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

• Sponsor: Biogen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03283371
• Collaborator: (none)
• Enrollment: 67
• Locations: 31
• Arms: 2
• Actual Duration (Months): 32
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy, Focal Seizures, Partial Seizures	Drug: Natalizumab; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional
• 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.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: Mar 20, 2018
• Actual Primary Completion Date: Jan 11, 2020
• Actual Study Completion Date: Nov 18, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35294
2	Research Site	Phoenix	Arizona	United States	85004
3	Research Site	Phoenix	Arizona	United States	85054
4	Research Site	San Diego	California	United States	92103
5	Research Site	Santa Monica	California	United States	90404
6	Research Site	Washington	District of Columbia	United States	20037
7	Research Site	Jacksonville	Florida	United States	32209
8	Research Site	Maitland	Florida	United States	32751
9	Research Site	Orlando	Florida	United States	32803
10	Research Site	Tallahassee	Florida	United States	32308
11	Research Site	Tampa	Florida	United States	33606
12	Research Site	Honolulu	Hawaii	United States	96817
13	Research Site	Chicago	Illinois	United States	60612
14	Research Site	Bethesda	Maryland	United States	20817
15	Research Site	Chevy Chase	Maryland	United States	20815
16	Research Site	Boston	Massachusetts	United States	02111
17	Research Site	Boston	Massachusetts	United States	02115
18	Research Site	Saginaw	Michigan	United States	48602
19	Research Site	Saint Louis	Missouri	United States	63110
20	Research Site	Camden	New Jersey	United States	08103
21	Research Site	Bronx	New York	United States	10467
22	Research Site	Rochester	New York	United States	14642
23	Research Site	Syracuse	New York	United States	13210
24	Research Site	Asheville	North Carolina	United States	28806
25	Research Site	Chapel Hill	North Carolina	United States	27514
26	Research Site	Durham	North Carolina	United States	27705
27	Research Site	Akron	Ohio	United States	44320
28	Research Site	Philadelphia	Pennsylvania	United States	19104
29	Research Site	Charleston	South Carolina	United States	29425
30	Research Site	Dallas	Texas	United States	75390
31	Research Site	Renton	Washington	United States	98055

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

• Study Protocol - May 30, 2018
• Statistical Analysis Plan - Feb 7, 2020

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT03283371
• Other Study ID Numbers: 101EP201; 2017-001995-45
• First Posted: Sep 14, 2017
• Last Update Posted: Dec 14, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Biogen: Drug Resistant Focal Epilepsy, Natalizumab, Seizure
• Additional relevant MeSH terms: Epilepsy; Seizures; Epilepsies, Partial; Natalizumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 31 investigational sites in United States from 20 March 2018 to 18 Nov 2020.
Pre-assignment Detail	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.

Arm/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)	Placebo to Natalizumab 300 mg (Open-label Phase)	Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
Arm/Group Description	Participants received natalizumab-matching placebo intravenous (IV) infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants who received natalizumab-matching placebo in Placebo-controlled Phase, received natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.	Participants who received natalizumab 300 mg in Placebo-controlled Phase, continued to receive natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.
Period Title: Placebo-controlled
STARTED	34	33	0	0
Number of Participants Dosed	34	32	0	0
COMPLETED	31	30	0	0
NOT COMPLETED	3	3	0	0
Period Title: Placebo-controlled
STARTED	0	0	31	30
COMPLETED	0	0	27	29
NOT COMPLETED	0	0	4	1

Baseline Characteristics

Arm/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)	Total
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Total of all reporting groups
Overall Participants	34	32	66
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.1 (12.17)	42.8 (14.56)	40.9 (13.41)
Sex: Female, Male (Count of Participants)
Female	16 47.1%	14 43.8%	30 45.5%
Male	18 52.9%	18 56.3%	36 54.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.9%	0 0%	1 1.5%
Asian	2 5.9%	1 3.1%	3 4.5%
Native Hawaiian or Other Pacific Islander	3 8.8%	1 3.1%	4 6.1%
Black or African American	8 23.5%	7 21.9%	15 22.7%
White	19 55.9%	23 71.9%	42 63.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.9%	0 0%	1 1.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT population is defined as all participants who were randomized and received any dose of study treatment.

Arm/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.
Measure Participants	34	32
Least Squares Mean (Standard Error) [log(seizure/28 days)]	-0.43 (0.162)	-0.58 (0.165)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Placebo-controlled Phase), Natalizumab 300 mg (Placebo-controlled Phase)
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5053
	Comments
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	LS Mean logarithmic difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.62 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The ITT population is defined as all participants who were randomized and received any dose of study treatment.

Arm/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.
Measure Participants	34	32
Number [percentage of responders]	17.6	31.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Placebo-controlled Phase), Natalizumab 300 mg (Placebo-controlled Phase)
	Comments	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).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2231
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.09
	Confidence Interval	(2-Sided) 95%; 0.64 to 6.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.
Measure Participants	34	31
Count of Participants [Participants]	1 2.9%	0 0%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.
Measure Participants	34	32
Baseline	16.23 (7.347)	17.54 (7.223)
Week 8	4.33 (50.740)	39.23 (130.988)
Week 12	2.41 (52.613)	32.59 (104.775)
Week 16	-0.40 (43.380)	44.04 (153.714)
Week 20	18.48 (101.318)	40.44 (144.768)
Week 24	4.27 (47.125)	33.92 (114.436)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The ITT population is defined as all participants who were randomized and received any dose of study treatment.

Arm/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.
Measure Participants	34	32
Number [percentage of participants]	6 17.6%	3 9.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Placebo-controlled Phase), Natalizumab 300 mg (Placebo-controlled Phase)
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6854
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.10 to 4.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)	Placebo to Natalizumab 300 mg (Open-label Phase)	Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants who received natalizumab-matching placebo in Placebo-controlled Phase, received natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.	Participants who received natalizumab 300 mg in Placebo-controlled Phase, continued to receive natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.
Measure Participants	34	32	31	30
AEs	22 64.7%	24 75%	20 30.3%	17 NaN
SAEs	1 2.9%	1 3.1%	3 4.5%	2 NaN

7. Other Pre-specified Outcome

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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)	Placebo to Natalizumab 300 mg (Open-label Phase)	Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants who received natalizumab-matching placebo in Placebo-controlled Phase, received natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.	Participants who received natalizumab 300 mg in Placebo-controlled Phase, continued to receive natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.
Measure Participants	34	32	31	30
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 NaN

8. Other Pre-specified Outcome

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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo (Placebo-controlled Phase)	Natalizumab 300 mg (Placebo-controlled Phase)	Placebo to Natalizumab 300 mg (Open-label Phase)	Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.	Participants who received natalizumab-matching placebo in Placebo-controlled Phase, received natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.	Participants who received natalizumab 300 mg in Placebo-controlled Phase, continued to receive natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.
Measure Participants	34	32	31	30
Baseline: Suicidal Ideation or Behavior (1-10)	0 0%	1 3.1%	1 1.5%	1 NaN
Week 4: Suicidal Ideation or Behavior (1-10)	0 0%	0 0%
Week 8: Suicidal Ideation or Behavior (1-10)	0 0%	0 0%
Week 12: Suicidal Ideation or Behavior (1-10)	0 0%	1 3.1%
Week 16: Suicidal Ideation or Behavior (1-10)	0 0%	3 9.4%
Week 20: Suicidal Ideation or Behavior (1-10)	1 2.9%	2 6.3%
Week 24: Suicidal Ideation or Behavior (1-10)	1 2.9%	2 6.3%
Week 28: Suicidal Ideation or Behavior (1-10)	3 8.8%	2 6.3%
Week 32: Suicidal Ideation or Behavior (1-10)	1 2.9%	2 6.3%
Week 36: Suicidal Ideation or Behavior (1-10)	1 2.9%	1 3.1%
Week 40: Suicidal Ideation or Behavior (1-10)	1 2.9%	2 6.3%
Week 44: Suicidal Ideation or Behavior (1-10)	1 2.9%	2 6.3%
Week 48: Suicidal Ideation or Behavior (1-10)	1 2.9%	2 6.3%
Week 60/End of Study (EOS): Suicidal Ideation or Behavior (1-10)	0 0%	2 6.3%

Adverse Events

Time Frame	From first dose up to 24 weeks after the last dose of study treatment (up to Week 68)
Adverse Event Reporting Description	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/Group Title	Placebo (Placebo-controlled Phase)		Natalizumab 300 mg (Placebo- Controlled Phase)		Placebo to Natalizumab 300 mg (Open-label Phase)		Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
Arm/Group Description	Participants received natalizumab-matching placebo IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.		Participants received natalizumab 300 mg IV infusion every 4 weeks in Placebo-controlled Phase for up to Week 24.		Participants who received natalizumab-matching placebo in Placebo-controlled Phase, received natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.		Participants who received natalizumab 300 mg in Placebo-controlled Phase, continued to receive natalizumab 300 mg IV infusion every 4 weeks in Open-label Phase for up to Week 48.
All Cause Mortality
	Placebo (Placebo-controlled Phase)		Natalizumab 300 mg (Placebo- Controlled Phase)		Placebo to Natalizumab 300 mg (Open-label Phase)		Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/32 (0%)		0/31 (0%)		0/30 (0%)
Serious Adverse Events
	Placebo (Placebo-controlled Phase)		Natalizumab 300 mg (Placebo- Controlled Phase)		Placebo to Natalizumab 300 mg (Open-label Phase)		Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)		1/32 (3.1%)		3/31 (9.7%)		2/30 (6.7%)
Gastrointestinal disorders
Large intestine perforation	0/34 (0%)		0/32 (0%)		0/31 (0%)		1/30 (3.3%)
Infections and infestations
COVID-19	0/34 (0%)		0/32 (0%)		1/31 (3.2%)		0/30 (0%)
Nervous system disorders
Seizure	1/34 (2.9%)		1/32 (3.1%)		1/31 (3.2%)		1/30 (3.3%)
Seizure cluster	0/34 (0%)		0/32 (0%)		1/31 (3.2%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	0/34 (0%)		0/32 (0%)		0/31 (0%)		1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Placebo (Placebo-controlled Phase)		Natalizumab 300 mg (Placebo- Controlled Phase)		Placebo to Natalizumab 300 mg (Open-label Phase)		Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/34 (44.1%)		17/32 (53.1%)		13/31 (41.9%)		9/30 (30%)
Blood and lymphatic system disorders
Anaemia	0/34 (0%)		2/32 (6.3%)		0/31 (0%)		0/30 (0%)
Eye disorders
Vision blurred	1/34 (2.9%)		2/32 (6.3%)		0/31 (0%)		0/30 (0%)
Gastrointestinal disorders
Nausea	1/34 (2.9%)		3/32 (9.4%)		0/31 (0%)		2/30 (6.7%)
Vomiting	1/34 (2.9%)		2/32 (6.3%)		0/31 (0%)		0/30 (0%)
Dental caries	0/34 (0%)		0/32 (0%)		0/31 (0%)		2/30 (6.7%)
General disorders
Fatigue	2/34 (5.9%)		1/32 (3.1%)		0/31 (0%)		0/30 (0%)
Chest discomfort	0/34 (0%)		0/32 (0%)		3/31 (9.7%)		0/30 (0%)
Infections and infestations
Influenza	2/34 (5.9%)		0/32 (0%)		0/31 (0%)		0/30 (0%)
Urinary tract infection	0/34 (0%)		0/32 (0%)		1/31 (3.2%)		2/30 (6.7%)
Nasopharyngitis	0/34 (0%)		0/32 (0%)		2/31 (6.5%)		0/30 (0%)
Injury, poisoning and procedural complications
Contusion	1/34 (2.9%)		2/32 (6.3%)		0/31 (0%)		0/30 (0%)
Fall	2/34 (5.9%)		4/32 (12.5%)		2/31 (6.5%)		3/30 (10%)
Skin laceration	0/34 (0%)		0/32 (0%)		2/31 (6.5%)		1/30 (3.3%)
Metabolism and nutrition disorders
Hyperglycaemia	0/34 (0%)		0/32 (0%)		2/31 (6.5%)		0/30 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/34 (5.9%)		2/32 (6.3%)		1/31 (3.2%)		2/30 (6.7%)
Back pain	3/34 (8.8%)		2/32 (6.3%)		0/31 (0%)		1/30 (3.3%)
Muscle spasms	0/34 (0%)		0/32 (0%)		2/31 (6.5%)		0/30 (0%)
Nervous system disorders
Amnesia	2/34 (5.9%)		0/32 (0%)		0/31 (0%)		0/30 (0%)
Dizziness	1/34 (2.9%)		5/32 (15.6%)		1/31 (3.2%)		2/30 (6.7%)
Headache	5/34 (14.7%)		6/32 (18.8%)		3/31 (9.7%)		3/30 (10%)
Somnolence	3/34 (8.8%)		0/32 (0%)		0/31 (0%)		0/30 (0%)
Syncope	2/34 (5.9%)		0/32 (0%)		0/31 (0%)		0/30 (0%)
Psychiatric disorders
Insomnia	2/34 (5.9%)		0/32 (0%)		0/31 (0%)		0/30 (0%)
Vascular disorders
Flushing	3/34 (8.8%)		0/32 (0%)		0/31 (0%)		0/30 (0%)
Hypertension	0/34 (0%)		0/32 (0%)		2/31 (6.5%)		0/30 (0%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.