Leucine-Rich Glioma Inactivated 1 Autoimmune Encephalitis
Conditions
Keywords
Leucine-Rich Glioma Inactivated 1 Autoimmune Encephalitis, Phase 2, Rozanolixizumab
Brief summary
The purpose of the study is to assess the efficacy of rozanolixizumab as measured by seizure freedom, change in cognitive function, use of rescue medication, onset of seizure freedom and to assess safety and tolerability.
Interventions
DRUGRozanolixizumab
* Pharmaceutical form: Solution for infusion * Route of administration: Subcutaneous use Subjects will receive rozanolixizumab in a pre-specified sequence during the Treatment Period.
DRUGPlacebo
* Pharmaceutical form: Solution for infusion * Route of administration: Subcutaneous use Subjects will receive placebo in a pre-specified sequence during the Treatment Period.
Sponsors
UCB Biopharma SRL
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Study participant must be ≥18 to ≤89 years of age * Study participant must be seropositive for leucine-rich glioma inactivated 1 (LGI1) antibody * Study participant must have ≥2 seizures/week during the Screening Period or have experienced such seizures that stopped following high dose corticosteroids (500 to 1000 milligram (mg) methylprednisolone (MP) equivalent/day): * Either faciobrachial dystonic seizures (FBDS) with or without other focal (partial) seizures including focal to bilateral tonic clonic * Or focal (partial) seizures including focal to bilateral tonic clonic and fulfil the following new-onset Autoimmune encephalitis (AIE) criteria * Study participant has initiated or re-initiated corticosteroids at a dose of 500 to 1000 mg MP equivalent/day within 42 days prior to randomization. Participants re-initiating corticosteroids are eligible only if re-initiation is due to seizure rebound and within the timeframe outlined. If the study participant has initiated a steroid taper, the study participant cannot receive an oral steroid dose lower than 40mg/day when randomized * Study participant with onset of disease symptom between 0 to 12 months prior to Screening, per investigator's assessment. * Study participant weighs at least 35 kg at Screening * A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: i) Not a woman of childbearing potential (WOCBP) OR ii) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 90 days after the final dose of study treatment
Exclusion criteria
* Study participant has a known hypersensitivity to any components of the study medication or any other anti-neonatal Fc receptor (FcRn) medications. * Study participant has a confirmed prior diagnosis of epilepsy or new onset seizures that are unrelated to LGI1 autoimmune encephalitis (AIE) or has any known or suspected medical cause for the onset of seizures other than possible AIE * Study participant has a known active neoplastic disease or history of neoplastic disease within 5 years of study entry * Study participant has renal impairment, defined as glomerular filtration rate (GFR) \<30mL/min/1.73m2 at the Screening Visit * Study participant has a clinically important active infection (including unresolved or not adequately treated infection) as assessed by investigator, including participants with a serious infection within 6 weeks prior to the first dose of investigational medicinal product (IMP) * Study participant has a history of chronic ongoing infections * Study participant has current unstable liver or biliary disease, per investigator assessment, defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis * Study participant has positive tuberculosis (TB) test at the Screening Visit * Study participant has a history of solid organ transplant or hematopoietic stem cell transplant * Study participant has undergone a splenectomy * Study participant has a current or medical history of primary immune deficiency * Study participant has received a live vaccination within 4 weeks prior to the Baseline Visit; or intends to have a live vaccination during the course of the study or within 8 weeks following the final dose of investigational medicinal product (IMP) * Study participant has previously received rozanolixizumab drug product * Alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) are \>3x upper limit of normal (ULN) * Study participant has a total IgG level ≤5.5 g/L at the Screening Visit * Study participant has absolute neutrophil count \<1500 cells/mm\^3 at the Screening Visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Seizure Free Study Participants at the End of the Treatment | From Baseline until the end of the Treatment (Week 25) | Seizure freedom was defined as a minimum of 28 consecutive days of no seizures of any type during the treatment and maintained until the end of the treatment (Week 25). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | From Baseline to Week 5, 13, 21 and 25 | The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) consists of 12 subtests that contribute to 5 age-based domain index scores (immediate memory, visuospatial/constructional, language, attention, delayed memory) that were aggregated for a total scale index score. All index scores have an age-based mean of 100, with a standard deviation (SD) of 15. The total scale score was calculated by taking the mean of the sum of the five index scores. Total possible scale index scores range from 40-135. Higher scores reflect better neurocognitive performance. The total scale index score is the score typically used to reflect global neurocognitive status. Baseline of RBANS is defined as the screening (Visit 1, Week -1) value. |
| Percentage of Participants With a Favorable Outcome in the Modified Rankin Scale (mRS) During the Treatment | From Baseline until the end of the Treatment (Week 25) | Percentage of participants with a favorable outcome in mRS during treatment, where favorable outcome defined as no worsening for participants with Baseline mRS score of ≤1 or improvement of ≥1 point for participants with Baseline mRS score of ≥2. The mRS is commonly used scale for measuring degree of disability or dependence in daily activities of people who suffered a stroke or other causes of neurological disability. The scale ranges from 0 (perfect health) to 6 (death). 0-No symptoms at all 1. No significant disability despite symptoms; able to carry out all usual activities 2. Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3. Moderate disability; requiring some help, but able to walk without assistance 4. Moderately severe disability; unable to walk and attend to own bodily needs without assistance 5. Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. Dead |
| Number of Participants Who Required Rescue Medication Due to an Absence or Loss of Clinical Benefit During the Treatment | From Baseline until the end of the Treatment (Week 25) | Study participants who required rescue medication due to an absence or loss of clinical benefit were discontinued blinded treatment and completed the assessments for the early discontinuation visit. |
| Time to First Occurrence of Seizure Freedom During the Treatment | From Baseline until the end of the Treatment (Week 25) | The time to first occurrence of seizure freedom was defined by the number of days after randomization to the first day of the first 28 consecutive days without seizures during the treatment. Time to first occurrence of 28 consecutive days of seizure freedom (days) during the treatment was calculated as date of first day of occurrence of 28 consecutive days of seizure freedom - Date of Randomization + 1. |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | From Baseline until the End of Study (Week 32) | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of investigational medicinal product (IMP), whether or not considered related to the IMP. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IMP, whether or not related to the IMP. A TEAE was defined as an AE starting on or after the time of first administration of IMP or any unresolved event already present before the first administration of IMP that worsens in intensity following exposure to treatment up to the end of the Treatment and including the 8-week (56 days) Safety-Follow Up (SFU). |
Countries
Australia, Belgium, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study started to enroll participants in September 2021 and concluded in April 2024.
Pre-assignment details
The Participant Flow refers to the Randomized Set (RS).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo as a subcutaneous (sc) infusion once a week (Q1W) for 25 weeks. | 6 |
| Rozanolixizumab (RLZ) Participants received rozanolixizumab as a sc infusion Q1W for 25 weeks. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lack of Efficacy | 2 | 2 |
| Overall Study | Permanently left due to new seizure recurrence | 0 | 1 |
| Overall Study | Permanently left due to seizure recurrence | 1 | 0 |
| Overall Study | Relapse With Insults | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Rozanolixizumab (RLZ) | Total |
|---|---|---|---|
| Age, Continuous | 60.7 Years STANDARD_DEVIATION 12.4 | 70.7 Years STANDARD_DEVIATION 11.4 | 65.7 Years STANDARD_DEVIATION 12.5 |
| Age, Customized 18 - <65 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Customized 65 - <85 years | 3 Participants | 5 Participants | 8 Participants |
| Age, Customized >=85 years | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 3 / 6 | 3 / 6 |
Outcome results
Primary
Number of Seizure Free Study Participants at the End of the Treatment
Seizure freedom was defined as a minimum of 28 consecutive days of no seizures of any type during the treatment and maintained until the end of the treatment (Week 25).
Time frame: From Baseline until the end of the Treatment (Week 25)
Population: The Randomized Set (RS) consisted of all enrolled study participants who were randomized to treatment arms.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Seizure Free Study Participants at the End of the Treatment | 1 Participants |
| Rozanolixizumab (RLZ) | Number of Seizure Free Study Participants at the End of the Treatment | 0 Participants |
Secondary
Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) consists of 12 subtests that contribute to 5 age-based domain index scores (immediate memory, visuospatial/constructional, language, attention, delayed memory) that were aggregated for a total scale index score. All index scores have an age-based mean of 100, with a standard deviation (SD) of 15. The total scale score was calculated by taking the mean of the sum of the five index scores. Total possible scale index scores range from 40-135. Higher scores reflect better neurocognitive performance. The total scale index score is the score typically used to reflect global neurocognitive status. Baseline of RBANS is defined as the screening (Visit 1, Week -1) value.
Time frame: From Baseline to Week 5, 13, 21 and 25
Population: The Randomized Set (RS) consisted of all enrolled study participants who were randomized to treatment arms. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Here, number analyzed signifies participants who were evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 5 | 4.5 score on a scale | Standard Deviation 2.6 |
| Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 13 | 7.0 score on a scale | Standard Deviation 2.9 |
| Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 21 | 7.0 score on a scale | Standard Deviation 7.3 |
| Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 25 | NA score on a scale | — |
| Rozanolixizumab (RLZ) | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 25 | NA score on a scale | — |
| Rozanolixizumab (RLZ) | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 5 | 2.2 score on a scale | Standard Deviation 11.3 |
| Rozanolixizumab (RLZ) | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 21 | NA score on a scale | — |
| Rozanolixizumab (RLZ) | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score at the End of the Treatment | Week 13 | 12.3 score on a scale | Standard Deviation 7.9 |
Secondary
Number of Participants Who Required Rescue Medication Due to an Absence or Loss of Clinical Benefit During the Treatment
Study participants who required rescue medication due to an absence or loss of clinical benefit were discontinued blinded treatment and completed the assessments for the early discontinuation visit.
Time frame: From Baseline until the end of the Treatment (Week 25)
Population: The Randomized Set (RS) consisted of all enrolled study participants who were randomized to treatment arms.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Required Rescue Medication Due to an Absence or Loss of Clinical Benefit During the Treatment | 3 Participants |
| Rozanolixizumab (RLZ) | Number of Participants Who Required Rescue Medication Due to an Absence or Loss of Clinical Benefit During the Treatment | 2 Participants |
Secondary
Percentage of Participants With a Favorable Outcome in the Modified Rankin Scale (mRS) During the Treatment
Percentage of participants with a favorable outcome in mRS during treatment, where favorable outcome defined as no worsening for participants with Baseline mRS score of ≤1 or improvement of ≥1 point for participants with Baseline mRS score of ≥2. The mRS is commonly used scale for measuring degree of disability or dependence in daily activities of people who suffered a stroke or other causes of neurological disability. The scale ranges from 0 (perfect health) to 6 (death). 0-No symptoms at all 1. No significant disability despite symptoms; able to carry out all usual activities 2. Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3. Moderate disability; requiring some help, but able to walk without assistance 4. Moderately severe disability; unable to walk and attend to own bodily needs without assistance 5. Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. Dead
Time frame: From Baseline until the end of the Treatment (Week 25)
Population: The Randomized Set (RS) consisted of all enrolled study participants who were randomized to treatment arms. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Analysis datasets were not generated an output when the n \< 3, therefore, no data obtained and reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Favorable Outcome in the Modified Rankin Scale (mRS) During the Treatment | NA percentage of participants |
| Rozanolixizumab (RLZ) | Percentage of Participants With a Favorable Outcome in the Modified Rankin Scale (mRS) During the Treatment | NA percentage of participants |
Secondary
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of investigational medicinal product (IMP), whether or not considered related to the IMP. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IMP, whether or not related to the IMP. A TEAE was defined as an AE starting on or after the time of first administration of IMP or any unresolved event already present before the first administration of IMP that worsens in intensity following exposure to treatment up to the end of the Treatment and including the 8-week (56 days) Safety-Follow Up (SFU).
Time frame: From Baseline until the End of Study (Week 32)
Population: The Safety Set (SS) consisted of all randomized study participants who received at least one dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Rozanolixizumab (RLZ) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
Secondary
Time to First Occurrence of Seizure Freedom During the Treatment
The time to first occurrence of seizure freedom was defined by the number of days after randomization to the first day of the first 28 consecutive days without seizures during the treatment. Time to first occurrence of 28 consecutive days of seizure freedom (days) during the treatment was calculated as date of first day of occurrence of 28 consecutive days of seizure freedom - Date of Randomization + 1.
Time frame: From Baseline until the end of the Treatment (Week 25)
Population: The Randomized Set (RS) consisted of all enrolled study participants who were randomized to treatment arms.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Occurrence of Seizure Freedom During the Treatment | 0.1 Weeks |
| Rozanolixizumab (RLZ) | Time to First Occurrence of Seizure Freedom During the Treatment | 0.1 Weeks |