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Hookworm Treatment for Relapsing Multiple SclerosisA Randomized Double-Blinded Placebo-Controlled Trial

Educational Objective
To assess the effects of hookworm treatment compared with placebo on relapsing multiple sclerosis.
1 Credit CME
Key Points

Question  What are the effects of hookworm treatment compared with placebo on relapsing multiple sclerosis?

Findings  In this randomized clinical trial that included 71 patients, the median cumulative numbers of new magnetic resonance imaging lesions were not significantly different between the groups, but approximately half of participants treated with hookworm vs approximately a quarter of those receiving placebo had no detectable magnetic resonance activity. Hookworm significantly increased T regulatory cell counts in peripheral blood.

Meaning  The data from this study suggest a possible, albeit mild, therapeutic effect of hookworm infection in relapsing multiple sclerosis that warrants further study.


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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: February 4, 2020.

Corresponding Authors: Cris S. Constantinescu, MD, PhD, Section of Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham, Queen’s Medical Centre, C Floor South Block, Nottingham NG7 2UH, England (cris.constantinescu@nottingham.ac.uk); David I. Pritchard, PhD, Immune Regulation Research Group, University of Nottingham School of Pharmacy, Nottingham NG7 2RD, England (david.pritchard@nottingham.ac.uk).

Published Online: June 15, 2020. doi:10.1001/jamaneurol.2020.1118

Author Contributions: Dr Constantinescu (principal investigator) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tanasescu, Tench, Constantinescu, Onion, Auer, Ranshaw, Pritchard.

Acquisition, analysis, or interpretation of data: Tanasescu, Tench, Constantinescu, Telford, Singh, Frakich, Onion, Auer, Gran, Evangelou, Falah, Cantacessi, Jenkins, Pritchard.

Drafting of the manuscript: Tanasescu, Tench, Constantinescu, Singh, Falah, Pritchard.

Critical revision of the manuscript for important intellectual content: Tanasescu, Tench, Constantinescu, Telford, Frakich, Onion, Auer, Gran, Evangelou, Ranshaw, Cantacessi, Jenkins, Pritchard.

Statistical analysis: Tench, Constantinescu, Onion.

Obtained funding: Constantinescu, Pritchard.

Administrative, technical, or material support: Constantinescu, Telford, Frakich, Onion, Auer, Falah, Ranshaw, Jenkins, Pritchard.

Supervision: Tanasescu, Tench, Constantinescu, Evangelou, Cantacessi, Pritchard.

Other - biological and immunological sample collection, flow cytometry setup design and data analysis: Gran.

Other - Qualified Person for MA (IMP) Investigational Medicinal Products (Clinical Trials): Ranshaw.

Other - MRI analysis: Singh.

Conflict of Interest Disclosures: Dr Tanasescu reported nonfinancial support from Biogen, Teva UK, and Sanofi Genzyme and personal fees from Sanofi Genzyme outside the submitted work. Dr Constantinescu reported grants from the Multiple Sclerosis Society of Great Britain and Northern Ireland, Forman Hardy Charitable Trust via University of Nottingham, and Bayer Pharmaceuticals during the conduct of the study; grants, personal fees, and nonfinancial support from Biogen; personal fees and nonsupport from Novartis, Teva, and Merck; and grants from Sanofi Genzyme outside the submitted work. Dr Auer reported grants from the National Institute of Health Research (NIHR) and nonfinancial support from UK Research and Innovation and Biogen outside the submitted work. Dr Gran reported personal fees from Merck, Roche, Biogen, and Teva UK; grants from Biogen Idec, Merck, Bayer Healthcare, Teva UK, Novartis, and Sanofi Genzyme; and nonfinancial support from Biogen, Merck, Bayer Healthcare, Teva UK, Novartis, and Sanofi Genzyme outside the submitted work. Dr Evangelou reported grants from Patient-Centered Outcomes Research Institute, NIHR, and the Medical Research Council, nonfinancial support from Biogen, and personal fees from Novartis outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by the MS Society of the Great Britain and Northern Ireland, the Forman Hardy Charitable Trust via the University of Nottingham, and an unrestricted grant from Bayer-Schering.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the Nottingham Clinical Trials Unit, the multiple sclerosis (MS) research coordinators and administrators within the MS clinical trials unit, and all the trial participants. We also thank Herb Sewell, PhD, DDS, FMedSci, Ian Hall, MD, PhD, FMedSci, and Christopher Hawkey, MD, PhD, FMedSci (University of Nottingham), for stimulating discussions and support.

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