Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000845437p
Ethics application status
Submitted, not yet approved
Date submitted
3/06/2025
Date registered
6/08/2025
Date last updated
6/08/2025
Date data sharing statement initially provided
6/08/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Effectiveness and safety of riluzole for the treatment of seizures in individuals with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE).
Scientific title
Double-blind, randomised, multi-crossover, placebo-controlled within-participant “N-of-1” trials to evaluate the safety and efficacy of riluzole for the treatment of seizures associated with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE).
Secondary ID [1] 314590 0
PRIME-001-TSA-Riluzle
Universal Trial Number (UTN)
U1111-1323-7806
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
SCN8A developmental and epileptic encephalopathy 337705 0
Condition category
Condition code
Neurological 334039 334039 0 0
Epilepsy
Human Genetics and Inherited Disorders 334285 334285 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Riluzole suspension. Oral, Percutaneous Endoscopic Gastrostomy (PEG) or Nasogastric Tube (NGT),

The Austin Clinical Trials Pharmacy will prepare and dispense the study medications (riluzole suspension and matching placebo). During the open-label dose exploration phase, the study medication (riluzole or placebo) will be dispensed at each study visit. During the multi-crossover randomised-controlled trial (MC RCT), the study medication will be dispensed in the first visit of each treatment period. Participants will be requested to bring unused study medication to the clinic at each visit. Study personal will count the suspension volume at study visits to check accountability. All dosages prescribed and administered to the participant and all dose changes during the study must be recorded on the Dosage Administration Record case report form (CRF). A medication information sheet will be provided to the participants detailing instructions for administration.

Participants will enter an initial open-label dose-exploration phase, to inform on doses that are tolerated and appear to be effective for that individual. If there is a significant improvement (as determined by the N-of-1 Steering Committee), the participant will be invited to enter the MC RCT, comprising 2 crossovers of riluzole and placebo treatment period (a total of 4 treatment periods). For participants without a signal of significant improvement at the highest tolerated (or permitted) dose, the study is terminate at the conclusion of the open-label dose-exploration phase. The pre-determined maximal permitted dose is 60mg/m2/day up to 100mg/day. The maximally tolerated dose is determined by review of dose-limiting toxicities.

Phase 1 - open-label dose-exploration phase:
1. Up-titration:
Week 1:
- Children (<16 yo) 30 mg/m2 (up to 50 mg/day)
- Adults 50mg/day

Week 2:
- Children (<16 yo) 60 mg/m2 (up to 100 mg/day)
- Adults 100mg/day

Week 3:
- Children (<16 yo) 90mg/m2 (up to 150mg/day
- Adults 150mg/day

2. Maintenance:
4 weeks at the maximally tolerated dose reached during the up-titration period, staying at same dose of up to:
- Children (<16 yo) 120 mg/m2 (up to 200mg/day)
- Adults 200mg/day

3. Down-titration:
3 days at 50% of the maintenance dose

Phase 2 - multi-crossover randomised controlled trial (MC RCT), comprising 4 randomised treatment periods (2 riluzole and 2 placebo).
Each period is 6 weeks and 3 days, comprising:
1. Up-titration:
- 1 week at 50% of the target dose established during the open-label dose exploration phase
2. Maintenance:
- 4 weeks at 100% of the target dose
3. Down-titration:
3 days at 50% of the target dose
4. Wash-out
7 days of no investigational treatment
Intervention code [1] 331215 0
Treatment: Drugs
Comparator / control treatment
The control is placebo oral suspension using the same excipients as the riluzole suspension. Placebo will be used in two of four treatment periods during the MC RCT. It will be administrated in an identical schedule to the active intervention.
Control group
Placebo

Outcomes
Primary outcome [1] 341702 0
Change in seizure frequency
Timepoint [1] 341702 0
Seizure frequency will be assessed using participant-completed seizure diaries, which are recorded daily throughout the study period. These diaries are reviewed by investigators at each study visit. For the initial open-label dose-exploration phase, the primary endpoint will be the change in seizure frequency (total seizure counts, excluding non-motor aware seizures) during the open-label maintenance period versus the baseline seizure frequency as assessed in the 4 weeks preceding the start of the dose exploration phase. During the MC RCT phase, the primary endpoint will be the incidence rate ratio of weekly seizure counts (excluding non-motor aware seizures) between the riluzole maintenance treatment periods versus the placebo maintenance treatment periods.
Secondary outcome [1] 448410 0
Safety outcome measures
Timepoint [1] 448410 0
Participants will be asked to record AEs from minus 28 days to day 253 (baseline visit to exit visit). The physical and neurological examinations will occur during every study visit: Baseline (D minus 28 ) Open-label dose-exploration (D1, 8, 15, 22, 29, 42) MC RCT (D56, 63, 70, 77, 90, 101, 108, 115, 122, 135, 146, 153, 160, 167, 180, 191. 198. 205, 212, 225) Laboratory safety assessments will occur: D minus 28, D1, D22, D42, D70, D90, D115, D135, D160, D180, D205, D225, D253
Secondary outcome [2] 448413 0
Clinical global impression
Timepoint [2] 448413 0
Baseline (D minus 28 ) Open-label dose-exploration (D1, 8, 15, 22, 29, 42) MC RCT (D56, 63, 70, 77, 90, 101, 108, 115, 122, 135, 146, 153, 160, 167, 180, 191. 198. 205, 212, 225)
Secondary outcome [3] 448415 0
Neuropsychology (optional; participants opt-in)
Timepoint [3] 448415 0
Baseline visit (D minus 28) End of open-label dose-exploration maintenance period. End of each MC RCT maintenance period.
Secondary outcome [4] 448417 0
Motor comorbidities (if applicable)
Timepoint [4] 448417 0
Baseline visit (D minus 28) End of open-label dose-exploration maintenance period. End of each MC RCT maintenance period.

Eligibility
Key inclusion criteria
1. A diagnosis of SCN8A-DEE documented by the presence of a pathogenic gain-of-function variant in the SCN8A gene.
2. Uncontrolled seizures despite treatment with antiseizure medication therapy
3. Age 2 – 65 years.
Minimum age
2 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or lactating women.
2. Hepatic disease or hepatic impairment.
3. Intolerance of riluzole.
4. Inability of the participant, parent/guardian, or person responsible to consent or follow study procedures.

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 from a statistic book
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
Crossover
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The total number of N-of-1 trials is expected to be <5 due to the rarity of SCN8A-DEE. A minimum of four crossover periods is selected for practical reasons to contain the randomisation phase to <6 months.

For the initial open-label dose-exploration phase, the primary endpoint will be the change in seizure frequency during the open-label maintenance period versus the baseline seizure frequency as assessed in the 4 weeks preceding the start of the dose exploration phase. During the MC RCT phase, the primary endpoint will be the incidence rate ratio of weekly seizure counts between the riluzole maintenance treatment periods versus the placebo maintenance treatment periods.

Explorative aggregate analysis will be performed with multiple N-of-1 trials of riluzole in participants with SCN8A-DEE with similar characteristics, provided data from at least 5 patients are available. Although participants who have received riluzole in the past (prior to the trial) for a period sufficient to determine seizure outcomes are eligible for participation in the trial, they will not be eligible for aggregate analysis of efficacy data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
25/08/2025
Actual
Date of last participant enrolment
Anticipated
26/06/2028
Actual
Date of last data collection
Anticipated
30/06/2029
Actual
Sample size
Target
5
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 319136 0
University
Name [1] 319136 0
University of Melbourne
Country [1] 319136 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
Country
Australia
Secondary sponsor category [1] 321603 0
Government body
Name [1] 321603 0
Austin Health
Address [1] 321603 0
Country [1] 321603 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 317730 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 317730 0
Ethics committee country [1] 317730 0
Australia
Date submitted for ethics approval [1] 317730 0
10/11/2024
Approval date [1] 317730 0
Ethics approval number [1] 317730 0

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

Contacts
Principal investigator
Name 141958 0
Prof Piero Perucca
Address 141958 0
Melbourne Brain Center, 245 Burgundy St, Heidelberg VIC 3084
Country 141958 0
Australia
Phone 141958 0
+61 0390357372
Fax 141958 0
Email 141958 0
[email protected]
Contact person for public queries
Name 141959 0
Greesha Zacharia
Address 141959 0
Melbourne Brain Center, 245 Burgundy St, Heidelberg VIC 3084
Country 141959 0
Australia
Phone 141959 0
+61 0390357361
Fax 141959 0
Email 141959 0
[email protected]
Contact person for scientific queries
Name 141960 0
Dr Shuyu Wang
Address 141960 0
Melbourne Brain Center, 245 Burgundy St, Heidelberg VIC 3084
Country 141960 0
Australia
Phone 141960 0
+61 0390357221
Fax 141960 0
Email 141960 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires approval by an ethics committee
• Requires a data sharing agreement between data requester and trial custodian or sponsor
What individual participant data might be shared?
• De-identified individual participant data:
• Published results
What types of analyses could be done with individual participant data?
• Systematic reviews and meta-analyses
When can requests for individual participant data be made (start and end dates)?
From:
After publication of main results
To:
Not yet decided
Where can requests to access individual participant data be made, or data be obtained directly?
• Email of trial custodian, sponsor or committee: [email protected]

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.