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

Primary Purpose

Epilepsy, Focal Seizures, Partial Seizures

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Natalizumab
Placebo
Sponsored by
Biogen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Epilepsy, Focal Seizures, Partial Seizures focused on measuring Drug Resistant Focal Epilepsy, Natalizumab, Seizure

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Natalizumab 300 mg

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
September 12, 2017
Last Updated
November 17, 2021
Sponsor
Biogen
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1. Study Identification

Unique Protocol Identification Number
NCT03283371
Brief Title
Phase 2 Efficacy, Safety, and Tolerability Study of Natalizumab in Focal Epilepsy
Acronym
OPUS
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Completed
Study Start Date
March 20, 2018 (Actual)
Primary Completion Date
January 11, 2020 (Actual)
Study Completion Date
November 18, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biogen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Epilepsy, Focal Seizures, Partial Seizures
Keywords
Drug Resistant Focal Epilepsy, Natalizumab, Seizure

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantInvestigatorOutcomes Assessor
Masking Description
Double-blind
Allocation
Randomized
Enrollment
67 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Natalizumab 300 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Natalizumab
Other Intervention Name(s)
Tysabri
Intervention Description
As specified in the treatment arm.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
As specified in treatment arms.
Primary Outcome Measure Information:
Title
Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment
Description
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.
Time Frame
Baseline, Week 8 to Week 24
Secondary Outcome Measure Information:
Title
Percentage of Responders During Weeks 8 to 24 of Treatment
Description
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.
Time Frame
Week 8 to Week 24
Title
Number of Participants Free From Seizures During Weeks 8 to 24 of Treatment
Description
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.
Time Frame
Week 8 to Week 24
Title
Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment
Description
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.
Time Frame
Baseline, Week 8, Week 12, Week 16, Week 20, Week 24
Title
Percentage of Participants With Inadequate Treatment Response During Weeks 8 to 24 of Treatment
Description
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.
Time Frame
Week 8 to Week 24
Other Pre-specified Outcome Measures:
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
From first dose up to 24 weeks after the last dose of study treatment (up to Week 68)
Title
Number of Participants With Clinically Significant Laboratory Abnormalities
Description
The laboratory assessments included hematology, blood chemistry, serology, urinalysis and vital signs assessment.
Time Frame
From first dose up to 16 weeks after the last dose of study treatment (up to Week 60)
Title
Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score
Description
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.
Time Frame
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Biogen
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Research Site
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85004
Country
United States
Facility Name
Research Site
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
Research Site
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
Research Site
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
Research Site
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20037
Country
United States
Facility Name
Research Site
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Research Site
City
Maitland
State/Province
Florida
ZIP/Postal Code
32751
Country
United States
Facility Name
Research Site
City
Orlando
State/Province
Florida
ZIP/Postal Code
32803
Country
United States
Facility Name
Research Site
City
Tallahassee
State/Province
Florida
ZIP/Postal Code
32308
Country
United States
Facility Name
Research Site
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Research Site
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96817
Country
United States
Facility Name
Research Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Research Site
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20817
Country
United States
Facility Name
Research Site
City
Chevy Chase
State/Province
Maryland
ZIP/Postal Code
20815
Country
United States
Facility Name
Research Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Research Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Research Site
City
Saginaw
State/Province
Michigan
ZIP/Postal Code
48602
Country
United States
Facility Name
Research Site
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Research Site
City
Camden
State/Province
New Jersey
ZIP/Postal Code
08103
Country
United States
Facility Name
Research Site
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
Research Site
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Research Site
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Research Site
City
Asheville
State/Province
North Carolina
ZIP/Postal Code
28806
Country
United States
Facility Name
Research Site
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Facility Name
Research Site
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Research Site
City
Akron
State/Province
Ohio
ZIP/Postal Code
44320
Country
United States
Facility Name
Research Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Research Site
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Research Site
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Research Site
City
Renton
State/Province
Washington
ZIP/Postal Code
98055
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34521687
Citation
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.
Results Reference
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Phase 2 Efficacy, Safety, and Tolerability Study of Natalizumab in Focal Epilepsy

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