Corticosteroids for Immune Reconstitution Inflammatory Syndrome (IRIS) (IRIS)

• ClinicalTrials.gov Identifier: NCT01211665
• Recruitment Status: Terminated
• First Posted: September 29, 2010
• Results First Posted: August 13, 2014
• Last Update Posted: September 5, 2014
• Sponsor: Biogen
• Collaborator: Elan Pharmaceuticals
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: July 29, 2010
• First Posted Date: September 29, 2010
• Results First Submitted Date: July 23, 2014
• Results First Posted Date: August 13, 2014
• Last Update Posted Date: September 5, 2014
• Study Start Date: September 2010
• Actual Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 23, 2014)

• Time Course Change in Functional Status Based on Karnofsky Performance Status Index Through 6 Months Following Completion of Plasma Exchange (PLEX) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline up to 6 months ]

Original Primary Outcome Measures (submitted: September 28, 2010)

• Time course change in functional status based on Karnofsky Performance Status Scale through 6 months following the completion of PLEX or Equivalent [ Time Frame: 6 months ]
• Survival at 6 months following the completion of PLEX or equivalent [ Time Frame: 6 months ]
• Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability [ Time Frame: 6 months ]
• Measure of symptom severity, treatment response and the efficacy of treatments using the Global Clinical Impression of Improvement (GCI-I) [ Time Frame: 6 months ]
• Measure cerebral dysfunction using Symbol Digit Modalities Test (SDMT) [ Time Frame: 6 months ]
• Measure Gadolinium enhancing lesions using Brain Magnetic Resonance Imaging (MRI) [ Time Frame: 6 months ]
• Mapping of brain activity using Magnetoencephalography (MEG) [ Time Frame: 6 months ]
• Laboratories (Chemokines, Cytokines, C-reactive protein, JCV load and cell count in cerebral fluid (CSF)) [ Time Frame: 6 months ]

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Corticosteroids for Immune Reconstitution Inflammatory Syndrome (IRIS)
• Official Title: High-Dose Corticosteroids for Immune Reconstitution Inflammatory Syndrome in Patients Who Develop Progressive Multifocal Leukoencephalopathy on Natalizumab
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Immune Reconstitution Inflammatory Syndrome
• Leukoencephalopathy, Progressive Multifocal

Intervention

• Drug: Methylprednisolone
  In intravenous form (for a daily dose of 1 g/day on treatment days).
  Other Names:

  • Medrol
  • Solu-Medrol
• Drug: Prednisolone
  Oral prednisolone used as a taper, with suggested dosages starting at 80 mg and tapering to 5 mg.
  Other Names:

  • Orapred
  • Prelone

Study Arms

• Experimental: 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.
  Intervention: Drug: Methylprednisolone
• Experimental: IVMP with oral prednisolone taper
  Intravenous methylprednisolone (IVMP) 1g/day for 6 days followed by an oral taper of prednisolone over 2 months (suggested dosages starting at 80 mg and tapering to 5 mg). If necessary, additional cycles of 1 g IVMP daily for 3 to 5 days can be administered at any time.
  Interventions:

  • Drug: Methylprednisolone
  • Drug: Prednisolone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 23, 2014): 3
• Original Estimated Enrollment (submitted: September 28, 2010): 20
• Actual Study Completion Date: February 2012
• Actual Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)

Eligibility 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/exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, United States

Administrative Information

• NCT Number: NCT01211665
• Other Study ID Numbers: 101JC404; 2010-020369-26 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Biogen
• Original Responsible Party: Biogen Idec Medical Director, Biogen Idec, Inc
• Current Study Sponsor: Biogen
• Original Study Sponsor: Same as current
• Collaborators: Elan Pharmaceuticals

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: August 2014