The RESOLVE Trial for people with Chronic Low Back Pain: Protocol for a randomised clinical trial

Authors:

Matthew K. Bagg1, 2, Markus Hübscher1, 2, Martin Rabey1, Benedict M. Wand4, Edel O’Hagan1, 2, G. Lorimer Moseley1, 3, Tasha R. Stanton1, 3, Chris G. Maher5, Stephen Goodall6, Sopany Saing6, Neil E. O’Connell7 , Hannu Luomajoki8, James H. McAuley1, 2

Institutional affiliations:

  1. Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia
  2. Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
  3. Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia
  4. School of Physiotherapy, The University of Notre Dame Australia, Fremantle, WA, Australia
  5. The George Institute for Global Health, University of Sydney, Australia
  6. Centre for Health Economics Research and Evaluation, UTS Business School, University of Technology Sydney, Australia
  7. Department of Clinical Sciences, Health Economics Research Group (HERG), Institute of Environment, Health and Societies, Brunel University London, Uxbridge, United Kingdom
  8. School of Health Professions, Zurich University of Applied Sciences (ZHAW), Institute of Physiotherapy, Winterthur, Switzerland

Human research ethics approval committee:The UNSW Human Research Ethics Committee(s) approved this study.

Human research ethics approval number:HC15357.

Protocol date: 12.8.16

Introduction

Low Back Pain (LBP) is the leading cause of disability worldwide 1,2 and represents a significant economic burden both in terms of health care delivery and cost to society 3–9. After an episode of LBP, pain and disability generally improve quickly and most people have returned to work within three-months 10–14. However for a modest proportion, the problem persists past three months10,13–15, resulting in chronic LBP (CLBP)16. Data from the USA suggests that this proportionhas increased over the previous twenty years 5,17, despite an increase in healthcare provision 18. Persistent LBP is difficult to treat 11, accounts for substantial productivity loss 3,9 and causes significant individual financial hardship 3,5–7,19–21.

Obtaining pain relief and improving function are of significant concern to people with CLBP 22,23. Unfortunately, randomised controlled trials have shown that most available treatments achieve modest improvements at best 24–40. These data suggest that alternative approaches to managing CLBP require investigation. Recently, interventions that are thought to target central nervous system (CNS) function have been developed and tested in small studies, with promising results 41–44. Several preliminary investigations have also combined these treatments with traditional treatments directed towards functioning of the back and these data suggest patients might obtain some additional benefit from a combined approach 45–48.

Treatment programs that combine CNS-directed and traditional interventions have yet to be tested in adequately powered, prospectively registered, randomised controlled trials. The RESOLVE Trial will be the first high quality assessment of two such treatment programs. The aim is to compare the effectiveness of the interventions at reducing pain intensity for people with CLBP at 18 weeks post-randomisation.

Design

Two-group, participant and assessor blinded, randomised clinical trial.

Methods

Setting

Participants will be recruited via community-based advertisements and primary care practices in Sydney, Australia.

Participants

Participants will be screened to determine whether they meet the following inclusion and exclusion criteria:

Inclusion Criteria: A primary complaint of pain in the area between the 12th rib and buttock crease with or without accompanying non-radicular leg pain; episode of persistent low back pain of at least 12 weeks duration; a mean pain intensity on a numerical rating scale (NRS) ≥ 3/10 in the past week; sufficient fluency in the English language to understand and respond to English language questionnaires and engage with the intervention; access to/availability of a person who is able to assist with part of the intervention at home; access to the internet; aged 18-70.

Exclusion Criteria: Known or suspected serious spinal pathology (fracture; malignant, inflammatory or infective diseases of the spine; cauda equina syndrome or widespread neurological disorder); suspected or confirmed pregnancy or less than six months post-partum; suspected radicular pain (dominant leg pain, positive neural tissue provocation tests and/or any two of altered strength, reflexes or sensation for the same nerve root, assessed clinically); spinal surgery < 12 months previously; scheduled for major surgery during the treatment or follow-up period; uncontrolled mental health condition that precludes successful participation; any contraindications to transcranial direct current stimulation, cranial electrical stimulation, pulsed electromagnetic energy or low-intensity laser therapy 49–51.

Details of the interventions

Trial clinicians (physiotherapists) will undergo specific training in delivery of the interventions. To ensure consistency of treatment delivery, the clinicians delivering the interventions will regularly audit each other’s treatment sessions. A researcher not involved in intervention delivery will undertake audits to ensure that the interventions are being conducted as described in the study protocol. Timelines for the delivery of each intervention are shown in Figures 1 and 2. Complete disclosure of the contents of the intervention has been made with the UNSW HREC (HC15357) and an embargoed project registration has been made on the Open Science Framework to meet the Declaration of Helsinki 52 requirement for transparent reporting of trial methods a priori(

Participants will be randomised to receive intervention A or intervention B. Both of the interventions contain treatments that target CNS function, combined with treatments directed towards functioning of the back. Participants are informed prior to providing informed consent that some of the treatments are not active. No further information is disclosed publicly to maintain the integrity of blinding.Adherence to the intervention will be monitored using an individual treatment diary and adverse events recorded through passive capture.

Intervention A:

Participants randomised to Intervention A will receive a twelve-session treatment program delivered as 60min sessions, scheduled approximately weekly, over a period of 12-18 weeks. All treatment sessions are one-on-one. There is a home treatment component entailing 30mins of training five times per week that finishes at session 12. The intervention comprises discussion of the participant’s low back pain experience, graded sensory training, graded motor imagery training and graded, precision-focused and feedback-enriched, functional movement training. The treatments are likely to overlap, as there is a variable allocation of time to each of the treatments within the clinic and home treatment sessions.

Discussion of the participant’s low back pain experience is conducted over the full treatment period. This is the main focus of the intervention during the first two weeks and continues in subsequent weeks alongside the other interventions. Graded sensory training commences in week three. The initial phase involves localisation training in which participants practice localising the site of tactile stimulation delivered to the low back. This is progressed to training of both localisation and discrimination of the type of stimulation (sharp or blunt) and finally graphaesthesia training in which participants practice recognising and interpreting letters and digits written on the back.

Graded motor imagery training commences in week two. The first stage involves implicit motor imagery using left-right judgement training (Recognise Online, NOIgroup, Adelaide, Australia) and entails distinguishing between images of the trunk rotated to the left or right. Task difficulty is progressed by increasing the complexity of the viewed images and the time available to view them. Explicit motor imagery begins in week three, this involves watching videos of others moving and then mental visualisation of the viewed movement. Progression is from simple, low-load movements to more complex, behaviourally relevant movements. Graded precision-focused and feedback-enriched functional retraining begins in week six. An individualised programme is provided to participants based on their relevant functional goals, assessed at baseline. Progression is from part practice to whole task practice in an environment with multiple opportunities for feedback.

Participant progress through the treatment programme will be guided by a standard progression protocol (Figure 1), with mandatory advancement at certain time points. Participants are free to progress ahead of schedule provided they meet key progression criteria for each component of the intervention. If sustained symptom increase occurs the treatment intensity will be reviewed and possibly reduced. Participants will not be required to stop any current treatment for their low back pain.

Intervention B:

Participants randomised to Intervention B will receive a twelve-session treatment program of the same duration and structure as Intervention A. The home training program finishes at session 11 to allow sufficient time for the return of the CES device. The intervention comprises discussion of the participant’s low back pain experience, transcranial direct current stimulation (tDCS), cranial electrical stimulation (CES), low-intensity laser therapy and pulsed electromagnetic energy. The treatments are not mutually exclusive and are likely to overlap, as there is a variable allocation of time to each of the treatments within clinic sessions.

Discussion of the participant’s low back pain experience is conducted over the full treatment period. This is the main focus of the intervention during the first two weeks. Discussion continues in subsequent weeks alongside the other interventions. tDCS (DC Stimulator, NeuroConn, Ilmenau, Germany) is delivered over eleven weeks and is applied to the motor and prefrontal cortices 53–58. Stimulation will be applied contralateral to the side of worst pain. Application parameters will vary according to a standard protocol. Cranial electrical stimulation is self-administered over eight weeks using a customised pre-programmed take-home device after the participant has received due instruction from the clinician. Low-intensity laser therapy (Model 300, Diolase, Mountain View, USA) is delivered over ten weeks. Participants will be positioned comfortably and the laser applied to the area of greatest pain for between 10 and 20 minutes. Application parameters will vary according to a standard protocol. Pulsed electromagnetic energy (Curapuls, Enraf-Nonius B.V., Rotterdam, The Netherlands) is delivered over seven weeks. Commencing in week six, pulsed electromagnetic energywill be applied after completion of the laser therapy to the area of greatest pain for between 10 and 20 minutes. Application parameters will be progressed according to a standard protocol. Should sustained symptom exacerbation occur, the appropriate parameters will be reviewed and possibly reduced. Participants will not be required to stop any current treatment for their low back pain.

Primary and secondary outcome measures and assessment points

The primary outcome is pain intensity measured on an 11-point numerical rating scale (NRS) at 18-weeks post-randomisation. This is a valid, reliable and responsive measure of pain intensity 59. Secondary outcomes are as follows and reflect the IMMPACT core outcome set for chronic pain trials 59(see also Table 1): .

i)Roland Morris Disability Questionnaire, a valid and reliable measure of low back related disability 60,61

ii)The depression subscale of the Depression, Anxiety and Stress Scale (DASS-21), a valid and reliable measure of depressive symptoms. 62

iii)Pain Catastrophising Scale, a valid and reliable measure of catastrophic thoughts relating to chronic pain. 63

iv)Tampa Scale of Kinesophobia 64, a valid and reliable measure of fear of movement 65,66.

v)Back Beliefs Questionnaire, a reliable questionnaire for examination of beliefs around the future consequences of low back pain 67,68.

vi)Pain Self-Efficacy Questionnaire, a valid and reliable measure of a person’s beliefs regarding their ability to undertake activities despite pain 69,70.

vii)EuroQoL (5-level) EQ-5D-5L, a valid and reliable measure of generic health status 71,72.

viii)Health care resource use (specific to LBP)and usual activities, to facilitate economic evaluation of the interventions.

ix)Credibility and Expectancy questionnaire, a valid and reliable measure of the credibility of an intervention, and expectations regarding treatment efficacy. 73

Assessment will occur at baseline and at 18, 26 and 52 weeks post-randomisation. Treatment credibility will be assessed at baseline and 2 weeks post randomisation only.All questionnaires will be accessible via secure web URLs emailed to participants individually. A clinical assessment of symptom distribution, current symptom characteristics and behaviour, functional limitations and behavioural responses to pain, history of the presenting complaint and any previous back complaints, medical history, general health status, information on tests and investigations and red flag screening is also undertaken at baseline.

Recruitment procedures

Recruitment will be conducted through both community advertisement and physiotherapy/general medical primary care practices. Primary care practitioners will be contacted using our clinician database and contact information freely available on the Internet. Practitioners will be invited to recruit participants and provided with training if they are interested.Involved practitioners will identify potentially suitable participants during their consultation, provide them brief information about the study and invite them to contact the research team. Posters will be distributed in the community and newspaper and radio advertisement campaigns will be run intermittently. Upon contact by the potential participant, a study researcher will explain the research, and with verbal consent, assess the potential participant for study eligibility over the telephone. Potential participants who are eligible to participate will be provided with the participant information statement and consent form (PICF) via email or post. They will have at least 24-hours opportunity to read the PICF. If the potential participant remains interested in participating in the study, they will be invited to a baseline session. The researcher will discuss the time demands of taking part in the study, and confirm that the participant is able to commit this time, to facilitate adherence to the interventions. During the baseline session, one researcher will review the study protocol with the participant, confirm eligibility and obtain written informed consent. Baseline outcome data will also be collected during this session, following which the participant will be randomised.

Randomisation procedures

A computer-generated allocation sequence will be used to allocate participants to receive either intervention A or intervention B. The allocation sequence will be prepared using a blocked randomisation model by a researcher with no involvement in the trial and concealed in 275 sequentially numbered, sealed, opaque envelopes. Following completion of the baseline assessments the treating clinician will open the envelope to reveal group allocation.

Blinding

Participants will be blind to group allocation and the study hypothesis. Blinding is an important component of valid RCTs because it ensures that treatment expectation is evenly matched between groups 74. It will not be possible to blind the treating clinicians. The outcome assessors and the statistician analysing the data will be blind to group allocation.

Anticipated dates of trial commencement and completion

Commencement December 2015. Completion September 2019

Statistical analysis including sample size calculations

Sample Size Calculations: We require 275 participants to detect a 1-point (SD=2.0) between-group difference in pain intensity (NRS), with 80% power, 5% significance level and accounting for up to 15% loss to follow-up. We consider this to be the smallest worthwhile effect that would justify implementation of the intervention. A one-point change on the NRS has been suggested to be the minimally important difference for pain intensity in chronic pain clinical trials 75. Sample size was calculated using the Glimmpse software 76. We calculated the effect size for an interaction effect between time (four repeated observations) and treatment, using an estimated intra-cluster correlation (correlation between the observations) with base 0.6 and decay rate 0.1.

Statistical analysis: A statistician blinded to group status will analyse the data separately for each outcome by intention-to-treat using linear mixed models, with random intercepts accounting for the repeated measures data. Linear contrasts will be constructed to compare the adjusted mean change (continuous variables) in outcome from baseline to each time point between intervention A and intervention B. This will provide effect estimates and 95% confidence intervals for any difference between the interventions. The primary conclusions about effectiveness will be based on pain intensity at 18 weeks.

Data management

Trial data integrity will be monitored by regularly scrutinising data files for omissions and errors. All manually entered data will be double entered and the source of any inconsistencies will be explored and resolved. Electronic data will be stored on password-protected servers at Neuroscience Research Australia and paper-form data stored in locked filing cabinets at Neuroscience Research Australia. Data will only be accessible to the research team. Study participants will be provided with an identification number. All recorded data will be coded using this number. A secure list of participant identification numbers will be kept separate from the de-identified data. All statistical analyses will be performed using de-identified data, with the statistician blinded to group. Results will be disseminated using group data to ensure confidentiality is preserved.

Participant follow-up adherence will be stimulated withcareful explanation of the time demands of participation, including follow-up during screening and at baseline, regular contact and encouragement from a researcher with a dedicated follow-up role, personalised correspondence and group newsletters. In addition, participants are reminded at their final intervention session of the value of their continued involvement until the 52-week follow-up.

Significance and implications for practice

Preliminary data suggest that combining treatments that target CNS function with traditional interventions is a promising approach to CLBP treatment. In the context of modest effects on pain intensity from most available treatments, this approach may lead to improved clinical outcomes for people with CLBP. The trial will determine which, if either, of two treatment programs that combine CNS-directed and traditional interventions is more effective at reducing pain intensity in a CLBP cohort andwill follow up participants for one year, providing important information on the persistence of any treatment effects. The applicability of the trial results to clinical physiotherapy practice should be enhanced by the inclusion of all people with chronic non-specific LBP from both the community and primary care settings. In addition, the flexible structure of the intervention is more closely reflective of real-world clinical practice than a rigid one-session per week design would be. CNS-directed interventions constitute a completely new treatment paradigm for CLBP management.The results have the potential to be far reaching and change current physiotherapy management of CLBP in Australia and internationally.