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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Epilepsy, Focal Seizures, Partial Seizures
Interventions Drug: Natalizumab
Other: Placebo
Enrollment 67
Recruitment Details Participants were enrolled at 31 investigational sites in United States from 20 March 2018 to 18 Nov 2020. Only primary results, the time point at which all participants completed their Week 24/early termination visit in the Placebo-controlled Phase is reported.
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.
Arm/Group Title Placebo (Placebo-controlled Phase) Natalizumab 300 mg (Placebo-controlled Phase)
Hide 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.
Period Title: Overall Study
Started 34 33
Number of Participants Dosed 34 32
Completed [1] 31 30
Not Completed 3 3
Reason Not Completed
Adverse Event             1             1
Lack of Efficacy             1             0
Withdrawal by Subject             1             1
Participants Did Not Receive Study Drug             0             1
[1]
Completed = Participants who completed the Placebo-controlled Phase and were eligible to receive natalizumab in the Open-label Phase.
Arm/Group Title Placebo (Placebo-controlled Phase) Natalizumab 300 mg (Placebo-controlled Phase) Total
Hide 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 Number of Baseline Participants 34 32 66
Hide Baseline Analysis Population Description
The Intent to Treat (ITT) population is defined as all participants who were randomized and received any dose of study treatment. Ethnicity was not collected in this study.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 34 participants 32 participants 66 participants
39.1  (12.17) 42.8  (14.56) 40.9  (13.41)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 32 participants 66 participants
Female
16
  47.1%
14
  43.8%
30
  45.5%
Male
18
  52.9%
18
  56.3%
36
  54.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 32 participants 66 participants
American Indian or Alaska Native
1
   2.9%
0
   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%
0
   0.0%
Unknown or Not Reported
1
   2.9%
0
   0.0%
1
   1.5%
1.Primary Outcome
Title Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 34 32
Least Squares Mean (Standard Error)
Unit of Measure: log(seizure/28 days)
-0.43  (0.162) -0.58  (0.165)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.5053
Comments [Not Specified]
Method Mixed Model for Repeated Measures (MMRM)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean logarithmic difference
Estimated Value -0.16
Confidence Interval (2-Sided) 95%
-0.62 to 0.31
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Responders During Weeks 8 to 24 of Treatment
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 34 32
Measure Type: Number
Unit of Measure: percentage of responders
17.6 31.3
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.2231
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.09
Confidence Interval (2-Sided) 95%
0.64 to 6.85
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants Free From Seizures During Weeks 8 to 24 of Treatment
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 34 31
Measure Type: Count of Participants
Unit of Measure: Participants
1
   2.9%
0
   0.0%
4.Secondary Outcome
Title Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 34 32
Mean (Standard Deviation)
Unit of Measure: percent change
Baseline Number Analyzed 34 participants 32 participants
16.23  (7.347) 17.54  (7.223)
Week 8 Number Analyzed 31 participants 30 participants
4.33  (50.740) 39.23  (130.988)
Week 12 Number Analyzed 31 participants 30 participants
2.41  (52.613) 32.59  (104.775)
Week 16 Number Analyzed 30 participants 30 participants
-0.40  (43.380) 44.04  (153.714)
Week 20 Number Analyzed 30 participants 30 participants
18.48  (101.318) 40.44  (144.768)
Week 24 Number Analyzed 29 participants 30 participants
4.27  (47.125) 31.23  (113.404)
5.Secondary Outcome
Title Percentage of Participants With Inadequate Treatment Response During Weeks 8 to 24 of Treatment
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 34 32
Measure Type: Number
Unit of Measure: percentage of participants
6 3
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.6854
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.10 to 4.57
Estimation Comments [Not Specified]
6.Other Pre-specified Outcome
Title Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide 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 Up to Week 68
Outcome Measure Data Not Reported
7.Other Pre-specified Outcome
Title Number of Participants With Clinically Significant Laboratory Abnormalities
Hide Description [Not Specified]
Time Frame Up to Week 60
Outcome Measure Data Not Reported
8.Other Pre-specified Outcome
Title Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score
Hide Description 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.
Time Frame Up to Week 60
Outcome Measure Data Not Reported
Time Frame Up to 24 Weeks
Adverse Event Reporting Description Safety population included 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)
Hide 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.
All-Cause Mortality
Placebo (Placebo-controlled Phase) Natalizumab 300 mg (Placebo- Controlled Phase)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/34 (0.00%)   0/32 (0.00%) 
Hide Serious Adverse Events
Placebo (Placebo-controlled Phase) Natalizumab 300 mg (Placebo- Controlled Phase)
Affected / at Risk (%) Affected / at Risk (%)
Total   1/34 (2.94%)   1/32 (3.13%) 
Nervous system disorders     
Seizure  1  1/34 (2.94%)  1/32 (3.13%) 
1
Term from vocabulary, MedDRA 22.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo (Placebo-controlled Phase) Natalizumab 300 mg (Placebo- Controlled Phase)
Affected / at Risk (%) Affected / at Risk (%)
Total   15/34 (44.12%)   17/32 (53.13%) 
Blood and lymphatic system disorders     
Anaemia  1  0/34 (0.00%)  2/32 (6.25%) 
Eye disorders     
Vision blurred  1  1/34 (2.94%)  2/32 (6.25%) 
Gastrointestinal disorders     
Nausea  1  1/34 (2.94%)  3/32 (9.38%) 
Vomiting  1  1/34 (2.94%)  2/32 (6.25%) 
General disorders     
Fatigue  1  2/34 (5.88%)  1/32 (3.13%) 
Infections and infestations     
Influenza  1  2/34 (5.88%)  0/32 (0.00%) 
Injury, poisoning and procedural complications     
Contusion  1  1/34 (2.94%)  2/32 (6.25%) 
Fall  1  2/34 (5.88%)  4/32 (12.50%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  2/34 (5.88%)  2/32 (6.25%) 
Back pain  1  3/34 (8.82%)  2/32 (6.25%) 
Nervous system disorders     
Amnesia  1  2/34 (5.88%)  0/32 (0.00%) 
Dizziness  1  1/34 (2.94%)  5/32 (15.63%) 
Headache  1  5/34 (14.71%)  6/32 (18.75%) 
Somnolence  1  3/34 (8.82%)  0/32 (0.00%) 
Syncope  1  2/34 (5.88%)  0/32 (0.00%) 
Psychiatric disorders     
Insomnia  1  2/34 (5.88%)  0/32 (0.00%) 
Vascular disorders     
Flushing  1  3/34 (8.82%)  0/32 (0.00%) 
1
Term from vocabulary, MedDRA 22.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: US Biogen Clinical Trial Center
Organization: Biogen
Phone: 866-633-4636
EMail: clinicaltrials@biogen.com
Layout table for additonal information
Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT03283371    
Other Study ID Numbers: 101EP201
2017-001995-45 ( EudraCT Number )
First Submitted: September 12, 2017
First Posted: September 14, 2017
Results First Submitted: December 24, 2020
Results First Posted: April 27, 2021
Last Update Posted: April 27, 2021