Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624001249549p
Ethics application status
Submitted, not yet approved
Date submitted
14/03/2024
Date registered
11/10/2024
Date last updated
13/10/2024
Date data sharing statement initially provided
11/10/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
"N-of-1" single participant trials of 4-aminopyridine (4-AP) as precision therapy for the treatment of neurologic manifestations associated with KCNA1 (Kv1.1) and KCNA2 (Kv1.2) epilepsies.
Scientific title
A series of double-blind, randomised, multi-crossover, placebo-controlled “N-of-1” trials to evaluate the safety and efficacy of 4-aminopyridine (4-AP) for the treatment of neurologic manifestations associated with KCNA1 (Kv1.1) and KCNA2 (Kv1.2) epilepsies.
Secondary ID [1] 311626 0
PRIME-001-TSA-4AP
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
epilepsy 333063 0
Condition category
Condition code
Neurological 329747 329747 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study intervention is 4-aminopyridine (4-AP) modified-release, a known blocker of several voltage-gated potassium channels, including Kv1. It will be administered as a capsule twice daily. Each participant is their own N-of-1 trial, comprising a open-label dose exploration phase, followed by the multi-crossover RCT phase (if a signal of benefit is detected during the open-label dose exploration phase).

There is a 9 week open-label dose-optimisation phase, which comprises 3 weeks of up-titration (weekly increments of 0.5mg/kg/day to a maximum daily increment of 20mg/day, up until a ceiling dose of 2.0mg/kg/day, maximum 80mg/day in twice daily dosing), 4 weeks of maintenance, 9 days of down-titration (by 1/4th of the maintenance dose every 3 days until cessation) and 3 days of wash out.

If there is a signal of benefit (as determined by the study investigators), the safety and efficacy of 4-aminopyridine will be formally tested in a double-blind multi-crossover randomized controlled trial (RCT) phase. The RCT phase will begin in the week following the conclusion of the open-label dose exploration phase and washout (week 10), and consists of 4 treatment periods (2 4-aminopyridine, 2 placebo) assigned in a random order. Each treatment period is 9 weeks, comprising the same schedule of up-titration, maintenance, down-titration and washout as the open-label phase. The RCT phase totals to 36 weeks.

Adherence will be monitored via drug tablet return.
Intervention code [1] 328116 0
Treatment: Drugs
Comparator / control treatment
Placebo microcellulose capsule
Control group
Placebo

Outcomes
Primary outcome [1] 337574 0
Average seizure frequency.
Timepoint [1] 337574 0
Daily during the 4-AP and placebo periods.
Primary outcome [2] 337575 0
Ataxia.
Timepoint [2] 337575 0
Weekly in the last 2 weeks of each treatment period.
Secondary outcome [1] 432360 0
Clinical global impression
Timepoint [1] 432360 0
Weekly throughout open-label dose-exploration phase and multi-crossover randomized control trial treatment periods (weeks 1-45).
Secondary outcome [2] 432361 0
Cognition
Timepoint [2] 432361 0
At the conclusion of each of the 4-AP and placebo periods.

Eligibility
Key inclusion criteria
- Willingness to provide written informed consent.
- Pathogenic gain-of-function (GoF) variants in KCNA1 or KCNA2.
- At least one of the following: uncontrolled seizures or ataxia, interfering with quality of life. If ataxia is absent, the minimum seizure frequency for eligibility is at least one seizure per week assessed over the preceding 4 weeks, with at least one seizure during each of the preceding 4 weeks (for the purpose of calculating seizure frequency, seizure clusters should be considered as one seizure).
- Age 1 – 60 years old. Although 4-AP has been trialled in individuals younger than 1 year old, the lower age limit is set in consideration of the clinical expertise of the primary study site (Austin Health).
- If a female of child bearing potential, documentation of negative pregnancy test at time of informed consent. Females of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and for 8 weeks after stopping treatment. Highly effective contraception is defined as either: total abstinence; sterilization; male partner sterilisation; or the use of any two of: hormonal contraception, intrauterine device (IUD) or barrier contraception. In case of use of oral contraception women should have been stable on the oral agent before taking study treatment for at least 3 months.
- Willingness and ability to follow study procedures, including reliable recording of self-reported outcomes.
Minimum age
1 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inability of the patient or a parent /legal guardian to give informed consent.
- Pregnant women will be excluded as there is a lack of high-quality scientific evidence demonstrating the safety of 4-AP in pregnancy.
- Inability of the patient/carer to follow study procedures, including reliable recording of self-reported outcomes (e.g. seizure diary).
- Renal impairment (creatinine clearance < 50 mL/min or eGFR less than 59 mL/min/1.73 m2).
- Any condition that, based on the investigator’s judgement, could adversely affect the safety of the planned interventions, or the feasibility of achieving the study objectives.

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
The people analysing the results/data
Intervention assignment
Other
Other design features
A series of double-blind, randomised, multi-crossover, placebo-controlled within-participant N-of-1 trials will be conducted. There is an initial open-label dose exploration phase, followed up 4 treatment periods in a randomised order. The participant will act as their own control with 2 intervention periods compared with 2 placebo periods.
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/10/2024
Actual
Date of last participant enrolment
Anticipated
1/03/2026
Actual
Date of last data collection
Anticipated
1/05/2026
Actual
Sample size
Target
5
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 315950 0
Government body
Name [1] 315950 0
National Health and Medical Research Council
Country [1] 315950 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
Country
Australia
Secondary sponsor category [1] 318128 0
None
Name [1] 318128 0
None
Address [1] 318128 0
Country [1] 318128 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314778 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 314778 0
Ethics committee country [1] 314778 0
Australia
Date submitted for ethics approval [1] 314778 0
22/04/2024
Approval date [1] 314778 0
Ethics approval number [1] 314778 0

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

Contacts
Principal investigator
Name 132694 0
Prof Piero Perucca
Address 132694 0
Melbourne Brain Center, 245 Burgundy St, Heidelberg VIC 3084
Country 132694 0
Australia
Phone 132694 0
+61 3 9035 7372
Fax 132694 0
Email 132694 0
piero.perucca@unimelb.edu.au
Contact person for public queries
Name 132695 0
Shuyu Wang
Address 132695 0
Melbourne Brain Center, 245 Burgundy St, Heidelberg VIC 3084
Country 132695 0
Australia
Phone 132695 0
+61423653840
Fax 132695 0
Email 132695 0
shuyu.wang3@unimelb.edu.au
Contact person for scientific queries
Name 132696 0
Shuyu Wang
Address 132696 0
Melbourne Brain Center, 245 Burgundy St, Heidelberg VIC 3084
Country 132696 0
Australia
Phone 132696 0
+61423653840
Fax 132696 0
Email 132696 0
shuyu.wang3@unimelb.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
Due to intellectual property concerns, IPD will not be shared.


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.