Intravenous immunoglobulin for maintenance treatment of multifocal motor neuropathy: A multi‐center, open‐label, 52‐week phase 3 trial

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg‐dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open‐label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand‐grip strength at week 52. This trial is registered with http://clinicaltrials.gov, number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN.


| INTRODUCTION
Multifocal motor neuropathy (MMN) is an immune-mediated peripheral neuropathy, characterized by progressive asymmetric distal muscle weakness predominantly in the upper extremities, and pure motor involvement. 1,2 Current therapeutic options for MMN are limited, and intravenous immunoglobulin (IVIg) therapy is only one established treatment; as MMN patients do not respond to corticosteroids or plasma exchange. 3,4 So far, 5 randomized, placebo-controlled trials of IVIg for MMN have shown significant short-term improvement in muscle strength, up to 12 weeks. [5][6][7][8][9] Based on these data, the joint European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) taskforce recommended IVIg (2 g/kg) as a first-line treatment for MMN. 1 The taskforce also proposed that "if this induction therapy is effective, repeated IVIg should be considered with the frequency of maintenance therapy dose are 1 g/kg every 2-4 weeks, or 2 g/kg every 1-2 months". However, there is limited evidence for the dose and interval of maintenance IVIg.
No long-term clinical trials that investigated the efficacy and safety of IVIg in MMN have been performed. Four retrospective studies have described MMN patients who have received repeated IVIg therapy over several years, and suggested that it may be used as the long-term treatment option for MMN. [10][11][12][13] In these reports, the IVIg regimen, interval, and treatment response varied among patients; some experienced sustained remission and others had gradual progression of muscle weakness presumably because of Wallerian degeneration. The aim of this clinical trial is to study the efficacy and safety of maintenance IVIg (1.0 g/kg every 3 weeks) for 52 weeks in patients with MMN.

| Study design and patients
This study was a multi-center, single-arm open phase 3 trial conducted at 11 Japanese tertiary hospitals. The study procedures were in accordance with the Declaration of Helsinki, and Japanese Good Clinical Practice criteria, and approved by the internal review board of each hospital. This study is registered with ClinicalTrials.gov, number NCT01827072.
A total of 13 patients with definite or probable MMN according to the EFNS/PNS clinical diagnostic criteria were enrolled. 4 The inclusion criteria were defined as (1) requiring a high-dose IVIg treatment (having declining motor function), (2)

| Procedures
The study design and trial profile are shown in Figure 1. After screening, IVIg (0.4 g/kg/d for consecutive 5 days) was administered as the induction treatment. This visit was regarded as week 1 in the induction period. After 3 weeks, IVIg was then administered (1.0 g/kg/d for 1 day, or 0.5 g/kg/d for consecutive 2 days) as the maintenance treatment. This visit was regarded as week 4 in the study. Glovenin-I (freeze-dried polyethylene glycol-treated human immunoglobulin, Nihon Pharmaceutical Co., Ltd., Tokyo, Japan) was used for maintenance treatment. The maintenance IVIg was administrated every 3 weeks from week 4 to week 49 in the maintenance period, with observation conducted until week 52. If additional treatment for MMN was needed, the patient dropped out.
For neurological assessment, MRC sum score, hand-grip strength, and Guy's Neurological Disability Scale (GNDS) score 15 were assessed at each visit. Each neurological assessment, except at week 52, was conducted before administration of IVIg.

| Outcome measures
The outcome measures were MRC sum score, hand-grip strength score, and GNDS score. Difference in the mean scores at week 1 and week 52 was calculated. These measures were not distinguished as primary and secondary because the number of MMN patients included in this trial was small. Safety assessments included any adverse event during the study period.

| Efficacy
Results of the outcome measures are shown in Table 2. The mean value of MRC sum score, hand-grip strength, and GNDS score
Three patients experienced serious adverse events, including coronary artery stenosis (n = 1), dysphagia (n = 1), and inguinal hernia (n = 1). None of them was considered to relate with IVIg.

| DISCUSSION
The present study showed that after conventional induction IVIg therapy, maintenance IVIg treatment (1.0 g/kg) every 3 week resulted in sustained clinical improvement for 52 weeks. The results were supported by sequential findings of MRC sum score, grip strength, and GNDS score. The maintenance IVIg therapy was not associated with clinically significant adverse effects. Our results show the long-term efficacy and safety of the maintenance IVIg.
In previous retrospective studies, a variable maintenance IVIg regimens, such as 1.0 g/kg every 2 to 4 weeks, or 2 g/kg every 1 to 2 months, were used dependent on patients' condition. Whereas disease activity, immunoglobulin metabolism, and response to treatment are presumably different among patients with MMN, the optimal dose and interval may be determined according to patients' situation. Nevertheless, this study revealed uniform regular maintenance IVIg administration was successful in almost of the MMN patients enrolled.
The regimen used in this trial can be an option to achieve sustained remission in MMN at least for 52 weeks.
In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), approximately 25% of patients have long-lasting remission without immunological treatment, 16,17 and prolonged maintenance therapy could be over treatment. However, such remitting course is rare for MMN, 10 and MMN patients may require maintenance therapy for more than 52 weeks. Therefore the duration of IVIg therapy, as well as, the optimal regimen, for longer maintenance IVIg for MMN patients should be evaluated in future studies.
A recent clinical trial for CIDP using the same maintenance dose (1.0 g/kg) and interval (every 3 weeks) for 52 weeks has also shown similar long-term efficacy. 18 In that study, 2 of the 49 enrolled elderly patients with hypertension or diabetes developed cerebral infarction.
Whereas thromboembolic events did not occur in the present study, hyperviscosity-induced thrombotic complications should be carefully monitored during a long-term IVIg treatment.
In conclusion, 52-week maintenance IVIg therapy appears to be safe and efficacious to prevent a relapse for MMN patients. The