Multiple Sclerosis
Conditions
Keywords
Early Multiple Sclerosis, MS, Clinically Isolated Syndrome
Brief summary
Patients who have been diagnosed with clinically isolated syndrome (CIS) often develop problems related to the central nervous system, which controls the nerves in the body. Some of these patients may later be diagnosed with multiple sclerosis (MS), a progressive disease of the nervous system. The purpose of this study is to determine if the drug atorvastatin is helpful to CIS patients. Study hypothesis: Early intervention with atorvastatin in patients with CIS will result in a state of immunological tolerance.
Detailed description
CIS is a single clinical event indicating temporary disruption of normal nerve function. CIS patients may have a loss of vision in one eye; trouble with balance; double vision; numbness in the face; and tingling, numbness, or weakness in the arms or legs. Some CIS patients may develop MS, but others may not. Studies have shown that when CIS is accompanied by magnetic resonance imaging (MRI)-detected brain lesions that are consistent with those seen in MS, there is a high risk of a second neurologic event and a diagnosis of MS within several years. This study will evaluate the efficacy of atorvastatin, an antihyperlipidemic, in the prevention of MS in CIS patients. This study will last 18 months. All participants must complete a 3- to 5-day course of corticosteroids at least 28 days before the baseline evaluations. This corticosteroid therapy must be initiated within 60 days of CIS onset. Participants will be randomly assigned to receive 80 mg of either atorvastatin or placebo by mouth daily for 12 months. Study visits will occur at screening and every 3 months thereafter until the end of the 18-month study. Blood collection will occur at selected visits, and other additional evaluations will be performed at Months 1 and 2. Selected participants will undergo MRI brain scans. Participants will be offered interferon beta-1a (Avonex®), free of charge, if they develop disease activity. Participants will be instructed to report any change in their health status to their treating physician within 48 hours of the onset of symptoms.
Interventions
DRUGAtorvastatin
atorvastatin at the dose of 80 mg/day. Participants will be allowed to decrease the daily dose to 40 mg/day if the higher dose is not well-tolerated
DRUGPlacebo
tablet form
Sponsors
Immune Tolerance Network (ITN)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Clinically isolated syndrome (CIS) as defined by an acute or subacute well-defined neurological event lasting at least 48 hours and consistent with MS (i.e., optic neuritis, spinal cord syndrome, brainstem/cerebellar syndromes). Other causes for optic neuritis other than CIS must be ruled out by an ophthalmologist. Patients with other clinically silent abnormal findings found upon neurological examination that are not attributable to the presenting symptom are not excluded. * Onset of CIS symptoms occurring within 90 days of randomization * Abnormal, unenhanced brain MRI with 2 or more clinically silent T2 lesions greater than or equal to 3 mm in diameter, at least one of which is periventricular in location or ovoid in shape * Willing to use acceptable methods of contraception * Have received 3 to 5 days of corticosteroid therapy within 60 days of CIS onset
Exclusion criteria
* Definite diagnosis of MS according to McDonald criteria * Previous history of neurological symptoms lasting more than 48 hours. Patients with a history of neurological symptoms lasting less than 48 hours will not be excluded. * Prior use of interferon, glatiramer acetate, cyclophosphamide, mitoxantrone, or plasmapheresis anytime prior to study entry * Use of interferon preparations (unless as specified by the protocol), glatiramer acetate, cyclophosphamide, mitoxantrone, or plasmapheresis during the study * Use of cyclosporine, fibric acid derivatives, niacin, erythromycin, or azole antifungal during the study * Received more than 5 g of methylprednisolone (or the equivalent of other IV corticosteroid) prior to study screening * Use of a cholesterol-lowering agent during the 3 months prior to study screening or need for such agents during the study * Previous history of severe side effects with statin therapy * Prior exposure to total lymphoid irradiation * History of substance abuse in the 12 months prior to study screening * History of systemic illness or medical condition that would limit the likelihood of completing the MRI procedures or would interfere with the measurement of a therapeutic effect * Implanted pacemakers, cochlear implants, defibrillators, or metallic objects on or inside the body * Uncontrolled hypertension, asthma, known malignancy other than skin cancer, symptomatic cardiac disease, epilepsy, insulin-dependent diabetes, or symptoms that can only be explained by systemic lupus erythematosus (SLE) or other autoimmune diseases * Active liver disease * Major medical illnesses or psychiatric impairment that in the investigator's opinion could interfere with the study * History of severe depression or suicidal ideation within 1 year of study entry * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Occurrence of ≥ 3 New T2 Lesions With or Without Gd+ Enhancement or Clinical Exacerbation Through 12 Months. | 12 months post-randomization | The occurrence of ≥ T2 lesions\[1\] with or without gadolinium lesion (Gd+) enhancement\[2\] or clinical exacerbation\[3\] through 12 months. A higher score indicates more severe disease 1. A new T2 lesion is an abnormal, hyperintense white-matter area visible on T2 weighted images that were not present on the baseline scan 2. A Gd+ enhancement is defined as a contrast enhancement visible on a new T2 lesion 3. A clinical exacerbation is a new neurological symptom that lasts more than 48 hours in a participant who has been neurologically stable for 30 days following start of study medication |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Are Diagnosed With Multiple Sclerosis According to the McDonald Criteria | 12 months post-randomization | Number of participants diagnosed with Multiple Sclerosis (MS) according to the McDonald criteria\[1\] 1. The McDonald criteria uses dissemination in time and space\[2\] established by Magnetic Resonance Image (MRI) findings to provide a clinical diagnosis for MS 2. Dissemination in time is established by a new T2 or gadolinium-enhancing (Gd+) lesion found on a repeat MRI. The presence of any 3 of the following establishes dissemination in space: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; ≥1 infratentorial lesion; ≥1 juxtacortical lesion; ≥3 periventricular lesions |
| Proportion of Participants Diagnosed With Multiple Sclerosis According to the McDonald Criteria | 18 months post-randomization | Number of participants diagnosed with Multiple Sclerosis (MS) according to the McDonald criteria\[1\] 1. The McDonald criteria uses dissemination in time and space\[2\] established by Magnetic Resonance Image (MRI) findings to provide a clinical diagnosis for MS 2. Dissemination in time is established by a new T2 or gadolinium-enhancing (Gd+) lesion found on a repeat MRI. The presence of any 3 of the following establishes dissemination in space: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; ≥1 infratentorial lesion; ≥1 juxtacortical lesion; ≥3 periventricular lesions |
Countries
Canada, United States
Participant flow
Recruitment details
Fourteen centers enrolled 83 participants and randomized 82 participants(one participant voluntarily withdrew prior to randomization) who had experienced clinically isolated syndrome and were at risk for developing Multiple Sclerosis (MS) (two or more lesions on Magnetic Resonance Image (MRI) scans) between February 14, 2005 and July 24, 2007.
Pre-assignment details
At a screening visit, participants underwent procedures to establish that all inclusion criteria were met and none of the exclusion criteria were met. Participants then signed an informed consent form.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Drug: Atorvastatin | 50 |
| Placebo Non-Active Comparator | 32 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Primary endpoint met. | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Started other MS therapy due to disease | 1 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 5 |
Baseline characteristics
| Characteristic | Atorvastatin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 33.6 years STANDARD_DEVIATION 9.4 | 33.9 years STANDARD_DEVIATION 8.6 | 33.7 years STANDARD_DEVIATION 9 |
| Number of Gd+ Lesions at Baseline | 0.7 Lesion Count STANDARD_DEVIATION 2.7 | 0.2 Lesion Count STANDARD_DEVIATION 0.5 | 0.5 Lesion Count STANDARD_DEVIATION 2.1 |
| Number of T2 Lesions at Baseline | 21.6 Lesion Count STANDARD_DEVIATION 17.6 | 19.5 Lesion Count STANDARD_DEVIATION 16.5 | 20.8 Lesion Count STANDARD_DEVIATION 17.1 |
| Region of Enrollment Canada | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 46 participants | 29 participants | 75 participants |
| Sex: Female, Male Female | 40 Participants | 23 Participants | 63 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 32 |
| other Total, other adverse events | 48 / 51 | 32 / 32 |
| serious Total, serious adverse events | 3 / 51 | 1 / 32 |
Outcome results
Primary
The Occurrence of ≥ 3 New T2 Lesions With or Without Gd+ Enhancement or Clinical Exacerbation Through 12 Months.
The occurrence of ≥ T2 lesions\[1\] with or without gadolinium lesion (Gd+) enhancement\[2\] or clinical exacerbation\[3\] through 12 months. A higher score indicates more severe disease 1. A new T2 lesion is an abnormal, hyperintense white-matter area visible on T2 weighted images that were not present on the baseline scan 2. A Gd+ enhancement is defined as a contrast enhancement visible on a new T2 lesion 3. A clinical exacerbation is a new neurological symptom that lasts more than 48 hours in a participant who has been neurologically stable for 30 days following start of study medication
Time frame: 12 months post-randomization
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | The Occurrence of ≥ 3 New T2 Lesions With or Without Gd+ Enhancement or Clinical Exacerbation Through 12 Months. | 26 Participants |
| Placebo | The Occurrence of ≥ 3 New T2 Lesions With or Without Gd+ Enhancement or Clinical Exacerbation Through 12 Months. | 18 Participants |
Comparison: This is the primary analysis of the primary endpointp-value: 0.929Log Rank
Comparison: This is the secondary analysis of the primary endpointp-value: 0.823Fisher Exact
Secondary
Proportion of Participants Diagnosed With Multiple Sclerosis According to the McDonald Criteria
Number of participants diagnosed with Multiple Sclerosis (MS) according to the McDonald criteria\[1\] 1. The McDonald criteria uses dissemination in time and space\[2\] established by Magnetic Resonance Image (MRI) findings to provide a clinical diagnosis for MS 2. Dissemination in time is established by a new T2 or gadolinium-enhancing (Gd+) lesion found on a repeat MRI. The presence of any 3 of the following establishes dissemination in space: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; ≥1 infratentorial lesion; ≥1 juxtacortical lesion; ≥3 periventricular lesions
Time frame: 18 months post-randomization
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Proportion of Participants Diagnosed With Multiple Sclerosis According to the McDonald Criteria | 37 Participants |
| Placebo | Proportion of Participants Diagnosed With Multiple Sclerosis According to the McDonald Criteria | 24 Participants |
p-value: 0.526Log Rank
Secondary
Proportion of Participants Who Are Diagnosed With Multiple Sclerosis According to the McDonald Criteria
Number of participants diagnosed with Multiple Sclerosis (MS) according to the McDonald criteria\[1\] 1. The McDonald criteria uses dissemination in time and space\[2\] established by Magnetic Resonance Image (MRI) findings to provide a clinical diagnosis for MS 2. Dissemination in time is established by a new T2 or gadolinium-enhancing (Gd+) lesion found on a repeat MRI. The presence of any 3 of the following establishes dissemination in space: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; ≥1 infratentorial lesion; ≥1 juxtacortical lesion; ≥3 periventricular lesions
Time frame: 12 months post-randomization
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Proportion of Participants Who Are Diagnosed With Multiple Sclerosis According to the McDonald Criteria | 29 Participants |
| Placebo | Proportion of Participants Who Are Diagnosed With Multiple Sclerosis According to the McDonald Criteria | 24 Participants |
p-value: 0.208Log Rank