Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000274370p
Ethics application status
Not yet submitted
Date submitted
9/02/2017
Date registered
22/02/2017
Date last updated
22/02/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Does naltrexone reduce pain or disability after a whiplash?
Scientific title
Does low dose naltrexone help to reduce pain or disability after a whiplash following a car crash? A pilot study of effects of low dose naltrexone on glial activation and neuroinflammatory process. The NALWHIP Study.
Secondary ID [1] 291151 0
None
Universal Trial Number (UTN)
U1111-1192-4123
Trial acronym
the NALWHIP study
Linked study record
none

Health condition
Health condition(s) or problem(s) studied:
whiplash injury
 302006 0
whiplash associated disorder
 302007 0
Condition category
Condition code
Musculoskeletal 301649 301649 0 0
Other muscular and skeletal disorders
Inflammatory and Immune System 301650 301650 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
a randomised, placebo-controlled pilot trial of low dose naltrexone given after a whiplash injury. 20 participants are needed in each group (total=40). The participants will enter the observation period (2 weeks) prior to commencing the treatment period. Low dose naltrexone (LDN) is equivalent to 4.5 mg daily, compounded in a specialist pharmacy and administered as an oral tablet at bed time for a total of 8 weeks (treatment period).
Intervention code [1] 297139 0
Treatment: Drugs
Comparator / control treatment
the control group will include 20 participants, who sustained a whiplash injury following a car crash in the preceding 4 weeks. They will undergo an observation period for 2 weeks prior to enter the control group. The participants will be given sham tablets which have the same colour and taste as the LDN tablet. Sham tablets are composed of a coated sweetener. Total period of control (placebo) treatment is 8 weeks.
Control group
Placebo

Outcomes
Primary outcome [1] 301045 0
the proportion of participants in each group with a reduction in the numerical pain score (NPS) of >=30 points (measured on a scale from 0-100). NPS reduction will be calculated from NPS at end of treatment period (each group) subtracted from the NPS in the observation period.
Timepoint [1] 301045 0
NPS reduction will be measured as the change in NPS at completion of the 8 weeks treatment period (each group) compared to the baseline NPS value at end of the 2 weeks observation period.
Primary outcome [2] 301149 0
the proportion of participants in each group with a reduction in the neck disability index (NDI) score of >=10 points(measured on a scale of 50 points, multiplied by 2 to give a maximum score of a 100 points), at end of treatment compared to NDI scores at end of the observation period.
Timepoint [2] 301149 0
the NDI scores reduction is calculated from the difference between the NDI at completion of the 8 weeks treatment period and the baseline NDI at end of the 2 weeks observation period.
Primary outcome [3] 301184 0
The proportion of participants in each group with a >=30% reduction in cold allodynia measured using quantitative sensory testing (QST) to cold at preselected anatomical sites at completion of the treatment period.
Timepoint [3] 301184 0
Cold allodynia at completion of the 8 weeks treatment period compared to that at end of the 2 weeks observation period.
Secondary outcome [1] 331570 0
the proportion of participants in each group with a reduction in the numerical pain score (NPS) of >=30 points (measured on a scale from 0-100) at follow up visits compared to baseline NPS at end of the observation period.
Timepoint [1] 331570 0
At 6 months post randomisation (follow up visits), compared to baseline NPS at end of the 2 weeks observation
Secondary outcome [2] 331571 0
the proportion of participants in each group with a reduction in the NDI score of >=10 points at follow up visits compared to baseline NDI scores at end of observation period.
Timepoint [2] 331571 0
At 6 months post randomisation (follow up visits), compared to baseline NDI at end of the 2 weeks observation period.
Secondary outcome [3] 331971 0
the proportion of participants in each group with a >=30 reduction in cold pain allodynia measured at preselected anatomical sites.
Timepoint [3] 331971 0
At 6 months from randomisation (follow up visit) compared to baseline value at end of the 2 weeks observation period.
Secondary outcome [4] 331972 0
the proportion of participants in each group with a reduction in DASS21 score (depression, anxiety, stress questionnaire) of >=6 points (maximum possible score of 63= worst symptoms imaginable) at completion of treatment period.
Timepoint [4] 331972 0
DASS21 at completion of the 8 weeks treatment period compared to baseline DASS21 at end of the 2 weeks observation period.

Eligibility
Key inclusion criteria
1- an adult who had a whiplash injury following a car crash in the past 4 weeks.
2- moderately severe initial injury (WAD class II and III).
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1- very severe whiplash injury (WAD IV)
2- pregnant patients.
3- patients with immune disorders or inflammatory arthritis e.g. multiple sclerosis, fibromyalgia, rheumatoid arthritis , systemic lupus erythematosus and Diabetes mellitus.
4- patients on opioid analgesics.
5- participants who have difficulty understanding English
6- participants who may have problems accessing online surveys/diaries to complete data entries.

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)
allocation to a group will be provide via sealed opaque envelops.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
simple randomisation using a toss of a coin.
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
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
the number of participants was calculated on the basis of the IMMPACT latest statement for proof of concept studies, power=80%, type-I error (false positive rate)=0.2. and a reduction of average pain by 30% compared to baseline average pain scores.
An experienced statistician will be recruited to analyse the data and help its interpretation. The p- value is chosen to be 0.2 per the IMMPACT latest statements on proof of concept studies, 2015 (higher type I error i.e. false positive rate is planned to increase the chance of detecting any efficacy of LDN).
All analyses were conducted using SPSS statistical package V. The primary clinical end-point was self-reported daily pain. Because this study used an intensive longitudinal design, assumptions of independent and identically distributed residuals could not be made, and therefore, the proper modelling of data interdependency across time was a significant concern. To test all models, the linear mixed model (LMM) approach was used. The LMM allows for correlated observations in the dependent variable. Denominator degrees of freedom were estimated via SPSS conventions when using LMMs with repeated-measures data.
To test the primary clinical outcome, the percentage of change in the level of pain from baseline was entered as the dependent variable, and the study day was entered as the repeated index. The optimal working correlation matrix for repeated measures was determined by contrasting the available options with the Bayesian information criterion, with autoregressive as the default structure. Baseline pain was calculated by averaging pain across the entire 14-day baseline period. To contrast the placebo and low-dose naltrexone conditions, the percentage of pain reduction from baseline was assessed during the final 3 days of each treatment condition. Condition (placebo versus low-dose naltrexone) was entered as a fixed factor. Two control variables were also tested in the model. First, baseline pain severity was entered. The baseline pain control variable was designed to determine if individuals with greater baseline severity were more likely to respond to placebo or low-dose naltrexone. Second, a linear time function was entered. The time variable was included to determine if change in pain could be attributed simply to natural improvement over time. The time variable was created by entering the observation day (days 1–70) for each outcome data point. The time variable was tested in a separate model to properly include the entire longitudinal data set, and to avoid artificial overlap with the condition X group interaction. The modelling approach was repeated for all secondary outcomes.
Differences in response rate between the placebo and LDN conditions and differences in proportions of other secondary outcomes and QSTs results are statistically assessed with a chi-square test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/09/2017
Actual
Date of last participant enrolment
Anticipated
1/07/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 7461 0
Joondalup Health Campus - Joondalup
Recruitment postcode(s) [1] 15287 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 295588 0
Hospital
Name [1] 295588 0
Joondalup Health Campus
Country [1] 295588 0
Australia
Primary sponsor type
University
Name
Notre Dame University Australia
Address
Notre Dame University
32 Mouat Street, Fremantle WA 6160
Australia
Country
Australia
Secondary sponsor category [1] 294422 0
None
Name [1] 294422 0
Address [1] 294422 0
Country [1] 294422 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 296910 0
Ethics committee address [1] 296910 0
Ethics committee country [1] 296910 0
Australia
Date submitted for ethics approval [1] 296910 0
01/03/2017
Approval date [1] 296910 0
Ethics approval number [1] 296910 0
Ethics committee name [2] 296912 0
Notre Dame Australia
Ethics committee address [2] 296912 0
32 Mouat Street, Fremantle WA 6160
Ethics committee country [2] 296912 0
Australia
Date submitted for ethics approval [2] 296912 0
01/03/2017
Approval date [2] 296912 0
Ethics approval number [2] 296912 0

Summary
Brief summary
Design: this is a randomised, double-blinded, placebo-controlled trial in patients with whiplash injury. it aims at testing whether a medicine we are trialling may reduce long term pain after a whiplash injury.
Each group will include 20 participants, who will be recruited after presenting to the emergency department at JHC. Detailed information sheet will be supplied to all participants prior to asking them to consent for the trail. Participants will voluntarily enter the trial, have their rights of declining participation and terminating their participation explained to them in the first interview and provided to them in writing. All their data will be secured on a computer, not shared with anyone outside this research group. All their personal details will be destroyed once data analysis and journal submission is complete.
You will be entering one of the groups by the order of chance using opaque sealed envelops. The investigators will have no prior knowledge which group you will fall into and no knowledge of which group you belong to during the phases of this study. If you are randomly selected into the treatment group, you will receive the active medicine, called low dose naltrexone. it is given as one tablet at bed time.
If you are randomly selected into the 'placebo' group, you will be give a' sham' tablet to take daily at bed time.

The study will run an observation period of 2 weeks, followed by a treatment period of 8 weeks, and a follow up visit at 6 months from the time you were randomised into a group.
Observation phase: all participants will have daily numerical pain scale reported (0-100), zero equals no pain at all and a 100 means the worst imaginable pain, highest neck disability index (NDI) will be measured based on a validated questionnaire, Sensory testing (called QST) of your sensitivity to graded cold on specific sites of the body will be tested,. An assessment of your stress, anxiety and depression will be conducted using a specific questionnaire (DASS21), This will be done at same time points as the measures of neck disability and skin testing.
A baseline blood test for inflammatory markers will obtained once from each participant.
Treatment phase: placebo group will receive sham tablets at bed time for 8 weeks, treatment group will receive LDN at bed time for 8 weeks. All participants will record their NPS at the same time of taking the tablet. NDI, QST and DASS21 will be conducted at end of treatment period, and CRP will be tested once at end of the 8 weeks treatment period.

Follow-up: at 6 months from entering a study group; we are planning to measure NPS, NDI, conduct QSTs, DASS21 and repeat the CRP test once per visit.
Trial website
none
Trial related presentations / publications
Public notes
none

Contacts
Principal investigator
Name 72406 0
Dr Yasir Al-Tamimi
Address 72406 0
Department of anaesthesia and pain management
Joondalup Health Campus
Shenton avenue, Joondalup WA 6027
Country 72406 0
Australia
Phone 72406 0
+618 94009400
Fax 72406 0
Email 72406 0
[email protected]
Contact person for public queries
Name 72407 0
Dr Yasir Al-Tamimi
Address 72407 0
Department of anaesthesia and pain management
Joondalup Health Campus
Shenton avenue, Joondalup WA 6027
Country 72407 0
Australia
Phone 72407 0
+61 8 94009400
Fax 72407 0
Email 72407 0
[email protected]
Contact person for scientific queries
Name 72408 0
Prof Eric Visser
Address 72408 0
Department of anaesthesia and pain management
Joondalup Health Campus
Shenton avenue, Joondalup WA 6027
Country 72408 0
Australia
Phone 72408 0
+61894009400
Fax 72408 0
Email 72408 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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