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

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ClinicalTrials.gov Identifier: NCT03283371
Recruitment Status : Completed
First Posted : September 14, 2017
Results First Posted : April 27, 2021
Last Update Posted : April 27, 2021
Sponsor:
Information provided by (Responsible Party):
Biogen

Tracking Information
First Submitted Date  ICMJE September 12, 2017
First Posted Date  ICMJE September 14, 2017
Results First Submitted Date  ICMJE December 24, 2020
Results First Posted Date  ICMJE April 27, 2021
Last Update Posted Date April 27, 2021
Actual Study Start Date  ICMJE March 20, 2018
Actual Primary Completion Date January 10, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 9, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 12, 2017)
Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment [ Time Frame: Week 8 to Week 24 ]
Seizures included in efficacy analyses are focal aware seizures (previously termed "simple partial seizures") with motor signs, focal impaired awareness seizures (previously termed "complex partial seizures"), and focal to bilateral tonic-clonic seizures (previously termed "partial onset with secondary generalization"). Focal aware seizures without motor signs will not be included. Seizure clusters (where individual seizures cannot be distinguished) will be counted as 1 seizure per cluster on each day that they are present.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 9, 2021)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 12, 2017)
  • Percentage of Responders [ Time Frame: Week 8 to Week 24 ]
    Responders were defined as participants with a ≥50% reduction from Baseline in seizure frequency (number of seizures per 28 days) during Weeks 8 to 24 of treatment.
  • Percentage of Participants Free from Seizures [ Time Frame: Week 8 to Week 24 ]
    Proportion of subjects free from seizures during Weeks 8 to 24 of treatment.
  • Percentage of Seizure-Free Days Gained [ Time Frame: Week 8 to Week 24 ]
    Seizure free days gained will be standardized over 28 days during weeks 8 to 24 of treatment compared with baseline.
  • Percentage of Participants with Inadequate Treatment Response [ Time Frame: Week 8 to Week 24 ]
    Inadequate treatment response will be defined as either modification of anti-epileptic drugs (AEDs) after Week 12 of the placebo-controlled phase due to lack of improvement or ongoing seizures or discontinuation of study treatment after the 8-week active run-in period due to lack of efficacy.
Current Other Pre-specified Outcome Measures
 (submitted: March 9, 2021)
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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: Up to Week 60 ]
  • Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score [ Time Frame: Up to Week 60 ]
    C-SSRS is a prospective assessment tool to evaluate suicidal ideation and behavior. C-SSRS score for suicidal ideation and behavior ranges from 0 to 10, where 0=No any suicidal ideation/behavior; 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; 6=Preparatory Acts or Behavior, 7=Aborted Attempt, 8=Interrupted Attempt, 9=Actual Attempt (nonfatal), 10=Completed Suicide.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 2 Efficacy, Safety, and Tolerability Study of Natalizumab in Focal Epilepsy
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Epilepsy, Focal Seizures, Partial Seizures
Intervention  ICMJE
  • Drug: Natalizumab
    As specified in the treatment arm.
    Other Name: Tysabri
  • Other: Placebo
    As specified in treatment arms.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Natalizumab
  • 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.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 22, 2020)
67
Original Estimated Enrollment  ICMJE
 (submitted: September 12, 2017)
70
Actual Study Completion Date  ICMJE November 18, 2020
Actual Primary Completion Date January 10, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03283371
Other Study ID Numbers  ICMJE 101EP201
2017-001995-45 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP