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Voronistat in Pediatric Patients With Drug Resistant Epilepsy

Primary Purpose

Refractory Epilepsy

Status
Unknown status
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Vorinostat 100 MG
Sponsored by
University of Calgary
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Refractory Epilepsy focused on measuring PEDIATRIC

Eligibility Criteria

2 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Alberta Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

TREATMENT

Arm Description

Participants will be administered 230 mg/m2/day of oral Vorinostat [100 mg tablets] in addition to standard of care anti-seizure medication for a duration of 6 weeks.

Outcomes

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events
The number of treatment emergent adverse events will be tabulated at each time point: adverse events, serious adverse events, and discontinuations due to adverse events.
Incidence of Drug Discontinuations due to Adverse Drug Reaction
The number of participants with drug discontinuations due to Adverse Drug Reaction will be tabulated at each time point: adverse events, serious adverse events, and discontinuations due to adverse events.

Secondary Outcome Measures

Proportion of participants who have at least a 50% reduction in seizures from baseline
Treatment response will be evaluated by calculating the proportion of response of participants who demonstrate a 50% reduction rate or greater at 6 weeks as compared to baseline.
Change in seizure status at each time point.
Seizure status will be tabulated 14 days following drug initiation; 30 days following drug initiation; 42 days following drug initiation; and 42 days following drug discontinuation. Seizure status will be defined as: significant response (at least 50% reduction in seizure frequency as compared to baseline, or no seizures while on medication; partial response (25% - 49% reduction in seizure frequency as compared to baseline); no change, (0 - 24% reduction in seizure frequency as compared to baseline); and worsening (increase in seizure frequency as compared to baseline).

Full Information

First Posted
September 13, 2018
Last Updated
March 26, 2019
Sponsor
University of Calgary
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1. Study Identification

Unique Protocol Identification Number
NCT03894826
Brief Title
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

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Unknown status
Study Start Date
December 10, 2018 (Actual)
Primary Completion Date
April 2020 (Anticipated)
Study Completion Date
October 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Calgary

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Epilepsy
Keywords
PEDIATRIC

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
TREATMENT
Arm Type
Experimental
Arm Description
Participants will be administered 230 mg/m2/day of oral Vorinostat [100 mg tablets] in addition to standard of care anti-seizure medication for a duration of 6 weeks.
Intervention Type
Drug
Intervention Name(s)
Vorinostat 100 MG
Other Intervention Name(s)
ZOLINZA
Intervention Description
Vorinostat administered by mouth, once daily at a dose of 230 mg/m2/day for a total of 6 weeks
Primary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events
Description
The number of treatment emergent adverse events will be tabulated at each time point: adverse events, serious adverse events, and discontinuations due to adverse events.
Time Frame
14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation
Title
Incidence of Drug Discontinuations due to Adverse Drug Reaction
Description
The number of participants with drug discontinuations due to Adverse Drug Reaction will be tabulated at each time point: adverse events, serious adverse events, and discontinuations due to adverse events.
Time Frame
14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation
Secondary Outcome Measure Information:
Title
Proportion of participants who have at least a 50% reduction in seizures from baseline
Description
Treatment response will be evaluated by calculating the proportion of response of participants who demonstrate a 50% reduction rate or greater at 6 weeks as compared to baseline.
Time Frame
42 days post drug initiation; change from baseline
Title
Change in seizure status at each time point.
Description
Seizure status will be tabulated 14 days following drug initiation; 30 days following drug initiation; 42 days following drug initiation; and 42 days following drug discontinuation. Seizure status will be defined as: significant response (at least 50% reduction in seizure frequency as compared to baseline, or no seizures while on medication; partial response (25% - 49% reduction in seizure frequency as compared to baseline); no change, (0 - 24% reduction in seizure frequency as compared to baseline); and worsening (increase in seizure frequency as compared to baseline).
Time Frame
14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males or females aged 2 - 17 years (inclusive) 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. Ability and willingness of family and/or caregiver (when appropriate) to give written informed consent and to comply with requirement of the study 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]) 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) 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) Corrected QT (QTc) interval of < 450 msec Prothrombin time (PTT) < 1.5 ULN/International Normalized Ratio (INR) < 1.5 ULN Participants on corticosteroids must be taking a stable or decreasing dose for at least 7 days prior to enrollment Exclusion Criteria: Treatment with valproic acid or other HDACi class drugs within at least the last 3 months at time of screening Enzyme-inducing AEDs (including oxcarbazepine (Trileptal), phenobarbital, phenytoin (Dilantin), topiramate (Topamax) Coumarin-derivative anti-coagulants 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) Neurosurgery within the past 12 months Use of Vagus Nerve Stimulator (VNS) where settings have not been stable for at least 6 months Planned surgery or other invasive medical treatment during screening of during treatment period Hypokalemia or hypomagnesemia 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 History of non-catheter related deep venous thrombosis Pleural effusion Malignancy within the past 5 years. Any serious medical condition that according to the investigator could interfere with the conduct of the study Serious comorbid disease in which the life expectancy of the patient is shorter than the duration of the trial Unwillingness or inability to comply with study requirements Positive pregnancy test, lactating females or heterosexually active participants not willing to use highly effective methods of contraception Participation in any clinical trial with an investigational drug, or therapy not approved by Health Canada, within one month prior to screening
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sabrina D'Alfonso, MSc
Phone
403-955-2745
Email
sabrina.d'alfonso@ahs.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Jong Rho, MD
Phone
403-955-2296
Email
jong.rho@ahs.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jong Rho, MD
Organizational Affiliation
University of Calgary
Official's Role
Principal Investigator
Facility Information:
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T3B6A8
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jong Rho, MD
Phone
403-955-2296
Email
jong.rho@ahs.ca
First Name & Middle Initial & Last Name & Degree
Sabrina D'Alfonso, MSc
Phone
403-955-2745
Email
sabrina.d'alfonso@ahs.ca
First Name & Middle Initial & Last Name & Degree
Jong Rho, MD
First Name & Middle Initial & Last Name & Degree
Luis Bello-Espinosa, MD
First Name & Middle Initial & Last Name & Degree
Juan-Pablo Appendino, MD
First Name & Middle Initial & Last Name & Degree
Deborah Kurrasch, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
IPD will not be shared with other researchers.
Citations:
PubMed Identifier
29373639
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.
Results Reference
result
PubMed Identifier
34389161
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.
Results Reference
derived

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Voronistat in Pediatric Patients With Drug Resistant Epilepsy

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