Supplementary appendix

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Supplementary appendix

This appendix formed part of the original submission and has been peer reviewed.

We post it as supplied by the authors.

Supplement to: Michaleff ZA, Maher CG, Lin C-WC, et al. Comprehensive physiotherapy

exercise programme or advice for chronic whiplash (PROMISE): a pragmatic randomised

controlled trial. Lancet 2014; published online April 4. http://dx.doi.org/10.1016/

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CHRONIC WHIPLASH EXERCISE TRIAL PROTOCOL

Web appendix 1: Trial protocol

Chronic Whiplash Exercise Trial

A randomised controlled trial of a comprehensive exercise program for chronic whiplash

The University of Sydney HREC reference number: 03-2009/11509 The University of Queensland project number: 2008002059

Study Protocol (Draft 7 dated 14/05/2010)

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Chronic Whiplash Exercise Trial Summary Sheet Name of Sponsors:

The George Institute For International Health The University of Queensland

Title of Study:

A randomised controlled trial of a comprehensive exercise program for chronic whiplash.

Principal Investigators:

Professor Chris Maher, The George Institute for International Health, Australia.

Associate Professor Michele Sterling, Centre for National Research on Disability and Rehabilitation Medicine (CONROD), University of Queensland, Australia.

Study Sites:

The study will recruit participants from Sydney and Brisbane. Study Period (years): January 2009 to

May 2012

Phase of Development: Phase III Duration: 3 years Objectives:

1. The primary aim of this randomised controlled trial is to establish the effectiveness of a comprehensive exercise program for people with chronic (symptoms > 3 months < 5 years duration) whiplash.

2. The second aim is to conduct an economic evaluation of the exercise program.

3. The third aim is to investigate if sensory hypersensitivity and symptoms of posttraumatic stress modify the effect of the program.

Methodology:

The study will be a randomised controlled trial comparing a comprehensive exercise program, consisting of 20 one-hour supervised exercise sessions over a twelve-week period, to an educational booklet for people with chronic whiplash. Outcomes measures will be assessed at baseline, 14 weeks, 6 and 12 months.

Participants will be recruited through written contact to claimants who are registered with the Motor Accidents Authority of New South Wales and through advertisements in Sydney and Brisbane print media.

Planned number of participants:

- Total: 172 participants (i.e. 86 participants from Sydney and 86 participants from Brisbane) - Comprehensive exercise program: 86 participants

- Advice and booklet: 86 participants

Diagnosis and main criteria for inclusion:

- Grade I or II whiplash of at least 3 months duration but less than 5 years duration.

- Currently experiencing at least moderate pain or moderate activity limitation due to pain (modified items 7 & 8 of SF36).

- Not currently receiving care for whiplash.

Duration of follow-up: One year

Statistical methods

Treatment efficacy variables: We will analyse the effect of treatment separately for each outcome using linear mixed models with time as a repeated factor. The model will account for correlation over time within participants, correlation within clinics and potential confounders (e.g. important prognostic factors).

Effect modifiers: Effect modification will be assessed by including a predictor-by-treatment group-by-time interaction term to the mixed models analyses. Effect modification will only be assessed for the primary outcome of average pain intensity over the last week.

Economic analysis: The cost-effectiveness of each mode of care will be assessed using the cost and health preference data (the latter of which will be used to generate QALYs).

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Chronic Whiplash Exercise Trial Summary Sheet (continued) Name of Sponsors:

The George Institute For International Health The University of Queensland

Contractual signatories

I confirm that I have read and agreed to the Chronic Whiplash Exercise Trial Draft 6, dated 4/09/2009 for the study titled ‘A randomised controlled trial of a

comprehensive exercise program for chronic whiplash’

Name Date Signature

Principal Investigator (NSW) Professor Chris Maher

Principle Investigator (QLD) Associate Professor Michele Sterling

The George Institute For International Health

The University of Queensland

Motor Accidents Authority NSW David Andrews

Motor Accidents Insurance Commission Queensland

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TABLE OF CONTENTS

1. ETHICS AND CONFIDENTIALITY ... 5

2. ADMINISTRATIVE STRUCTURE ... 6

3. INTRODUCTION ... 7

4. OBJECTIVES ... 11

4.1 Aims and hypotheses of the study ... 11

5. STUDY DESIGN ... 12 5.1 Design ... 12 5.2 Participants ... 14 5.2.1 Participant recruitment ... 14 5.2.2 Inclusion criteria ... 14 5.2.3 Exclusion criteria ... 14 5.3 Study Interventions ... 16 5.3.1 Baseline assessment ... 16 5.3.2 Randomisation ... 16 5.3.3 Educational booklet ... 16

5.3.4 Comprehensive exercise program ... 16

5.3.5 Treatment sites ... 18

5.3.6 Follow up ... 18

5.3.7 Premature discontinuation of randomised intervention ... 18

5.4 Study Outcomes ... 18 5.4.1 Outcomes Assessments ... 18 5.4.2 Primary outcome ... 18 5.4.3 Secondary outcomes ... 18 5.4.4 Participant diary ... 19 5.4.5 Economic evaluation ... 19

5.4.6 Reporting of adverse events ... 19

5.5 Study Sequence ... 20

5.5.1 Telephone screening... 20

5.5.2 Baseline Assessment ... 20

5.5.3 Randomisation ... 20

5.5.4 Physiotherapy treatment clinic ... 21

5.5.5 14 weeks, 6 and 12 month follow up assessments ... 21

5.6 Quality Assurance ... 22

5.6.1 Monitoring of study sites ... 22

5.6.2 Data integrity... 22

5.7 Statistical Issues ... 22

5.7.1 Statistical analysis and methodological considerations ... 22

5.7.2 Sample size ... 22

5.8 Indemnity ... 23

5.9 Publications and reports ... 23

5.10 Funding ... 23

5.11 Timeline ... 23

6. REFERENCES: ... 24

7. APPENDICES ... 26

Appendix 1 – Promise advertisement ... 26

Appendix 3 – Phone screening ... 30

Appendix 6 – Telephone script to arrange follow-up assessments ... 34

Appendix 9 – Outcome assessments ... 41

Appendix 10 – Measuring cervical spine range of movement: inclinometer method ... 57

Appendix 11– Measuring cold pain threshold over the cervical spine... 58

Appendix 12 – Measuring pressure pain threshold over the cervical spine and the tibialis anterior ... 59

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1. Ethics and confidentiality

Approval for the Chronic Whiplash Exercise Trial has been obtained from the University of Sydney Human Research Ethics Committee (03-2009/11509) and the University of Queensland Human Research Ethics Committee

(2008002059). Written informed consent, complying with local requirements, will be obtained from all participants prior to entry into the study. The study will not commence in any centre until all the necessary documentation has been completed.

In obtaining informed consent, the study staff will provide the potential participant with information about the purposes, methods, possible risks and benefits of participating in the study. All potential participants will have an opportunity to discuss the trial with study staff. The participant and the person obtaining informed consent will each sign and date two copies of the consent form, one copy of which will be provided to the participant and the other copy of which will be stored in the participant’s case record folder. Involvement in the study will be voluntary and all participants will have the opportunity to withdraw from the study at any time without prejudice to their current or future medical management. In the event of a participant wishing to withdraw from the study, they will be required to verbally contact study staff and notify them of their decision.

Modifications to the protocol, participant information sheet or consent form will be submitted to the ethics committee for approval and appended to this document. Such modifications will only be implemented once ethics committee approval has been obtained, unless an amendment is being made to eliminate immediate hazards to study participants.

All data generated by the study will remain strictly confidential and no report will contain any information that would allow an individual participant in the study to be identified. However, in order to facilitate complete data collection and follow-up individual contact details will be collected at registration and secured in locked filing cabinets with limited access. These details will be stored separate from other data. Participant records at treatment provider clinics will be identified by participant name or initials and their unique randomisation number.

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2. Administrative structure

This investigator-initiated study is sponsored by The George Institute For International Health and The University of Queensland. The study is funded by the Motor Accidents Authority of New South Wales, Motor Accidents Insurance Commission Queensland and the National Health and Medical Research Council. The principle investigators and co-investigators will be responsible for overseeing all aspects of the trial and they will be responsible for the preparation and publication of the principal results of the study.

The study will be conducted in Sydney and Brisbane. Each site will be responsible for participant recruitment, follow up and coordination of the trial.

PRINCIPLE INVESTIGATORS Professor Chris Maher

The George Institute For International Health and University of Sydney

Tel: (02) 9657 0382 Fax: (02) 9657 0301

Email: [email protected]

Associate Professor Michele Sterling

Centre for National Research on Disability and Rehabilitation Medicine (CONROD)

University of Queensland Tel:(07) 3365 5344 Fax: (07) 3346 4603

CO-INVESTIGATORS Professor Gwendolen Jull

School of Health and Rehabilitation Sciences University of Queensland

Tel: (07) 3365 1114 Fax: (07) 3365 1622 Email: [email protected]

Dr Trudy Rebbeck

Specialist Musculoskeletal Physiotherapist Discipline of Physiotherapy

University of Sydney Tel: (02) 9363 0490 Fax: (02) 9326 2203

Associate Professor Jane Latimer

Matt Roodveldt

University of Queensland

Professor Luke Connelly University of Queensland Tel: (02) 9926 7351 Fax: (02) 99061859

Miss Zoe Michaleff

Tel: (02) 9657 0321 Fax: (02) 9657 0301

Dr Christine Lin

Stephanie Valentin

University of Queensland Research assistant

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3. Introduction

3.1 Background

3.1.1 The problem of chronic whiplash

The most common injury following a motor vehicle accident is a whiplash injury to the neck and this injury is of particular concern because it usually results in persisting pain and disability in an otherwise healthy young adult2 3. At present, there is no known effective treatment for those who suffer persistent pain following a whiplash injury. In our view part of the reason for the lack of attention to whiplash is that many people under-estimate the significance of this health problem. The media has likely contributed to this misconception as it has often trivialised whiplash by commonly depicting people who feign an injury. The reality is quite different.

In Australia and abroad the personal and economic burden of whiplash is enormous. For example, in New South Wales in the period 1989-1998 there were 50,000 whiplash claims costing ~$1.5billion4. Whiplash is also notoriously difficult to manage with the most frequent outcome following a whiplash injury being persisting pain and disability. Our research in NSW2 and in Queensland3 revealed that ~60% of people are still in pain and disabled 6 months after the original accident. The ongoing symptoms affect quality of life with our data showing SF36 scores markedly lower than Australian norms2. Our recent systematic review of the prognosis of acute whiplash revealed similar health outcomes in other countries around the World5. With the number of cars in the World to double over the next 30 years there is an urgent need for effective and affordable treatments for chronic whiplash.

3.1.2 Limited treatment options for chronic whiplash

The 2007 Cochrane review6 concluded that there are no clearly effective non-surgical treatments for chronic whiplash. The few trials published subsequent to the review do not change this conclusion. The reality is that available treatments have at best very small effects. There is however one surgical technique where there is clear evidence of efficacy: radiofrequency neurotomy7. With this surgical procedure a needle is used to burn, and so destroy, the nerves that transmit pain from the damaged zygapophyseal joints in the lower cervical spine. This treatment is only indicated for the sub-group of patients whose symptoms arise from these joints. Moreover there are major limitations to this treatment. The procedure is technically difficult surgery and offers only temporary relief of symptoms and needs to be repeated when the nerves recover and pain returns. Because of these limitations radiofrequency neurotomy, on its own, cannot provide a solution to the problem of chronic whiplash. For the majority of sufferers with chronic whiplash there are currently no proven effective therapies.

3.1.3 Developing an effective exercise program for chronic whiplash

Over the last five years the chief investigators have been working to develop an effective treatment for chronic whiplash that avoided the limitations of neurotomy. The first developments were two different exercise programs: graded activity and specific exercise. The programs were evaluated in separate randomised controlled trials8 9 with each trial demonstrating that the program was effective. While these results were very promising, and have been published in the leading journal Pain, it was apparent that only 10-20% of participants had a completely successful outcome (see Figure 1). In the investigators’ opinion this success rate was too low to represent a solution to the problem of chronic whiplash. Further

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greater results. Accordingly we developed a comprehensive exercise program that combined both approaches yet could still be readily implemented by any physiotherapist.

The principle investigators conducted a small uncontrolled phase I/II trial that provided results which confirmed our hypothesis (see Figure 2). This comprehensive program had a much higher success rate with 56% of subjects having minimal or no disability at the end of the program. This success rate approximates that of radiofrequency neurotomy (58%) but importantly avoids the serious limitations of this treatment.

3.1.4 Why the better effect with both treatments combined?

We believe that there are sound theoretical reasons to explain why the comprehensive exercise program would provide a substantially greater probability of success. The initial specific neck exercise program restores the functions of the muscles that control and support the neck. The graded activity program improves the patient’s general fitness and teaches the patient how to successfully undertake activities of daily living that they find problematic. Without first ensuring that the neck musculature is able to control and support the neck a graded activity program could potentially exacerbate a patient’s symptoms.

Similarly unless a specific exercise program is followed by a graded activity program the improved support and control of the neck may not translate into improved ability to participate in activities of daily living. It is only when both treatments are combined in an integrated package that the foundations for success are provided.

Based upon the exciting results of the pilot study and its strong biological rationale, we now propose to definitively establish the effectiveness of this comprehensive program in a large phase III randomised controlled trial.

3.1.5 Predicting response to treatment: effect modifiers

In our pilot trial we found that ~60% of subjects responded to the comprehensive exercise program. It would obviously be of great value to be able to identify people with a high likelihood of success so that treatment resources are not wasted on people who will not respond to this program. We believe that we may be able to identify this group based upon clinical characteristics.

Our research has demonstrated that whiplash is not a homogeneous condition. Rather sub-groups can be identified that display varying degrees of physical and psychological disturbance11 12. Most patients demonstrate a fairly uncomplicated clinical presentation of mild to moderate levels of pain and disability, mild psychological distress and motor dysfunction. At the other end of the spectrum, there is a group of whiplash patients (approx 25%) who demonstrate a complex clinical picture including moderate/severe levels of pain and disability associated with marked sensory disturbance (widespread hyperalgesia,

probablity of a successful outcome

0% 20% 40% 60% 80% 100%

Graded activity Specific exercise

New program

Figure 1. Superior results of the comprehensive exercise program. Figure shows % of subjects with minimal or no disability following graded activity, specific exercise and the new comprehensive exercise program.

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sympathetic nervous system dysfunction) indicative of central nervous system hypersensitivity13 14. In association with sensory disturbance these patients also display symptoms of a moderate posttraumatic stress reaction15.

We have shown that the presence of sensory hypersensitivity and/or symptoms of posttraumatic stress are strongly predictive of poor long-term outcome3 15. Additionally the presence of sensory changes in chronic whiplash moderated the effects of our specific exercise treatment intervention9. The influence of

posttraumatic stress on the effects of exercise intervention in whiplash has never been investigated. It is likely that these factors will also influence the effects of a combined exercise therapy approach and for this reason we believe their evaluation as potential treatment effect modifiers is mandatory.

3.2 Summary

The aim of the proposed research is to determine the effectiveness of a comprehensive exercise program for chronic whiplash. Currently, for the majority of sufferers with chronic whiplash there are no proven therapies available to manage this personal and financially costly condition. Promising results have been identified in randomised controlled trials evaluating the effects of different exercise programs, graded activity and specific exercise. However, success rates from these studies were too low to represent a solution to the problem of chronic whiplash and further development was necessary.

A comprehensive exercise program that combined both specific exercises and graded activity was developed. A small uncontrolled phase I/II trial provided evidence that this new exercise program had a much higher success rate with 56% of subjects having minimal or no disability at the end of the program. This success rate approximates that of radiofrequency neurotomy (58%) but avoids such invasive surgical techniques.

Based upon the exciting results of the pilot study and the strong biological rationale for the superior results with the combined program we now propose to definitively establish the effectiveness of the new program in a large phase III randomised controlled trial.

3.2.1 Planned outcomes

Our choice of outcomes is consistent with the recommendations of the Cochrane Back Review Group16 and our previous study of the responsiveness of these measures17. Measures of symptoms, global recovery, functional status, quality of life and side effects will be taken. We have chosen a patient-specific measure of functional status because there is evidence that this is more responsive than a condition-specific measure18. We have included the most widely used whiplash-specific (Whiplash Disability Questionnaire) and neck-specific (Neck Disability Index) measures of functional status to allow comparison of our results with those from other studies.

The main study results will be submitted for publication in a prominent journal with all actively

collaborating investigators acknowledged. The George Institute Marketing and Communication staff will ensure that both the conduct and the results of this study are widely and reliably publicised in the general media, including newspaper, radio talk-back program and TV news items.

3.2.2 Potential Significance

This study will provide a definitive evaluation of the effectiveness and cost-effectiveness of a

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The new therapy has resulted from collaboration between Australia’s leading whiplash researchers from The George Institute For International Health and The University of Queensland. This collaboration has allowed us to successfully combine two philosophically and procedurally disparate interventions into a new, simple procedure. The two components have been tested in separate clinical trials and the comprehensive program in a small phase I/II trial. This rigorous scientific approach to developing new treatments is rare in the field of spinal pain and represents a major advance. A search of the WHO

International Clinical Trials Registry Platform Search Portal on 28/07/09 revealed no planned or completed trial that would duplicate our work.

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4. Objectives

4.1 AIMS AND HYPOTHESES OF THE STUDY

• The primary aim of this project is to establish the effectiveness of a comprehensive exercise program for chronic whiplash. This program integrates specific motor relearning and graded activity exercises and will be assessed in terms of pain, disability, patient’s global impression of recovery and quality of life.

• The second aim is to conduct an economic evaluation of this comprehensive exercise program.

• The third aim is to investigate if sensory hypersensitivity and symptoms of posttraumatic stress modify the effect of the comprehensive program.

It is hypothesised that:

• The effect of the comprehensive exercise program will be greater than that of an educational booklet where effect is measured in terms of pain, disability, patient’s global impression of recovery and quality of life.

• The comprehensive exercise program will be more cost-effective than an educational booklet.

• The presence of sensory hypersensitivity and/or symptoms of posttraumatic stress modify the effect of the comprehensive program.

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5. Study design 5.1 DESIGN

The study will be a randomised controlled trial evaluating the comprehensive exercise program (specific motor relearning and graded activity exercise) for people with chronic whiplash. A total of 172 voluntary participants with chronic (symptoms > 3 months <5 years duration) whiplash will be randomly allocated to receive either 20 one hour sessions of the comprehensive exercise program over 12 weeks in conjunction with the educational booklet or the educational booklet alone (86 participants per group). Outcomes will be measured at 14 weeks, 6 and 5 years. Results of the treatment program will be supplemented by an economic evaluation of the direct and indirect costs incurred by both the comprehensive exercise program participants and those receiving the educational booklet only.

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COMPREHENSIVE EXERCISE PROGRAM + EDUCATIONAL BOOKLET

Concealed random allocation at the trial centre. Referral and initial appointment organised for

participant at Physiotherapy treatment site.

ADVICE AND EDUCATIONAL BOOKLET Participants are allowed to contact the physiotherapist by phone (up to two times only) to

clarify information/exercises contained in the educational booklet

Figure 5.1 Study design

Exclusion criteria:

•Serious spinal pathology (e.g.

metastatic disease of the spine, spinal fracture).

•Nerve root compromise.

•Spinal surgery in the past 12 months. •Co-existing medical condition which

would severely restrict participation in the exercise program.

•Any of the contraindications to

exercise listed in the ACSM guideline1.

Invitation to participate in the study from list of claimants registered with MAA or through print media.

Trial centre screening + baseline measures - Age, gender, level of education

- Outcomes - Effect modifiers

14 week assessment (outcomes, side effects, other pain-related treatments and costs) Week 1 – 4: Specific exercise program assessment

and prescription (2 sessions per week for 4 weeks)

Week 5 – 12: Graded activity program assessment and prescription

(12 sessions over 8 weeks)

Volunteers respond.

Participants screened for eligibility via phone call.

Inclusion criteria:

• Grade I or II whiplash (duration > 3 months < 5 years).

• Moderate pain OR moderate activity limitation due to pain.

• Not currently receiving care for whiplash.

• Aged between 18 and 65 years old.

• Proficient in written and spoken English • Able to attend 4 assessment sessions at the trial

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5.2 PARTICIPANTS

5.2.1 Participant recruitment

A total of 172 participants with chronic (symptoms > 3 months <5 years duration) whiplash will be recruited from the Brisbane and Sydney sites. Participants will be identified through advertisements (Appendix 1) in local and larger metropolitan print media. In NSW participants will also be recruited with the assistance of the Motor Accidents Authority (MAA). The MAA will identify claimants from their database who have sustained a whiplash injury in a motor vehicle accident between two and eleven months previously, this allows time for people to respond and be assessed. These claimants will have a letter sent to them courtesy of the MAA (Appendix 2) informing them of the study and inviting them to participate.

People who respond to the invitation to participate in the study will subsequently be screened via a telephone call to identify their eligibility to participate in the trial (Appendix 3). Screening will include a Physical Readiness Questionnaire (PAR-Q) and questions assessing for “red flags”. A positive response to questions in these two screening tools will result in either further review at the trial centre to clarify the response or exclusion from participating in the trial.

Volunteers who meet the phone screening criteria will be asked to attend the trial centre where written consent (Appendix 4), and baseline measures will be obtained. A neurological examination will be completed if indicated by the screening procedures (Appendix 5). Immediately following baseline assessment, participants will be randomised and allocated to either the treatment (comprehensive exercise program and educational booklet) or the control group (educational booklet only).

A record will be kept of the number of invitations sent out by the MAA (NSW only), the number of potential participants who volunteer to participate, the number of people screened and their eligibility status, if ineligible the reason for their ineligibility will also be documented. The researchers will only have access to the number of invitations, and not to the original records to ensure confidentiality. Therefore, researchers will not have any information about potential participants unless they are recruited into the study.

5.2.2 Inclusion criteria

Participants will be included if they meet all of the following inclusion criteria:

• Grade I or II whiplash of at least 3 months duration but less than 5 years duration (Figure 5.2). • Currently experiencing at least moderate pain OR moderate activity limitation due to pain (modified

items 7 & 8 of SF36).

• Not currently receiving care for whiplash. • Aged between 18 years and 65 years old. • Proficient in written and spoke English. 5.2.3 Exclusion criteria

Participants will be excluded if they have any of the following:

• Known or suspected serious spinal pathology (e.g. metastatic disease of the spine). • Confirmed fracture or dislocation at time of injury.

• Nerve root compromise.

• Spinal surgery in the past 12 months.

• Any coexisting medical condition which would severely restrict participation in the exercise program e.g. traumatic brain injury.

• Any of the contraindications to exercise listed in the ACSM guideline1 as assessed using the PAR-Q and listed below:

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Absolute Contraindications to exercise

1. A recent significant change in the resting ECG suggesting infarction or other acute cardiac events. 2. Recent complicated myocardial infarction.

3. Unstable angina.

4. Uncontrolled ventricular dysrhythmia.

5. Uncontrolled atrial dysrhythmia that compromises cardiac function. 6. 3rd degree A-V block.

7. Acute congestive heart failure. 8. Severe aortic stenosis.

9. Suspected or known dissecting aneurysm. 10. Active or suspected myocarditis or pericarditis. 11. Thrombophlebitis or intracardiac thrombi. 12. Recent systemic or pulmonary embolus. 13. Acute infection.

14. Significant emotional distress (psychosis).

Relative Contraindications

1. Resting diastolic blood pressure > 120 mmHg or resting systolic blood pressure >200 mmHg. 2. Moderate valvular heart disease.

3. Known electrolyte abnormalities (hypokalemia, hypomagnesemia). 4. Fixed-rate pacemaker (rarely used).

5. Frequent or complex ventricular ectopy. 6. Ventricular aneurysm.

7. Cardiomyopathy, including hypertrophic cardiomyopathy.

8. Uncontrolled metabolic disease (e.g. diabetes, thyrotoxicosis, or myxedema). 9. Chronic infectious disease (e.g. mononucleosis, hepatitis, AIDS).

10. Neuromuscular, musculoskeletal, or rheumatoid disorders that are exacerbated by exercise. 11. Advanced or complicated pregnancy.

Figure 5.2 – Clinical Classification of Grades of WAD WAD CLASSIFICATION

0 No complaint about the neck. No physical sign(s).

I Neck complaint of pain, stiffness or tenderness only. No physical sign(s).

II Neck complaint AND musculoskeletal sign(s).

Musculoskeletal signs include decreased range of motion and point tenderness. III Neck complaint AND neurological sign(s).

Neurological signs include decreased or absent tendon reflexes, weakness and sensory deficits.

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5.3 STUDY INTERVENTIONS

5.3.1 Baseline assessment

Participants who meet the inclusion criteria will attend the trial centre where all of the primary, secondary baseline measures as well as the effect modifiers will be obtained by a blinded investigator.

5.3.2 Randomisation

Participants will be randomly allocated to treatment group. The randomisation schedule will be generated by an independent investigator using a computer program prior to the commencement of the trial. Randomisation will be stratified for each of the trial centres (NSW and QLD) however not for each individual treatment clinics. Consecutively numbered, sealed, opaque envelopes will be used to conceal randomisation.

Allocation will occur immediately following the baseline assessment. At this time, an independent (unblinded) researcher will select the next envelope in the box, record the participant’s randomisation number and then open the envelope. In this way concealment of allocation and blinding of baseline measures is ensured. Participants will be considered to have entered the study at the time that the envelope is opened. The independent researcher who randomised the participant will then arrange the initial appointment with the treatment provider site within one week of randomisation. The participant proforma and randomisation envelope will be sent to the treatment clinic prior to the participant’s initial appointment. Those randomised to receive the comprehensive exercise program and educational booklet will have one hour allocated to the initial consultation whilst those in the booklet only group will have a half hour consultation.

Participants in both groups will be asked not to seek other treatments and where possible not to change current medications for the twelve-week trial period. Furthermore, the insurance company handling the participant’s claim and the nominated general practitioner will be notified in writing of the individual’s participation in the trial. They will be asked within reason to refrain from referring or suggesting additional or alternative treatments to the individual for the initial twelve weeks after randomisation.

5.3.3 Educational booklet

All participants will be provided with the educational booklet ‘Whiplash injury recovery: a self management guide’ written by Professor Gwen Jull and published by the Motor Accident Insurance Commission of Queensland19 The booklet provides information about whiplash, provides advice on how to manage symptoms of whiplash and explains and illustrates an exercise program for whiplash.

Participants randomised to receive the educational booklet alone will have one, half-hour physiotherapy consultation where the participant will have time to read the booklet provided, have any questions clarified and be shown the exercises. Participants in this group will, if required, be able to contact the

physiotherapist by phone on two occasions to clarify the information/exercise contained in the educational booklet. These participants will subsequently be followed up at the trial centre at 14 weeks, 6 and 12 months after the baseline assessment.

5.3.4 Comprehensive exercise program

Participants in the exercise group will in addition to the educational booklet receive the comprehensive exercise program outlined below. Twenty, one-hour treatment session will be delivered by physiotherapists trained specifically to implement the trial treatment over a 12 week period (Table 5.3.4). Please refer to the ‘Therapists Protocol’ for more detail.

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Table 5.3.4 Outline of the Comprehensive Exercise Program Week Sessions per

week

Components

1 2 Specific motor relearning exercise component:

_{Baseline & follow-up assessments to guide initial prescription & progression of}

program

Exercises to improve cervical and scapular muscle control, kinaesthesia & balance

Manual therapy if indicated

_{Education and advice}

_{Progressive home exercise program, aerobic exercise program}

2 2

3 2

4 2

TRANSITION

5 2 Graded activity component:

Baseline & follow-up assessments to guide initial prescription & progression of program

_{Supervised gym-based exercise to improve the participant’s functional abilities –}

progress aerobic, range of motion, strength, endurance, coordination and functional exercises.

_{Daily home program including exercise & graded increase of physical activities} _{Graded activity program using Cognitive Behavioural Therapy (CBT) principles} Discharge session to reinforce progress and plan for continued activity

6 2 7 2 8 2 9 1 10 1 11 1 12 1

Specific motor relearning exercise component (8 sessions over 4 weeks)

The program begins with a clinical examination of the cervical muscles and the axio-scapular-girdle muscles and includes tests that assess ability to recruit the muscles in a coordinated manner, tests of balance, cervical kinaesthesia and eye movement control and tests of muscle endurance at low levels of maximum voluntary contraction. The specific impairments that are identified are then addressed with an exercise program that is supervised and progressed by the physiotherapist with cognitive behaviour principles (e.g. positive reinforcement and encouragement of skill acquisition by modelling) implemented as required. This specific treatment program has been described in detail20 and focuses on activating and improving the co-ordination and endurance capacity of the neck flexor, extensor and scapular muscles in specific exercises and functional tasks, and a graded program directed to the postural control system, including balance exercises, head relocation exercises and exercises for eye movement control. Manual therapy and/or general whole body aerobic exercise will be prescribed as required by the treating physiotherapist. Participants are expected to practise at home the motor skills they are learning in the therapy sessions. These exercises will be outlined in a home exercise diary which will also be used to monitor participant’s compliance with the program.

Graded activity component (12 sessions over 8 weeks)

Transition to the graded activity program is flexible and is dependant on the individual’s progress through the earlier stage. The graded activity program can therefore commence between weeks four to six. At the first graded activity exercise session, baseline measures of upper and lower body mobility, coordination, strength and aerobic fitness are taken. From these measures an individualised, sub-maximal, progressive activity program will be developed to train those functions found to be inadequate for performance of

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pre-CHRONIC WHIPLASH EXERCISE TRIAL PROTOCOL

goals, and by encouraging self-reinforcement. Daily physical activity at home will be encouraged and monitored using a diary. Written and illustrated exercise instructions will be provided.

5.3.5 Treatment sites

Treatment sites in Sydney and Brisbane will be located in areas easily accessible by public transport. Prior to the commencement of the trial physiotherapists at each treatment site will be provided with a trial and a therapist protocol, they will also be trained to implement the comprehensive exercise program by senior investigators at a one day workshop.

5.3.6 Follow up

Measures of outcomes will be taken at 14 weeks, 6 and 12 months after randomisation. To maximise attendance at these follow-ups, appointments will be made by phone (Appendix 6) and then a letter (Appendix 7) will be sent confirming appointment and a phone call 24hours before. Every attempt (within ethical constraints) will be made to obtain outcome data, regardless of the participant’s compliance with the trial protocol. Assessments will be conducted by a blinded investigator. At each follow up, information on the use of other pain-related treatments e.g. health services or medications will be obtained through the economic cost diary. Only at the 14 week follow up will information about side effects be collected from all participants using open-ended questioning.

5.3.7 Premature discontinuation of randomised intervention

Participants will have the opportunity to withdraw from the study at any time without prejudice to their current or future medical management. In the event of a participant wishing to withdraw from the study, they will be required to verbally contact study staff and notify them of their decision. Regardless of whether the participant continues to adhere to one or both of the intervention arms, the follow-up schedule should continue unchanged for all randomised participants. If any participant is not able to attend all of the scheduled visits then as far as possible, follow-up should be completed by other means (e.g. alternate visits or telephone up), unless the participant states that he/she also wishes to withdraw from the follow-up assessments.

5.4 STUDY OUTCOMES

5.4.1 Outcomes Assessments

At the baseline assessment, personal characteristics (age, gender, level of education) and information about symptoms of whiplash will be collected (Appendix 8). The following outcome measures will be assessed at baseline, 14 weeks, 6 months and 12 months (Appendix 9).

5.4.2 Primary outcome

1. Average pain intensity over last week (numerical rating 0-10 scale)22

5.4.3 Secondary outcomes

1. Average pain intensity over last 24 hours (numerical 0 to 10 scale)22 2. Patient’s global impression of recovery (-5 to +5 scale)22

3. Patient-generated measure of disability (Patient-Specific Functional Scale)23 4. Neck-specific measure of disability (Neck Disability Index)24

5. Generic measure of health status (SF-36)25

6. Whiplash-specific measure of disability (Whiplash Disability Questionnaire)26 7. Measures of physical impairment (Cervical range of movement – Appendix 10)27

5.4.3 Effect modifiers

1. Cold pain threshold measured over the cervical spine3 (Appendix 11).

2. Pressure pain threshold measured over the cervical spine and the tibialis anterior3 (Appendix 12). 3. Posttraumatic stress symptoms using the Impact of Events Scale (IES)3.

4. Pain Catastrophising Scale (PCS)

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6. Self-report Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS).

5.4.4 Participant diary

All participants will be assisted to complete an economic cost diary, in addition to this those randomised to the exercise group will be required to complete a home exercise diary to monitor their compliance with the exercise program.

Economic cost diary

The economic cost diary (Appendix 14) will be used to identify all the direct and indirect costs associated with the individual’s whiplash injury as they arise. Direct costs can include healthcare costs, transportation costs, medication costs and time spent by family members or volunteers providing care. Indirect costs primarily involve the participant’s lost economic productivity due to poor health.

The collection of economic information will coincide with the 14 week, 6 and 12 month follow up assessments. At this time, participants will be asked to recall all direct and indirect costs incurred over the previous two weeks, as a result of their whiplash injury. This method of economic data collection is consistent with Australian Bureau of Statistics National Health Survey.

The home exercise diary

Those randomised to receive the comprehensive exercise program are expected to complete a home exercise diary (Appendix 15). The home exercise diary will be used to outline the prescribed exercises as well as to monitor the compliance with the exercises as the participant will tick the days on which they complete their program. The treating therapist will assist in the collecting of this data by transposing a copy of the participant’s compliance into the therapist proforma.

5.4.5 Economic evaluation

Direct costs (e.g. general practitioner, physiotherapy, chiropractor and pharmaceutical services) will be calculated using schedule consultation fees taken from the Medicare Benefits Schedule, worker’s compensation schemes and the Pharmaceutical Benefits Scheme. Direct health-care and non-health care costs which are not captured by these formal schemes will be identified in participant cost diaries.

Participants’ will be assisted to complete cost diaries in order to capture the direct costs; for example, other professional care, transportation costs and time spent by family members or volunteers providing care. The indirect costs associated with their injury include the participant’s lost economic productivity due to poor health. A shadow wage rate will be used to identify the opportunity cost of time spent away from work due to their injury. These costs will be calculated using income and employment data collected at the baseline assessment.

Using utility weights derived from participant preferences to health states, the Quality Adjusted Life Years (QALYs) for each participant will be measured. The two widely used techniques to measure directly the preferences of individuals are the visual analogue scale and the standard gamble (Appendix 13). These techniques will be applied to derive upper- and lower-bound estimates of QALYs. These three techniques for eliciting health preferences – or “utility” weights as they are usually called – have different theoretical foundations and are also known to be subject to biases of various kinds 28-30. Using more than one of these methods to derive upper- and lower-bound estimates of QALYs provides an empirical capacity to conduct sensitivity analyses on the QALY denominator of the Cost-utility Analysis ratio.

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Examples of an AE do not include anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

A serious adverse event (SAE) is one that is life threatening requires inpatient hospitalisation or will result in persistent or significant disability or incapacity.

All adverse events will be reported to the Adverse Events Committee for the trial (Chris Maher, Michele Sterling). In NSW, concerns will be addressed to Chris via phone on (02) 9657 0382. In Qld, contact Michele on (07) 3365 5344. In the unlikely event of a SAE, trial recruitment and treatment should be put on hold pending advice from the Adverse Events Committee. The Adverse Events Committee will report all AE and SAE to the relevant ethics committee.

5.5 STUDY SEQUENCE

5.5.1 Telephone screening

• Assess the participants’ eligibility, willingness and ability to participate • Complete the phone screening assessment forms (Appendix 3)

5.5.2 Baseline Assessment

At the baseline assessment the trial coordinator will ensure the following is completed: • Participant informed consent form (Appendix 4)

• Contact detail form

• Baseline demographic form • Questionnaires

– Average pain over the last week (0-10 scale) – Average pain over the last 24 hours (0-10 scale) – Global perceived effect (GPE -5 to + 5 scale) – Neck disability index (NDI)

– SF-36

– Whiplash disability questionnaire (WDQ) – Impact of Events Scale (IES)

– Pain Catastrophising Scale (PCS)

– Post Traumatic Stress Diagnostic Scale (PDS)

– Self-report Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS)

– Patient specific functional scale (PSFS)

• Cervical spine range of movement assessment (Appendix 10) • Cold pain threshold over the cervical spine (Appendix 11)

• Pressure pain threshold measured over the cervical spine and the tibialis anterior (Appendix 12) 5.5.3 Randomisation

Immediately following the baseline assessment participants will be randomised. For all participants an independent researcher will:

- Select the next envelope in the box and attach it to the competed participant proforma. - Use the randomisation schedule to allocate the next available participant number.

- Arrange an initial physiotherapy appointment within one week of randomisation. For participants randomised to receive the educational booklet the initial appointment will be half-hour in duration, for those randomised to receive the comprehensive exercise program the initial appointment will be one hour in duration.

- The sealed randomisation envelope and the participant proforma will then be sent to the physiotherapy clinic. The envelope will be opened by the treating physiotherapist and will serve as a confirmation of group allocation.

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5.5.4 Physiotherapy treatment clinic

Participants assigned to the educational booklet

The initial consultation for participants randomised to receive the educational booklet will be a maximum of half hour duration. During which the physiotherapist will:

- Provide the participant with the educational booklet

- Give the participant a short period of time to review the booklet - Discuss and clarify the concepts raised in the booklet

- Show the participant the exercises

Participants in this group will also be able to contact the physiotherapist by phone on two occasions to clarify the information/exercise contained in the educational booklet.

- Remind the participant of the 14 week, 6 month and 12 month follow up assessments to be completed at the trial centre.

For participants assigned to the comprehensive exercise program:

The initial consultation for participants randomised to comprehensive exercise program will be a maximum of one hour duration. During which the physiotherapist will:

- Complete the initial assessment as per the ‘Participant proforma’

- Outline exercises to be completed as part of their home exercise program, making sure a copy of the exercise prescribed are also recorded in the participant proforma.

- Arrange a follow up appointment, as per frequency set out in the table under 5.3.4.

5.5.5 14 weeks, 6 and 12 month follow up assessments

To be completed by all participants at 14 weeks, 6 and 12 months: • Questionnaires

– Average pain over the last week (0-10 scale) – Average pain over the last 24 hours (0-10 scale) – Global perceived effect (GPE -5 to + 5 scale) – Neck disability index (NDI)

– SF-36

– Whiplash disability questionnaire (WDQ) – Impact of Events Scale (IES)

– Pain Catastrophising Scale (PCS)

– Post Traumatic Stress Diagnostic Scale (PDS)

– Self-report Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS)

– Patient specific functional scale (PSFS) • Adverse effects of treatment (14 week assessment only

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5.6 QUALITY ASSURANCE

The study will be conducted in accordance with the protocol, Manual of Procedures, ICH Guidelines for Good Clinical Research Practice and with all relevant local ethical regulations.

5.6.1 Monitoring of study sites

Prior to commencement of the study, treatment provider sites will be provided with a copy of the Trial and Treatment Protocols. Further, the physiotherapists delivering the trial treatments will be trained to deliver the interventions by experts in the Physiotherapy field. Therapists will be required to sign a clinical trial agreement form which specifies trial obligations, requirements and payments.

During the trial, regular contact will be made with the treatment provider sites to ensure that the trial is being conducted according to the protocol and any concerns regarding the implementation of treatment can be addressed in a timely manner. All Physiotherapists will have an advice and treatment session audited by one of the investigators (MS, GJ, TR) to ensure that the therapy is of high quality and in accordance with the protocol.

5.6.2 Data integrity

The integrity of trial data will be monitored by regularly scrutinising data sheets for omissions and errors. Data will be double entered and the source of any inconsistencies will be explored and resolved.

5.7 STATISTICAL ISSUES

5.7.1 Statistical analysis and methodological considerations

Treatment efficacy variables: We will analyse the effect of treatment separately for each outcome using linear mixed models with time as a repeated factor. The model will account for correlation over time within participants, correlation within clinics and potential confounders (e.g. important prognostic factors). Confounding will be assessed by examining the effect of the potential confounders on the results obtained from the analyses. Any potential confounder whose inclusion changes the estimated treatment effects by a clinically relevant amount will be retained as a confounder. We will obtain estimates of the effect of the intervention by constructing linear contrasts to compare the mean change in outcome from baseline to each time point between the treatment and control groups, with adjustment for the other variables.

Effect modifiers: Only those variables listed as effect modifiers in Section 5.4.3 will be assessed for effect modification. This will be done by including a predictor-by-treatment group-by-time interaction term to the mixed models analyses. Effect modification will only be assessed for the primary outcome of average pain intensity over the last week.

5.7.2 Sample size

Brookes and colleague’s31 simulations demonstrate that when testing for effect modification, trials have the same power to detect an interaction effect that is twice the size of the main effect. We argue that small interaction effects are not clinically significant and we have planned the study with sufficient power to detect the following clinically important interaction effects: (NB the study can detect main effects half this size)

• 2.0 units on the 0-10 Pain intensity scale (estimate for SD= 2.0),

• 1.5 units on the 0-10 Patient Specific Functional Scale (estimate for SD = 1.5), • 30 units on the 0-130 Whiplash Disability Questionnaire (estimate for SD = 30),

• 2.0 units on the -5 to +5 Global perceived effect impression of recovery scale (estimate for SD 2.0),

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• 6 units on the 0-50 Neck Disability Index (estimate for SD =5.6)

• 15 points on the 0-100 SF36 physical summary score (estimate for SD =10.0) • 15 points on the 0-100 SF36 mental summary score (estimate for SD = 11.0).

We have taken the SD estimates from the previous trials we completed that recruited a similar patient cohort8 9 and a published study of the Whiplash Disability Questionnaire26. With specifications of alpha =0.05, power =0.80 and allowing for up to 10% loss to follow-up and 10% treatment non-compliance, a sample size of 86 participants per group will allow us to detect an interaction effect size equal to 1.0 times the SD (the smallest interaction effect size we have specified above) and a treatment main effect of 0.5SD. We understand the study is somewhat overpowered for the main effect of treatment but it is crucial to adequately power the study for the interaction effect

5.8 INDEMNITY

The George Institute For International Health and the University of Queensland shall at all times indemnify their study investigators and their staff from claims that may be made against them for any injury sustained by a study participant as a consequence of effects of the interventions used in the study in accordance with this protocol provided the ‘Medicines Australia form of Indemnity for Clinical Trials’ has been signed.

5.9 PUBLICATIONS AND REPORTS

The main study results will be submitted for publication in a prominent journal with all actively collaborating investigators acknowledged. The George Institute Public Affairs and Marketing staff will ensure that both the conduct and the results of this study are widely and reliably publicised in the general media, including newspaper, radio talk-back program and TV news items.

Individuals meeting the International Committee of Medical Journal Editors (ICMJE) authorship requirements1 are eligible for authorship on study publications. Provision of trial treatment does not meet ICMJE authorship requirements; however trial physiotherapists can elect to be acknowledged in trial publications.

5.10 FUNDING

The Chronic Whiplash Exercise Trial is funded by a grant from the University of Sydney, University of Queensland, Motor Accidents Authority New South Wales, Motor Accidents Insurance Commission Queensland and National Health and Medical Research Council. The study was initiated and designed by the investigators, independently of The George Institute For International Health, University of

Queensland, Motor Accidents Authority NSW and Motor Accidents Insurance Commission Queensland, and the data will be collected, analysed and published independently of these parties.

5.11 TIMELINE

1. All participating personnel will be trained for the trial by July 2009. 2. Recruitment of participants will commence at the end of August 2009.

3. 100% of participants will be recruited and treatment completed by December 2010. 4. 100% of 12 month follow-up data collected and entered by December 2011. 5. Data analysis and manuscript completed by May 2012.

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6. References:

1. Dwyer G, Davis S, editors. ACSM's health-related physical fitness assessment manual / American College of Sports Medicine. Philadelphia: Lippincott Williams & Wilkins, 2005.

2. Rebbeck T, Sindhusake D, Cameron I, Rubin G, Feyer A-M, Walsh J, et al. A prospective cohort study of health outcomes following whiplash associated disorders in an Australian population. Injury

Prevention 2006; 12:93-86.

3. Sterling M, Jull G, Vicenzino B, Kenardy J, Darnell R. Physical and psychological factors predict outcome following whiplash injury. Pain 2005; 114(1-2):141-8.

4. Motor Accidents Authority of NSW. Whiplash and the NSW Motor Accidents Scheme. Statistical Information Paper No 7. Sydney: Motor Accidents Authority of NSW, 1999.

5. Kamper S, Rebbeck T, Maher C, McAuley J, Sterling M. Course and prognostic factors of whiplash: a systematic review and meta-analysis. Pain 2008; 138: 617-629.

6. Verhagen AP, Scholten-Peeters G, van Wijngaarden S, de Bie RA, Bierma-Zeinstra SMA. Conservative treatments for whiplash [Systematic Review]. Cochrane Database of Systematic Reviews 2007; 4:4. 7. Lord SM, Barnsley L, Wallis BJ, McDonald GJ, Bogduk N. Percutaneous radio-frequency neurotomy for

chronic cervical zygapophyseal-joint pain. New England Journal of Medicine 1996; 335(23):1721-6. 8. Stewart MJ, Maher CG, Refshauge KM, Herbert RD, Bogduk N, Nicholas M. Randomized controlled trial

of exercise for chronic whiplash-associated disorders. Pain 2007; 128(1-2):59-68.

9. Jull G, Sterling M, Kenardy J, Beller E. Does the presence of sensory hypersensitivity influence outcomes of physical rehabilitation for chronic whiplash? - A preliminary RCT. Pain 2007; 129(1-2):28-34. 10. Hayden JA, van Tulder MW, Tomlinson G. Systematic review: strategies for using exercise therapy to

improve outcomes in chronic low back pain. Annals of Internal Medicine 2005; 142(9):776-85. 11. Sterling M, Jull G, Vicenzino B, Kenardy J. Characterization of acute whiplash-associated disorders.

Spine 2004; 29(2):182-8.

12. Sterling M. A proposed new classification system for whiplash associated disorders--implications for assessment and management. Manual Therapy 2004; 9(2):60-70.

13. Sterling M, Jull G, Vicenzino B, Kenardy J, Darnell R. Development of motor system dysfunction following whiplash injury. Pain 2003; 103(1-2):65-73.

14. Sterling M, Jull G, Vicenzino B, Kenardy J. Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery. Pain 2003; 104(3):509-17.

15. Sterling M, Jull G, Kenardy J. Physical and psychological factors maintain long-term predictive capacity post-whiplash injury. Pain 2006; 122(1-2):102-108.

16. van Tulder MW, Furlan A, Bombardier C, Bouter L, and the Editorial Board of the Cochrane

Collaboration Back Review Group. Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group. Spine 2003; 28(12):1290-1299.

17. Stewart M, Maher CG, Refshauge KM, Bogduk N, Nicholas M. Responsiveness of pain and disability measures for chronic whiplash. Spine 2007; 32(5):580-5.

18. Westaway M, Stratford P, Binkley J. The patient-specific functional scale: validation of its use in persons with neck dysfunction. Journal of Orthopaedic and Sports Physical Therapy 1998; 27(5):331-338. 19. Jull G. Whiplash injury recovery a self-management guide.

http://www.maic.qld.gov.au/forms-publications-stats/pdfs/whiplash-injury-recovery-booklet.pdf, 2005.

20. Jull G, Treleaven J, Falla D, Sterling M, O'Leary S. A therapeutic exercise approach for cervical disorders. In: Boyling J, Jull G, editors. Grieves' Modern Manual Therapy of the Vertebral Column. 3 ed. Edinburgh: Elsevier Churchill Livingstone, 2004:451-470.

21. Nicholas M, Tonkin L. Persisting pain: using cognitive-behavioural principles for activity-based pain management. In: Refshauge K, Gass E, editors. Musculoskeletal Physiotherapy. Clinical science and evidence-based practice. 2nd ed. Oxford: Butterworth Heinneman, 2004.

22. Pengel L, Maher C, Refshauge K. Responsiveness of pain, disability and physical impairment outcomes in subjects with low back pain. Spine 2004; 29:879-883.

23. Westaway MD, Stratford PW, Binkley JM. The patient-specific functional scale: validation of its use in persons with neck dysfunction. Journal of Orthopaedic and Sports Physical Therapy 1998; 27(5):331-8.

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24. Vernon H, Mior S. The neck disability index: A study of reliability and validity. Journal of Manipulative and Physiological Therapeutics 1991; 14(7):409-415.

25. Ware J, Sherbourne C. The MOS 36-item short-form health survey (SF-36). 1. Conceptual framework and item selection. Med Care 1992; 30:473-483.

26. Willis C, Niere KR, Hoving JL, Green S, O'Leary EF, Buchbinder R. Reproducibility and responsiveness of the Whiplash Disability Questionnaire. Pain 2004; 110(3):681-8.

27. Hole D, Cook J, Bolton J. Reliability and concurrent validity of two instruments for measuring cervical range of motion: effects of age and gender. Manual Therapy 1995; 1:36-42.

28. Bleichrodt H. A new explanation for the difference between Time Trade-Off Utilities and Standard Gamble Utilities. Health Economics 2002; 11(5):447-456.

29. Brazier J. Use of visual analogue scales in economics evaluation. Expert Review of Pharmacoeconomics and Outcomes Research 2003; 3(3):293-302.

30. Oliver A. The internal consistency of the Standard Gamble tests after adjusting for prospect theory. Health Economics 2003; 22(4):659-674.

31. Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technology Assessment 2001; 5(33):1-56.

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7. Appendices

APPENDIX 1 – PROMISE ADVERTISEMENT

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A

PPENDIX

2 –

M

OTOR

A

CCIDENTS

A

UTHORITY LETTER OF INVITATION PARTICIPANT INFORMATION SHEET

Insert Name Insert Address

Re: A randomised controlled trial of a comprehensive exercise program for chronic whiplash I am writing on behalf of the Motor Accidents Authority (MAA) of NSW to invite you to participate in a physiotherapy research study for the treatment of whiplash. The MAA is the NSW Government department that oversees all aspects of the Compulsory Third Party (Green Slips) scheme including the number and type of claims. You have been invited to participate in the research because the MAA claims information indicates that you have had a whiplash injury in the last 5 years.

The MAA and National Health and Medical Research Council are funding this important research to find out about the best treatment for chronic whiplash. While there is no clear agreement about what treatments work best for chronic whiplash, we do know that long term neck pain has many negative effects on people’s enjoyment of life.

This research will be conducted by experts at the George Institute for International Health, The University of Sydney, and The University of Queensland. The study consists of a 12-week program that begins with exercises for the neck and then progresses to exercise for the whole body. The treatments offered by the study are free.

Your participation in this trial is purely voluntary and be assured that your details will remain confidential at all times. Participation in the study will not affect your ongoing medical treatment or relationship with medical staff.

If you are interested in participating or would like further details please contact the George Institute study coordinator Zoe Michaleff. For your information, we have attached a detailed information sheet about the study. Phone: (02) 9657 0321 Fax: (02) 9657 0301 Email: [email protected] Yours Sincerely Carmel Donnelly A/ General Manager

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ABN 15 211 513 464

Musculoskeletal Division

George Institute for International Health Level 7, 341 George St, Sydney, NSW

Sydney Medical School

Prof Christopher Maher, PhD Director, Musculoskeletal Division

The George Institute for International Health Professor, Sydney Medical School

The University of Sydney

PO Box M201, Missenden Rd Sydney, NSW 2050 AUSTRALIA Telephone: +61 2 9657 0382 Facsimile: +61 2 9657 0301 Email: [email protected]

A randomised controlled trial of a comprehensive exercise program for chronic whiplash

Sydney Investigators

Prof Chris Maher, A/Prof Jane Latimer, Dr Christine Lin, Dr Trudy Rebbeck, Miss Zoe Michaleff

PARTICIPANT INFORMATION STATEMENT

This study is funded by the Motor Accidents Authority of New South Wales, Motor Accidents Insurance Commission of Queensland and the National Health and Medical Research Council. Data is being collected in Sydney and Brisbane. The Sydney site is led by Professor Chris Maher and Associate Professor Jane Latimer of the George Institute for International Health. The Brisbane site is led by Associate Professor Michele Sterling and Professor Gwen Jull from the University of Queensland.

There are no medical treatments that have been shown to be effective for chronic or persistent whiplash. You are invited to take part in a research study evaluating physiotherapy treatment of chronic or persistent whiplash. The aim is to investigate the effectiveness and cost-effectiveness of a comprehensive exercise program for chronic whiplash. The exercise program begins with exercises for the neck and then progresses to exercise for the whole body. At present we do not know if this program is helpful for people with chronic whiplash. The only way to find this out is to conduct a randomised controlled trial.

If you agree to participate in this study, you will be requested to complete assessments at enrolment and then 14 weeks, 6 and 12 months later. The assessments comprise of some questionnaires and a physical examination. The first assessment will take one hour and the follow-ups 30 minutes. You will also need to complete a diary to record your health care costs for whiplash.

Questionnaires

You will be asked to complete a series of questionnaires seeking information on the accident history, current symptoms, any treatment received to date, compensation status, employment status and weekly income along with time lost from paid

employment and unpaid duties (e.g. home duties). You will also be asked to complete questionnaires relating to how your neck pain is affecting your daily activities and in what way your neck pain is affecting you personally.