Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001946202
Ethics application status
Approved
Date submitted
20/11/2018
Date registered
30/11/2018
Date last updated
31/03/2023
Date data sharing statement initially provided
30/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Neuroinflammation and PET-CT imaging as a diagnostic tool following spinal cord injury
Scientific title
The 18-kDa translocator protein radioligand [18F]GE-180 as a diagnostic and prognostic biomarker following spinal cord injury: A PET-CT pilot study
Secondary ID [1] 295131 0
Nil known
Universal Trial Number (UTN)
U1111-1224-2902
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spinal Cord Injury 308224 0
Condition category
Condition code
Injuries and Accidents 307250 307250 0 0
Other injuries and accidents
Neurological 307251 307251 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Neurological examination:
Prior to Scan 1 (baseline), the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) physical examination of participants will be conducted by qualified SCI physicians in order to assess the nature and degree of injury and to classify neurological status as part of the formal screening process. This assessment will be used as the baseline neurological score to confirm the participant’s motor, sensory impairment and neurological levels. This neurological examination will be repeated at study completion (6 months following PET-CT; Cohort 1 Only).

Neuropathic pain assessment:
Participants will be asked to complete the Visual Analogue Scale (VAS), Numerical Pain Rating Scale (Lichert Scale), and The Neuropathic Pain Diagnostic Questionnaire. These examinations will be repeated at study completion (6 months following PET-CT; Cohort 1 only).

Biochemical assessment:
Blood collection for genotyping will be conducted once, and sampling for biochemical analysis will be conducted once. 35mL of venous blood will be drawn from the cubital fossa using RAH standard care venepuncture and infection control protocols. Blood will be collected into EDTA vacutainer tubes. Blood (25mL) will be cryo-stabilised (8°C) and transported on ice and centrifuged and serum aliquoted into 5mL vacutainer tubes for immediate analysis. Analyses will include CBE – leukocyte counts/percentages, haematocrit (5mL) and, MBA – glucose, cholesterol, LDL, HDL, total protein (5mL) on commercial platforms. Unused serum (15mL) will be stored in 5mL aliquots at -20°C for biochemical analysis. Five (mls) of serum will be stored for 2-years against the contingency of low assay yield. The assay repertoire may be expanded as new studies appear in the literature. Unused serum will be disgorged and destroyed at the end of study.

PET-CT assessment:
Administration of GEH120714 ([18F]GE-180; 100-270 Megabecquerel (MBq), intravenous administration) in spinal cord injured participants.

All participants will be scanned at the Clinical & Research Imaging Centre (Dr. Jones & Partners, SAHMRI) and/or Royal Adelaide Hospital (Nuclear Medicine Department). Cohort 1 participants, PET-CT scans will be performed on 1 occasion: baseline (either 3 months ± 4 weeks, 6 months ± 4 weeks, 9 months ± 4 weeks, or >12 months and <24 ± 4 weeks post injury). For Cohort 2 participants, PET-CT scans will be performed on 1 occasion: >24 months post-injury. Participants will be likely be scheduled in batches of three per visit day over 3 scanners. All data acquisition will occur using one of three, compatible (6-slice CT) PET-CT Scanners (BiographTM, Seimens Healthineers, Australia).

On scan days prior to PET scanning, an antecubital venous cannula will be inserted for [18F]GE-180 administration. All participants will receive a maximum dose 270 MBq of [18F]GE-180 by a slow, single bolus intravenous injection (<10mL) over 10 seconds, followed immediately with a normal saline flush (10 mL).

Prior to the scan, participants will be transferred to the scanner platform using a pat slide, or electric hoist, as per the clinical treatment plan manual handling requirement. Participants will be positioned and secured in a recumbent position (supine with knees in ~ 30 degrees flexion, hips extended, arms down) on the scanner platform with their head secured in a holding using foam wedges and Velcro straps. Emission data from the head to mid-thigh will be acquired using a whole-body scanner (BiographTM , MCT flow 64 slice cameras) operated by an AHPRA-accredited Nuclear Medicine technologist. Attenuation correction of the images will be performed using a low-dose CT scan to allow standard corrections for tissue scatter and anatomical localisation. Whole Body acquisition will begin at 60 minutes post-injection of the radiotracer. Estimated PET acquisition time is 45 minutes for whole body scan.

MRI Assessment:
MRI scans will be performed once on all participants. Cohort 1 participants, MRI scans will be performed on 1 occasion: baseline (either 3 months ± 4 weeks, 6 months ± 4 weeks, 9 months ± 4 weeks, or >12 months and <24 ± 4 weeks post injury). For Cohort 2 participants, MRI scans will be performed on 1 occasion: >24 months post-injury. Standard MRI safety screening will be performed (attached) to ensure included participants are safe for MRI. Prior to the scan, participants will be transferred to the scanner platform using a pat slide, or electric hoist, as per the clinical treatment plan manual handling requirement. Participants will be positioned and secured in a recumbent position (supine with knees in ~ 30 degrees flexion, hips extended, arms down) on the scanner platform with their head secured in a holding using foam wedges and Velcro straps. Structural T-weighted, and diffusion-weighted MRI will be performed on each participant. MRI will be performed on a Siemens 3-tesla MAGNETOM Skyra MRI scanner (Siemens, Erlangen, Germany). Co-registration of MRI with PET-CT images will provide additional anatomical information.
Intervention code [1] 301459 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 306204 0
Neuroinflammation at the level of injury (spinal cord) assessed by PET-CT analysis of radioligand [18F]GE-180 emission signature(s) following spinal cord injury.
Timepoint [1] 306204 0
Baseline (3, 6 months, or 1-year) and 2-years post-injury.
Primary outcome [2] 308184 0
Neurological function (ISNCSC; grade A-D) predicted by PET-CT analysis of radioligand [18F]GE-180 emission signature(s) following spinal cord injury.
Timepoint [2] 308184 0
Baseline (3, 6 months, or 1-year) and 2-years post-injury.
Primary outcome [3] 308259 0
Neurological function (ISNCSC; grade A-D) predicted by composite biochemical assesment of neuroinflammatory markers (TNF-alpha, TNF-R1, IL-1beta, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IP-10, MCP-1, IFN-alpha, IFN-gamma, eotaxin, GM-CSF, MIG, MIP-1alpha, MIP-1beta, and RANTES) following spinal cord injury.
Timepoint [3] 308259 0
Baseline (3, 6 months, or 1-year) and 2-years post-injury.
Secondary outcome [1] 347871 0
Neuroinflammation in exploratory brain regions assessed by PET-CT analysis of radioligand [18F]GE-180 emission signature(s) following spinal cord injury.
Timepoint [1] 347871 0
Baseline (3, 6, 9 or between 12 and 24 months post-injury; Cohort 1) or 2-years or more post-injury (Cohort 2).
Secondary outcome [2] 354196 0
Neuropathic pain assessed by composite analysis of [18F]GE-180 emission signature(s) and composite biochemical assesment of neuroinflammatory markers (TNF-alpha, TNF-R1, IL-1beta, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IP-10, MCP-1, IFN-alpha, IFN-gamma, eotaxin, GM-CSF, MIG, MIP-1alpha, MIP-1beta, and RANTES).
Timepoint [2] 354196 0
Baseline (3, 6, 9 or between 12 and 24 months post-injury; Cohort 1) or 2-years or more post-injury (Cohort 2).
Secondary outcome [3] 354197 0
Neuroinflammation in the rostral (5cm above) regions of injured spinal cord assessed by PET-CT analysis of radioligand [18F]GE-180 emission signature(s).
Timepoint [3] 354197 0
Baseline (3, 6, 9 or between 12 and 24 months post-injury; Cohort 1) or 2-years or more post-injury (Cohort 2).
Secondary outcome [4] 354315 0
Neuroinflammation in the caudal (5cm below) regions of injured spinal cord assessed by PET-CT analysis of radioligand [18F]GE-180 emission signature(s).
Timepoint [4] 354315 0
Baseline (3, 6, 9 or between 12 and 24 months post-injury; Cohort 1) or 2-years or more post-injury (Cohort 2).

Eligibility
Key inclusion criteria
1. Male, or female
2. Aged between 18 and 75 years (inclusive)
6. Medically stable, in the opinion of the treating physician
3. 4. Have sustained a complete or incomplete, traumatic spinal cord injury, or, have a non-traumatic spinal cord injury (e.g. a spinal cord injury caused by multiple sclerosis, amyotrophic lateral sclerosis, cancer metastasis to spine)
4. Have complete or incomplete SCI, taking complete as the absence of sensory and motor functions in the lowest sacral segments, as per the International Standard for the Neurological Classification of SCI (ISNCSCI) 2011 revision
5. Have International Standard for the Neurological Classification of SCI (ISNCSCI) Grade A, Grade B, Grade C or Grade D at acute admission
6. Have neurological level between C4 and L1, taking this as the most caudal segment with normal motor and sensory functions on both sides of the body (ISNCSCI; revised 2011)
7. Have submitted to either spinal instrumentation (carbon fibre, or metal fixation in situ), or conservative stabilisation
8. Are agreeable to sequence analysis for the r.s. 6971 phenotype
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or breastfeeding
2. Have history of stroke, or TBI, brachial plexus lesion, or any other serious medical condition; e.g. malignancies, psychiatric, or illicit drug-dependence, which is likely to influence the patient’s ability to participate
3. Have active osteomyelitis, Paget’s disease, or severe kypho/scoliosis
4. Have spasticity, or autonomic dysreflexia (AD) unresponsive to standard care, as advised by the treating physician
5. Have pressure ulcer(s) on the pelves or proximal femur, or other contraindications to participating in the PET-CT imaging protocol, or outcome assessments, as advised by the treating physician
6. Have medical history of alcohol dependence or medical/ cultural contraindication to alcohol exposure
7. Have active, or previous participation in investigational drug study within 30 days of enrolment
8. Considered unwilling, unable or unlikely to comply with the study protocol
9. Have English language competency insufficient to understand research procedures, or are unable to provide informed consent.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
In the absence of prior data allowing determination of intraspinal inflammatory response, and if this is related to genotype, we have set the sample size at 24, to generate exploratory feasibility data and examine safety.

Comparisons of NSUVs and SUVR values will be made using means, or medians and proportions; with 95% confidence intervals as appropriate. All end-points and analyses have been prospectively categorised as either primary or secondary or tertiary. Differences in both primary and secondary endpoints will be tested independently at the 0.05 level of significance, using a one way ANCOVA model. The model will include the baseline value of a given outcome in question as a covariate.

Ordinal logistic regression will be conducted on [18F]GE-180 (TSPO) expression and all biochemical samples. Bootstrapping will be conducted to produce rankings between each measure as a predictor of injury severity, to produce a final prediction model. This will then be compared to the observed ASIA impairment score, to determine the accuracy at predicting the ‘true’ injury severity of SCI patients. To assess the relationship of [18F]GE-180 (TSPO) expression, structural (MRI/CT) and biochemical markers, neuropathic pain and neurological status, Pearson correlation coefficients will be calculated at baseline, and each quarter until final follow up, of patient scores.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/12/2018
Actual
26/02/2020
Date of last participant enrolment
Anticipated
31/12/2023
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
24
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 11105 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 22918 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 299722 0
Government body
Name [1] 299722 0
Lifetime Support Authority
Country [1] 299722 0
Australia
Funding source category [2] 299725 0
Charities/Societies/Foundations
Name [2] 299725 0
Neil Sachse Centre for Spinal Cord Research
Country [2] 299725 0
Australia
Primary sponsor type
Other
Name
South Australian Health and Medical Research Institute
Address
South Australian Health and Medical Research Institute
North Terrace, Adelaide SA, 5000, Australia
Country
Australia
Secondary sponsor category [1] 300879 0
University
Name [1] 300879 0
Adelaide Medical School, The University of Adelaide
Address [1] 300879 0
Adelaide Healh and Medical Sciences Building, The University of Adelaide, Adelaide SA 5000
Country [1] 300879 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300612 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 300612 0
Ethics committee country [1] 300612 0
Australia
Date submitted for ethics approval [1] 300612 0
11/06/2018
Approval date [1] 300612 0
25/09/2018
Ethics approval number [1] 300612 0
HREC/18/CALHN/297, R20180516

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84214 0
Prof Brian JC Freeman
Address 84214 0
Spinal Services
Spinal Unit 5g-531,
Royal Adelaide Hospital, Port Rd, Adelaide, SA 5000
Country 84214 0
Australia
Phone 84214 0
+618 7074 2024
Fax 84214 0
+618 7074 6198
Email 84214 0
[email protected]
Contact person for public queries
Name 84215 0
Ryan O'Hare Doig
Address 84215 0
Level 7, Neil Sachse Centre for Spinal Cord Research
South Australian Health and Medical Research Institute
North Terrace, Adelaide, SA 5000
Country 84215 0
Australia
Phone 84215 0
+61 8 8128 4744
Fax 84215 0
Email 84215 0
[email protected]
Contact person for scientific queries
Name 84216 0
Ryan O'Hare Doig
Address 84216 0
Level 7, Neil Sachse Centre for Spinal Cord Research
South Australian Health and Medical Research Institute
North Terrace, Adelaide, SA 5000
Country 84216 0
Australia
Phone 84216 0
+61 8 8128 4744
Fax 84216 0
Email 84216 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual data of published results only will be available. Other (unpublished) data, such as additional de-identified individual data of primary and/or secondary outcomes may be available upon reasonable request.
When will data be available (start and end dates)?
No data will be available until completion and publication of the full study. Data will then become available 12 months after publication.
Available to whom?
Available to anyone upon reasonable request.
Available for what types of analyses?
Meta analysis, genotyping, protocol analysis
How or where can data be obtained?
By emailing the primary or co-ordinating investigators.

[email protected]
[email protected]
james.swift.sa.gov.au


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16012Informed consent form  [email protected]
16013Ethical approval  [email protected]



Results publications and other study-related documents

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