Phase 2 Efficacy, Safety, and Tolerability Study of Natalizumab in Focal Epilepsy (OPUS)
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| ClinicalTrials.gov Identifier: NCT03283371 |
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Recruitment Status :
Completed
First Posted : September 14, 2017
Results First Posted : April 27, 2021
Last Update Posted : December 14, 2021
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Sponsor:
Biogen
Information provided by (Responsible Party):
Biogen
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Epilepsy, Focal Seizures, Partial Seizures | Drug: Natalizumab Other: Placebo | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 67 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention 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 (Participant, Investigator, Outcomes Assessor) |
| Masking Description: | Double-blind |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | March 20, 2018 |
| Actual Primary Completion Date : | January 11, 2020 |
| Actual Study Completion Date : | November 18, 2020 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Pyridoxal 5'-phosphate-dependent epilepsy
Autosomal dominant partial epilepsy with auditory features
Drug Information available for:
Natalizumab
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Natalizumab
As specified in the treatment arm.
Other Name: Tysabri |
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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.
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Other: Placebo
As specified in treatment arms. |
Primary Outcome Measures :
- Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment [ Time Frame: Baseline, Week 8 to Week 24 ]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 [ Time Frame: Week 8 to Week 24 ]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 [ Time Frame: Week 8 to Week 24 ]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 [ Time Frame: Baseline, Week 8, Week 12, Week 16, Week 20, Week 24 ]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 [ Time Frame: Week 8 to Week 24 ]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.
Other Outcome Measures:
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose up to 24 weeks after the last dose of study treatment (up to Week 68) ]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.
- Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: From first dose up to 16 weeks after the last dose of study treatment (up to Week 60) ]The laboratory assessments included hematology, blood chemistry, serology, urinalysis and vital signs assessment.
- Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score [ 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) ]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.
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| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03283371
Locations
| United States, Alabama | |
| Research Site | |
| Birmingham, Alabama, United States, 35294 | |
| United States, Arizona | |
| Research Site | |
| Phoenix, Arizona, United States, 85004 | |
| Research Site | |
| Phoenix, Arizona, United States, 85054 | |
| United States, California | |
| Research Site | |
| San Diego, California, United States, 92103 | |
| Research Site | |
| Santa Monica, California, United States, 90404 | |
| United States, District of Columbia | |
| Research Site | |
| Washington, District of Columbia, United States, 20037 | |
| United States, Florida | |
| Research Site | |
| 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 | |
| United States, Hawaii | |
| Research Site | |
| Honolulu, Hawaii, United States, 96817 | |
| United States, Illinois | |
| Research Site | |
| Chicago, Illinois, United States, 60612 | |
| United States, Maryland | |
| Research Site | |
| Bethesda, Maryland, United States, 20817 | |
| Research Site | |
| Chevy Chase, Maryland, United States, 20815 | |
| United States, Massachusetts | |
| Research Site | |
| Boston, Massachusetts, United States, 02111 | |
| Research Site | |
| Boston, Massachusetts, United States, 02115 | |
| United States, Michigan | |
| Research Site | |
| Saginaw, Michigan, United States, 48602 | |
| United States, Missouri | |
| Research Site | |
| Saint Louis, Missouri, United States, 63110 | |
| United States, New Jersey | |
| Research Site | |
| Camden, New Jersey, United States, 08103 | |
| United States, New York | |
| Research Site | |
| Bronx, New York, United States, 10467 | |
| Research Site | |
| Rochester, New York, United States, 14642 | |
| Research Site | |
| Syracuse, New York, United States, 13210 | |
| United States, North Carolina | |
| Research Site | |
| Asheville, North Carolina, United States, 28806 | |
| Research Site | |
| Chapel Hill, North Carolina, United States, 27514 | |
| Research Site | |
| Durham, North Carolina, United States, 27705 | |
| United States, Ohio | |
| Research Site | |
| Akron, Ohio, United States, 44320 | |
| United States, Pennsylvania | |
| Research Site | |
| Philadelphia, Pennsylvania, United States, 19104 | |
| United States, South Carolina | |
| Research Site | |
| Charleston, South Carolina, United States, 29425 | |
| United States, Texas | |
| Research Site | |
| Dallas, Texas, United States, 75390 | |
| United States, Washington | |
| Research Site | |
| Renton, Washington, United States, 98055 | |
Sponsors and Collaborators
Biogen
Investigators
| Study Director: | Medical Director | Biogen |
Study Documents (Full-Text)
Documents provided by Biogen:
Documents provided by Biogen:
Study Protocol [PDF] May 30, 2018
Statistical Analysis Plan [PDF] February 7, 2020
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Biogen |
| ClinicalTrials.gov Identifier: | NCT03283371 |
| Other Study ID Numbers: |
101EP201 2017-001995-45 ( EudraCT Number ) |
| First Posted: | September 14, 2017 Key Record Dates |
| Results First Posted: | April 27, 2021 |
| Last Update Posted: | December 14, 2021 |
| Last Verified: | November 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Biogen:
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Drug Resistant Focal Epilepsy, Natalizumab, Seizure |
Additional relevant MeSH terms:
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Epilepsy Seizures Epilepsies, Partial Brain Diseases Central Nervous System Diseases |
Nervous System Diseases Neurologic Manifestations Natalizumab Immunologic Factors Physiological Effects of Drugs |