This is a phase II, double blind, placebo-controlled, multicenter, randomized study of the efficacy and safety of atorvastatin (80 mg/day) in participants with a recent history of one episode of CIS and at least two silent ovoid MRI lesions suggestive of MS. Clinically isolated syndrome (CIS) is defined as a neurological disturbance of the kind seen in MS that lasts at least 48 hours, can be proved by subjective report or objective observation, and excludes pseudoattacks and single paroxysmal episodes (see protocol section 3.4.1). One hundred fifty-two participants who meet the inclusion/exclusion criteria will be randomized (3:2) to receive either atorvastatin or placebo in a blinded fashion. The subjects will be enrolled over a period of approximately 18 months. The rationale for a 3:2 randomization is to increase the number of participants who receive the active treatment and to minimize the likelihood of false-negative results (beta error) by having enough participants in the placebo group. The higher chance of receiving the active drug may also facilitate the recruitment process. Participants will be enrolled within 90 days of CIS onset. Participants with at least two silent ovoid T2 bright areas in the deep white matter on a clinical MRI who also meet other inclusion/exclusion criteria will be offered participation in the treatment phase of this study. All participants must complete a 3-day course of corticosteroids that is started within 60 days of CIS onset and discontinued at least 28 days before the baseline evaluation. The eligible participants will be randomized to either oral atorvastatin (80 mg/day) or placebo (3:2). The study participants will be evaluated at baseline, months 1, 2 and 3, and then every 3 months by physical examinations, adverse event assessment, EDSS, MSFC, and MRI scans. In addition, concomitant medications will be recorded, and samples for immunological assays (see section 9) will be obtained. Those who meet the primary endpoint will be offered the standard of care for MS (interferon β-1a, Avonex®), as outlined in section 3.2, and will remain in the study and continue to receive atorvastatin or placebo. No greater risk of adverse events is expected with the dual therapy of atorvastatin and interferon β-1a. The participants are monitored monthly for 6 months for abnormal aminotransferase levels when initiating interferon β-1a.

Plan to Share IPD: Yes Plan Description: Data access is provided to the public in: 1.) the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts that also provides data analysis tools available to researchers; and 2.) TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal that makes data from the consortium's clinical trials available to the public.

instance of dataset

available with registration

STAyCIS

National Institute of Allergy and Infectious Diseases (NIAID)

Drug: Atorvastatin 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 Other Name: Lipitor Drug: Placebo tablet form Other Name: Placebo Treatment

registration required

Multiple Sclerosis

Scott Zamvil, MD, PhD

Emmanuelle Waubant, MD, PhD

University of California, San Francisco

Study Chair

Atorvastatin (Lipitor) Therapy in Patients With Clinically Isolated Syndrome (CIS) at Risk for Multiple Sclerosis

82

The Occurrence of ≥ 3 New T2 Lesions With or Without Gd+ Enhancement or Clinical Exacerbation Through 12 Months. [ Time Frame: 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 A new T2 lesion is an abnormal, hyperintense white-matter area visible on T2 weighted images that were not present on the baseline scan A Gd+ enhancement is defined as a contrast enhancement visible on a new T2 lesion 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

Proportion of Participants Who Are Diagnosed With Multiple Sclerosis According to the McDonald Criteria [ Time Frame: 12 months post-randomization ] Number of participants diagnosed with Multiple Sclerosis (MS) according to the McDonald criteria[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 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 [ Time Frame: 18 months post-randomization ] Number of participants diagnosed with Multiple Sclerosis (MS) according to the McDonald criteria[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 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

NCT00094172

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

2009-05-01

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy and Safety of Atorvastatin in Patients With Clinically Isolated Syndrome and High Risk of Conversion to Multiple Sclerosis (ITN020AI)

Experimental: Atorvastatin 80 mg/day Intervention: Drug: Atorvastatin Placebo Comparator: Placebo Once daily. Intervention: Drug: Placebo

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.

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.

Allocation: Randomized Intervention Model: Parallel Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Prevention

Canada, United States

2005-05-01

ITN TrialShare