Phase 2 Efficacy, Safety, and Tolerability Study of Natalizumab in Focal Epilepsy

Study Overview
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Brief Summary
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The primary efficacy objective of the study is to determine if adjunctive therapy of natalizumab 300 mg intravenous (IV) every 4 weeks reduces the frequency of seizures in adult participants with drug-resistant focal epilepsy. The secondary efficacy objective is to assess the effects of natalizumab versus placebo in drug-resistant focal epilepsy on additional measures of seizure frequency.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Exploring the Efficacy, Safety, and Tolerability of Natalizumab (BG00002) as Adjunctive Therapy in Adult Subjects With Drug-Resistant Focal Epilepsy

Conditions
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Epilepsy, Focal Seizures, Partial Seizures

Intervention / Treatment
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* Drug: Natalizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must have focal epilepsy diagnosed on clinical grounds and as applicable supported by electroencephalogram findings [Scheffer 2017] and brain imaging. Participants with multifocal epilepsy may be included if all other entry criteria are met. Must have a drug-resistant epilepsy defined as failure of adequate trials of 2 (or more) tolerated and appropriately chosen and used AEDs (whether as monotherapies or in combination) [Kwan 2010]. Experiences 6 or more seizures during the 6-week prospective baseline period and is not seizure free for more than 21 consecutive days during the prospective baseline period Key Exclusion Criteria: Focal aware seizures without motor signs are the only seizure type. Diagnosis of generalized, combined generalized and focal, or unknown epilepsy Known progressive structural CNS lesion. History of seizures occurring in predominantly clustered patterns, as determined by the Investigator, over the 12 months prior to the Screening Visit (Week -6) or during the 6-week prospective baseline period, where individual seizures cannot be counted. History of status epilepticus within the previous 6 months. Known history or presence of non-epileptic seizures. NOTE; Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a 6-month randomized, double-blind, placebo-controlled study to assess the efficacy, safety, and tolerability of natalizumab as adjunctive therapy in the treatment of adult subjects with drug-resistant focal epilepsy. The placebo-controlled phase is followed by a 6-month open-label phase during which all subjects receive natalizumab.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Natalizumab 300 mg<br>Participants will undergo a prospective baseline period of 6 weeks (Weeks -6 to 0) followed by placebo controlled phase to receive natalizumab 300 mg intravenous (IV) infusion every 4 weeks from Week 0 to Week 24. Participants will continue to receive natalizumab 300 mg IV infusion every 4 weeks for up to an additional 24 weeks in open label phase. | Drug: Natalizumab<br>* As specified in the treatment arm.<br>* Other names: Tysabri;|
| Placebo Comparator: Placebo<br>Participants will undergo a prospective baseline period of 6 weeks (Weeks -6 to 0) followed by placebo controlled phase to receive natalizumab matching placebo intravenous (IV) infusion every 4 weeks from Week 0 to Week 24. Participants will then receive natalizumab 300 mg IV infusion every 4 weeks for 24 weeks in open label phase. | Other: Placebo<br>* As specified in treatment arms.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment | Seizures included were focal aware seizures with motor signs, focal impaired awareness seizures and focal to bilateral tonic-clonic seizure. Focal aware seizures without motor signs were not included. Seizure clusters (where individual seizures cannot be distinguished) were counted as 1 seizure per cluster on each day that they are present. Study baseline seizure frequency (number of seizures per 28 days) was calculated based on participant's seizure diary data during prospective baseline phase. Seizure frequency (SF) at post baseline visit was calculated based on sum of the seizures reported in participant seizure diary and the number of days with non-missing SF data in participant seizure diary on or after the previous visit date. Change from Baseline are based on natural log transformation of baseline SF or SF at post baseline visit correspondingly. For log-transformation, the quantity 0.2 {ln(x+0.2)} was added to the SF at post baseline visit to account for 0 seizure count. | Baseline, Week 8 to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders During Weeks 8 to 24 of Treatment | Responders were defined as participants with >=50% reduction from study baseline in seizure frequency during Weeks 8 to 24. Study baseline seizure frequency (number of seizures per 28 days) was calculated based on participants' seizure diary data during the prospective Baseline Phase (number of seizures during Baseline Phase/number of days with non-missing seizure frequency*28). Participants who withdrew from treatment or required protocol specified modifications of antiepileptic drug (AEDs) prior to Week 24 (completion of the Placebo-controlled Phase) or death related to Epilepsy were considered as non-responders in the analysis. Seizure frequency at post baseline visit was calculated based on the sum of the seizures reported in the subject seizure diary and the number of days with non-missing seizure frequency data in the subject seizure diary on or after the previous visit date. | Week 8 to Week 24 | 
| Number of Participants Free From Seizures During Weeks 8 to 24 of Treatment | Seizure free is defined as a participant with no seizure reported and no missing diary during Weeks 8 to 24. Participants who withdrew from treatment, required modifications of AEDs prior to Week 24 (completion of the Placebo-controlled Phase), or any missing diary data during Weeks 8 to 24 of treatment were not considered as seizure free in the analysis. | Week 8 to Week 24 | 
| Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Study baseline seizure free days (number of seizure free days per 28 days) was calculated based on the diary data during the prospective baseline Phase (Number of seizures during baseline Phase/Number of days with non-missing seizure frequency*28). Seizure frequency at post baseline visit was calculated based on the sum of the seizures reported in the subject seizure diary and the number of days with non-missing seizure frequency data in the subject seizure diary on or after the previous visit date. | Baseline, Week 8, Week 12, Week 16, Week 20, Week 24 | 
| Percentage of Participants With Inadequate Treatment Response During Weeks 8 to 24 of Treatment | Inadequate treatment response includes participants who withdraw from treatment due to lack of efficacy or require protocol specified modifications of antiepileptic drugs (AEDs) prior to Week 24 (completion of the placebo- controlled phase) or death related to Epilepsy. | Week 8 to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Resistant Focal Epilepsy, Natalizumab, Seizure