} xx needs to be completed by, XX/XX/XXXX. Please go to https://www.backtoaction.org at your earliest convenience to complete. Reminder, your login is your email address.

Thank you, Site PM
The primary outcome variables are numerical pain rating scale (NRS) for low back pain and the Roland Morris disability questionnaire. These variables will be modeled with linear mixed effects regression over baseline and weeks 2, 4, 6, and 12. We will include terms in the model for time (as a categorical variable), site, group, site by group, time by group and site by time by group interactions, and the variables in the minimization algorithm. We will choose the covariance matrix by comparing the maximized log likelihoods and the Bayesian Information Criteria for several covariance pattern models against the unstructured covariance. Diagnostics of the conditional predicted values and conditional residuals will allow us to assess the assumption of normality and fit for the model.
The main results will be based on the final models for the 2 primary outcome variables at the primary endpoint of 6 weeks. If the site by time by group interaction is significant at the 0.05 level, results will be reported by site. Adjusted between group means and 95% confidence intervals will be reported for all endpoints using the estimates for the time by group interactions. This will allow us to compare the results with those in the pilot study (primary endpoint 4 weeks with a 2 week interim assessment) and to investigate the longer term outcomes. Secondary analyses will be consistent with the recent NIH Task Force recommendations for a minimum dataset for chronic low back pain. In particular, responder analyses will be conducted for a range of improvement levels at week 6. General estimating equations with a working covariance matrix will be used to estimate the differences in proportions between groups, adjusting for site, site by group interaction and the minimization variables.
We will use two approaches to sensitivity analyses to examine the possible effects of missing data on the results obtained from using all observed data. Prior to the conducting the sensitivity analyses, we will identify baseline variables that are predictive of missing outcomes with logistic regression models. Our first approach will be under the assumption that data are missing at random. We will use the Markov Chain Monte Carlo method in SAS Proc MI to impute missing values for each of the primary outcome variables based on the final mixed model covariates, the observed outcome variable at baseline and weeks 2, 3, 6 and 12, and the baseline variables predictive of missing data. We will analyze the resulting datasets for each of 20 imputations with the linear mixed effects models that are fit with all observed data and use SAS Proc MIAnalyze to combine the results. The second approach will be under the assumption that data are missing not at random. Here we will follow the pattern mixture approach described by Carpenter and Kenward (2007). We will first impute missing values as described above for the missing at random approach and then for each participant in each treatment group for each imputation, we will decrease the imputed observation by different amounts representing different patterns of responses. We will then analyze the resulting datasets for each pattern and combine the estimates as described above. If the sensitivity analyses shows us that conclusions differ between the results based on the observed data and that based on full datasets under different missingness assumptions, we will report multiple sets of results.