Hookworm Treatment for Relapsing Multiple Sclerosis: A Randomized Double-Blinded Placebo-Controlled Trial

Abstract

Importance: Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS.

Objective: To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS.

Design, setting, and participants: This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-to-treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-three patients were screened; of these, 71 were recruited (2 ineligible/declined).

Interventions: Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment.

Main outcomes and measures: The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood.

Results: Patients (mean [SD] age, 45 [9.5] years; 50 women [71%]) were randomized to receive hookworm (35 [49.3%]) or placebo (36 [50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 [51.4%] vs 10/36 [27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 [4.4%]; placebo, 34 [3.9%]; P = .01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo.

Conclusions and relevance: Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity.

Trial registration: ClinicalTrials.gov Identifier: NCT01470521.

Figure 1.. Trial Profile

Flow chart of participants and visits during the trial. At month 9 (m9), the primary end point, eradication offered. DMT indicates disease-modifying therapy; m15, month 15; MRI, magnetic resonance imaging. ^aIntention-to-treat population.

Figure 2.. New Magnetic Resonance Imaging (MRI) Lesions, Changes in Treg Cells, and Eosinophils During the Trial

A, New MRI lesions during the trial. Total new lesion count (new, newly enhancing, and enlarging lesions) in the placebo participants (26 [74%]) and the participants who received hookworm (HW) (28 [78%]) with complete MRI data. B, Change in cluster of differentiation (CD) 4+CD25^highCD127^negT cells and CD4+CD25^highFoxp3+T cells in the 2 groups during the trial. The y-axis indicates the change in the percentage of CD4+CD25^highCD127^negT cells of total CD4+T cells. The x-axis indicates the time (months). All participants with measurement used. The solid circle marker is HW (n = 35). The hollow circle is the placebo (n = 36). The error bars are ± 2 SE. C, Changes in eosinophil counts during the trial.