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Trial registered on ANZCTR


Registration number
ACTRN12622000634774
Ethics application status
Approved
Date submitted
18/02/2022
Date registered
29/04/2022
Date last updated
11/10/2022
Date data sharing statement initially provided
29/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of cannabidiol (CBD) on chronic pain following spinal cord injury
Scientific title
A randomised, double-blind, placebo-controlled, cross-over, pilot trial exploring the effects of cannabidiol (CBD) on chronic pain following spinal cord injury
Secondary ID [1] 306471 0
Nil known
Universal Trial Number (UTN)
U1111-1277-2048
Trial acronym
SCICBD Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic pain 325330 0
Spinal cord injury 325331 0
Condition category
Condition code
Injuries and Accidents 322716 322716 0 0
Other injuries and accidents
Anaesthesiology 323117 323117 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blinded, placebo-controlled, crossover, pilot trial assessing the effects of cannabidiol (CBD) in patients with chronic pain following spinal cord injury. The investigational product is an orally administered soft gel capsule containing 200 mg CBD isolate.

Eligible participants will be randomised to receive either 6-weeks of treatment with CBD or 6-weeks of treatment with matched placebo, with a 4-week washout period. Allocation to treatment group will be randomised and blinded for both participants and study personnel.

Treatment Group A (Cannabidiol)
Participants will administer CBD on a fixed schedule starting with 200 mg/day (one capsule) on Day 1-4; 400 mg/day (two capsules) from Day 5-8; 600 mg/day (three capsules) on Day 9-12); 800 mg/day (four capsules) from Day 13 until end of Week 6.

Participants will be required to return all used and/or any unused bottles of medication to the study site pharmacy. Compliance with the study medication will be reviewed by the clinical trial pharmacy staff at the end of each treatment arm.
Intervention code [1] 322898 0
Treatment: Drugs
Comparator / control treatment
Treatment Group B (Placebo)
Participants will administer placebo on the same fixed schedule, matching the same number of capsules per day as active treatment.

Placebo capsules will be indistinguishable from active treatment. Placebo capsules contain the same excipient as the investigational product but does not contain any cannabinoids.
Control group
Placebo

Outcomes
Primary outcome [1] 330514 0
Change in average intensity of ongoing pain as measured on a Visual Analogue Scale (VAS) when compared to placebo
Timepoint [1] 330514 0
Assessed for 7 days (on Monday, Wednesday and Friday of each week, three times a day) prior to the start and at the end of each treatment arm.
Secondary outcome [1] 406494 0
Change in diffusivity markers of astrogliosis as determined by magnetic resonance imaging (MRI) and electroencephalography (EEG) when compared to placebo
Timepoint [1] 406494 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [2] 406496 0
Change in resting infra-slow oscillations in the ascending pain pathway via magnetic resonance imaging (MRI) and electroencephalography (EEG) when compared to placebo.
Timepoint [2] 406496 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [3] 406497 0
Change in thalamic blood flow as assessed via magnetic resonance imaging (MRI) and electroencephalography (EEG) when compared to placebo.
Timepoint [3] 406497 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [4] 406498 0
Change in thalamocortical rhythm power as assessed via magnetic resonance imaging (MRI) and electroencephalography (EEG) when compared to placebo.
Timepoint [4] 406498 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [5] 406499 0
To determine the effect of CBD administration on FAAH genotype expression via analysis of blood samples when compared to placebo.
Timepoint [5] 406499 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [6] 407918 0
Change in levels of endocannabinoids and related lipids as determined by analysis of blood samples when compared to placebo.
Timepoint [6] 407918 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [7] 407919 0
Change in peripheral inflammatory markers as determined by analysis of blood plasma when compared to placebo.
Timepoint [7] 407919 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [8] 407921 0
Change in severity of pain on the Brief Pain Inventory (BPI) questionnaire when compared to placebo
Timepoint [8] 407921 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [9] 407922 0
Change in pain-related catastrophic thinking as measured on the Pain Catastrophising Scale (PCS) when compared to placebo.
Timepoint [9] 407922 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [10] 408887 0
Change in intensity of ongoing neuropathic pain as measured on the Douleur Neuropathique-4 Questionnaire (DN4) when compared to placebo.
Timepoint [10] 408887 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [11] 408890 0
Change in the total score of the 12-item Neuropathic Pain Questionnaire (NPQ) when compared to placebo.
Timepoint [11] 408890 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [12] 408901 0
Change in negative emotional states as measured by the Depression, Anxiety and Stress Scale - 21 Items (DASS-21) when compared to placebo.
Timepoint [12] 408901 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [13] 408902 0
Change in self-reported anxiety as measures on the State-Trait Anxiety Inventory (STAI) questionnaires when compared to placebo.
Timepoint [13] 408902 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [14] 408917 0
Change in sleep quality as determined using the Pittsburgh Sleep Quality Index (PSQI) questionnaire when compared to placebo.
Timepoint [14] 408917 0
Assessed at Week 0 (baseline) and at 6 weeks post commencement of intervention.
Secondary outcome [15] 408918 0
Change in objective sleep parameters as measured by actigraphy when compared to placebo.
Timepoint [15] 408918 0
Assessed for 7 continuous days prior to the start and at the end of each treatment arm.

Eligibility
Key inclusion criteria
(a) Complete or incomplete spinal cord injury as determined using the ASIA scale;
(b) Below-level neuropathic pain for minimum 3 months duration;
(c) Adult (18 years and over) who is able to provide informed consent; and
(d) Proficient in English (must not require an English translator)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(a) Spinal cord injury in acute stage of recovery (<12 months post-acute spinal cord injury or at the medical doctor’s discretion);
(b) If on pain relieving medications must be on stable dose for at least 6 weeks prior to beginning our trial. This includes all prescription medications for pain including opioids or adjuvant pain medications such as Pregabalin, Amitriptyline and SSRIs. Paracetamol and over-the-counter NSAIDs (e.g., ibuprofen, aspirin, naproxen) within the recommended adult dosage permitted as needed. If there has been recent dose titration then we would wait for a stable 6-week period before entering the individual into the trial.
(c) If on pain relieving medications, they must not be changed in dosage during the trial period;
(d) Cannabis or any other drug or alcohol dependence, as per the International Statistical Classification of Diseases 10th Revision (ICD)-10 criteria or at a medical doctor’s discretion;
(e) Reported use of cannabis within the past 3 months (or at the medical officer’s discretion);
(f) Urine drug test positive for drugs (cannabis – THC only, meth/amphetamines, and cocaine) at each visit;
(g) A history of (self-reported) allergic reaction (e.g. rhinitis, urticaria, contact dermatitis, anaphylaxis) to cannabis, cannabis products or cannabinoids;
(h) A history of (self-reported) a clinically significant adverse response to CBD;
(i) A history of moderate-to-severe hepatic impairment as determined by the medical doctor;
(j) Use of medication(s) that may influence CBD metabolism (e.g. inducers or inhibitors of the CYP450 enzyme system) as determined by the medical doctor;
(k) Unable to undergo MRI brain imaging as identified via 'NeuRA MRI Safety Screening Questionnaire';
(l) A history of a major psychiatric disorder within the previous 12 months except for clinically managed mild anxiety and/or depression as determined via clinical interview using the Diagnostic and Statistical Manual of Mental Disorders (DSM)-V criteria or at the medical doctor’s discretion;
(m) Current suicide ideation as determined via clinical interview with the medical doctor;
(n) Pregnancy or lactation - women shall be advised to use reliable contraception for the duration of drug therapy and a urine pregnancy test will be performed where necessary;
(o) Patients with quadriplegia secondary to cervical spine injury.

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)
After obtaining informed consent, participants will be randomly allocated to order of treatment (i.e. CBD-Placebo or Placebo-CBD). Method of allocation concealment will involve numbered containers and central randomisation by computer. Allocation concealment will only be known by the drug distributer, clinical trial pharmacist and an independent study investigator (the statistician performing the randomisation), none of whom have direct contact with the participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation schedule will be created by computer software (i.e. computerised sequence generation), and by the order of participant enrolment. The schedule will include a list of 40 ‘treatment orders’ that will be randomly generated in to balanced blocks of four (i.e. in which each sequence appears twice).
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
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
This trial will test the hypothesis that CBD treatment will reduce ongoing pain. A significant improvement in pain will be classified as a reduction in ongoing pain greater than 30% which is statistically significant compared to placebo as measured by a one-sided t-test with a p-value less than 0.05.

Functional MRI images will be motion corrected, heart, respiratory, global signal and movement modelled and removed, spatially normalized and smoothed. Three analysis procedures will be used to determine significant differences between CBD and placebo on SCI pain: i) resting infra-slow oscillatory activity assessed using fast Fourier transform and differences in 0.03-0.06Hz power determined; ii) resting functional connectivity between ventroposterior thalamus and cortex; and iii) resting connectivity within the descending pain modulation system. Significant differences will be determined using random effects procedures (p<0.05, family wise error corrected for multiple comparisons).

Brain responses to acute noxious stimuli will assess central sensitization and simultaneous noxious stimuli endogenous pain modulation pathway functioning. Arterial spin labelling (ASL) images will be converted into cerebral blood flow (CBF) maps, spatially normalized, smoothed and differences between CBD and placebo determined using random effects procedures (p<0.05, family wise error corrected for multiple comparisons). Diffusion tensor images (DTI) will be motion corrected and mean diffusivity and fractional anisotropy map calculated. Additionally, two diffusivity models will be calculated, one consistent with the presence of microglia and another with that of astrocytes. Diffusivity maps will be spatially normalized and smoothed and significant differences between groups determined using random effects procedures (p<0.05, family wise error corrected for multiple comparisons). Magnetic resonance spectroscopy (MRS) data will be processed using jMRUI. “ON” and “OFF" subspectra will be subtracted resulting in GABA-edited difference spectra to measure GABA at 3.01ppm and Glx at 3.75ppm. Significant differences will be determined using (p<0.05, two-sample t-tests).

EEG data will be filtered, artefacts removed and full-band (0.01–100Hz) fast Fourier transformed, power values calculated, logged, plotted and differences between groups over the entire frequency band and within infra-slow, theta, alpha, and beta ranges determined (p<0.05, one-way ANOVA). Differences in power across each EEG channel will be determined (p<0.05, two-sample t-tests). Relationships between pain intensity, EEG power, resting state thalamocortical connectivity, resting infra-slow oscillations as well as markers of astrocyte activation determined. Regression analyses will be performed to determine the relationship between these imaging measures and pain ratings, peripheral inflammatory markers, and questionnaire results by use of traditional statistical methods including t-test calculations and analysis of variance, as appropriate.

The trial hypothesises that CBD will lead to a reduction in the presence of peripheral inflammatory markers in the CBD treatment component. This will be analysed by comparing CBD peripheral inflammatory markers to placebo using traditional statistical methods including t-test calculations, analysis of variates and regression analysis, as appropriate. A similar approach will also be taken with the measure of depression, anxiety and stress levels, with a reduction in anxiety suggested to occur during the CBD treatment.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2023
Actual
11/07/2022
Date of last participant enrolment
Anticipated
1/05/2024
Actual
Date of last data collection
Anticipated
1/07/2024
Actual
Sample size
Target
40
Accrual to date
7
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 36831 0
2031 - Randwick
Recruitment postcode(s) [2] 36830 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 310819 0
Government body
Name [1] 310819 0
NSW Office of Science and Medical Research (OSMR) grant
Country [1] 310819 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
The University of Sydney
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 312069 0
None
Name [1] 312069 0
N/A
Address [1] 312069 0
N/A
Country [1] 312069 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310385 0
The University of Sydney Human Research Ethics Committee (HREC 1)
Ethics committee address [1] 310385 0
University of Sydney
Camperdown NSW 2006
Ethics committee country [1] 310385 0
Australia
Date submitted for ethics approval [1] 310385 0
03/09/2021
Approval date [1] 310385 0
09/02/2022
Ethics approval number [1] 310385 0
2021/936

Summary
Brief summary
Background:
Approximately half of all spinal cord injury patients develop chronic pain. Current treatments for this pain have proven to be largely ineffective and many have significant side-effects. We will examine whether a novel non-intoxicating component of cannabis, cannabidiol (CBD), can reduce pain. Using modern brain imaging techniques, we aim to determine if pain reductions result from normalisation of brain, immune, psychological and sleep function. In addition, we aim to identify a biomarker that will predict whether an individual will respond to CBD treatment, easing suffering, saving time and reducing costs.

Study Aim:
To determine the impact of CBD treatment on chronic pain following SCI and to investigate biological changes associated with reduced pain.

Hypothesis:
We hypothesise that CBD treatment will reduce ongoing pain to a significantly greater degree than placebo. Furthermore, we hypothesize that pain relief during CBD treatment will be associated with reduced diffusivity markers of astrogliosis, reduced resting infra-slow oscillations in the ascending pain pathway, restored thalamic blood flow to control levels and reduced thalamocortical rhythm power. We also hypothesize that CBD treatment will reduce ongoing peripheral inflammatory markers, improve sleep and psychological state and that this will correlate with a reduction in ongoing pain. Finally, we hypothesize that pain relief during CBD treatment will be associated with pre-trial levels of endogenous pain modulatory ability and endocannabinoid levels.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117470 0
Prof Luke Henderson
Address 117470 0
University of Sydney. M02F, Level 1, Brain and Mind Centre, University of Sydney, 94 Mallett Street, Camperdown, NSW, 2050
Country 117470 0
Australia
Phone 117470 0
+61 293517063
Fax 117470 0
Email 117470 0
luke.henderson@sydney.edu.au
Contact person for public queries
Name 117471 0
Miss Anastasia Suraev
Address 117471 0
University of Sydney. M02F, Level 6, Brain and Mind Centre, University of Sydney, 94 Mallett Street, Camperdown, NSW, 2050
Country 117471 0
Australia
Phone 117471 0
+61439804551
Fax 117471 0
Email 117471 0
anastasia.suraev@sydney.edu.au
Contact person for scientific queries
Name 117472 0
Prof Luke Henderson
Address 117472 0
University of Sydney. M02F, Level 1, Brain and Mind Centre, University of Sydney, 94 Mallett Street, Camperdown, NSW, 2050
Country 117472 0
Australia
Phone 117472 0
+61 293517063
Fax 117472 0
Email 117472 0
luke.henderson@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All original research data will remain strictly confidential. The de-identified research data will be disseminated via conference presentations, peer-reviewed journal publications and media, as applicable, at the completion of the trial. There are no commercial interests that are likely to delay or restrict the dissemination of these results. Eligible authors of publications will include investigators who provide substantial contribution to the conception and design of the study, or the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content; and final approval of the version to be published.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15145Study protocol  luke.henderson@sydney.edu.au
15146Informed consent form  luke.henderson@sydney.edu.au
15147Ethical approval  luke.henderson@sydney.edu.au



Results publications and other study-related documents

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