Clinical trial NCT03894826: Voronistat in Pediatric Patients With Drug Resistant Epilepsy
Official title: A Phase 2 Clinical Trial Testing the Safety and Efficacy of Voronistat in Pediatric Patients With Drug Resistant Epilepsy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Refractory Epilepsy
Keywords: PEDIATRIC
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2019-03-29
Enrollment: 12
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The study evaluates the safety, tolerability, and efficacy of Vorinostat in addition to standard of care anti-epileptic drugs in pediatric patients with medically refractory epilepsy. All participants entering the treatment phase will receive Vorinostat.

Detailed description: Vorinostat is a potent inhibitor of histone deacetylases (HDAC). HDACs catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. Valproic acid, a broad anti-epileptic drug, commonly used as first line treatment in epilepsy, has also been shown to inhibit HDAC activity .

It is it is anticipated that Vorinostat in a population of pediatric patients with epilepsy will be well-tolerated, similar to that seen with valproic acid and other normally prescribed anti-epileptic drugs.

Participants consenting to participate will enter a 4-week screening period to ensure eligibility. Eligible participants will then enter the 6-week treatment phase. Participants will be seen for a final Safety Follow-up visit 6 weeks after end of treatment. Participants who are enrolled and complete all study procedures will be in the study for a total of 16 weeks.

Eligibility criteria: Inclusion Criteria:

1. Males or females aged 2 - 17 years (inclusive)
2. Medically intractable epilepsy, defined as having failed at least 2 standard anti-seizures therapies and experiencing at least 3 motor seizures per week, separated by at least 24 hours that are quantifiable by observation (e.g. discrete episodes of motor activity). Participants experiencing other seizure types in addition to motor seizures may also be enrolled but must meet the minimal requirement for motor seizures.
3. Ability and willingness of family and/or caregiver (when appropriate) to give written informed consent and to comply with requirement of the study
4. Adequate bone marrow function (defined as an absolute neutrophil count (ANC) of \> 2 x 109/L; platelet count of \> 150 x 109/L; hemoglobin of \> 110 g/L \[3-11 years\], \> 120 g/L \[females 12 years or over\], \> 125 g/L \[males 12-14 years\], \> 137 g/L \[males 15 years or older\])
5. Adequate renal function (defined as serum creatinine \< 1.5X age-adjusted upper limit of normal \[ULN\], or glomerular filtration rate ≥ 70 mL/min/1.73 m2)
6. Adequate hepatic function (defined as total bilirubin \<1.5 times ULN, and alanine aminotransferase \[ALT\] and aspartate transaminase \[AST\] \< 3 times ULN, and albumin \>33 g/L)
7. Corrected QT (QTc) interval of \< 450 msec
8. Prothrombin time (PTT) \< 1.5 ULN/International Normalized Ratio (INR) \< 1.5 ULN
9. Participants on corticosteroids must be taking a stable or decreasing dose for at least 7 days prior to enrollment

Exclusion Criteria:

1. Treatment with valproic acid or other HDACi class drugs within at least the last 3 months at time of screening
2. Enzyme-inducing AEDs (including oxcarbazepine (Trileptal), phenobarbital, phenytoin (Dilantin), topiramate (Topamax)
3. Coumarin-derivative anti-coagulants
4. Participants being considered for surgery for management of seizures during screening or who will be receiving surgery during for management of seizures during study period (includes all neurosurgery for the management of seizures or device implantation for the management of seizures)
5. Neurosurgery within the past 12 months
6. Use of Vagus Nerve Stimulator (VNS) where settings have not been stable for at least 6 months
7. Planned surgery or other invasive medical treatment during screening of during treatment period
8. Hypokalemia or hypomagnesemia
9. Participants starting or currently on any neurometabolic diet (including but not limited to ketogenic diet; medium-chain triglyceride diet; modified Atkins diet; low glycemic index diet) during study
10. History of non-catheter related deep venous thrombosis
11. Pleural effusion
12. Malignancy within the past 5 years.
13. Any serious medical condition that according to the investigator could interfere with the conduct of the study
14. Serious comorbid disease in which the life expectancy of the patient is shorter than the duration of the trial
15. Unwillingness or inability to comply with study requirements
16. Positive pregnancy test, lactating females or heterosexually active participants not willing to use highly effective methods of contraception
17. Participation in any clinical trial with an investigational drug, or therapy not approved by Health Canada, within one month prior to screening

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation
measure: Incidence of Drug Discontinuations due to Adverse Drug Reaction
timeFrame: 14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation
Secondary outcomes:
measure: Proportion of participants who have at least a 50% reduction in seizures from baseline
timeFrame: 42 days post drug initiation; change from baseline
measure: Change in seizure status at each time point.
timeFrame: 14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
Study officials:
affiliation: University of Calgary
name: Jong Rho, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ibhazehiebo K, Gavrilovici C, de la Hoz CL, Ma SC, Rehak R, Kaushik G, Meza Santoscoy PL, Scott L, Nath N, Kim DY, Rho JM, Kurrasch DM. A novel metabolism-based phenotypic drug discovery platform in zebrafish uncovers HDACs 1 and 3 as a potential combined anti-seizure drug target. Brain. 2018 Mar 1;141(3):744-761. doi: 10.1093/brain/awx364.
citation: Garcia AA, Koperniku A, Ferreira JCB, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends Pharmacol Sci. 2021 Oct;42(10):829-844. doi: 10.1016/j.tips.2021.07.002. Epub 2021 Aug 10.