MS disease activity in RESTORE

Study design.

In this phase 4, randomized, multicenter, partially placebo-controlled, parallel-group exploratory study, patients with MS receiving natalizumab were randomized into 3 treatment arms in a 1:1:2 ratio: natalizumab:placebo:alternate immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a] [Avonex, Biogen Idec Inc., Cambridge, MA], glatiramer acetate [GA] [Copaxone, Teva Neuroscience, Kansas City, MO], or methylprednisolone [MP]). In the other-therapies group, patients and their neurologist selected the immunomodulatory therapy on an individual basis; as such, the distribution of patients receiving IM IFN-β-1a, GA, and MP was not randomized, and the groups were unbalanced (figure 1). Planned enrollment was approximately 160 patients randomized 1:1:2 natalizumab:placebo:other therapies. As an exploratory study, the sample and randomization allocation were chosen to evaluate trends in radiologic and clinical disease recurrence in each group. Patients from 31 sites in North America and Europe were randomized using a centralized interactive voice response system at the baseline visit, and randomization was stratified by country and pretreatment disease activity (high vs low). High disease activity was defined as ≥2 relapses within 12 months prior to initiating natalizumab therapy. The study was performed between March 2010 and November 2011.

• Download figure
• Open in new tab
• Download powerpoint

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.

Standard protocol approvals, registrations, and patient consents.

Each site's institutional review board reviewed and approved the study protocol and amendments, and all participants provided written informed consent. The study was performed in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guideline on Good Clinical Practice and is registered with ClinicalTrials.gov, number NCT01071083.

Primary research question.

This analysis of patients with MS who were relapse-free for 1 year on natalizumab therapy was conducted to compare clinical and MRI outcomes during natalizumab treatment interruption with those in patients remaining on natalizumab. While the effects of alternative therapies during natalizumab interruption were also assessed, RESTORE was not designed to compare the efficacy of the different alternative 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. Because of differences in baseline characteristics and the open-label design, the comparisons with the alternative immunotherapies group provide Class IV evidence.

Patients.

RESTORE enrolled patients between 18 and 60 years of age with relapsing forms of MS who had been treated with natalizumab for at least 12 months prior to randomization and who had no relapses during those 12 months.

Exclusion criteria included the presence of gadolinium-enhancing (Gd+) lesions on screening MRI; presence of antinatalizumab antibodies at screening; history of significant infectious illness or significant disease other than MS; and inability to undergo monthly MRI scans for 6 months. Patients were also excluded if they received immunosuppressive treatment within 24 months prior to randomization; treatment with IV immunoglobulin, plasmapheresis, or cytapheresis within 12 months prior to randomization; or treatment with systemic corticosteroids within 3 months prior to randomization.

Interventions.

At the baseline visit (day 0), all patients received a standard 300-mg natalizumab infusion. Starting at week 4, patients randomized to natalizumab or placebo received infusions every 4 weeks through week 24 in a double-blind fashion. Patients randomized to other therapies who chose IM IFN-β-1a or GA received their first injections on day 0. Patients randomized to other therapies who chose MP received infusions every 4 weeks starting at week 12. All 3 other therapies were administered open-label. 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 final visit.

At week 28, patients resumed open-label infusions of natalizumab and stopped placebo or other therapy. Participants were followed for an additional 24 weeks, concluding the study at week 52.

Treatment for MS disease recurrence.

If a patient experienced protocol-defined evidence of MS disease recurrence during the randomized treatment period, the investigator had the option of administering high-dose corticosteroid treatment as per local standard of care or restarting open-label natalizumab infusions. Because natalizumab discontinuation has been linked to severe clinical relapses in some studies,^15,18,19 disease recurrence criteria incorporated subclinical measures of radiographic disease activity as detected by every-4-week brain MRI scans. This method allowed physicians to use radiographic criteria to initiate treatment with corticosteroids or restart natalizumab.

Disease recurrence criteria were (1) 1 Gd+ lesion of >0.8 cm³ in volume, (2) 2 or more Gd+ lesions of any size, as reported by the Central MRI Reading Center (NeuroRx Research, Montreal, Canada), or (3) a relapse defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours and associated with any of the following: an increase of ≥1 grade in ≥2 functional scales of the Expanded Disability Status Scale (EDSS); an increase of ≥2 grades in one functional scale of the EDSS; an increase of ≥1.0 in the overall EDSS score if the previous overall EDSS score was 0.0–5.5; or an increase of ≥0.5 if the previous overall EDSS score was >5.5.

Patients who restarted natalizumab during the randomized treatment period entered the follow-up period immediately and were followed on open-label natalizumab for 24 weeks. The end of the follow-up period for these patients was considered “week 52,” even though their total study time may have been less than 52 weeks.

Assessments.

The objective of this study was to assess radiographic and clinical disease activity in patients with MS undergoing up to a 24-week interruption of natalizumab therapy. The time course to return of radiologic or clinical evidence of MS activity was assessed by Gd+ lesions on cranial MRI and clinical relapse.

Evaluations of quality of life (QOL) using a Visual Analogue Scale (VAS), fatigue using the Modified Fatigue Impact Scale, and cognition using the Symbol Digit Modalities Test (SDMT) were performed at the same time points as clinical, MRI, and laboratory evaluations (every 4 weeks during the randomized treatment period starting at week 0, at the time of suspected relapse, and at the final visit). EDSS was assessed at day 0, at week 28, at the time of suspected relapse, and at the final visit. EDSS and SDMT evaluations were performed by clinical staff blinded to treatment assignment. The Central MRI Reading Center that performed MRI assessments was blinded to treatment allocation. Investigators assessed patient safety by physical examination (including vital signs), concomitant therapy and procedure recording, laboratory tests, and adverse event and serious adverse event recording.

Statistical analysis.

All efficacy analyses were performed on an evaluable population that completed the study through at least week 4 and did not incur any of the following major protocol deviations: testing positive for anti-IFN-β-1a antibodies and choosing IFN-β-1a as an alternative immunomodulatory therapy, not receiving the day 0 (baseline) natalizumab dose, and being previously randomized into the study.

Baseline comparisons were performed using a 1-way analysis of variance for continuous variables and Fisher exact test for proportions. Other proportions are presented with exact binomial confidence intervals and were compared using Fisher exact test. Kaplan-Meier analyses were performed and p values from log-rank tests are provided.