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A Randomized, Double-Blind, Placebo-Controlled Trial CLINICAL TRIALS SECTION EDITOR: IRA SHOULSON, MD Intravenous Immunoglobulin Treatment Following the First Demyelinating Event Suggestive of Multiple Sclerosis A Randomized, Double-blind, Placebo-Controlled Trial Anat Achiron, MD, PhD; Irena Kishner, MD; Ida Sarova-Pinhas, MD; Havi Raz, BA; Meir Faibel, MD; Yael Stern, MD; Mor Lavie, MA; M. Gurevich, PhD; Mark Dolev, MD; David Magalashvili, MD; Yoram Barak, MD Background: Intravenous immunoglobulin (IVIg) has cally definite multiple sclerosis was significantly lower been reported to reduce disease activity in patients with in the IVIg treatment group compared with the placebo relapsing-remitting multiple sclerosis. We assessed the group (rate ratio, 0.36 [95% confidence interval, 0.15- effect of IVIg treatment in patients after the first neuro- 0.88]; P=.03). Patients in the IVIg treatment group had logical event suggestive of demyelinative disease and a significant reduction in the volume and number of T2- evaluated the occurrence of a second attack and dissemi- weighted lesions and in the volume of gadolinium- nation in time demonstrated by brain magnetic reso- enhancing lesions as compared with the placebo group nance imaging within the first year from onset. (P=.01, P=.01, and P=.03, respectively). Treatment was well tolerated, compliance was high, and incidence of ad- Methods: We conducted a randomized, placebo- verse effects did not differ significantly between groups. controlled, double-blind study in 91 eligible patients en- rolled within the first 6 weeks of neurological symp- Conclusions: Intravenous immunoglobulin treatment toms. Patients were randomly assigned to receive IVIg for the first year from onset of the first neurological event treatment (2-g/kg loading dose) or placebo, with boost- suggestive of demyelinative disease significantly lowers ers (0.4 g/kg) given once every 6 weeks for 1 year. Neu- the incidence of a second attack and reduces disease ac- rological and clinical assessments were done every 3 tivity as measured by brain magnetic resonance months, and brain magnetic resonance imaging was per- imaging. formed at baseline and the end of the study. Results: The cumulative probability of developing clini- Arch Neurol. 2004;61:1515-1520 ULTIPLE SCLEROSIS stage, patients are diagnosed with the first (MS) is a chronic in- neurological event suggestive of MS be- flammatory demyelin- cause the diagnosis of clinically definite MS ating disease affecting requires the occurrence of a second neu- the brain and spinal rological event or dissemination in time cord, in which infiltrating lymphocytes, demonstrated by brain magnetic reso- M 2-4 predominantly T cells, and macrophages nance imaging (MRI). The evolution of lead to damage of the myelin sheath.1 Dis- the disease has been shown to be affected Author Affiliations: Multiple ease onset is characterized by impair- by the time to occurrence of the second Sclerosis Center (Drs Achiron, ment in 1 or more of the following path- attack, as well as by the number of at- Kishner, Sarova-Pinhas, Stern, ways: motor, sensory, cerebellar, visual, tacks within the first year.5,6 Prospective Gurevich, Dolev, Magalashvili, follow-up studies demonstrate that the and Barak and Mss Raz and CME course available at proportion of patients who will progress Lavie) and Neuroradiology Unit to definite MS within the first year follow- (Dr Faibel), Sheba Medical www.archneurol.com ing the initial event is as high as 56.7%.7 Center, Tel-Hashomer, Israel; and the Sackler School of Moreover, estimates of cognitive impair- Medicine, Tel-Aviv University, brainstem, or cognitive, as well as symp- ment among patients diagnosed with prob- Tel-Aviv, Israel (Drs Achiron, toms of fatigue and urinary tract dysfunc- able MS showed that 57% are affected Sarova-Pinhas, Faibel, and tion, all compatible with central nervous within 1 month from onset.8 These find- Barak). system involvement. During this early ings, taken together with previous stud- (REPRINTED) ARCH NEUROL / VOL 61, OCT 2004 WWW.ARCHNEUROL.COM 1515 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 ies9,10 demonstrating axonal loss early in the course of At the pharmacy, containers and tubing of IVIg or saline were the disease, support the rationale for early treatment fol- wrapped in sealed opaque bags. At baseline and once every 3 lowing the first demyelinative event suggestive of MS. months, blood was obtained for hematologic and serum chem- With the advent of immunomodulating drugs, 2 large istry analysis. studies (ETOMS11 and CHAMPS12) were designed to as- sess the efficacy of interferon-␤ treatment initiated after STUDY PROCEDURES the first demyelinating event. Both studies demon- AND END POINTS strated a significant beneficial effect of early treatment on disease course. Each patient was evaluated by an examining neurologist who was unaware of the patient’s treatment assignment. Subse- Intravenously administered immunoglobulin (IVIg) quent examinations were scheduled once every 3 months. In treatment has been reported to be beneficial in the 13 each examination, a complete neurological status was per- treatment of patients with relapsing-remitting MS. formed and disability was scored in accordance with the Ex- Relapse rate, relapse severity, progression of disability, panded Disability Status Scale (EDSS).15 During a suspected re- and disease activity evaluated by brain MRI were all lapse, a patient was examined twice in the same visit. The found to be positively affected by IVIg treatment. This changes on neurological examination to determine whether a treatment has several advantages; it can be administered relapse had occurred were based on the neurological exami- during pregnancy and lactation, safety is established, nation performed by 2 evaluating neurologists both unaware and the favorable adverse effects profile leads to good of treatment assignment. On confirmation of a relapse by any compliance.14 1 of the 2 neurologists, the patient was withdrawn from the study. Relapse was defined as the onset of new neurological The present randomized, double-blind, placebo- symptoms suggestive of white matter involvement, occurring controlled trial was designed to evaluate the effects of for a period of at least 48 hours and accompanied by objective IVIg treatment on the rate of occurrence of the second neurological findings assessed by the EDSS. attack as well as dissemination in time demonstrated by The primary end point was defined as the number of pa- brain MRI during the first year from onset of neurologi- tients who experienced a second attack thereby fulfilling the cal symptoms. criteria for the diagnosis of MS within 1 year. Secondary out- come measures were the change in MRI disease burden, neu- rological disability (EDSS), and cognitive performance. METHODS MRI LESION LOAD SUBJECTS Brain MRI was performed at baseline and at study completion The study was conducted at the Multiple Sclerosis Center, or discontinuation. Examinations were obtained using a 2.0-T Sheba Medical Center, Tel-Hashomer, Israel, from March imager (Elscint, Haifa, Israel). For each MRI examination, the 1998 until March 2003. The study protocol and informed following data were acquired: (1) sagittal T1-weighted local- consent forms were approved by the institutional review izer images (repetition time, 500 milliseconds; echo time, 12 board, and all patients gave written informed consent for milliseconds), 24-cm field of view, 256ϫ180 matrix; (2) axial participation. Eligible subjects were aged between 15 and 50 dual spin-echo (proton density and T2) weighted sequences years, with the first well-defined neurological event consis- (repetition time, 5500 milliseconds; echo time, 16-128 milli- tent with demyelination and confirmed by neurological seconds), 22-cm field of view, 256ϫ256 matrix; (3) axial T1- examination and brain MRI. These patients were defined as weighted images (repetition time, 500 milliseconds; echo time, having the first demyelinating event suggestive of MS (clini- 12 milliseconds), 24-cm field of view, 256ϫ180 matrix be- cal probable MS C2 or clinical probable MS C3, according to fore and after intravenous administration of 0.1 mmol/kg of gado- Poser criteria,2 or possible MS according to McDonald crite- linium–pentetic acid. All examinations covered the brain from ria3). The onset of the neurological symptoms was limited to the level of the foramen magnum to the higher convexity of 90 days prior to randomization. Partial or complete regression the skull, using 3-mm slice thickness and no interslice gap, yield- of the neurological symptoms to exclude a primary progres- ing 44 contiguous images. The number and volume of MS le- sive course was a requisite for participation. Patients also had sions were quantified by the MSAnalyse computerized soft- to have abnormal brain MRI results according to Fazekas cri- ware as previously described.16 teria.4 Patients were excluded if they had IgA deficiency, a positive pregnancy test, sensitivity to gadolinium contrast STATISTICAL ANALYSIS material or sensitivity to human blood products. We calculated that 91 patients would be needed for the study, TREATMENT ASSIGNMENT AND MONITORING given an estimated 1-year rate to develop a second attack in the placebo group of 50%,7 an absolute effect of treatment of The study was a priori designed as a randomized, double- 30%, a 5% probability of a type I error (2-tailed), and a power blind, placebo-controlled trial. Patients’ allocation
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