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Voronistat in Pediatric Patients With Drug Resistant Epilepsy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03894826
Recruitment Status : Recruiting
First Posted : March 29, 2019
Last Update Posted : March 29, 2019
Sponsor:
Information provided by (Responsible Party):
University of Calgary

Tracking Information
First Submitted Date  ICMJE September 13, 2018
First Posted Date  ICMJE March 29, 2019
Last Update Posted Date March 29, 2019
Actual Study Start Date  ICMJE December 10, 2018
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
  • Incidence of Treatment-Emergent Adverse Events [ Time Frame: 14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation ]
    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 [ Time Frame: 14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
  • Proportion of participants who have at least a 50% reduction in seizures from baseline [ Time Frame: 42 days post drug initiation; change 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. [ Time Frame: 14 days post drug initiation; 30 days post drug initiation; 42 days post drug initiation; 42 days following drug discontinuation ]
    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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Voronistat in Pediatric Patients With Drug Resistant Epilepsy
Official Title  ICMJE A Phase 2 Clinical Trial Testing the Safety and Efficacy of Voronistat in Pediatric Patients With Drug Resistant Epilepsy
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Refractory Epilepsy
Intervention  ICMJE Drug: Vorinostat 100 MG
Vorinostat administered by mouth, once daily at a dose of 230 mg/m2/day for a total of 6 weeks
Other Name: ZOLINZA
Study Arms  ICMJE Experimental: TREATMENT
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: Drug: Vorinostat 100 MG
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 26, 2019)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2020
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sabrina D'Alfonso, MSc 403-955-2745 sabrina.d'alfonso@ahs.ca
Contact: Jong Rho, MD 403-955-2296 jong.rho@ahs.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03894826
Other Study ID Numbers  ICMJE VOR-17-2471
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: IPD will not be shared with other researchers.
Responsible Party University of Calgary
Study Sponsor  ICMJE University of Calgary
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jong Rho, MD University of Calgary
PRS Account University of Calgary
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP