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Trial registered on ANZCTR


Registration number
ACTRN12620001254987p
Ethics application status
Submitted, not yet approved
Date submitted
22/10/2020
Date registered
23/11/2020
Date last updated
23/11/2020
Date data sharing statement initially provided
23/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2 Randomised Controlled Trial of Sodium Selenate as a
Disease Modifying Treatment for Probable Progressive Supranuclear
Palsy
Scientific title
A Phase 2 Randomised Controlled Trial of Sodium Selenate as a
Disease Modifying Treatment for Probable Progressive Supranuclear
Palsy
Secondary ID [1] 302603 0
None
Universal Trial Number (UTN)
U1111-1260-0102
Trial acronym
SEL003
Linked study record

Health condition
Health condition(s) or problem(s) studied:
progressive supranuclear palsy 319491 0
Condition category
Condition code
Neurological 317456 317456 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Sodium selenate, 15 mg three times a day, 52 weeks, oral tablet. Participants will be required to return unused tablets to site at each visit to monitor compliance with dosing regimen
Intervention code [1] 318889 0
Treatment: Drugs
Comparator / control treatment
Placebo (microcrystalline cellulose), three times a day, 52 weeks, oral tablet
Control group
Placebo

Outcomes
Primary outcome [1] 325487 0
To assess the efficacy of a supranutritional dose of sodium selenate (Na2SeO4) in patients with progressive supranuclear palsy as measured by change in brain MRI composite volume between active and placebo groups.

Brain composite volume will be measured on MRI. Individual MRIs will be registered to a template and masks of specific regions (the frontal lobe, midbrain, and third ventricle) applied to individual images to determine volume of each region. MRI composite = frontal lobe +midbrain- 3rd ventricle.
Timepoint [1] 325487 0
Change from baseline to 52 weeks post-initiation of treatment
Secondary outcome [1] 388119 0
To assess the efficacy of a supranutritional dose of sodium selenate (Na2SeO4) in patients with progressive supranuclear palsy as measured by change in progressive supranuclear palsy rating scale (PSPRS) score between active and placebo groups.

The PSPRS is a clinician administered rating scale which assesses the presence and severity of PSP symptoms. It is validated and widely used in staging disease severity in PSP
Timepoint [1] 388119 0
Change from baseline to 52 weeks post-initiation of treatment
Secondary outcome [2] 388120 0
To assess the efficacy of a supranutritional dose of sodium selenate (Na2SeO4) in patients with progressive supranuclear palsy as measured by change in clinical global impression of change (CGIC) score between active and placebo groups.

The CGIC is a clinician administered rating scale of disease severity. It is validated and widely used across a wide range of diseases.
Timepoint [2] 388120 0
Change from baseline to 52 weeks post-initiation of treatment
Secondary outcome [3] 388121 0
To assess the efficacy of a supranutritional dose of sodium selenate (Na2SeO4) in patients with progressive supranuclear palsy as measured by change in mean diffusivity in the midbrain measured on diffusion MRI between active and placebo groups.
Mean diffusivity maps will be generated from diffusion MRI. Individual MRIs will be registered to a template and the mask for the midbrain applied to determine values of mean diffusivity.
Timepoint [3] 388121 0
Change from baseline to 52 weeks post-initiation of treatment
Secondary outcome [4] 388122 0
To assess the safety and tolerability of sodium selenate in patients with progressive supranuclear palsy
Safety and tolerability will be measured by the frequency and severity of adverse events, anf the rate of study withdrawal.
Diary cards will be used to record adverse events (solicited and unsolicited) between clinical visits. Safety laboratory tests, 12-lead ECG, physical and neurological examinations will be conducted at clinical visits. In the event of a clinically significant abnormality being detected, this will be recorded as an adverse event.
Known side effects of sodium selenate treatment include; headache, nausea, lethargy, fatigue, alopecia (mild), nail changes and muscle cramps. All adverse events are mild and reversible.
Timepoint [4] 388122 0
Change from baseline to 52 weeks post-initiation of treatment

Eligibility
Key inclusion criteria
1. Male or female (aged 40 years or over). All participants of reproductive potential must be using effective contraception for the duration of the trial and for 4 weeks following cessation of the investigational medicinal product (IMP). Female participants of non-childbearing potential must be either surgically sterile (hysterectomy and/or oophorectomy) or postmenopausal at least 1 year. All female participants must have a negative plasma hCG pregnancy test at screening.
2 Subjects must have a diagnosis of Probable PSP established in accordance with the MDS Criteria (Hoglinger et al., 2017).
3. Subjects must have a lumbar puncture performed within 14 days prior to Baseline (Visit 2).
4. Subjects must have an MRI scan during the screening period and prior to Baseline (Visit 2), with no gross structural abnormality indicative of a neurological disorder other than PSP.
5. Subjects must be able to walk a minimum of 5 steps with minimal assistance (walker allowed).
6. Subjects must be living in the community and have at least 10 contact hours per week with a responsible carer. The carer should be capable of ensuring the subject's compliance with the medication, be prepared to attend with the subject for assessment and be willing to participate in completing the various assessments throughout the period of the subject’s involvement in the Study.
7. Written informed consent must be obtained from the subject or legally authorised representative (as required by local laws and regulations), and the participant’s carer.
Minimum age
40 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subject has participated in a clinical investigation of a medication or device within the 3 months prior to the Screening Visit (Visit 1).
2. Subject in whom a lumbar puncture is contra-indicated.
3. Subject has a history of alcohol and/or drug abuse, defined as meeting DSM-V criteria for substance use disorder. This applies to alcohol and/or any illicit drug, including cannabis within the 6 months prior to the Screening Visit (Visit 1).
4. Subject who is unlikely to comply with trial visit schedule or with trial medication.
5. Subject has a known sensitivity to selenium or sodium selenate or any medicine or vitamin containing sodium selenate, similar agents or any of the excipients (including microcrystalline cellulose) used.
6. Subject has current evidence or history of neurological, psychiatric or any other illness that could contribute to PSP-like symptoms.
7. Subject has a known history of familial Alzheimer’s Disease.
8. Subject has a known genetic variant that confers likelihood of another neurodegenerative condition (eg C9Orf72, PSEN1, SYNJ1, PRNP).
9. Subject has a significant medical disease, with the exception of PSP that:
a) is not adequately controlled by therapy; and/or
b) in the opinion of the investigator may interfere with the patient’s ability to complete the study or might impact on the patient’s PSP symptoms
10. Subject has current evidence of unstable diabetes.
11. Subject has significant impairment of any of the following for the age of the subject, which may compromise safety of the subject/validity of the data:
a) Renal function (i.e. estimated glomerular filtration rate (eGFR) less than 30)
b) Hepatic function (i.e. abnormal liver function tests greater than 2 x upper limit of normal)
c) Haematological function.
12. Subject in whom it is anticipated that there will be a definite indication for the commencement of other licensed drug for the treatment of PSP symptoms within the 64-
week period of trial participation.
13. Subject is currently taking any of the following: Carbamazepine, digoxin, phenobarbitone, warfarin or any other medication that has a narrow margin between effective dose and toxic dose or between effective dose and ineffective dose, where the subject would be at risk if the levels were elevated or fell due to interaction with sodium selenate.
14. Subject has started taking other medication known to have an effect on movement, mood or cognition within the 4 weeks prior to the Screening Visit (Visit 1); or has changed their dose of these medications within the 6 weeks prior to the Screening Visit (Visit 1).
Examples of such drugs include:
a) Dopaminergic drugs (leva-dopa, COMT inhibitors, amantadine)
b) Anticholinergics, for example ipratropium, oxitropium or tiotropium bromide
c) Hypnotics, sedatives and anxiolytics, for example barbiturates, benzodiazepines, serotonin 1A agonists, hydroxyzine, zolpidem or zopiclone
d) Antidepressants, for example tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitor (MAOIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants, buspirone, reboxetine or trazodone
e) Antiepileptics, for example barbiturates, benzodiazepines, ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, primidone, topiramate, valproate or vigabatrin
f) Antipsychotics, for example butyrophenones, phenothiazines, thioxanthenes, amisulpride, aripiprazole, clozapine, olanzapine, paliperidone or quetiapine.
g) Memory-enhancing drugs, for example aniracetam, oxiracetam, piracetam or pramiracetam.
h) Nutraceutical supplements containing selenium

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 involved contacting the holder of the allocation schedule who was "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
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
Statistical power has thus been determined on the primary outcome variable (change in brain MRI composite). Previous studies indicate that the mean annual rate of composite volume change in PSP is -12.9% (SD = 7.1). The mean atrophy rate in controls is 3.76%. A sample size of 46 patients would render the study sensitive to a medium effect size (Cohen’s d = 0.50, alpha = 5%, power = 80%). This would be equivalent to detecting a 7% rate of decline, which is a 46% decline in atrophy. This would represent a clinically meaningful treatment effect.
Withdrawal rates are high in studies of patients with PSP (typically 25-40%), therefore we anticipate a sample size of 70 will allow for adequate power given a withdrawal rate of 35%.

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)
NSW,QLD,SA,VIC
Recruitment hospital [1] 17869 0
The Alfred - Melbourne
Recruitment hospital [2] 17870 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 17871 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 17872 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 17873 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [6] 17874 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 31726 0
3004 - Melbourne
Recruitment postcode(s) [2] 31727 0
3050 - Parkville
Recruitment postcode(s) [3] 31728 0
5000 - Adelaide
Recruitment postcode(s) [4] 31729 0
4029 - Herston
Recruitment postcode(s) [5] 31730 0
2010 - Darlinghurst
Recruitment postcode(s) [6] 31731 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 307032 0
Government body
Name [1] 307032 0
NHMRC (MRFF)
Address [1] 307032 0
16 Marcus Clarke St,
Canberra ACT 2601
Country [1] 307032 0
Australia
Primary sponsor type
Hospital
Name
Alfred Health
Address
55 Commercial Road
Melbourne
3004 VIC
Country
Australia
Secondary sponsor category [1] 307600 0
None
Name [1] 307600 0
Address [1] 307600 0
Country [1] 307600 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307162 0
Alfred Health HREC
Ethics committee address [1] 307162 0
55 Commercial Road
Melbourne
VIC 3004
Ethics committee country [1] 307162 0
Australia
Date submitted for ethics approval [1] 307162 0
26/10/2020
Approval date [1] 307162 0
Ethics approval number [1] 307162 0

Summary
Brief summary
This study will investigate a new drug, sodium selenate, for the treatment of progressive supranuclear palsy (PSP). Up to 70 patients with PSP will be recruited in to the study. Half of the patients will receive 52 weeks of treatment with sodium selenate (15 mg three times a day), and the other half a placebo (a sugar pill). The main outcome of the study will be the change in volume of specific brain regions over 52 weeks, comparing the treatment group to the placebo group. Additional outcomes will look at the overall safety and tolerability of the treatment, the change in mean diffusivity (a measure of neurodegeneration) on MRI, and the rate of disease progression observed in patients over the 52 weeks of treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106246 0
Prof Terence O'Brien
Address 106246 0
Level 6, The Alfred Centre
99 Commercial Road
Melbourne
3004 VIC
Country 106246 0
Australia
Phone 106246 0
+61418370566
Fax 106246 0
Email 106246 0
te.obrien@alfred.org.au
Contact person for public queries
Name 106247 0
Dr Lucy Vivash
Address 106247 0
Level 6, The Alfred Centre
99 Commercial Road
Melbourne
3004 VIC
Country 106247 0
Australia
Phone 106247 0
+61 3 9903 0860
Fax 106247 0
Email 106247 0
lucy.vivash@monash.edu
Contact person for scientific queries
Name 106248 0
Dr Lucy Vivash
Address 106248 0
Level 6, The Alfred Centre
99 Commercial Road
Melbourne
3004 VIC
Country 106248 0
Australia
Phone 106248 0
+61 3 9903 0860
Fax 106248 0
Email 106248 0
lucy.vivash@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All deidentified trial data will be publically available
Additionally - imaging and biospecimens will be available to genuine researchers upon request (and justification) to the study team
When will data be available (start and end dates)?
Immediately following publication of study results, no end date
Available to whom?
Deidentified trial data will be publically available to anyone who wishes to access it.
Imaging and biospecimen data will be made available to researchers who supply a proposal to the study team/ lead HREC. Not all imaging/biospecimen data will be freely available due to participants being given the option of specified/extended/unspecified consent for the long-term use of these data.
Available for what types of analyses?
Main trial data will be available for any types of analyses.
Imaging and biospecimen data will be given to achieve the aims of submitted proposals in alignment with any restrictions placed on future use of data
How or where can data be obtained?
Main study data - Australia Data Archive. This is will publish the data, making it available to download via the ADA website (www.ada.edu.au)
Imaging and biospecimens - direct contact with study team (see contact information page for phone/emails of PI and PM) or lead HREC (research@alfred.org.au)
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 9519 0
Study protocol
Citation [1] 9519 0
Link [1] 9519 0
Email [1] 9519 0
Other [1] 9519 0
to be supplied upon approval
Attachment [1] 9519 0
Type [2] 9520 0
Statistical analysis plan
Citation [2] 9520 0
Link [2] 9520 0
Email [2] 9520 0
Other [2] 9520 0
to be supplied at a later date
Attachment [2] 9520 0
Type [3] 9521 0
Informed consent form
Citation [3] 9521 0
Link [3] 9521 0
Email [3] 9521 0
Other [3] 9521 0
to be supplied upon approval
Attachment [3] 9521 0
Type [4] 9522 0
Ethical approval
Citation [4] 9522 0
Link [4] 9522 0
Email [4] 9522 0
Other [4] 9522 0
to be supplied upon approval
Attachment [4] 9522 0
Summary results
No Results