Immune Reconstitution Inflammatory Syndrome, Leukoencephalopathy, Progressive Multifocal
Conditions
Keywords
IVMP, corticosteroids, IRIS, Progressive Multifocal Leukoencephalopathy, Immune reconstitution inflammatory syndrome, PML
Brief summary
The objectives of this study are to explore the effects of administering high-dose corticosteroids to participants who developed progressive multifocal leukoencephalopathy (PML) while on natalizumab as measured by time-course change in functional status based on Karnofsky Performance Status Index through 6 months following the completion of plasma exchange (PLEX; or equivalent), survival at 6 months following the completion of PLEX (or equivalent), and incidence and severity of adverse events (AEs) and serious adverse events (SAEs); to characterize the evolution of immune reconstitution inflammatory syndrome (IRIS) as measured by time course changes in Global Clinical Impression of Improvement (GCI-I), Symbol Digit Modalities Test (SDMT), brain magnetic resonance imaging (MRI), magnetoencephalography (MEG), chemokines, cytokines, C-reactive protein (CRP), John Cunningham virus (JCV) load and cell count in cerebrospinal fluid (CSF); and to characterize the time course elimination of serum natalizumab concentrations in the study population following the last PLEX (or equivalent) procedure.
Interventions
DRUGMethylprednisolone
In intravenous form (for a daily dose of 1 g/day on treatment days).
DRUGPrednisolone
Oral prednisolone used as a taper, with suggested dosages starting at 80 mg and tapering to 5 mg.
Sponsors
Elan Pharmaceuticals
Biogen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have been receiving natalizumab for multiple sclerosis (MS) prior to the diagnosis or suspicion of Progressive multifocal leukoencephalopathy (PML). * Subject must be willing to undergo or have completed plasma exchange (PLEX) prior to initiating study treatment. Key
Exclusion criteria
* History of severe allergic or anaphylactic reactions or known hypersensitivity to any drug including hypersensitivity to corticosteroids. NOTE: Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time Course Change in Functional Status Based on Karnofsky Performance Status Index Through 6 Months Following Completion of Plasma Exchange (PLEX) | Baseline up to 6 months | The Karnofsky Performance Status Index (KPSI) is an assessment tool intended to assist clinicians and caretakers in gauging a patient's functional status and ability to carry out activities of daily living. A KPSI of 100=normal, no complaints, no evidence of disease; 90=able to carry on normal activity, minor signs or symptoms of disease; 80=normal activity with effort, some signs or symptoms of disease; 70=cares for self, unable to carry on normal activity or do active work; 60=requires occasional assistance but is able to care for most personal needs; 50=requires considerable assistance and frequent medical care; 40=disabled, requires special care and assistance; 30=severely disabled, hospitalization is indicated, although death is not imminent; 20=very sick, hospitalization is necessary, active support treatment is necessary; 10=moribund, fatal processes progressing rapidly; 0=dead. |
| Number of Participants Who Survived at 6 Months Following Completion of Plasma Exchange (PLEX) | 6 months | Following the completion of rapid removal of natalizumab using PLEX or equivalent. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | from the first dose of study treatment through the end of the treatment period (6 months) + a 4-week post-treatment period | AE=any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAE=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 (a life-threatening event); however, this does not include an event that, had it occurred in a more severe form, might have caused death; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above. |
| Severity of AEs and SAEs | from the first dose of study treatment through the end of the treatment period (6 months) + a 4-week post-treatment period | AEs and SAEs were categorized as mild, moderate or severe according to the following criteria: Mild=barely noticeable to participant or does not make participant uncomfortable; does not influence performance or functioning; prescription drug not ordinarily needed for relief of symptom(s) but may be given because of personality of participant. Moderate=of a sufficient severity to make participant uncomfortable; performance of daily activity is influenced; participant is able to continue in study; treatment for symptom(s) may be needed. Severe=symptoms cause severe discomfort; symptoms cause incapacity or significant impact on participant's daily life; severity may cause cessation of treatment with study treatment; treatment for symptom(s) may be given and/or participant hospitalized. Please see Outcome Measure 3 for AE and SAE definitions. |
| Time Course Change in the Global Clinical Impression of Improvement (GCI-I) Scale | Screening to 6 months following completion of PLEX (participants began treatment with intravenous methylprednisolone (IVMP) within 2 weeks after PLEX [or equivalent]). | The GCI-I scale is a 7-point scale that assesses how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention, and rates it as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. |
| Time Course Change in Cerebral Dysfunction Using the Symbol Digit Modalities Test (SDMT) | Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]). | The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution. |
| Time Course Changes in Brain Magnetic Resonance Imaging (MRI) | Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]). | The brain MRI data collected included: progressive multifocal leukoencephalopathy (PML) lesion localization, T2 hyperintense lesion volume, and signs of cerebral edema. |
| Time Course Change in Magnetoencephalography (MEG) Results | Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]). | MEG was used to map brain activity. |
| Time Course Change in Clinical Laboratory Values | Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]). | Clinical laboratory values included chemokines, cytokines, C-reactive protein (CRP), John Cunningham (JC) virus load, and cell count in cerebrospinal fluid. |
| Time Course Elimination of Serum Natalizumab Concentration Following Plasma Exchange (PLEX) or Equivalent | Baseline up to 6 months | — |
Countries
Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pulsed IVMP Intravenous methylprednisolone (IVMP) 1 g/day administered the first 3 days of each weekly cycle, and repeated for 3 additional cycles (totaling 4 cycles). If necessary, 2 additional weekly cycles of 1 g IVMP daily for 3 days can be administered at the discretion of the investigator. | 2 |
| IVMP With Oral Prednisolone Taper Intravenous methylprednisolone (IVMP) 1g/day for 6 days followed by an oral taper over 2 months. If necessary, additional cycles of 1 g IVMP daily for 3 to 5 days can be administered at any time. | 1 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Pulsed IVMP | IVMP With Oral Prednisolone Taper | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 2 / 2 | 1 / 1 |
Outcome results
Primary
Number of Participants Who Survived at 6 Months Following Completion of Plasma Exchange (PLEX)
Following the completion of rapid removal of natalizumab using PLEX or equivalent.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pulsed IVMP | Number of Participants Who Survived at 6 Months Following Completion of Plasma Exchange (PLEX) | 1 participants |
| IVMP With Oral Prednisolone Taper | Number of Participants Who Survived at 6 Months Following Completion of Plasma Exchange (PLEX) | 1 participants |
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE=any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAE=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 (a life-threatening event); however, this does not include an event that, had it occurred in a more severe form, might have caused death; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above.
Time frame: from the first dose of study treatment through the end of the treatment period (6 months) + a 4-week post-treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pulsed IVMP | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| Pulsed IVMP | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| IVMP With Oral Prednisolone Taper | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 participants |
| IVMP With Oral Prednisolone Taper | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 participants |
Primary
Severity of AEs and SAEs
AEs and SAEs were categorized as mild, moderate or severe according to the following criteria: Mild=barely noticeable to participant or does not make participant uncomfortable; does not influence performance or functioning; prescription drug not ordinarily needed for relief of symptom(s) but may be given because of personality of participant. Moderate=of a sufficient severity to make participant uncomfortable; performance of daily activity is influenced; participant is able to continue in study; treatment for symptom(s) may be needed. Severe=symptoms cause severe discomfort; symptoms cause incapacity or significant impact on participant's daily life; severity may cause cessation of treatment with study treatment; treatment for symptom(s) may be given and/or participant hospitalized. Please see Outcome Measure 3 for AE and SAE definitions.
Time frame: from the first dose of study treatment through the end of the treatment period (6 months) + a 4-week post-treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pulsed IVMP | Severity of AEs and SAEs | Moderate SAE | 1 events |
| Pulsed IVMP | Severity of AEs and SAEs | Mild AE | 3 events |
| Pulsed IVMP | Severity of AEs and SAEs | Mild SAE | 1 events |
| Pulsed IVMP | Severity of AEs and SAEs | Moderate AE | 3 events |
| Pulsed IVMP | Severity of AEs and SAEs | Severe AE | 0 events |
| Pulsed IVMP | Severity of AEs and SAEs | Severe SAE | 2 events |
| IVMP With Oral Prednisolone Taper | Severity of AEs and SAEs | Severe AE | 0 events |
| IVMP With Oral Prednisolone Taper | Severity of AEs and SAEs | Moderate AE | 1 events |
| IVMP With Oral Prednisolone Taper | Severity of AEs and SAEs | Moderate SAE | 1 events |
| IVMP With Oral Prednisolone Taper | Severity of AEs and SAEs | Severe SAE | 0 events |
| IVMP With Oral Prednisolone Taper | Severity of AEs and SAEs | Mild AE | 5 events |
| IVMP With Oral Prednisolone Taper | Severity of AEs and SAEs | Mild SAE | 1 events |
Primary
Time Course Change in Cerebral Dysfunction Using the Symbol Digit Modalities Test (SDMT)
The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution.
Time frame: Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]).
Population: This study was stopped prematurely due to lack of enrollment; this analysis was not performed.
Primary
Time Course Change in Clinical Laboratory Values
Clinical laboratory values included chemokines, cytokines, C-reactive protein (CRP), John Cunningham (JC) virus load, and cell count in cerebrospinal fluid.
Time frame: Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]).
Population: This study was stopped prematurely due to lack of enrollment; this analysis was not performed.
Primary
Time Course Change in Functional Status Based on Karnofsky Performance Status Index Through 6 Months Following Completion of Plasma Exchange (PLEX)
The Karnofsky Performance Status Index (KPSI) is an assessment tool intended to assist clinicians and caretakers in gauging a patient's functional status and ability to carry out activities of daily living. A KPSI of 100=normal, no complaints, no evidence of disease; 90=able to carry on normal activity, minor signs or symptoms of disease; 80=normal activity with effort, some signs or symptoms of disease; 70=cares for self, unable to carry on normal activity or do active work; 60=requires occasional assistance but is able to care for most personal needs; 50=requires considerable assistance and frequent medical care; 40=disabled, requires special care and assistance; 30=severely disabled, hospitalization is indicated, although death is not imminent; 20=very sick, hospitalization is necessary, active support treatment is necessary; 10=moribund, fatal processes progressing rapidly; 0=dead.
Time frame: Baseline up to 6 months
Population: This study was stopped prematurely due to lack of enrollment; this analysis was not performed.
Primary
Time Course Change in Magnetoencephalography (MEG) Results
MEG was used to map brain activity.
Time frame: Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]).
Population: This study was stopped prematurely due to lack of enrollment; no data on this endpoint was collected.
Primary
Time Course Change in the Global Clinical Impression of Improvement (GCI-I) Scale
The GCI-I scale is a 7-point scale that assesses how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention, and rates it as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
Time frame: Screening to 6 months following completion of PLEX (participants began treatment with intravenous methylprednisolone (IVMP) within 2 weeks after PLEX [or equivalent]).
Population: This study was stopped prematurely due to lack of enrollment; this analysis was not performed.
Primary
Time Course Changes in Brain Magnetic Resonance Imaging (MRI)
The brain MRI data collected included: progressive multifocal leukoencephalopathy (PML) lesion localization, T2 hyperintense lesion volume, and signs of cerebral edema.
Time frame: Screening to 6 months following completion of PLEX (participants began treatment with IVMP within 2 weeks after PLEX [or equivalent]).
Population: This study was stopped prematurely due to lack of enrollment; this analysis was not performed.
Primary
Time Course Elimination of Serum Natalizumab Concentration Following Plasma Exchange (PLEX) or Equivalent
Time frame: Baseline up to 6 months
Population: This study was stopped prematurely due to lack of enrollment; this analysis was not performed.