A Study of Soticlestat as an Add-on Therapy in Children, Teenagers, and Adults With Lennox-Gastaut Syndrome
- Registration Number
- NCT04938427
- Lead Sponsor
- Takeda
- Brief Summary
The aims of the study are:
* to learn if soticlestat, when given as add-on therapy, reduces the number of major motor drop seizures in children, teenagers, and adults with Lennox-Gastaut Syndrome.
* to assess the safety profile of soticlestat when given in combination with other therapies.
Participants will receive their standard antiseizure therapy, plus either tablets of soticlestat or placebo. A placebo looks just like soticlestat but will not have any medicine in it. Participants will take soticlestat or placebo for 16 weeks, followed by a gradual dose reduction for 1 week. Then, participants will be followed up for 2 weeks.
- Detailed Description
The drug being tested in this study is called soticlestat (TAK-935). Soticlestat will be assessed for efficacy, safety, and tolerability in pediatric and adult participants with LGS.
The study will enroll approximately 234 patients. Participants will be randomly assigned (by chance, like flipping a coin) in a 1:1 ratio to receive standard of care (SOC) plus one of the following adjunctive therapies which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):
1. Soticlestat
2. Placebo (dummy inactive pill - this is a tablet/mini-tablet that looks like the study drug but has no active ingredient)
Participants will receive soticlestat or matching placebo based on their weight in the 4-week Titration Period. Following the Titration Period, participants will continue to receive the same dose in the 12-week Maintenance Period. The dose will then be down-tapered if participants decide to discontinue the treatment and/or are not deemed eligible to continue in Open-label extension (OLE).
This multi-center trial will be conducted worldwide. The overall time to participate in the study will be from 22-25 weeks. At the end of the treatment period, participants have the option to either complete the study and taper off the investigational product or to enter the OLE if they meet eligibility requirements. If participants discontinue, they will be followed-up on phone call approximately 14 days after the last dose of study drug for safety.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 270
- Has documented clinical diagnosis of LGS.
- Has had ≥8 MMD seizures each month in the 3 months prior to Screening based on the historical information and has had ≥8 MMD seizures per 28 days during the 4 to 6 week prospective Baseline Period.
- Weighs ≥10 kg at the Screening Visit (Visit 1).
- Failure to control seizures despite appropriate trials of at least 1 ASM based on historical information, and is currently on an antiseizure therapy or other treatment options considered as standard of care (SOC).
- Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening visit (Visit 1); the dosing regimen and manufacturer should remain constant throughout the study. (Artisanal cannabidiols will not be counted as ASMs.)
- Currently taking 0 to 3 ASMs at stable doses for at least 4 weeks before the Screening Visit (Visit 1); Fenfluramine and cannabidiol (Epidiolex) are allowed where available and counted as an ASM. ASM dosing regimen must remain constant throughout the study.
- Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months immediately before Screening (Visit 1). For the purpose of this exclusion criterion, status is defined as continuous seizure activity lasting longer than 5 minutes or repeated seizures without return to Baseline in between seizures.
- 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.
- Considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the participant has attempted suicide within 12 months before the Screening Visit (Visit 1). Participants who have positive answers on item numbers 4 or 5 on the Columbia suicide severity rating scale (C-SSRS) before dosing (Visit 2) are excluded. This scale will only be administered to participants aged ≥6 years.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Soticlestat Soticlestat Participants weighing \<45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with the dose tapered down if participants decided to discontinue the treatment. Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with the dose tapered down if participants decided to discontinue the treatment. Placebo Placebo Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment.
- Primary Outcome Measures
Name Time Method Percent Change From Baseline in Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Full Treatment Period Baseline; Full Treatment Period: Weeks 1 to 16 MMD seizure frequency per 28 days was defined as the total number of MMD seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the full 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 Major Motor Drop (MMD) Seizure Frequency Per 28 Days During the Maintenance Period Baseline; Maintenance Period: Weeks 5 to 16 MMD seizure frequency per 28 days was defined as the 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 was defined as (frequency of seizures per 28 days during the Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
- Secondary Outcome Measures
Name Time Method Longest MMD Seizure-free Interval During the Full Treatment Period Full Treatment Period: Weeks 1 to 16 Longest MMD Seizure-free Interval was defined as the longest time period that the participant remained MMD seizure-free after initiation of the treatment. A linear model with treatment group and age stratum as factors was used for analysis.
Number of Days When Rescue Antiseizure Medication (ASM) is Used During the Full Treatment Period Full Treatment Period: Weeks 1 to 16 Use of rescue ASM was recorded in the case report form (CRF) along with start and end date of medication. Based on
the start and end dates for all rescue ASMs taken by a participant, the number of days during the Full Treatment Period when rescue ASM was used was derived.Percentage of Responders During the Maintenance Period Maintenance Period: Weeks 5 to 16 Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the Maintenance Period. Percentages are rounded off to the nearest single decimal place.
Percentage of Responders During the Full Treatment Period Full Treatment Period: Weeks 1 to 16 Responders are defined as those with ≥50% reduction from Baseline in MMD seizures during the Full Treatment Period. Percentages are rounded off to the nearest single decimal place.
Percentage of Participants With ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, >75% to ≤100% Reduction in MMD Seizure During the Full Treatment Period Full Treatment Period: Weeks 1 to 16 Percent reduction from Baseline (%) is defined as \[(Full Treatment Period MMD Seizure Frequency - Baseline MMD Seizure Frequency) divided by Baseline MMD Seizure Frequency\] multiplied by 100. Data is reported as reduction of ≤0%, \>0% to ≤25%, \>25% to ≤50%, \>50% to ≤75%, \>75% to ≤100% or more in seizures from Baseline. Percentages are rounded off to the nearest single decimal place.
Percentage of Participants With Caregiver Global Impression of Improvement (Care GI-I) Scale Responses as Per the Parent/Caregiver Reported Impression at Week 16 Week 16 The Care GI-I is a 7-point Likert scale that the caregiver used to rate improvement in overall seizure control, behavior, safety and tolerability after the initiation of study drug relative to Baseline (before treatment with the study drug). The participant was 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 completed the Care GI-I via interview. Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place.
Percentage of Participants With Clinical Global Impression of Improvement (CGI-I) Scale Responses as Per the Investigator Reported Impression at Week 16 Week 16 The CGI-I (Clinician) is a 7-point Likert scale that the investigator 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 the study drug). The participant was 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 investigator or designee will complete the CGI-I. Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place.
Percentage of Participants With CGI-I Nonseizure Symptoms Instrument Responses for Each Domain as Per the Investigator Reported Impression at Week 16 Week 16 The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the investigator used to rate improvement in the symptoms and impacts in select nonseizure domains (alertness, communication, and disruptive behaviors) since initiating the study drug. The participant was rated by the investigator for each domain 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). Lower scores indicated improvement. Data for percentage of participants categorized based on the responses for each domain are presented. Percentages are rounded off to the nearest single decimal place.
Change From Baseline in Quality of Life Inventory-Disability (QI-Disability) Total Score at Week 16 Baseline, Week 16 The QI-Disability tool is a parent/caregiver-reported questionnaire evaluated the 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. Each QI-Disability item is rated on a Likert scale of: Never, Rarely, Sometimes, Often, and Very Often. Items were linearly transformed to a scale of 0 to 100, with higher scores representing better quality of life. Domain scores are calculated by averaging item scores. The domain scores are summed and divided by 6 to yield a total score. The total score ranges from 0 to 100, with higher scores indicating a better quality of life. A negative change from Baseline implies deteriorating quality of life. Mixed-effects model for repeated measures (MMRM) was used for analysis.
Percentage of Participants With CGI-I Seizure Intensity and Duration Instrument Responses as Per the Parent/Caregiver Reported Impression at Week 16 Week 16 The CGI-I seizure intensity and duration instrument was used by the parent/caregiver to rate changes in intensity and/or duration of the most impactful seizures from the first assessment. The participant's symptoms were 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). Lower scores indicate improvement. Percentages are rounded off to the nearest single decimal place.
Percent Change From Baseline in Frequency of All Seizures Per 28 Days During the Maintenance Period Baseline; Maintenance Period: Weeks 5 to 16 Seizure frequency per 28 days was defined as the total number of seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the Maintenance 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 Frequency of All Seizures Per 28 Days During the Full Treatment Period Baseline; Full Treatment Period: Weeks 1 to 16 Seizure frequency per 28 days was defined as the total number of seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
Change From Baseline in Percentage of MMD Seizure-free Days During the Full Treatment Period Baseline up to Week 16 MMD Seizure-free days was defined as the number of days the participant remained MMD seizure free after initiation of the treatment. The change from baseline in percentage of MMD seizure-free days, was defined as the percentage of seizure-free days during the Full Treatment Period minus the percentage of seizure-free days during the Baseline. A linear model with treatment group and age stratum as factors and baseline percentage as a covariate was used for analysis.
Trial Locations
- Locations (98)
St. Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Pecsi Tudomanyegyetem
🇭🇺Pecs, Baranya, Hungary
Fondazione Policlinico Universitario A Gemelli
🇮🇹Roma, Lazio, Italy
Stichting Epilepsie Instellingen Nederland
🇳🇱Zwolle, Overijssel, Netherlands
Children and Youth Health Care Institute of Vojvodina
🇷🇸Novi Sad, Serbia
NYU Comprehensive Epilepsy Center
🇺🇸New York, New York, United States
Northwell Health Physician Partners - Neurology at Lenox Hill
🇺🇸New York, New York, United States
Institute of Neurology and Neurosurgery at Saint Barnabas, LLC
🇺🇸Livingston, New Jersey, United States
Pediatric Neurology PA
🇺🇸Winter Park, Florida, United States
Center For Neurosciences
🇺🇸Tucson, Arizona, United States
UZ Antwerpen PIN
🇧🇪Edegem, Antwerpen, Belgium
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Premier Healthcare Inc.
🇺🇸New York, New York, United States
The Second Affiliated Hospital of Guangzhou Medical University
🇨🇳Guangzhou, Guangdong, China
Midatlantic Epilepsy and Sleep Center
🇺🇸Bethesda, Maryland, United States
Xiangya Hospital Central South University
🇨🇳Changsha, Hunan, China
Austin Hospital
🇦🇺Heidelberg, Victoria, Australia
Cook Children's Medical Center - Jane and John Justin Neurosciences Center
🇺🇸Fort Worth, Texas, United States
Beijing Children's Hospital,Capital Medical University
🇨🇳Beijing, Beijing, China
Hopital Universitaire des Enfants Reine Fabiola
🇧🇪Brussels, Belgium
MultiCare Institute for Research & Innovation (Tacoma)
🇺🇸Tacoma, Washington, United States
Child and Family Research Institute
🇨🇦Vancouver, British Columbia, Canada
Peking University First Hospital
🇨🇳Beijing, Beijing, China
Yasuhara Childrens Clinic
🇯🇵Neyagawa-Shi, Osaka, Japan
Osaka City General Hospital
🇯🇵Osaka-Shi, Osaka, Japan
Childrens University Hospital
🇱🇻Riga, Latvia
Municipal Institution Dnipropetrovsk Regional Children Clinical Hospital of DRC
🇺🇦Dnipro, Dnipropetrovs'ka Oblast, Ukraine
Communal Non-commercial Enterprise Iv-Frank Regional Childrens Clinical Hosp of Iv-Frank RC
🇺🇦Ivano-Frankivsk, Ukraine
Hospital Regional Universitario de Malaga Hospital General
🇪🇸Malaga, Spain
UGMK-Zdorojie, LLC
🇷🇺Ekaterinburg, Russian Federation
National Center of Neurology and Psychiatry
🇯🇵Kodaira-Shi, Tokyo, Japan
Hospital Universitario Vall d'Hebron - PPDS
🇪🇸Barcelona, Spain
Fukuoka Children's Hospital
🇯🇵Fukuoka-Shi, Hukuoka, Japan
Centro de Neurologia Avanzada
🇪🇸Sevilla, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸Valencia, Spain
Okayama University Hospital
🇯🇵Okayama-city, Okayama, Japan
Aichi Medical University Hospital
🇯🇵Nagakute-Shi, Aiti, Japan
ASST di Pavia - Fondazione Istituto Neurologico Mondino IRCCS
🇮🇹Pavia, Lombardia, Italy
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
University of California Benioff Children's Hospital
🇺🇸San Francisco, California, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
University of Utah - Primary Children's Hospital - PPDS
🇺🇸Salt Lake City, Utah, United States
Children's Hospital Colorado.
🇺🇸Denver, Colorado, United States
National Hospital Organization Shizuoka Institute of Epilepsy and Neurological Disorders
🇯🇵Shizuoka-Shi, Sizuoka, Japan
Klinikum der Johann-Wolfgang Goethe-Universitat
🇩🇪Frankfurt am Main, Hessen, Germany
WellSpan Oncology Research
🇺🇸York, Pennsylvania, United States
David Geffen School of Medicine at UCLA
🇺🇸Los Angeles, California, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Clinical Integrative Research Center of Atlanta
🇺🇸Atlanta, Georgia, United States
Minnesota Epilepsy Group PA
🇺🇸Roseville, Minnesota, United States
Medical University of South Carolina Children Hospital - PIN
🇺🇸Charleston, South Carolina, United States
Queensland Childrens Hospital
🇦🇺South Brisbane, Queensland, Australia
Hospital For Sick Children
🇨🇦Toronto, Ontario, Canada
Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Children's Hospital of Chongqing Medical University
🇨🇳Chongqing, Chongqing, China
Shenzhen Children's Hospital
🇨🇳Shenzhen, Guangdong, China
Wuhan Childrens hospital
🇨🇳Wuhan, Hubei, China
Jiangxi Provincial Children's Hospital
🇨🇳Nanchang, Jiangxi, China
Guangzhou Women And Children's Medical Center
🇨🇳Guangzhou, Guangdong, China
The First Hospital of Jilin University
🇨🇳Changchun, Jilin, China
CHRU Dijon Hopital General
🇫🇷Dijon, Cote-d'Or, France
Children's Hospital of Shanghai
🇨🇳Shanghai, Shanghai, China
Children's Hospital of Fudan University
🇨🇳Shanghai, Shanghai, China
Hopital Roger Salengro
🇫🇷Lille, Nord, France
Krankenhaus Mara gGmbH - Epilepsiezentrum Bethel
🇩🇪Bielefeld, Nordrhein-Westfalen, Germany
Hopitaux de La Timone
🇫🇷Marseille, France
Hopital Robert Debre
🇫🇷Paris, France
Schon Klinik Vogtareuth
🇩🇪Vogtareuth, Bayern, Germany
Hopital Necker - Enfants Malades
🇫🇷Paris, France
Attikon University General Hospital
🇬🇷Chaidari, Attiki, Greece
Kleinwachau Sachsisches Epilepsiezentrum Radeberg Gemeinnutzige Gmbh
🇩🇪Radeberg, Sachse, Germany
University General Hospital of Larissa
🇬🇷Larisa, Greece
Orszagos Mentalis, Ideggyogyaszati es Idegsebeszeti Intezet
🇭🇺Budapest, Hungary
Bethesda Gyermekkorhaz
🇭🇺Budapest, Hungary
Hippokration Hospital
🇬🇷Thessaloniki, Greece
Szent Janos Korhaz es Eszak-Budai Egyesitett Korhazak
🇭🇺Budapest, Hungary
Ospedale Bellaria
🇮🇹Bologna, Emilia-Romagna, Italy
Azienda Ospedaliero Universitaria A Meyer - INCIPIT - PIN
🇮🇹Firenze, Toscana, Italy
National Hospital Organization Nagasaki Medical Center
🇯🇵Omura-Shi, Nagasaki, Japan
Kumamoto-Ezuko Medical Center for The Severely Disabled
🇯🇵Kumamoto-Shi, Kumamoto, Japan
National Hospital Organization Nishi-Niigata Chuo National Hospital
🇯🇵Niigata-Shi, Niigata, Japan
Osaka University Hospital
🇯🇵Suita-Shi, Osaka, Japan
Kempenhaeghe - PPDS
🇳🇱Heeze, Noord-Brabant, Netherlands
Szpital Kliniczny im. H.Swiecickiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
🇵🇱Poznan, Poland
Uniwersyteckie Centrum Kliniczne
🇵🇱Gdansk, Poland
Centrum Medyczne Plejady
🇵🇱Krakow, Malopolskie, Poland
Clinic for Neurology and Psychiatry for Children and Youth
🇷🇸Belgrade, Serbia
Mother and Child Health Care Institute of Serbia Dr Vukan Cupic
🇷🇸Belgrade, Serbia
University Clinical Center Nis
🇷🇸Nis, Serbia
Clinica Universidad Navarra
🇪🇸Pamplona, Navarra, Spain
University of Iowa Hospitals & Clinics - (CRS)
🇺🇸Iowa City, Iowa, United States
Centre Neurologique William Lennox
🇧🇪Ottignies-Louvain-la-Neuve, Brabant Wallon, Belgium
CNPE Clinical Hospital Psychiatry of the Executive Body of the Kyiv City Council KCSA
🇺🇦Kyiv, Ukraine
Communal Non-profit Enterprise City Childrens Clinical Hospital #6 of DCC
🇺🇦Dnipro, Dnipropetrovs'ka Oblast, Ukraine
SI Ukr. Med. Rehabilitation Center For Children With Organic Injury of Nervous System of MoH of Ukr
🇺🇦Kyiv, Ukraine
Alberta Childrens Hospital
🇨🇦Calgary, Alberta, Canada
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States