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Trial registered on ANZCTR


Registration number
ACTRN12615001377527
Ethics application status
Approved
Date submitted
12/09/2015
Date registered
17/12/2015
Date last updated
22/01/2019
Date data sharing statement initially provided
22/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Perispinal Etanercept therapy in Australian patients with chronic stroke.
Scientific title
Phase I/II clinical trial of Perispinal Etanercept in Australian patients with Chronic Stroke.
Secondary ID [1] 287463 0
PSECS-01
Universal Trial Number (UTN)
U1111-1174-3242
Trial acronym
PSECS-01
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Stroke 296186 0
Condition category
Condition code
Stroke 296465 296465 0 0
Ischaemic
Stroke 296466 296466 0 0
Haemorrhagic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Enbrel (Etanercept, 25 mg mixed with 1.8 ml of non-bacteriostatic sterile water.
) delivered by perispinal injection using a short (27g x 0.5 inch) needle twice over a space of 2 weeks administered by clinical investigators including an anaesthetist, neurologist and a general practitioner. Monitoring of adherence by log of dose timings. Change made prior to any patient enrolment.
Intervention code [1] 292838 0
Rehabilitation
Intervention code [2] 292839 0
Treatment: Drugs
Comparator / control treatment
Saline Control
Control group
Placebo

Outcomes
Primary outcome [1] 296089 0
Sustained Change in Chronic Post-Stroke Pain measured by vNPRS-FPS at one week after treatment 2, compared with baseline in the two groups, perispinal etanercept (PSE) group compared to placebo group:

Chuang LL, Wu CY, Lin KC, Hsieh CJ. Relative and absolute reliability of a vertical numerical pain rating scale supplemented with a faces pain scale after stroke. Phys Ther. 2014;94(1):129-38. doi:10.2522/ptj.20120422.
Timepoint [1] 296089 0
Primary Outcome Measure (1) will be the change in chronic, intractable post-stroke pain as measured by the 11-point (0-10) vNPRS-FPS from immediately pre-treatment (baseline) compared with vNPRS-FPS at one week after treatment 2 (PSE versus placebo group).
Primary outcome [2] 307535 0
Primary outcome (2): Overall Change in Chronic Post-Stroke Pain
Second Primary Outcome Measure: Outcome Measure 2, Overall Change in Chronic Post-Stroke Pain, perispinal etanercept versus placebo groups:
The vertical Numerical Pain Rating Scale supplemented with a faces pain scale (vNPRS-FPS) for self-reported pain intensity has been found to be a reliable pain measurement instrument after stroke.
Chuang LL, Wu CY, Lin KC, Hsieh CJ. Relative and absolute reliability of a vertical numerical pain rating scale supplemented with a faces pain scale after stroke. Phys Ther. 2014;94(1):129-38. doi:10.2522/ptj.20120422.
Timepoint [2] 307535 0
Changes in vNPRS-FPS (compared with baseline) at all measured timepoints, perispinal etanercept versus placebo groups. vNPRS-FPS will be checked immediately prior to treatment 1; about 30 minutes after treatment 1; 1 day after treatment 1 (by telephone); one week after treatment 1 (by telephone); immediately prior to treatment 2; about 30 minutes after treatment 2; 1 day after treatment 2 (by telephone); 1 week after treatment 2; immediately before treatment 3.
Primary outcome [3] 307536 0
Primary Outcome (3): Safety and Tolerability assessed by incidence of adverse events noted either by investigators or by self-reporting of caregivers during course of therapy. Known serious adverse events include possible anaphylaxis (exceedingly rare), adverse events assessed are those known for ENBREL including injection site reactions or increased risk of infections. Generally, it is well tolerated and a commonly used therapy for rheumatoid arthritis.
Timepoint [3] 307536 0
During the course of the trial and after the trial assessing for any adverse events
Secondary outcome [1] 317464 0
Composite changes in physical mobility and movement after Chronic Stroke. This will involve use of commonly applied upper-extremity motor scales, the Action Research Arm Test (ARAT) or the Fugl-Meyer Assessment (FMA), in evaluating recovery of upper-extremity function. These assess the ability to handle objects differing in size, weight and shape and therefore can be considered to be an arm-specific measure of activity limitation.

Fastest feasible 10-meter walk test (and repeat measurement by return). Short-distance walking speed and timed walking distance.
The velocity of a 10-meter walk (2 measurements of 10m each) and walking endurance are considered distinct outcomes in clinical trials of stroke rehabilitation. Comfortable velocities used for each task in subjects with chronic hemiparesis can be measured for significant differences. The fastest feasible 10-meter velocity augments these measures.

Recording of changes in the difficulty and patient’s ability to stand unassisted from a seated position in a chair to an erect upright standing position. Arising from sitting to standing, howmany repetitions within 20 seconds based on a standard 43cm chair height or time to do 5 repetitions of sitting to standing position.
Timepoint [1] 317464 0
Baseline, after first treatment, and 1 week after the second treatment, including 1week after completion at end of randomized trial involvement (4 weeks). Follow up treatments may also be assessed for additional improvements on open-label, if indicated.
Secondary outcome [2] 317818 0
Composite Neurological Assessments.
Assessment of neurological changes in special senses/sensation including hearing, taste, touch and feeling, as well as spasticity and other measures as determined by a neurologist.
Timepoint [2] 317818 0
Baseline and directly after each treatment including within 1-2 hours following the first treatment at Week 1 and the second treatment at Week 2, completed within 1-2 hours post-treatment. Possible monthly assessments on follow up of individual patients completing involvement on trial and after completion of their on-trial study involvement to determine the duration of any outcome effects. Additional treatments may be included with the investigational drug as part of an open-label assessment, should improvements be indicated..
Secondary outcome [3] 317819 0
Changes in FDG-PET functional analysis of brain metabolism in the areas of the penumbra. FDG/PET as a potential biomarker.
Timepoint [3] 317819 0
Selected patients will receive a scan at baseline and within 6-10 days after the first injection (in Group 1 or further groups as required) or, alternatively after a second injection depending on the extent of the penumbra region visible on baseline PET scans.
Secondary outcome [4] 317820 0
Cognitive Assessments
Mini mental state examination (MMSE) and MOCA and Frenchay Aphasia Screening (FAS) developed to provide healthcare professionals working with patients who might have aphasia with a quick and simple method to identify the presence of a language deficit. The FAS is intended to be used as a screening device to identify those patients having communication difficulties.
Timepoint [4] 317820 0
Baseline, after first treatment, and 1 week after the second treatment, as well as 1week after completion at end of randomized trial involvement (over 4 weeks). Follow up treatments may also be assessed for additional improvements on open-label, if indicated.
Secondary outcome [5] 319601 0
Goniometric measurements may include angle of arm extension and angular measurements of passive upper arm and elbow from resting to maximum possible vertical elevation as well as ability to cross the arm over to touch the ear on the opposite side of the head from each arm.
Timepoint [5] 319601 0
Baseline, after first and second treatments (within 1-2 hours), and 1 week after the second treatment, including 1week after completion at end of randomized trial involvement (at 4 weeks).
Secondary outcome [6] 319602 0
The BEC depression test will also be applied.
Timepoint [6] 319602 0
Baseline, after first and second treatments (within 1-2 hours), and 1 week after the second treatment, including 1 week after completion at end of randomized trial involvement (at 4 weeks).
Secondary outcome [7] 319605 0
Composite Assessment of Motor and Process Skills (AMPS) is an observational assessment that allows for the simultaneous evaluation of motor and process skills and their effect on the ability of an individual to perform complex or instrumental and personal activities of daily living (ADL). The AMPS is comprised of 16 motor and 20 process skill items. The AMPS assessment will also be applied together with the Berg Balance Scale (BBS)- the most commonly used assessment tool across the continuum of stroke rehabilitation.
Timepoint [7] 319605 0
Baseline, after first and second treatments (within 1-2 hours), and 1 week after the second treatment, including 1week after completion at end of randomized trial involvement (at 4 weeks).
Secondary outcome [8] 319609 0
Composite assessments of change in Chronic Stroke pain assessed by using the dynomometer and by the MEDOC TSA-II neurosensory analyzer for pain assessment as testing device.
Timepoint [8] 319609 0
Baseline, after first and second treatments (within 1-2 hours), and 1 week after the second treatment, including 1week after completion at end of randomized trial involvement (at 4 weeks).
Secondary outcome [9] 351352 0
Change in Fatigue Assessment Scale (“FAS”).
Timepoint [9] 351352 0
Baseline and after first and second PSE dose and 1 month after second dose compared with baseline FAS measurement.

Eligibility
Key inclusion criteria
1. Chronic neurological impairment, including hemiparesis, following stroke that occurred at least 6 months and not more than 10 years prior to screening for this study.
2. A previous ischemic or hemorragic stroke in 1). the territory of the right or left middle cerebral artery (MCA); or 2). subarachnoid hemorrhage.
3. Age between 30-80. Age at 80 maximum to avoid possible morbidity on trial.
4. Stroke-induced cognitive impairment by history (difficulty with memory or cognition). The chronic stroke is associated with severe cognitive impairment and assessment of cognitive function by MMSE score is 16-25, or Montreal Cognitive Assessment (MOCA) score is measured in the range of 12-24, inclusive performed upon assessment during enrolment.
5. Individual has walking impairment but is ambulatory (with or without a quad cane or single point cane or walker) without assistance from another individual.
6. Chronic and intractable neuropathic pain due to stroke with pain score between 4 to 8 inclusive on the vertical assessment score.
Minimum age
30 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Dementia or cognitive impairment prior to date of stroke
2. Brain stem stroke
3. More than one stroke in the past 3 years
4. Pain score of less than 4 or above 8 out of 10 on the vertical assessment scale (VAS)
5. Parkinson’s Disease or Parkinsonian symptoms
6. Dementia with Lewy bodies
7. Multiple sclerosis
8. Demyelinating disease
9. History of tuberculosis
10. Positive PPD
11. HIV infection
12. History of hepatitis
13. History of deep fungal infection (coccidiodomycosis, histoplasmosis, blastomycosis)
14. Active infection
15. Indwelling urinary catheter
16. Lymphoma, active or in the past
17. Cancer
18. Uncontrolled diabetes mellitus
19. Patients using any other immunosuppressive medication, including Kineret (Anakinra) or Abatacept, or glucocorticoids.
20. Use of a TNF inhibitor (etanercept, infliximab, etc.) in the past
21. Congestive Heart Failure
22. Non-ambulatory
23. Less than two months since hospitalization for any cause
24. Pregnancy
25. Psychosis or use of anti-psychotic medication (e.g. olanzapine, quetiapine, clozapine, aripiprazole, haloperidol, flupenazine, risperidone, ziprasidone)
26. History of Alcohol abuse
27. Autoimmune disorder
28. Previous neck surgery (such as cervical fusion)
29. Severe or unstable concomitant condition or disease (e.g., known significant neurologic deficit, cancer, hematologic, or coronary disease), or chronic condition (e.g., psychiatric disorder), which, in the opinion of the investigator, would affect the assessment of the safety and tolerability of perispinal Etanercept.
30. Not taking an anticoagulant or an anti-platelet drug
31. No severe aphasia, as investigators need to be able to converse with the patients from the outset to reasonably assess their medical condition.

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)
Patients will be assigned to a randomized study treatment only if they meet all of the inclusion criteria and none of the exclusion criteria. Every subject who passes the initial screening based on inclusion/exclusion testing will be included as intent to treat as they are assessed and entered into the test pool. Patients from the test pool will be eligible for the study and invited to participate. The study will begin as patients enter from the test pool onto the trial after acceptance and approval by signing the consent forms. A final round of screening will occur as patients attend the clinic for their initial diagnosis and validation as suitable for enrolment by the trial neurologist. Simple randomisation into two groups will then occur.Allocation concealment means that the person who determined if a subject was eligible for inclusion in the trial was unaware, when this decision was made, to which group the subject would be allocated. Allocation is concealed using sealed opaque envelopes placed in the treatment container and only opened in the case of a serious adverse event. Assignments are made using randomization by computer. All investigators and patients/caregivers are blinded to the allocation. Allocation is otherwise only known by contacting the preparation pharmacist who has the allocation schedule at a discrete location remote from the clinical trials unit.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer based random number generator
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
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical analyses will involve the use of the most recent SPSS Statistical Analysis Software program available at Griffith University. The data will be entered onto spreadsheets using Microsoft Excel and then processed via SPSS for student’s t-test, univariate analysis and logistic regression and other suitable tests as required.
Analyses will include comparison of outcomes between the ACTIVE arm and the PLACEBO control arm in terms of scores from cognitive function tests as well as differences from baseline in the ACTIVE arm. The data will be presented including standard deviation about the mean. An interim first analysis will be done for this study after the initial dose of therapy for the first group of 20 patients given its relatively short duration. Sample Size and Power Estimation
The sample size of 20 patients per each group, and may involve up to 4 successive groups of 20 to provide a maximum total of 80 completed patients on trial if necessary. The sample size is based on the published data from the Phase I Open Label trials reported previously. The assumption is that the population of patients is normally distributed. The quantitative measurement software used was that developed by Dr David Schoenfeld(dschoenfeld@partners.org) at the Harvard website http://hedwig.mgh.harvard.edu/sample_size/js/js_parallel_quant.html and was validated by the trial biostatistician

Power calculation based on previous improvements in cognitive impairment by VAS Pain test.
The values used for this power calculation were taken from those reported previously in Table 8 (Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs. 2012 Dec;26(12):1051-70.) as one discriminator, with an improvement + Standard Deviation (SD) of 16.1 ( + 6.84) to 19.6 (+ 6.37).
Results for n= 107 patients from Table 8, obtained after 1 injection of Perispinal Etanercept treatment, were used for the power calculation shown below. Again the results show that the power is sufficiently high at nearly 90% as follows:
At baseline for the group the MOCA Mean score (SD) was 16.1 (+ 6.84).
After treatment there was an improvement with a Mean score (SD): 19.6 (+ 6.37). Thus,

value for mu1:
7.1
value for mu2:
2.3
Hence, Change in mu = 4.8
value for sigma (change is approx. 1 SD) = 2.81
1 Sided Test value for alpha:
.005
value for power:
1.000
The sample size (for each sample separately) is:
20
Hence, the power of our study based on previous data from improvements in VAS pain score analysis is approaching 100% with only 20 patients. Using a paired test gives a 100% power to detect the effect at alpha = 0.005.
Power calculation based on previous improvements in cognitive impairment by MOCA.
The values used for this power calculation were taken from those reported previously in Table 8 (Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs. 2012 Dec;26(12):1051-70.) as one discriminator, with an improvement + Standard Deviation (SD) of 16.1 ( + 6.84) to 19.6 (+ 6.37).
Results for n= 107 patients from Table 8, obtained after 1 injection of Perispinal Etanercept treatment, were used for the power calculation shown below. Again the results show that the power is sufficiently high at nearly 90% as follows:
At baseline for the group the MOCA Mean score (SD) was 16.1 (+ 6.84).
After treatment there was an improvement with a Mean score (SD): 19.6 (+ 6.37). Thus,
value for mu1:
20.8
value for mu2:
25.1
Hence, Change in mu = 3.5
value for sigma (change is approx. 1 SD) = 6.84
1 Sided Test value for alpha:
.05
value for power:
0.87
The sample size (for each sample separately) is:
20
Hence, the power of our study based on previous data from MOCA analysis is approaching 90% with 40 patients in each group. Using a paired test gives a 90% power to detect the effect at alpha = 0.05 and 67% for alpha = 0.005. For a 1 tailed test, the calculation gives a 96% power at alpha = 0.05.
Based on either of these test results, the study is predicted to be suitably empowered with the number of patients to reach significance and detect the improvements in outcome which are predicted.

Recruitment
Recruitment status
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] 4336 0
Gold Coast Hospital - Southport
Recruitment postcode(s) [1] 10480 0
4222 - Griffith University

Funding & Sponsors
Funding source category [1] 292034 0
Charities/Societies/Foundations
Name [1] 292034 0
Stroke Recovery Trial Fund
Address [1] 292034 0
Horizon Accounting
21 Russell Street
Toowoomba
Queensland 4350
Country [1] 292034 0
Australia
Funding source category [2] 300557 0
Charities/Societies/Foundations
Name [2] 300557 0
Stroke Recovery Trial Fund
Address [2] 300557 0
PO BOX 478
Darling Heights
QLD 4350
Country [2] 300557 0
Australia
Primary sponsor type
University
Name
Griffith University
Address
Gold Coast Campus
Parklands Drive
Southport,
Qld 4222.
Country
Australia
Secondary sponsor category [1] 290704 0
Individual
Name [1] 290704 0
Assoc. Prof. Stephen Ralph
Address [1] 290704 0
School of Medical Science, Parklands Drive, Gold Coast campus Griffith University, Southport. QLD 4222
Country [1] 290704 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293520 0
Griffith University Human Research Ethics Committee
Ethics committee address [1] 293520 0
Griffith University,
Gold Coast Campus
Parklands Drive
Southport,
Qld 4222.
Ethics committee country [1] 293520 0
Australia
Date submitted for ethics approval [1] 293520 0
Approval date [1] 293520 0
19/05/2015
Ethics approval number [1] 293520 0
MSC/10/14/HREC

Summary
Brief summary
The primary aim of the study is to determine the safety and tolerability of perispinal injection of Etanercept in subjects who have had a stroke and have stable and persistent chronic neurological dysfunction, cognitive impairment, and chronic and intractable pain due to stroke. The effects of the perispinal Etanercept treatment on neurological dysfunction, cognitive impairment, and chronic post-stroke pain will be examined as secondary aims by neurological examination as well as by the use of standarized measures.
Trial website
https://www.griffith.edu.au/health/menzies-health-institute-queensland/research/stroke
Trial related presentations / publications
Public notes
Attachments [3] 561 561 0 0

Contacts
Principal investigator
Name 60290 0
Dr Ventzislav Bonev
Address 60290 0
Corbett Medical Services
Gold Coast Neurology
159 Nerang St. Southport, QLD 4215
Country 60290 0
Australia
Phone 60290 0
+61755032400
Fax 60290 0
Email 60290 0
bookings@corbett.com.au
Contact person for public queries
Name 60291 0
A/Prof Stephen Ralph
Address 60291 0
School of Medical Science, Parklands Drive, Gold Coast campus Griffith University, Southport. QLD 4222 Australia
Country 60291 0
Australia
Phone 60291 0
+61755528583
Fax 60291 0
Email 60291 0
stroke-interest@griffith.edu.au
Contact person for scientific queries
Name 60292 0
A/Prof Stephen Ralph
Address 60292 0
School of Medical Science, Parklands Drive, Gold Coast campus Griffith University, Southport. QLD 4222 Australia
Country 60292 0
Australia
Phone 60292 0
+61755528583
Fax 60292 0
Email 60292 0
stroke-interest@griffith.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
No Results