Clinical trial NCT05873062: Safety, Blood Levels and Effects of AUT00201 in Patients With MEAK
Official title: A Randomized, Double-blind, Placebo-controlled, Crossover Study of the Effects of Single Doses of AUT00201 in Patients With Myoclonus Epilepsy and Ataxia Due to Potassium (K+) Channel Mutation (MEAK)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myoclonus Epilepsies, Progressive
Keywords: MEAK
EPM7
Lead sponsor: Autifony Therapeutics Limited
Sponsor class: INDUSTRY
First posted: 2023-05-24
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Subjects will be randomized in a 1:1 ratio to one of the two treatments with 3-5 subjects per treatment sequence. Each subject will receive both treatments (100 mg AUT00201 and placebo) with a washout period of 1 day between single doses.
Primary purpose: BASIC_SCIENCE

Brief summary: A randomized, double-blind, placebo-controlled, crossover study to assess the safety, tolerability, and pharmacokinetics of single doses of AUT00201 at 100 mg or matching placebo in patients with myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK).

Detailed description: 6 to 10 patients aged 18 years and older, diagnosed with MEAK will be enrolled in the study. Patients will be administered a single dose of AUT00201 and matching placebo in a crossover design. The study is comprised of an outpatient screening and procedure orientation followed by approximately 5 days of an inpatient stay at a clinical research unit. After screening/orientation (Visit 1), and baseline assessments (Visit 2), patients will be administered a single dose of 100 mg of AUT00201 or matching placebo the morning of Visit 3. PK assessments will be done at Visits 3, 4, 5, and 6 from predose and up to 27 hours postdose. Visit 4 will be a washout day for patients. At Visit 5 patients will be administered the crossover treatment. At Visit 6 patients will be discharged from the unit. Safety and tolerability assessments will be conducted throughout. PD parameters will also be assessed. Patients will be followed up by telephone 14 days after discharge.

Eligibility criteria: Inclusion Criteria:

* Male or female patients aged 18 years or older at time of consenting.
* Diagnosed with MEAK, based on documented genetic evidence of the presence of the KCNC1 (c.959G\>A; p.Arg320His) variant.
* If take anticonvulsants, must be on a stable anticonvulsant regiment for at least 30 days prior to Visit 1 and anticipated to remain stable throughout the study or if not on an anticonvulsant regimen, must be stable in regards to seizures for at least 30 days prior to Visit 1 and anticipated to remain stable throughout the study.
* Must be able to participate and willing to give written informed consent. If patient is unable to provide written informed consent, a legally authorized representative can sign on their behalf.
* Must be willing to perform study assessments and comply with the study protocol.
* If the patient is dependent on a caregiver and/or will need assistance either travelling to the site, whilst attending clinic visits and/or helping to document study assessment responses provided by the patient (eg, questionnaires administered on a tablet device), they must have an identified caregiver, considered reliable by the Investigator, to provide support to the patient for the duration of the study. The caregiver must be willing and able to provide support to the patient and, if required, stay for the duration of the study.
* Medically stable based on Investigator's judgement for at least 90 days prior to Visit 1.
* Women of childbearing potential must have a negative urine pregnancy test on Visit 2.
* If a vagal nerve stimulator is used, it must be implanted at least 150 days before Day. -1, and parameters must be stable for at least 30 days before Visit 1 and expected to remain stable throughout the study.
* If a ketogenic diet is followed, it must be stable for at least 30 days before Visit 1 and expected to remain stable throughout the study.
* Willing to comply with contraceptive requirements.
* Able to speak, read and understand English at a fluent level

Exclusion Criteria:

* Known pathogenic mutation in another gene that causes epilepsy or a different mutation in the KCNC1 gene than the c.959G\>A variant.
* Clinically significant metabolic, hepatic, hematological, pulmonary, cardiovascular, gastrointestinal, or urological disorder.
* Clinically significant abnormal vital signs or laboratory test results.
* Hypersensitivity to AUT00201 or any of the excipients.
* Any medical condition or other factors, as judged by the Investigator, which may interfere with the patient's participation in this study and/or compromise the patient's ability to safely complete the study.
* Known to abuse drugs or those who test positive on urine screen for drugs of abuse will be excluded based on Investigator's judgement.
* Positive hepatitis B surface antigen or hepatitis C antibody.
* Clinically significant abnormality on the 12-lead electrocardiogram.
* Having received an investigational product 90 days prior to Visit 1.
* Currently using felbamate \<1 year prior to Visit 1, or any evidence of ongoing hepatic or bone marrow dysfunction associated with current/prior felbamate treatment. Patients who are currently using felbamate for \>1 year prior to Visit 1 and have no evidence of ongoing hepatic or bone marrow dysfunction associated with felbamate treatment are allowed.
* Currently using vigabatrin and having received vigabatrin for \<2 years prior to Visit 1.
* Suicidal ideation with some intent to act within 6 months prior to Visit 1 based upon response in the Columbia-Suicide Severity Rating Scale (positive response to questions 4 or 5 of the suicidal ideation section) and as judged by the Investigator as having a significant impact on trial participation or patient safety. History of suicidal behavior within 1 year prior to Visit 1.

Primary outcomes:
measure: Number of Participants With Treatment-Related Adverse Events After Single Dose Treatment of AUT00201 Compared to Placebo
timeFrame: 19 Days
Secondary outcomes:
measure: Change From Baseline in Cortical Inhibition; as Measured by Paired-pulse Transcranial Magnetic Stimulation (ppTMS) at Short Interval Cortical Inhibition (SICI) Inter-stimulus-intervals (ISI): the Outcome is the Average %-Inhibition at SICI 2.5 and 3ms ISI
timeFrame: 2 - 4 hours post dose
measure: Pharmacokinetics: Maximum Plasma Concentrations (Cmax) of AUT00201
timeFrame: 27 hours
measure: Pharmacokinetics: Area Under the Plasma Concentration-time Curve (AUC) of AUT00201 to the Last Observed Quantifiable Concentration
timeFrame: 27 hours
measure: Change From Baseline in Measures of Dysarthria as Assessed by Speaking Rate Metric From Automated Standardized Speech Test.
timeFrame: 1 hour post dose
measure: Change From Baseline in Myoclonus Index (MI; a Measure of Positive Myoclonus) Evaluated With EMG and Accelerometer
timeFrame: 0-4 hours post dose
measure: Change From Baseline in Measures of Dysarthria as Assessed by Buttercup Count From Automated Standardized Speech Test.
timeFrame: 1 hour post-dose
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania, Penn Epilepsy Center
state: Pennsylvania
Study officials:
affiliation: Penn Epilepsy Center, Department of Neurology
name: Michael Gelfand, MD
role: PRINCIPAL_INVESTIGATOR
References: