A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome

• ClinicalTrials.gov Identifier: NCT05163314
• Recruitment Status: Recruiting
• First Posted: December 20, 2021
• Last Update Posted: February 21, 2024
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: December 15, 2021
• First Posted Date: December 20, 2021
• Last Update Posted Date: February 21, 2024
• Actual Study Start Date: March 4, 2022
• Estimated Primary Completion Date: May 22, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 23, 2023)

• Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE) [ Time Frame: Up to 4 years ]
  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug.
• Change from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Up to 4 years ]
  C-SSRS systematically tracks suicidal ideation and behavior. The total score range is 0 (no ideation is present) to 5 (active suicidal ideation with specific plan and intent). The higher the score, the greater one's suicidal ideation.
• Change from Baseline in Body Weight for All Age Groups [ Time Frame: Up to 4 years ]
• Change from Baseline in Height for All Age Groups [ Time Frame: Up to 4 years ]
• Absolute Value for Tanner Stage for Children 6 to 17 Years of Age During the Study [ Time Frame: Up to 4 years ]
  Tanner assessment score is used to document the stage of development of puberty by assessing the secondary sexual characteristics, rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size).
• Absolute Value for Insulin-like Growth Factor 1 (IGF-1) for Children 2 to 17 Years of Age During the Study [ Time Frame: Up to 4 years ]

Original Primary Outcome Measures (submitted: December 15, 2021)

• Number of Participants With At Least One Adverse Event (AE) [ Time Frame: Up to 4 years ]
  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.
• Change from Baseline in the Columbia-Suicide Severity Rating Scale (C-SSRS) Categorization Based on Columbia Classification Algorithm of Suicide Assessment Categories 1, 2, 3, 4, and 5 for Participants Aged ≥6 Years [ Time Frame: Up to 4 years ]
• Number of Participants With Clinically Significant Change from Baseline in Ophthalmological Evaluations at Week 52, Reported as Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Week 52 ]
  The ophthalmologic evaluations will include- 1. Age and developmentally appropriate quantitative visual acuity 2. Bilateral red reflex test (also known as Bruckner transillumination test), to assess for lens abnormalities 3. Postinstillation of mydriatic eye drop (cyclopentylate is contraindicated in population with epilepsy), slit lamp (portable acceptable) examination for anterior or posterior lens opacities concerning for cataracts after adequate pupil dilation 4. Indirect and or direct ophthalmoscopy of the optic nerve and retina after adequate pupillary dilation which will be reported as TEAEs. A TEAE is defined as an AE with an onset that occurs after receiving study drug.
• Change from Baseline in Body Weight for Children Aged 10 to 17 Years [ Time Frame: Up to 4 years ]
• Change from Baseline in Height for Children Aged 10 to 17 Years [ Time Frame: Up to 4 years ]
• Change from Baseline in Insulin-like Growth Factor 1 (IGF-1) for Children Aged 10 to 17 Years [ Time Frame: Up to 4 years ]
• Change from Baseline (Visit 1) in Tanner Stage for Children Aged 10 to 17 Years [ Time Frame: Up to 4 years ]
  Tanner assessment score is used to document the stage of development of puberty by assessing the secondary sexual characteristics, rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size).

Current Secondary Outcome Measures (submitted: December 15, 2021)

• Percent Change from Baseline in Total Seizure Frequency per 28 Days for DS and LGS Participants [ Time Frame: Up to 4 years ]
  Seizure frequency per 28 days is defined as total number of seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline is defined as (frequency of seizures per 28 days during Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
• Percent Change from Baseline in Convulsive Seizure Frequency per 28 Days in DS Cohort [ Time Frame: Up to 4 years ]
  Convulsive seizure frequency per 28 days is defined as total number of convulsive seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline will be defined as (frequency of convulsive seizures per 28 days during Treatment Period - frequency of convulsive seizures per 28 days at Baseline) divided by the frequency of convulsive seizures per 28 days at Baseline multiplied by 100.
• Percent Change from Baseline in Major Motor Drop (MMD) Seizure Frequency per 28 Days in LGS Cohort [ Time Frame: Up to 4 years ]
  MMD seizure frequency per 28 days is defined as total number of MMD seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline will be defined as (frequency of MMD seizures per 28 days during the Treatment Period - frequency of MMD seizures per 28 days at Baseline) divided by the frequency of MMD seizures per 28 days at Baseline multiplied by 100.
• Clinical Global Impression of Improvement (CGI-I) Score [ Time Frame: Up to 4 years ]
  The CGI-I Clinician is a 7-point Likert scale that the investigator uses to rate a participant's change (improvement) in overall seizure control, behavior, safety and tolerability, after the initiation of study drug relative to Baseline (before treatment with study drug). The participant will be rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Higher score will indicate worse symptoms.
• Caregiver Global Impression of Improvement (Care GI-I) Score [ Time Frame: Up to 4 years ]
  The Care GI-I is a 7-point Likert scale that the caregiver uses to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with study drug). The participant will be rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The parent/caregiver will complete the Care GI-I via interview. Higher score will indicate worse symptoms.
• CGI-I Seizure Intensity and Duration Score [ Time Frame: Up to 4 years ]
  The CGI-I seizure intensity and duration instrument is used by the parent/caregiver to rate improvement in intensity and duration of convulsive seizures (DS Cohort) or MMD seizures (LGS Cohort) from Baseline. The participant's symptoms will be rated on 7-point scale as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Higher score will indicate worse symptoms.
• CGI-I Nonseizure Symptoms Score [ Time Frame: Up to 4 years ]
  The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the investigator uses to rate improvement in the symptoms and impacts in select nonseizure domains since initiating the study drug. The participant will be rated on 7-point scale by the investigator as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). At Baseline, a symptoms form is completed by the clinician in collaboration with the primary caregiver to assess the participants status based on the presence of any nonseizure symptoms. Higher score will indicate worse symptoms.
• Change in Quality of Life Inventory-Disability (QI-Disability) Score [ Time Frame: Up to 4 years ]
  The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluates quality of life in children with intellectual disabilities. It contains 32 items covering 6 domains of quality of life: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Scores are from a 5-point Likert scale and then are transformed to a scale of 0 to 100. Possible scores range from 0-100, with higher scores indicating better quality of life.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Soticlestat as an Add-on Therapy in Children and Adults With Dravet Syndrome or Lennox-Gastaut Syndrome
• Official Title: A Phase 3, Prospective, Open-Label, Multisite, Extension of Phase 3 Studies To Assess the Long-Term Safety and Tolerability of Soticlestat as Adjunctive Therapy in Subjects With Dravet Syndrome or Lennox-Gastaut Syndrome (ENDYMION 2)

Brief Summary

The main aim of the study is to learn if soticlestat, when given as an add-on therapy, reduces the number of seizures in children and adults with Dravet Syndrome (DS) or Lennox-Gastaut Syndrome (LGS).

Participants will receive their standard anti-seizure therapy, plus tablets of soticlestat. There will be scheduled visits and follow-up phone calls throughout the study.

Detailed Description

The drug being tested in this study is called soticlestat (TAK-935). Soticlestat administered long-term in pediatric and adult participants who participated in an antecedent soticlestat Phase 3 clinical study will be assessed for additional safety and tolerability data along with efficacy analysis, as well as palatability and acceptability of soticlestat in the pediatric population.

The study will enroll approximately 400 participants.

All participants will receive soticlestat based on their weight in the 2-week Titration Period (for participants who roll over from an antecedent double-blind study). Following the Titration Period, participants will continue to receive the same dose in the Maintenance Period. At the end of maintenance period, the dose will be down-tapered (unless already at the lowest dose) and then stopped. Participants not tolerating minimum dose of 100 mg twice a day (BID) will be discontinued from the study.

This multi-center trial will be conducted worldwide. The overall time to participate in the study will be approximately 4 years, or until the study is stopped at the discretion of the sponsor, or the product is approved and launched. Participants who discontinue study drug treatment before the completion of the study, will continue to be followed per protocol and maintain a daily seizure diary until the final follow-up phone call.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Dravet Syndrome (DS)
• Lennox Gastaut Syndrome (LGS)

Intervention

Drug: Soticlestat

Soticlestat mini-tablets or tablets

Other Name: TAK-935

Study Arms

Experimental: Soticlestat

Participants with DS and LGS will receive:Participants weighing <45kg:Soticlestat,mini-tablets,titrated from lower dose level(60mg to 140mg) to higher dose(100mg to 200mg) twice daily(BID),based on body weight,orally/via enteral feeding tubes including but not limited to nasogastric(NG)-tube,gastrostomy tube(G-tube),MIC-KEY button,upto 2 weeks in Titration Period. Will continue to receive dose they are on at end of Titration Period,for approximately 4 years in Maintenance Period.Dose will be tapered down to lower dose(not less than lowest dose level based on weight)every 3 days until study drug is discontinued(upto 1week) in Taper Period.Participants weighing ≥45kg/adults:Soticlestat mini-tablets/tablets with starting dose of 200mg BID followed by 300mg BID,up to 2 weeks in Titration Period.Will continue to receive 300mg BID for approximately 4 years in Maintenance Period.Dose will be tapered down upto 100mg every 3 days until study drug is discontinued(up to 1 week) in Taper Period.

Intervention: Drug: Soticlestat

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 23, 2023): 400
• Original Estimated Enrollment (submitted: December 15, 2021): 376
• Estimated Study Completion Date: May 22, 2026
• Estimated Primary Completion Date: May 22, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Participant must have:

• Been previously enrolled in a phase 3 soticlestat clinical study.

Exclusion Criteria:

1. Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive tumors, or other abnormality that may impact the ability to participate in the study or that may potentially confound the study results. It is the responsibility of the investigator to assess the clinical significance; however, consultation with the medical monitor may be warranted.
2. Abnormal and clinically significant ECG abnormality at Visit 1 including QT interval with Fridericia correction method (QTcF) >450 milliseconds (ms) confirmed with a repeat ECG using manual measurement of QTcF.
3. Participant is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property. Participants who have positive answers on item numbers 4 or 5 on the CSSRS before dosing are excluded. This scale will only be administered to participants aged ≥6 years.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 56 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Takeda Contact; +1-877-825-3327; medinfoUS@takeda.com

• Listed Location Countries: Australia, Belgium, Brazil, Canada, China, France, Germany, Greece, Hungary, Italy, Japan, Latvia, Mexico, Netherlands, Poland, Russian Federation, Serbia, Spain, Ukraine, United States

Administrative Information

• NCT Number: NCT05163314
• Other Study ID Numbers: TAK-935-3003; 2021-002482-17 ( EudraCT Number ); jRCT2051210182 ( Registry Identifier: jRCT ); 2022-502802-34 ( Other Identifier: EU CTIS )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda
• Original Responsible Party: Same as current
• Current Study Sponsor: Takeda
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: February 2024