A Phase 2B, Multicenter, 30-week, Prospective, Cross-over, Double-blind, Randomized, Placebo-controlled Study Followed by a 52-Week Open-label Extension Study to Evaluate the Efficacy and Safety of Basimglurant Adjunctive to Ongoing Anticonvulsive Therapy in Children, Adolescents, and Young Adults with Seizures Associated with Tuberous Sclerosis Complex
试验速览
- 阶段
- 2 期
- 状态
- Other
- 入组人数
- 54
- 试验地点
- 7
- 主要终点
- To evaluate the efficacy of a double-blind, daily basimglurant administration, adjunctive to ongoing anticonvulsive therapy compared with placebo adjunctive to ongoing anticonvulsive therapy in patients with Tuberous Sclerosis Complex (TSC).
研究概览
简要总结
TuberousSclerosis Complex (TSC) is an orphan condition with limited treatment optionsand high medical need, impacting over one million individuals worldwide. It isa genetic disorder characterized by the uncontrolled growth of numerous benign tumoursin many parts of the body including the brain, where it might lead to treatmentresistant seizures causing serious or life-threatening complications and oftenresulting in developmental and behavioural problems. TSC is one of the leadinggenetic causes of epilepsy, with about 85% of TSC patients suffering fromassociated seizures, frequently refractory to treatment. With onset in earlychildhood and life-long duration, TSC is a disease impacting whole families.This condition has a profound impact on health, quality of life, and bothdirect and indirect financial costs representing a long-term burden to society.
Currenttreatment of epilepsy associated with TSC is almost identical to those withepilepsy not related to TSC, focusing on a variety of anti-convulsant for bothgeneralized and focal epilepsy. However, even adjunctive standard of caretherapies often provides limited efficacy and intolerable side effects. Thereis a need for safe and well-tolerated treatments that provide seizure control,to prevent any deleterious effect on psychomotor development of childrenaffected by this condition.
Basimglurant(NOE-101) is an investigational negative allosteric modulator of metabotropicglutamate receptor 5 (mGluR5). It decreases neuronal excitability caused byoveractive glutamatergic signalling and normalizes overactive neuronal activityin key brain areas. Demonstrating robust CNS engagement, basimglurant has thepotential to provide safe and effective seizure control in children,adolescents, and young adults with TSC.
Thisstudy is designed to validate the efficacy observed in a transgenic animalmodel. In this model,2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine(CTEP), an analogue of basimglurant reduced the frequency and duration ofseizures in a TSC2 knock down mouse model. Further effect was observed on theincreased protein synthesis a landmark feature of TSC. The mGluR5 CTEP wasfound to normalize protein synthesis in two independent experiments.
The goal of the study is to show that basimglurant provideseffective seizure control in children, adolescents, and young adults with TSC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
入排标准
- 年龄范围
- 12.00 Year(s) 至 30.00 Year(s)（—）
- 性别
- All
入选标准
- •Ability and willingness to provide informed assent or written consent, or consent from their legal representative and willingness to comply with the study procedures.
- •Fluency in the language of the investigator, study staff and the informed assent or consent form when applicable.
- •Age 5 to 30 years.
- •A documented history of TSC, diagnosed according to the International Tuberous Sclerosis Complex diagnostic criteria of 2021 and including a record of either genetic test or MRI/CT scan documenting tumours.
- •Continued seizures associated with TSC (including absences, atonic, tonic, tonic-clonic or myoclonic) despite adequate dosage of at least 2 or more appropriate antiseizure drugs (AEDs) at adequate doses, within approximately the previous 3 years.
- •Refractory seizure treatment status, defined as between 3 and 20 per month over the last year and at least 5 or more seizures within the past 30 days.
- •Currently receiving one or more anti-epileptic drugs (AEDs) with no change in doses in the 30 days prior to enrolment in the study and no planned dose change during the study and through the primary endpoint.
- •All medications or interventions for epilepsy (including ketogenic diet and any neurostimulation devices for epilepsy) must have been stable for 30 days prior to screening and the patient must be willing to maintain a stable regimen throughout the study.
- •The ketogenic diet and neurostimulation treatments are not considered AEDs for the purpose of this study.
- •Patients or their caregiver must be willing to complete daily PRO assessments.
- •For female patients of childbearing potential: a.
- •willingness to undergo serum or urinary pregnancy testing at screening and during the trial period.
- •willingness to use contraception.
排除标准
- •Etiology of a patient’s seizures is a progressive neurologic disease other than TSC.
- •Anoxic episode requiring resuscitation within 6 months of screening.
- •Patient weight below 15kg.
- •Clinically significant unstable medical conditions other than epilepsy including, but not limited to, cardiovascular, gastrointestinal, renal, hepatic, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or other major physical impairment that is not stable in the opinion of the investigator and could affect the safety of the patient throughout the study, influence the findings of the study or their interpretation, or might impede the patient’s ability to complete the entire duration of the study.
- •Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening which, in the opinion of the investigator, may put the patient at risk because of his/her participation in the study, or might influence the results of the study, or the patient’s ability to complete the entire duration of the study.
- •Clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to screening or randomization, other than epilepsy.
- •Current or past use of recreational or medicinal cannabis within the three months prior to study entry and unwillingness to abstain for the duration of the study or a positive result on a urine tetrahydrocannabinol (THC) panel test.
- •Epidiolex is an AED and is therefore allowed for the treatment of TSC with no change in doses in the 30 days prior to enrolment in the study and no planned dose change during the study and through the primary endpoint).
- •Participation in a clinical trial involving another investigational product (IP) in the previous 6 months or at any time in a gene therapy clinical trial.
- •Patient has previously had brain surgery for the treatment of epilepsy.
- •(Surgery for removal of tumours ≥6 months prior to entry into the study is acceptable.).
- •Patient has bipolar disorder.
- •Subject is currently taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known exacerbate epilepsy.
- •An exception will be made for prophylactic medication such as medications for idiopathic nephrotic syndrome or asthma.
- •Pregnancy or lactation.
结局指标
主要结局
To evaluate the efficacy of a double-blind, daily basimglurant administration, adjunctive to ongoing anticonvulsive therapy compared with placebo adjunctive to ongoing anticonvulsive therapy in patients with Tuberous Sclerosis Complex (TSC).
时间窗: 86 weeks including 4 week of placebo then 30 weeks of DB study, and 52 weeks of OL study
次要结局
- Change from baseline in Sheehan Disability Scale (SDS score at Week 16 in Period 2 and at Week 30 in Period 4.(Adverse events,)