MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study

Abstract

Objective: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.

Methods: Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks.

Results: Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%-29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.

Conclusions: MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.

Classification of evidence: This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.

Figure 1. Study design

Patients provided signed consent at week −4 and underwent screening. Patients were enrolled at their next monthly visit (day/week 0) if they did not have subclinical disease activity as evidenced by gadolinium-enhancing lesions on MRI and met all other eligibility criteria. At day/week 0, natalizumab-treated patients were randomized into 1 of 3 treatment arms in a 1:1:2 ratio: natalizumab (no natalizumab treatment interruption), placebo (natalizumab treatment interruption), or other therapies (IM interferon β-1a [IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP] as determined by the patient or the investigator; natalizumab treatment interruption). All patients received natalizumab infusion on day 0. IM IFN-β-1a or GA was started on day 0, following natalizumab infusion, and MP was started at week 12 (other-therapies group). Placebo infusions began (placebo group) or natalizumab infusions continued (natalizumab group) at week 4. If a patient in any treatment arm developed protocol-defined multiple sclerosis disease recurrence, treatment with high-dose corticosteroids or restarting natalizumab, at the investigators' discretion, was permitted. Following the 28-week randomized treatment period, placebo and other therapies were discontinued and natalizumab was restarted in the placebo and other-therapies groups and continued through week 52 (study end) in the follow-up period. Clinical, MRI, and laboratory evaluations were performed every 4 weeks during the randomized treatment period starting at week 0, at the time of suspected relapse, and at the week 52 follow-up visit. Expanded Disability Status Scale was assessed at day 0, at week 28, at the time of suspected relapse, and at the week 52 follow-up visit.

Figure 2. Time to MRI disease recurrence, relapse, and restarting natalizumab prior to week 28 due to disease recurrence

Time to (A) MRI disease recurrence, (B) relapse, and (C) restarting natalizumab prior to week 28 due to disease recurrence. GA = glatiramer acetate; IFN-β-1a = interferon β-1a; MP = methylprednisolone. p Values from log-rank tests are as follows: (A) p < 0.0001, (B) p = 0.0843, (C) p < 0.0001.