Worms for Immune Regulation of Multiple Sclerosis

Phase 2

Completed

• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Interventions: Biological: Placebo; Biological: Hookworm larvae

• Registration Number: NCT01470521
• Lead Sponsor: University of Nottingham

Brief Summary

The purpose of this study is to determine whether people with MS who are exposed to a small number of hookworms will have less inflammation and less MS disease activity.

Detailed Description

There is evidence that certain parasitic infections may protect against autoimmune or inflammatory diseases, including multiple sclerosis (MS), asthma and type1 diabetes. The 'hygiene hypothesis' postulates exposure to infectious agents confers protection against these disorders. One putative mechanism depends on the activity of regulatory T cells (Treg), naturally occurring or induced cells that prevent excessive immune activation and autoimmunity. Reports in the last 5 years lend credence to the hygiene hypothesis in MS: epidemiological investigations show an inverse relationship to infections with the nematode Trichuris, and a study with serial clinical, immunological and MRI follow-up shows MS patients developing intestinal parasitoses have much milder disease course compared with uninfected matched MS controls followed over 5 years. A role for Treg and also a novel population of B regulatory (Breg) cells is suggested in this study. The University of Nottingham has extensive experience with human parasite research and have completed essential safety studies of controlled infection with hookworm in normal volunteers and people with atopy. Asthma and Crohn's disease studies are underway and show an immunological effect even with 10 larvae. This is the first controlled parasite exposure study in patients with relapsing MS with in 36 patients 25 hookworm larvae vs 36 patients with placebo. Patients will be followed clinically (relapse rate, disability scores), immunologically and radiologically (serial MRI scans with Gadolinium) for 1 year. The cumulative number of new and active lesions on T2 weighted MRI will be the primary outcome measure. Regulatory network induction (Treg induction, Breg/Tr1 and NK) will be the immunological secondary outcome measure. Relapse rate will be secondary clinical outcome measure. A number of clinical, MRI and immune parameters will be exploratory measures. Cytokine profiles, eosinophil and egg counts, IgE and IgG subsets and IgE/IgG4 ratios will be measured, to relate altered immune responses to disease modulation. Immune responses will be assessed to neuroantigen and to mitogen, and parasite antigens (excretory/secretory products). This study will be an essential early step in assessing the potential for therapeutic immunomodulation with parasites in MS.

Study Timeline

• Study First Submitted: 2011-11-09
• Study First Submitted QC: 2011-11-09
• Study First Posted: 2011-11-11
• Study Start: 2011-12
• Status Verified: 2016-01
• Primary Completion: 2016-01
• Study Completion: 2016-01
• Last Update Submitted: 2016-01-28
• Last Update Posted: 2016-01-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 72

Inclusion Criteria

• Relapsing remitting MS (RRMS) (McDonald criteria) and secondary MS with super imposing relapse on condition that they fulfil the next conditions, MRI scan consistent with MS by Barkhof or Fazekas criteria
• Patients with at least 1 relapse in the last 12 months or 2 in the last 24 months;
• Patients with Expanded disability status scale (EDSS) score in the range of 0 to 5.5 at the screening and week 0 visit
• Patients of both genders, age >18 years and < 65 years
• Women of child bearing potential, (who have a negative pregnancy test) must agree to use methods of medically acceptable forms of contraception during the study.
• Be able and willing to comply with study visits and procedures per protocol.
• Understand and sign consent form at the screening

Exclusion Criteria

No populations at risk of severe illness or death will be included in this study

• Life expectancy < 6 months.
• Patient is < 5 years free of malignancy, except treated basal cell skin cancer or cervical carcinoma in situ.
• Patient with grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)
• Patients with severe and/or uncontrolled medical condition.
• Pregnancy, lactation or intention to become pregnant during the course of the study (please also see above under inclusion criterion 5)
• Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
• Anaemia (Hb <10 g/dL for females, <11 g/dL for males)
• Prior or present evidence of parasitic infection; prior treatment with anti-helminthic drugs in the last 6 years.
• Patient with serious medical or psychiatric illness that could potentially interfere with the completion of the study treatment according to this protocol
• History of poor compliance or history of drug/alcohol abuse, or excessive alcohol consumption that would interfere with the ability to comply with the study protocol,
• Severe asthma, allergy, other autoimmune disease or any condition that the physician judges could be detrimental to subjects participating in this study; including deviations deemed clinically important from normal clinical laboratory

Previous treatment

• Treatment with interferon or glatiramer acetate within 8 weeks prior to baseline or immunosuppressive drugs within 12 weeks prior to baseline
• Treatment with bone marrow transplantation, total lymphoid irradiation, monoclonal antibodies (other than natalizumab, umbilical cord stem cells, AIMSPRO at any time prior to baseline
• Treatment with corticosteroids or ACTH within 4 weeks prior to baseline
• Treatment with any investigational agent within 12 weeks prior to baseline

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participant will receive pharmacopoeial grade water
Hookworm larvae (Necator americanus)	Hookworm larvae	Participants will receive 25 live hookworm larvae

Primary Outcome Measures

Name	Time	Method
The cumulative number of new or enlarging Gd+ lesions at month 9	Month 9

Secondary Outcome Measures

Name	Time	Method
Change in expanded disability status scale (EDSS) at month 9	Month 9
Cumulative number of newly active lesions (new GD+ T1; new and enlarging T2) at month 9	Month 9
Percentage of cells positive simultaneously for CD4, CD25, foxp3	End of trial

Trial Locations

Locations (1)

University of Nottingham; 🇬🇧 Nottingham, Nottinghamshire, United Kingdom