Acute Brainstem/Cerebellar Syndrome, Multiple Sclerosis, Optic Neuritis, Transverse Myelitis
Conditions
Keywords
Multiple sclerosis, Interferon Beta, MRI, Optic neuritis, Transverse Myelitis
Brief summary
The current study is a continuation of the 5 year extension study of the phase III CHAMPS study (see reference). This study was designed to determine if immediate initiation of therapy with Interferon Beta-1a (AVONEX) after a first attack of multiple sclerosis (MS) continues to delay the development of further attacks (CDMS) and the development of neurological disability over a 10 year period of observation. The initial 5 year extension study, called CHAMPIONS5, reported that immediate initiation of interferon Beta-1a (AVONEX) after a first attack of MS continued to delay the development of CDMS and lowered relapse rates compared to delayed initiation of disease modifying treatment (usually with AVONEX) either at the time of a second attack or at the end of the phase III study (24 months). The study was extended to 10 years to determine if these effects are sustained and result in less long term permanent disability.
Detailed description
The CHAMPS study determined that immediate initiation of interferon beta 1a therapy (AVONEX) immediately following a first clinical demyelinating event in high risk patients (i.e. those with at least 2 asymptomatic white matter lesions on cranial MR imaging \> 3 mm in diameter or ovoid) delayed the development of clinical definite Multiple Sclerosis (CDMS)(as defined by a second, clinically verifiable attack involving another part of the central nervous system) over 2 years of observation and significantly decreased the development of new or enlarging white matter lesions on MRI over 18 months (see reference). The current study is a long term extension of a cohort of CHAMPS study site and participants. The three main aims of the study are as follows: 1. To determine the long term neurological outcome in patients treated with interferon beta 1a (AVONEX) from onset of a first clinical demyelinating event 2. To determine if immediate initiation of AVONEX therapy (the CHAMPS Avonex treatment group) confers long term benefits compared to delayed initiation of therapy (the CHAMPS placebo group) on the rate of development of CDMS, annualized relapse rates, the development of permanent disability and MR measures of disease activity and progression. 3. To determine predictors of long term disease activity and disability in patients following a first clinical demyelinating event
Interventions
DRUGinterferon beta 1a 30 ug IM once weekly
Immediate treatment group refers to those patients who were randomized to the interferon beta 1a 30 ug IM once weekly treatment arm of the original, controlled phase III CHAMPS study; Delayed treatment group refers to those patients who were randomized to the placebo group during the original controlled, phase III CHAMPS study and did not start treatment, if at all, until they completed the CHAMPS study protocol at a later date.
Sponsors
Biogen
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Open label study: The outcome committee determined the primary outcome event (the development of Clinically definite MS) without knowledge of original treatment assignment and the central MRI reading center was not aware of original treatment assignments
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Previous participation in CHAMPS study * Participation in a study site willing to participate in the CHAMPIONS10 extension study * Willingness to enroll in the CHAMPIONS 10 extension * Willingness to sign informed consent
Exclusion criteria
* Discovery of an alternative neurological disorder other than MS as a cause of initial neurological symptoms * A severe systemic disease with likely mortality within 3 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Development of Clinical Definite Multiple Sclerosis (CDMS) Over 10 Years | 10 years | Percent cumulative probability of developing CDMS over 10 years . CDMS was defined as the development of new visual or neurological symptoms discrete from the patients initial event with objective findings on examination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate | 10 years | annualized # of relapses between years 0 and 10 |
| Number of Participants With an EDSS > 3.5 at Study Completion | 10 years | The EDSS is an ordinal scale of neurological impairment in Multiple Sclerosis with a range of 0 to 10 with 0.5 increments. A score of 0 is normal and 10 is death from MS. Scores from 1 to 3.5 are considered mild impairment , 4.0 to 6.5 is moderate and greater than 6.5 is severe impairment. |
| The Number of New or Enlarging MRI T2 Lesions at 10 Years | 10 years | These are counts of new or significantly enlarged lesions over 10 years on brain MRI reflecting interval radiographic disease activity |
Countries
Canada, United States
Participant flow
Recruitment details
Participants in the CHAMPIONS 5 year extension study were offered participation in the 10 year extension if their study site participated in the 10 year extension. Study arms were already establish at the onset of CHAMPIONS 10 extension
Participants by arm
| Arm | Count |
|---|---|
| Immediate Treatment Group Initiation of treatment with Interferon Beta 1a IM once weekly immediately after onset of a first demyelinating syndrome in high risk individuals
interferon beta 1a 30 ug IM once weekly: Immediate treatment group refers to those patients who were randomized to the interferon beta 1a 30 ug IM once weekly treatment arm of the original, controlled phase III CHAMPS study; Delayed treatment group refers to those patients who were randomized to the placebo group during the original controlled, phase III CHAMPS study and did not start treatment, if at all, until they completed the CHAMPS study protocol at a later date. | 81 |
| Delayed Treatment Group Delayed initiation of of Interferon beta-1a IM once weekly at diagnosis of clinically definite MS, at conclusion of initial CHAMPS study or during long term observation
interferon beta 1a 30 ug IM once weekly: Immediate treatment group refers to those patients who were randomized to the interferon beta 1a 30 ug IM once weekly treatment arm of the original, controlled phase III CHAMPS study; Delayed treatment group refers to those patients who were randomized to the placebo group during the original controlled, phase III CHAMPS study and did not start treatment, if at all, until they completed the CHAMPS study protocol at a later date. | 74 |
| Total | 155 |
Baseline characteristics
| Characteristic | Delayed Treatment Group | Total | Immediate Treatment Group |
|---|---|---|---|
| Age, Continuous | 34 years STANDARD_DEVIATION 7 | 34 years STANDARD_DEVIATION 7 | 35 years STANDARD_DEVIATION 7 |
| Brainstem/Cerebellar at onset | 19 Participants | 40 Participants | 21 Participants |
| EDSS 2.0-2.5 at onset | 15 Participants | 39 Participants | 24 Participants |
| EDSS < 2.0 at onset | 55 Participants | 102 Participants | 47 Participants |
| EDSS > 2.5 at onset | 4 Participants | 14 Participants | 10 Participants |
| Family History of MS | 7 Participants | 19 Participants | 12 Participants |
| Gad enhancing lesions at onset | 17 Participants | 43 Participants | 26 Participants |
| Median T2 lesion # at onset | 13 lesion counts | 13 lesion counts | 13 lesion counts |
| Median T2 lesion vol at onset | 1774 mm^3 | 1930 mm^3 | 2063 mm^3 |
| Optic neuritis at onset | 38 Participants | 78 Participants | 40 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Non White | 5 Participants | 14 Participants | 9 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White | 69 Participants | 141 Participants | 72 Participants |
| Sex: Female, Male Female | 53 Participants | 113 Participants | 60 Participants |
| Sex: Female, Male Male | 21 Participants | 42 Participants | 21 Participants |
| Spinal cord syndrome at onset | 17 Participants | 37 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 155 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Rate of Development of Clinical Definite Multiple Sclerosis (CDMS) Over 10 Years
Percent cumulative probability of developing CDMS over 10 years . CDMS was defined as the development of new visual or neurological symptoms discrete from the patients initial event with objective findings on examination.
Time frame: 10 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Group | Rate of Development of Clinical Definite Multiple Sclerosis (CDMS) Over 10 Years | 58 Percent cumulative probability |
| Delayed Treatment Group | Rate of Development of Clinical Definite Multiple Sclerosis (CDMS) Over 10 Years | 69 Percent cumulative probability |
p-value: 0.001Regression, Cox
Secondary
Annualized Relapse Rate
annualized # of relapses between years 0 and 10
Time frame: 10 years
Population: Analysis only in 10 year completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Immediate Treatment Group | Annualized Relapse Rate | 0.16 annualized relapses per year | Standard Deviation 0.18 |
| Delayed Treatment Group | Annualized Relapse Rate | 0.33 annualized relapses per year | Standard Deviation 0.41 |
p-value: 0.02Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With an EDSS > 3.5 at Study Completion
The EDSS is an ordinal scale of neurological impairment in Multiple Sclerosis with a range of 0 to 10 with 0.5 increments. A score of 0 is normal and 10 is death from MS. Scores from 1 to 3.5 are considered mild impairment , 4.0 to 6.5 is moderate and greater than 6.5 is severe impairment.
Time frame: 10 years
Population: Numbers of patients completing 10 year evaluations
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Immediate Treatment Group | Number of Participants With an EDSS > 3.5 at Study Completion | 7 Participants |
| Delayed Treatment Group | Number of Participants With an EDSS > 3.5 at Study Completion | 5 Participants |
p-value: 0.61Fisher Exact
Secondary
The Number of New or Enlarging MRI T2 Lesions at 10 Years
These are counts of new or significantly enlarged lesions over 10 years on brain MRI reflecting interval radiographic disease activity
Time frame: 10 years
Population: Analysis restricted to those participants with MRI scans able to evaluate at 10 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Immediate Treatment Group | The Number of New or Enlarging MRI T2 Lesions at 10 Years | 5 # of new or enlarging T2 lesions |
| Delayed Treatment Group | The Number of New or Enlarging MRI T2 Lesions at 10 Years | 7 # of new or enlarging T2 lesions |
p-value: 0.5Fisher Exact