None listed
Conditions
Brief summary
This trial is a treatment specific appendix in a modular component of the Precision Therapies in Monogenic Epilepsies (PRIME) master protocol, for a series of N-of-1 studies of precision therapies in monogic epilepsies. It uses a within-participant, controlled, multi-crossover design to test the hypothesis that 4-AP, a potassium channel blocker, improves seizure control and/or ataxia associated with epilepsies due to gain-of-function (GoF) variants in the voltage-gated potassium channel genes KCNA1 (Kv1.1) and KCNA2 (Kv1.2).
Interventions
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-titr
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.
Sponsors
Austin Health
Study design
Allocation
Randomised controlled trial
Intervention model
Other
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
1 Years to 60 Years
Healthy volunteers
No
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.
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.
Outcome results
None listed