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NCT03283371: OPUS

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

Completed Phase 2 Results posted Last updated 14 December 2021
What this trial tests

Phase 2 trial testing Natalizumab in Epilepsy, Focal Seizures, Partial Seizures in 67 participants. Completed in 18 November 2020.

Timeline
20 March 2018
Primary endpoint
11 January 2020
18 November 2020

Quick facts

Lead sponsorBiogen
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingtriple
Primary purposetreatment
Enrollment67
Start date20 March 2018
Primary completion11 January 2020
Estimated completion18 November 2020
Sites31 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Biogen — full company profile →

Who can join

Adults 18 to 75, any sex, with Epilepsy, Focal Seizures, Partial Seizures. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in Log-Transformed Seizure Frequency During Weeks 8 to 24 of Treatment Primary · 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

GroupValue95% CI
Placebo (Placebo-controlled Phase)-0.43± 0.162
Natalizumab 300 mg (Placebo-controlled Phase)-0.58± 0.165
Percentage of Responders During Weeks 8 to 24 of Treatment Secondary · 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 consi

GroupValue95% CI
Placebo (Placebo-controlled Phase)17.6
Natalizumab 300 mg (Placebo-controlled Phase)31.3
Number of Participants Free From Seizures During Weeks 8 to 24 of Treatment Secondary · 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.

GroupValue95% CI
Placebo (Placebo-controlled Phase)1
Natalizumab 300 mg (Placebo-controlled Phase)0
Percent Change From Baseline of Seizure-Free Days Change During Weeks 8 to 24 of Treatment Secondary · 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.

Baseline
GroupValue95% CI
Placebo (Placebo-controlled Phase)16.23± 7.347
Natalizumab 300 mg (Placebo-controlled Phase)17.54± 7.223
Week 8
GroupValue95% CI
Placebo (Placebo-controlled Phase)4.33± 50.740
Natalizumab 300 mg (Placebo-controlled Phase)39.23± 130.988
Week 12
GroupValue95% CI
Placebo (Placebo-controlled Phase)2.41± 52.613
Natalizumab 300 mg (Placebo-controlled Phase)32.59± 104.775
Week 16
GroupValue95% CI
Placebo (Placebo-controlled Phase)-0.40± 43.380
Natalizumab 300 mg (Placebo-controlled Phase)44.04± 153.714
Week 20
GroupValue95% CI
Placebo (Placebo-controlled Phase)18.48± 101.318
Natalizumab 300 mg (Placebo-controlled Phase)40.44± 144.768
Week 24
GroupValue95% CI
Placebo (Placebo-controlled Phase)4.27± 47.125
Natalizumab 300 mg (Placebo-controlled Phase)33.92± 114.436
Percentage of Participants With Inadequate Treatment Response During Weeks 8 to 24 of Treatment Secondary · 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.

GroupValue95% CI
Placebo (Placebo-controlled Phase)6
Natalizumab 300 mg (Placebo-controlled Phase)3
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Secondary · 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 participa

AEs
GroupValue95% CI
Placebo (Placebo-controlled Phase)22
Natalizumab 300 mg (Placebo-controlled Phase)24
Placebo to Natalizumab 300 mg (Open-label Phase)20
Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)17
SAEs
GroupValue95% CI
Placebo (Placebo-controlled Phase)1
Natalizumab 300 mg (Placebo-controlled Phase)1
Placebo to Natalizumab 300 mg (Open-label Phase)3
Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)2
Number of Participants With Clinically Significant Laboratory Abnormalities Secondary · 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.

GroupValue95% CI
Placebo (Placebo-controlled Phase)0
Natalizumab 300 mg (Placebo-controlled Phase)0
Placebo to Natalizumab 300 mg (Open-label Phase)0
Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)0
Number of Participants With Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) or C-SSRS Score Secondary · 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

Baseline: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo (Placebo-controlled Phase)0
Natalizumab 300 mg (Placebo-controlled Phase)1
Placebo to Natalizumab 300 mg (Open-label Phase)1
Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)1
Week 4: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo (Placebo-controlled Phase)0
Natalizumab 300 mg (Placebo-controlled Phase)0
Week 8: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo (Placebo-controlled Phase)0
Natalizumab 300 mg (Placebo-controlled Phase)0
Week 12: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo (Placebo-controlled Phase)0
Natalizumab 300 mg (Placebo-controlled Phase)1
Week 16: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo (Placebo-controlled Phase)0
Natalizumab 300 mg (Placebo-controlled Phase)3
Week 20: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo (Placebo-controlled Phase)1
Natalizumab 300 mg (Placebo-controlled Phase)2
Week 24: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo (Placebo-controlled Phase)1
Natalizumab 300 mg (Placebo-controlled Phase)2
Week 28: Suicidal Ideation or Behavior (1-10)
GroupValue95% CI
Placebo to Natalizumab 300 mg (Open-label Phase)3
Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)2

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose up to 24 weeks after the last dose of study treatment (up to Week 68). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo (Placebo-controlled Phase)
Serious: 1/34 (3%)
Deaths: 0/34
Natalizumab 300 mg (Placebo- Controlled Phase)
Serious: 1/32 (3%)
Deaths: 0/32
Placebo to Natalizumab 300 mg (Open-label Phase)
Serious: 3/31 (10%)
Deaths: 0/31
Natalizumab 300 mg to Natalizumab 300 mg (Open-label Phase)
Serious: 2/30 (7%)
Deaths: 0/30

Serious adverse events (5 terms)

ReactionSystemPlacebo (Placebo-controlle…Natalizumab 300 mg (Placeb…Placebo to Natalizumab 300…Natalizumab 300 mg to Nata…
SeizureNervous system disorders
Seizure clusterNervous system disorders
Large intestine perforationGastrointestinal disorders
COVID-19Infections and infestations
Pneumonia aspirationRespiratory, thoracic and mediastinal disorders
Other adverse events (25 terms — click to expand)

ReactionSystemPlacebo (Placebo-controlle…Natalizumab 300 mg (Placeb…Placebo to Natalizumab 300…Natalizumab 300 mg to Nata…
HeadacheNervous system disorders
DizzinessNervous system disorders
FallInjury, poisoning and procedural complications
NauseaGastrointestinal disorders
Back painMusculoskeletal and connective tissue disorders
SomnolenceNervous system disorders
FlushingVascular disorders
Chest discomfortGeneral disorders
AnaemiaBlood and lymphatic system disorders
Vision blurredEye disorders
VomitingGastrointestinal disorders
FatigueGeneral disorders
InfluenzaInfections and infestations
ContusionInjury, poisoning and procedural complications
ArthralgiaMusculoskeletal and connective tissue disorders
AmnesiaNervous system disorders
SyncopeNervous system disorders
InsomniaPsychiatric disorders
Dental cariesGastrointestinal disorders
Urinary tract infectionInfections and infestations
NasopharyngitisInfections and infestations
Skin lacerationInjury, poisoning and procedural complications
HyperglycaemiaMetabolism and nutrition disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
HypertensionVascular disorders

Most-reported serious reactions: Seizure, Seizure cluster, Large intestine perforation, COVID-19, Pneumonia aspiration.

Data from ClinicalTrials.gov NCT03283371 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Epileptic seizures.
    Anwar H, Khan QU, Nadeem N, Pervaiz I, et al · · 2020 · cited 83× · PMID 32577498 · DOI 10.15190/d.2020.7
  2. The neurovasculature as a target in temporal lobe epilepsy.
    Reiss Y, Bauer S, David B, Devraj K, et al · · 2023 · cited 36× · PMID 36599709 · DOI 10.1111/bpa.13147
  3. Targeting Inflammatory Mediators in Epilepsy: A Systematic Review of Its Molecular Basis and Clinical Applications.
    Costagliola G, Depietri G, Michev A, Riva A, et al · · 2022 · cited 36× · PMID 35359659 · DOI 10.3389/fneur.2022.741244
  4. Safety and Efficacy of Natalizumab as Adjunctive Therapy for People With Drug-Resistant Epilepsy: A Phase 2 Study.
    French JA, Cole AJ, Faught E, Theodore WH, et al · · 2021 · cited 18× · PMID 34521687 · DOI 10.1212/wnl.0000000000012766
  5. Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy.
    Boleti APA, Cardoso PHO, Frihling BEF, de Moraes LFRN, et al · · 2024 · cited 14× · PMID 38248286 · DOI 10.3390/brainsci14010071
  6. Immune Mechanism of Epileptogenesis and Related Therapeutic Strategies.
    Aguilar-Castillo MJ, Cabezudo-García P, Ciano-Petersen NL, García-Martin G, et al · · 2022 · cited 11× · PMID 35327518 · DOI 10.3390/biomedicines10030716
  7. Use of an electronic seizure diary in a randomized, controlled trial of natalizumab in adult participants with drug-resistant focal epilepsy.
    Patel J, Feng W, Chen K, French JA, et al · · 2021 · cited 8× · PMID 33831649 · DOI 10.1016/j.yebeh.2021.107925
  8. Immunomodulatory interventions for focal epilepsy.
    Panebianco M, Walker L, Marson AG. · · 2023 · cited 1× · PMID 37842826 · DOI 10.1002/14651858.cd009945.pub3

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