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Trial registered on ANZCTR


Registration number
ACTRN12618001291279
Ethics application status
Approved
Date submitted
9/07/2018
Date registered
31/07/2018
Date last updated
31/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Personalized Treatments for Acute Whiplash Injuries: a pilot study
Scientific title
Personalized Treatments for Acute Whiplash Injuries: a pilot study
Secondary ID [1] 294295 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute whiplash 306998 0
Condition category
Condition code
Injuries and Accidents 306093 306093 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The primary aim of this feasibility study is to conduct a series of N-of-1 trials comparing the effectiveness of a) evidence-based advice (EBA), b) paracetamol and EBA, c) naproxen and EBA, and d) both paracetamol, naproxen and EBA to reduce daily neck pain and to prevent chronic pain at 3 months following whiplash injury in 15 'at-risk' individuals. Using a novel multiple baseline design, all patients will receive a randomized sequence of three cycles of ten day treatment triplets. Data from first 3 days of each treatment period will be discarded to ensure no carryover. Followup questionnaires will be administered at approximately 3 months following trial completion. Intervention will commence as soon as possible but within 2-weeks of injury and continue for 12 weeks.

Intervention: All patients will be provided with an advice booklet Whiplash Injury Recovery: A Self Help Guide (2nd edition),co-authored by Prof Sterling and published by the Motor Accident Insurance Commission (MAIC), Qld. It provides information about whiplash; assurance about prognosis; advice to stay active and resume working as well as information on correct posture; pictorial descriptions of specific exercises for the neck and upper limbs and information on resuming functional daily activities. This second edition of the booklet was written based on consumer and health care professional feedback via focus groups. The booklet is based on the recommendations of the current Australian Guidelines for Whiplash Management. Patients will receive 2 x 500 mg paracetamol capsules orally four times daily or naproxen sodium 2 x 137.5 mg capsules four times daily or capsules containing 500 mg paracetamol and 137.5 mg naproxen sodium, 2 capsules four times daily. A double dummy design will be used.

Adherence with the study medications will be assessed in three ways: (1) daily self-recorded medication intake, (2) the trial staff will ask about adherence during the planned telephone-based reviews starting at 1 week post randomization and (3) counts of returned tablets following the completion of treatment. Participants will be asked to return all unused tablets for counting at the end of the treatment period in a reply paid post satchel.
Intervention code [1] 300594 0
Treatment: Drugs
Intervention code [2] 301872 0
Treatment: Other
Comparator / control treatment
Patients will be their own control.
Control group
Active

Outcomes
Primary outcome [1] 305124 0
Daily neck pain intensity, and neck pain intensity at trial completion. Neck pain intensity is measured on the continuous numeric rating scale (NRS) of 0 to 10, and will represent the patients' self-report of average pain intensity during last 24 hours.

Timepoint [1] 305124 0
Every 24 hours for 3.5 months with primary time point at 3 months post-injury.
Primary outcome [2] 305125 0
Confidence to perform daily activities measured through patients’ self-report of confidence to perform daily activities in the presence of neck pain or disability using a scale from 0 to 6, with 0 meaning not confident at all and 6 meaning completely confident.
Timepoint [2] 305125 0
Every 24 hours for 3.5 months with primary time point at 3 months post-injury.
Primary outcome [3] 305693 0
Adverse effects: Individual adverse effects and severity using the National Cancer Institutes of Health: Common Terminology Criteria for Adverse Events v3.0
Timepoint [3] 305693 0
At the end of each treatment period and at 3 month follow up. The primary time point is 3 months post-injury.
Secondary outcome [1] 344260 0
Neck Disability Index (NDI)
Timepoint [1] 344260 0
End of each treatment period and at 3 month follow-up.
Secondary outcome [2] 344261 0
Patient global impression of change (-5 to +5 scale)
Timepoint [2] 344261 0
At the end of each treatment period and during 3 month follow-up.
Secondary outcome [3] 344262 0
PTSD Checklist for DSM-5 (PCL-5);
Timepoint [3] 344262 0
At the end of each treatment period and at 3 month follow-up.
Secondary outcome [4] 344263 0
Depression & Anxiety Stress Scales (DASS-21)
Timepoint [4] 344263 0
At the end of each treatment period and at 3 month follow-up.
Secondary outcome [5] 344264 0
ED-5Q-5L
Timepoint [5] 344264 0
At the end of each treatment period and at 3 month follow-up.
Secondary outcome [6] 344265 0
Management decision at review 2 weeks post n-of-1 trial
Timepoint [6] 344265 0
2 weeks post n-of-1 trial
Secondary outcome [7] 344266 0
Number of patients who lodge a compensation claim. This will be measured through patients' self-report of compensation claims in the post-trial diary and 3 month follow-up diary.
Timepoint [7] 344266 0
At the end of the trial and 3 month follow up
Secondary outcome [8] 347063 0
Pain Catastrophising Scale
Timepoint [8] 347063 0
At the end of each treatment period and at 3 month follow-up.

Eligibility
Key inclusion criteria
• Individuals with Grade II WAD and within 2 weeks of injury.
• Moderate to high risk according to the Whiplash Risk Stratification Tool (WhipPredict), a validated tool for predicting ongoing moderate/severe disability following acute whiplash injury.
• Initial Numerical Rating Score (NRS) pain score of 5 or greater.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Pre-existing serious spinal pathology (e.g. metastatic disease of the spine);
• Confirmed fracture or dislocation at time of injury (WAD IV);
• WAD III (neurological compromise eg decreased reflexes, muscle power);
• Previous whiplash injury or neck pain condition requiring treatment, and still symptomatic;
• Long term use of Paracetamol or NSAIDs for other chronic conditions (e.g. back pain, joint pain/arthritis)
• Long term analgesics such as opiates, tramadol, etc and adjunctive analgesics for neuropathic pain such as pregabalin, amitriptyline, etc
• Known hypersensitivity to paracetamol or naproxen or to any excipients (hives, blisters, rash, dyspnea and wheezing);
• Asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs;
• History of renal insufficiency (eGFR<60ml/min/1.73m2 or ACR >3 mg/mmol)
• Patients on diuretics, angiotensin converting enzyme inhibitors or angiotensin receptor blockers
• Severe active liver disease that in the clinican’s judgement excludes the patient;
• Patients who are severely malnourished, anorexic, septic, have a low body mass index or are chronic heavy users of alcohol.
• Women who are pregnant or breastfeeding
• History of severe or uncontrolled psychiatric illness or substance abuse
• Patients who are smokers or obese (BMI > 30)
• Inability to speak and write in English (participants will be required to complete questionnaires written in English only)
• Older than 65 years
• Use of concomitant drugs that increase the risk of upper GI bleeds/perforation e.g. anticoagulants, antiplatelet drugs, or corticosteroids
• Current H. pylori infection or past infection where the clinician considers a risk of upper GI bleeding persists.
• Prior history of peptic ulcer disease and/or gastrointestinal bleeding
• History of inflammatory bowel disease
• Uncontrolled hypertension, symptomatic heart failure and persistent peripheral edema.
• Cardiovascular risk/history greater than or equal to 10% within 5 years or history of established CVD (eg unstable angina or MI, not including hypertension).
• Patients undergoing or planning to have surgery during the next three months.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The randomisation process and double dummy design will ensure concealed allocation. The randomisation schedule will be created by the study statistician and study medication will be prepared according to the randomisation schedule by an independent pharmacist, and sealed in medication kits. Research staff, besides the statistician, will not have access to the randomisation schedule.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation codes in variable block sizes of 4-6 will be generated by the study statistician following standard statistical procedures and sent to the study dispensing pharmacy. Each individual receives interventions 2, 3 and 4 in a randomised sequence within a triplet, over three treatment triplets, which controls for sequencing effects. Each tier is randomised separately; each MBD is independent of the others.

The schedule will be kept in a sealed envelope in a locked filing cabinet in the pharmacy, and will be in the 24hr on-call bag after hours in case unblinding is needed. Study medication will be prepared according to the randomisation schedule by an independent pharmacist, and sealed in medication kits. Following baseline assessment, research staff will provide the next kit to the participant.

Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
A series of N-of-1 trials nested within a Multiple Baseline Design
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We will use a Bayesian modelling framework which accounts for a changing baseline and also provides inference at individual and group level. We have developed an empirical Bayesian hierarchical model for the pain trajectory of natural recovery for the high-risk group with initial NRS>=5. Data are from a prospective longitudinal study of prognostic factors for poor functional recovery and from the control arm (usual care) of an RCT. Thus, we can predict the recovery expected. Data from EBA alone and from each phase of the N-of-1 trials with active medication treatment will be aggregated using a Bayesian hierarchical model where random effects account for repeated measures (within patients) over time. As the patients in Sterling et al (2010) are different from those in this study, we cannot assume our empirical model will be directly transferrable. Demographics of our sample will be compared to those of the high risk group with NRS >=5 from Sterling et al (2010). We will calibrate the model using data from phase A to ensure our model for natural recovery is applicable to this study. Then, when on an intervention, the outcome will be judged based on what is predicted by the empirical model (for a given point in time). It is unknown how (or if) each intervention will affect pain. Typically, in N-of-1 trials where natural recovery does not need to be accounted for, treatment effects are assumed to be additive. This will be explored in our analysis but we will also consider including treatment effects in other ways, eg treatment effect may depend on severity, and thus multiplicative effects would be appropriate. Further, treatment may increase the rate of recovery so treatment effect may need to be included in a non-additive manner. This is a problem of model choice, and, as no prior data are available to inform this problem, we will be guided by what information is available in the data, adopting formal model selection techniques from Bayesian statistics to determine the preferred approach. The inclusion of additional covariates eg age, gender, will also be explored, and decisions about inclusion made through formal model choice procedures. On estimating the model for natural recovery and appropriately including intervention effects, overall participant response against natural recovery will be calculated as follows: 1) posterior mean differences in population and individual expected outcomes compared to natural recovery at the end of the trial and at 3 months follow up will be evaluated with associated 95% credible intervals; and 2) the posterior probability that the intervention effect is >= average of 1.5 NRS points better than natural recovery will be estimated. We will take >= 1.5 points on NRS scale to be a clinically significant difference. For each intervention, a patient will be deemed a responder to that intervention if the corresponding individual level difference to natural recovery is >= 1.5 NRS points. If there is >= 1.5 NRS points difference between two interventions, they will be deemed to respond better to that intervention. Effect sizes will be calculated when we know how the interventions will be included in the model (additive, multiplicative, etc).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 10804 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 10805 0
Caboolture Hospital - Caboolture
Recruitment hospital [3] 10806 0
Redcliffe Hospital - Redcliffe
Recruitment postcode(s) [1] 22544 0
4029 - Herston
Recruitment postcode(s) [2] 22545 0
4510 - Caboolture
Recruitment postcode(s) [3] 22546 0
4020 - Redcliffe

Funding & Sponsors
Funding source category [1] 298943 0
University
Name [1] 298943 0
Faculty of Health and Behavioural Sciences - University of Queensland
Address [1] 298943 0
Level 4, Social Sciences Building (24)
Campbell Road
The University of Queensland
St Lucia QLD 4072, Australia
Country [1] 298943 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
The University of Queensland
St Lucia QLD 4072, Australia
Country
Australia
Secondary sponsor category [1] 298156 0
None
Name [1] 298156 0
Address [1] 298156 0
Country [1] 298156 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299879 0
University of Queensland Human Research Ethics Committee A [EC00456]
Ethics committee address [1] 299879 0
The University of Queensland
Cumbrae-Stewart Building #72
Brisbane, Queensland 4072
Australia
Ethics committee country [1] 299879 0
Australia
Date submitted for ethics approval [1] 299879 0
20/12/2017
Approval date [1] 299879 0
21/12/2017
Ethics approval number [1] 299879 0
2017001870

Summary
Brief summary
The primary aim of this feasibility study is to conduct a series of N-of-1 trials comparing the effectiveness of a) evidence-based advice, b) paracetamol and EBA, c) naproxen and EBA, and d) both paracetamol, naproxen and EBA to reduce daily neck pain and to prevent chronic pain at 3 and 6 months following whiplash injury in 'at-risk' individuals.

The hypotheses are that, in people with acute whiplash injury:
1. Paracetamol, naproxen, and evidence-based advice will be more effective and safer than (i) paracetamol plus advice (ii) naproxen plus advice or (iii) advice alone in reducing neck pain intensity at 3 and 6 months following whiplash injury.
2. Paracetamol, naproxen, and evidence-based advice will be more effective and safer (i) paracetamol plus advice (ii) naproxen plus advice or (iii) advice alone in reducing disability, depression, posttraumatic stress symptoms and pain catastrophizing at 3 and 6 months following whiplash injury.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81846 0
Dr Jane Nikles
Address 81846 0
Recover Injury Research Centre
Level 7 Oral Health Centre
288 Herston Road
Herston QLD 4006 Australia
Country 81846 0
Australia
Phone 81846 0
+61 408 599 033
Fax 81846 0
Email 81846 0
catherine.nikles@uq.edu.au
Contact person for public queries
Name 81847 0
Dr Jane Nikles
Address 81847 0
Recover Injury Research Centre
Level 7 Oral Health Centre
288 Herston Road
Herston QLD 4006 Australia
Country 81847 0
Australia
Phone 81847 0
+61 408 599 033
Fax 81847 0
Email 81847 0
uqjnikle@uq.edu.au
Contact person for scientific queries
Name 81848 0
Dr Jane Nikles
Address 81848 0
Recover Injury Research Centre
Level 7 Oral Health Centre
288 Herston Road
Herston QLD 4006 Australia
Country 81848 0
Australia
Phone 81848 0
+61 408 599 033
Fax 81848 0
Email 81848 0
uqjnikle@uq.edu.au

No information has been provided regarding IPD availability
Summary results
No Results