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

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

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.

Study Overview

• Status: Completed
• Conditions: Epilepsy, Focal Seizures, Partial Seizures
• Intervention / Treatment: Drug: Natalizumab; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Research Site
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Research Site
    • Phoenix, Arizona, United States, 85054
      • Research Site
  • California
    • San Diego, California, United States, 92103
      • Research Site
    • Santa Monica, California, United States, 90404
      • Research Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Research Site
    • Maitland, Florida, United States, 32751
      • Research Site
    • Orlando, Florida, United States, 32803
      • Research Site
    • Tallahassee, Florida, United States, 32308
      • Research Site
    • Tampa, Florida, United States, 33606
      • Research Site
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Research Site
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Research Site
    • Chevy Chase, Maryland, United States, 20815
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Research Site
    • Boston, Massachusetts, United States, 02115
      • Research Site
  • Michigan
    • Saginaw, Michigan, United States, 48602
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Research Site
  • New York
    • Bronx, New York, United States, 10467
      • Research Site
    • Rochester, New York, United States, 14642
      • Research Site
    • Syracuse, New York, United States, 13210
      • Research Site
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Research Site
    • Chapel Hill, North Carolina, United States, 27514
      • Research Site
    • Durham, North Carolina, United States, 27705
      • Research Site
  • Ohio
    • Akron, Ohio, United States, 44320
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Research Site
  • Washington
    • Renton, Washington, United States, 98055
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Natalizumab 300 mg; 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; As specified in the treatment arm.; Other Names: Tysabri
Placebo Comparator: Placebo; 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; As specified in treatment arms.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect.	From first dose up to 24 weeks after the last dose of study treatment (up to Week 68)
Number of Participants With Clinically Significant Laboratory Abnormalities	The laboratory assessments included hematology, blood chemistry, serology, urinalysis and vital signs assessment.	From first dose up to 16 weeks after the last dose of study treatment (up to Week 60)
Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score	C-SSRS is a prospective assessment tool to evaluate suicidal ideation and behavior. C-SSRS score for suicidal ideation ranges from 1 to 10, where 1=Wish to be Dead; 2=Nonspecific Active Suicidal Thoughts; 3=Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; 4=Active Suicidal Ideation with Some Intent to Act, without Specific Plan; 5=Active Suicidal Ideation with Specific Plan and Intent; and for suicidal behavior ranges from 6=Preparatory Acts or Behavior, 7=Aborted Attempt, 8=Interrupted Attempt, 9=Actual Attempt (nonfatal), 10=Completed Suicide. Participants with a C-SSRS score between 1-10 are reported in this outcome measure.	Placebo-controlled Phase: Baseline, Weeks 4, 8, 12, 16, 20 and 24; Open-label Phase: Baseline, Weeks 28, 32, 36, 40, 44, 48 and 60/End of Study (EOS)

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• French JA, Cole AJ, Faught E, Theodore WH, Vezzani A, Liow K, Halford JJ, Armstrong R, Szaflarski JP, Hubbard S, Patel J, Chen K, Feng W, Rizzo M, Elkins J, Knafler G, Parkerson KA; OPUS Study Group. Safety and Efficacy of Natalizumab as Adjunctive Therapy for People With Drug-Resistant Epilepsy: A Phase 2 Study. Neurology. 2021 Nov 2;97(18):e1757-e1767. doi: 10.1212/WNL.0000000000012766. Epub 2021 Sep 14.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2018
• Primary Completion (Actual): January 11, 2020
• Study Completion (Actual): November 18, 2020

Study Registration Dates

• First Submitted: September 12, 2017
• First Submitted That Met QC Criteria: September 12, 2017
• First Posted (Actual): September 14, 2017

Study Record Updates

• Last Update Posted (Actual): December 14, 2021
• Last Update Submitted That Met QC Criteria: November 17, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Drug Resistant Focal Epilepsy, Natalizumab, Seizure
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Epilepsies, Partial; Physiological Effects of Drugs; Immunologic Factors; Natalizumab
• Other Study ID Numbers: 101EP201; 2017-001995-45 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No