Epilepsy, Focal Seizures, Partial Seizures
Conditions
Keywords
Drug Resistant Focal Epilepsy, Natalizumab, Seizure
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.
Interventions
DRUGNatalizumab
As specified in the treatment arm.
OTHERPlacebo
As specified in treatment arms.
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Double-blind
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Free From Seizures During Weeks 8 to 24 of Treatment | 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. |
| Percentage of Responders During Weeks 8 to 24 of Treatment | 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. |
| Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | 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. |
| Number of Participants With Clinically Significant Laboratory Abnormalities | 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 Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 31 investigational sites in United States from 20 March 2018 to 18 Nov 2020.
Pre-assignment details
A total 67 participants with drug-resistant focal epilepsy were enrolled and randomized in this study. Of which, 66 participants received at least one dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Placebo-controlled Phase) Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24. | 34 |
| Natalizumab 300 mg (Placebo-controlled Phase) Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24. | 32 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open-label Phase | Adverse Event | 0 | 0 | 2 | 0 |
| Open-label Phase | Other | 0 | 0 | 1 | 1 |
| Open-label Phase | Withdrawal by Subject | 0 | 0 | 1 | 0 |
| Placebo-controlled | Adverse Event | 1 | 1 | 0 | 0 |
| Placebo-controlled | Lack of Efficacy | 1 | 0 | 0 | 0 |
| Placebo-controlled | Participants Did Not Receive Study Drug | 0 | 1 | 0 | 0 |
| Placebo-controlled | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo (Placebo-controlled Phase) | Natalizumab 300 mg (Placebo-controlled Phase) | Total |
|---|---|---|---|
| Age, Continuous | 39.1 years STANDARD_DEVIATION 12.17 | 42.8 years STANDARD_DEVIATION 14.56 | 40.9 years STANDARD_DEVIATION 13.41 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 7 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 19 Participants | 23 Participants | 42 Participants |
| Sex: Female, Male Female | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 32 | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 15 / 34 | 17 / 32 | 13 / 31 | 9 / 30 |
| serious Total, serious adverse events | 1 / 34 | 1 / 32 | 3 / 31 | 2 / 30 |
Outcome results
Primary
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.
Time frame: Baseline, Week 8 to Week 24
Population: ITT population is defined as all participants who were randomized and received any dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Placebo-controlled Phase) | Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment | -0.43 log(seizure/28 days) | Standard Error 0.162 |
| Natalizumab 300 mg (Placebo-controlled Phase) | Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment | -0.58 log(seizure/28 days) | Standard Error 0.165 |
Comparison: Analysis is based on MMRM and adjusted for natural log-transformed baseline seizure frequency, high seizure frequency category (\>=24 seizures and \<24 seizures), structural etiology category (yes and no), visit, treatment and treatment by visit interaction. An unstructured variance-covariance matrix is used in the model.p-value: 0.505395% CI: [-0.62, 0.31]Mixed Model for Repeated Measures (MMRM)
Secondary
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.
Time frame: Week 8 to Week 24
Population: The ITT population is defined as all participants who were randomized and received any dose of study treatment. Here, number of participants analyzed signifies number of participants who were analyzed in this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Placebo-controlled Phase) | Number of Participants Free From Seizures During Weeks 8 to 24 of Treatment | 1 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants Free From Seizures During Weeks 8 to 24 of Treatment | 0 Participants |
Secondary
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.
Time frame: Week 8 to Week 24
Population: The ITT population is defined as all participants who were randomized and received any dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Placebo-controlled Phase) | Percentage of Participants With Inadequate Treatment Response During Weeks 8 to 24 of Treatment | 6 percentage of participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percentage of Participants With Inadequate Treatment Response During Weeks 8 to 24 of Treatment | 3 percentage of participants |
Comparison: Based on the logistic regression model with a term for treatment group and with adjustment for log-transformed baseline seizure frequency, high seizure frequency category (\>=24 seizures and \<24 seizures) and structural etiology category (yes and no) are considered as covariates.p-value: 0.685495% CI: [0.1, 4.57]Regression, Logistic
Secondary
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.
Time frame: Week 8 to Week 24
Population: The ITT population is defined as all participants who were randomized and received any dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Placebo-controlled Phase) | Percentage of Responders During Weeks 8 to 24 of Treatment | 17.6 percentage of responders |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percentage of Responders During Weeks 8 to 24 of Treatment | 31.3 percentage of responders |
Comparison: Based on logistic regression with a term for treatment group and with adjustment for natural log-transformed baseline seizure frequency, high seizure frequency category (\>=24 seizures and \<24 seizures) and structural etiology category (yes and no).p-value: 0.223195% CI: [0.64, 6.85]Regression, Logistic
Secondary
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.
Time frame: Baseline, Week 8, Week 12, Week 16, Week 20, Week 24
Population: ITT population is defined as all participants who were randomized and received any dose of study treatment. Here, number analyzed signifies number of participants analyzed at specific timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Baseline | 16.23 percent change | Standard Deviation 7.347 |
| Placebo (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 8 | 4.33 percent change | Standard Deviation 50.74 |
| Placebo (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 12 | 2.41 percent change | Standard Deviation 52.613 |
| Placebo (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 16 | -0.40 percent change | Standard Deviation 43.38 |
| Placebo (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 20 | 18.48 percent change | Standard Deviation 101.318 |
| Placebo (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 24 | 4.27 percent change | Standard Deviation 47.125 |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 20 | 40.44 percent change | Standard Deviation 144.768 |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Baseline | 17.54 percent change | Standard Deviation 7.223 |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 16 | 44.04 percent change | Standard Deviation 153.714 |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 8 | 39.23 percent change | Standard Deviation 130.988 |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 24 | 33.92 percent change | Standard Deviation 114.436 |
| Natalizumab 300 mg (Placebo-controlled Phase) | Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment | Week 12 | 32.59 percent change | Standard Deviation 104.775 |
Other Pre-specified
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.
Time frame: From first dose up to 24 weeks after the last dose of study treatment (up to Week 68)
Population: The safety population is defined as all participants who were randomized and received any dose of study treatment and were used for the analysis of safety data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (Placebo-controlled Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 22 Participants |
| Placebo (Placebo-controlled Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 24 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 20 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 17 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
Other Pre-specified
Number of Participants With Clinically Significant Laboratory Abnormalities
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)
Population: The safety population is defined as all participants who were randomized and received any dose of study treatment and were used for the analysis of safety data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Placebo-controlled Phase) | Number of Participants With Clinically Significant Laboratory Abnormalities | 0 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Clinically Significant Laboratory Abnormalities | 0 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Clinically Significant Laboratory Abnormalities | 0 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Clinically Significant Laboratory Abnormalities | 0 Participants |
Other Pre-specified
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.
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)
Population: The safety population is defined as all participants who were randomized and received any dose of study treatment and were used for the analysis of safety data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 24: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Placebo (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 12: Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Placebo (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 4: Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Placebo (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 16: Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Placebo (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Baseline: Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Placebo (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 20: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Placebo (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 8: Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 24: Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Baseline: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 4: Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 8: Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 12: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 16: Suicidal Ideation or Behavior (1-10) | 3 Participants |
| Natalizumab 300 mg (Placebo-controlled Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 20: Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 40: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 32: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 44: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 28: Suicidal Ideation or Behavior (1-10) | 3 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 48: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 36: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 60/End of Study (EOS): Suicidal Ideation or Behavior (1-10) | 0 Participants |
| Placebo to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Baseline: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 60/End of Study (EOS): Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 28: Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 32: Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 36: Suicidal Ideation or Behavior (1-10) | 1 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 40: Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 44: Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Week 48: Suicidal Ideation or Behavior (1-10) | 2 Participants |
| Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase) | Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score | Baseline: Suicidal Ideation or Behavior (1-10) | 1 Participants |