Multiple SclerosisPhase 2WIRMS-1NCT00630383
Immunoregulation by Controlled Parasite Exposure in Multiple Sclerosis.
A Phase 2 study testing Live Hookworm Larvae and Histamine in people with Multiple Sclerosis, run by University of Nottingham at 1 site in United Kingdom.
Trial summary
The aim of the study is to determine whether controlled infection with a clinically safe number of larvae of hookworm results in an immune response that is protective in relapsing MS. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Multiple Sclerosis
- What is being tested?
- Live Hookworm Larvae and Histamine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Feb 2008to May 2008
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Patients with documented multiple sclerosis relapsing remitting or secondary progressive with relapses, according to McDonald's criteria, and an MRI scan consistent with MS according to Fazekas criteria
- Patients with at least 1 relapse in the last 12 months
- Patients with EDSS score in the range of 0 to 5.5 at the baseline visit
- Patients of both genders, age >18 years and < 60 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, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed.
Who cannot join
- 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.
- Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
Show all 16Show fewer
- 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
- 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 or immunosuppressive drugs within 26 weeks prior to baseline
- Treatment with bone marrow transplantation, total lymphoid irradiation, monoclonal antibodies, 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Nottingham University Hospital NHS Trust
Nottingham, Nottinghamshire, NG7 2UH
About this study
The aim of the study is to determine whether controlled infection with a clinically safe number of larvae of hookworm results in an immune response that is protective in relapsing MS.
Read the detailed description
Studies have shown that there may be an inverse relationship between infections with worms including hookworms and inflammatory diseases including multiple sclerosis (MS). This has been explained by a protective immune reaction that is triggered by the hookworm in the body that dampens inflammation. In mice with MS, infections with some mouse worms reduced the inflammation and damage to their brain. The primary purpose of this study is to determine whether people with MS who are exposed to a small number of hookworms will develop this protective immune reaction that may reduce MS disease activity. We also plan to determine the effect of the hookworms on relapses during 1 year study.
A study of people with MS naturally infected with intestinal parasites did show significant protection over 5 years, and the levels of biological markers of the infection and some immune substances triggered by it were similar to the ones we obtained with controlled infection in normal volunteers, allergic and asthmatic peoples. We think the study has a genuine potential to benefit people with MS, and there is known interest in the MS patient community. At the therapeutic doses proposed here, this is an innocuous infection. Natural hookworm infection affects 1 billion people worldwide, often without symptoms unless the parasite load is very high. Our controlled exposure studies have shown good tolerability and safety; the risk of infecting others and auto-infection virtually is nil in Western standard hygiene conditions. Many people with MS when asked stated they would prefer an innocuous infection with microscopic larvae to a man-made product that may have more side effects. If the protective mechanisms are determined these studies may also lead to new ways of treating MS, possibly by selecting only the specific chemical components of the worms and the immune response to them that confer protection.
The increase in MS in the Western world, along with other autoimmune inflammatory diseases and asthma may be attributed to decreased exposure to infections such as gut parasites due to improved hygiene ('the hygiene hypothesis'). In animal models, controlled parasite infections including hookworms and related worms protect against MS-like disease. Parasites have evolved host-specific molecular mechanisms to dampen or condition the excessive immune responses against them and thus survive. These parasites induce regulatory mechanisms including Treg and a novel class of B cells that also dampen immune responses called Breg and were recently shown to improve MS in natural infection. They may suppress a class of lymphocytes that cause most damage in MS, Th17 cells. We will produce, with controlled exposure, a similar response to those associated with protective natural exposure in MS. We have the unique combination of expertise in hookworm biology, controlled parasite exposure and immunology of MS and MS trials and our data from our other human studies indicate this is a safe and tolerable intervention of significant potential.
- Conditions
- Multiple Sclerosis
- Being tested
- Live Hookworm Larvae, Histamine
- Keywords
- Parasite, Necator, immune regulation, regulatory T cells, foxp3, cytokines, multiple sclerosis, hygiene hypothesis
- Medical subject headings
- Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Live Hookworm LarvaeBiological
Also called Hookworm, Necator Americanus
25 live hookworm will be applied to the arm and will infect transdermally. They will be eradicated after 48 weeks.
HistamineOther
0.01% histamine solution is pipetted onto a plaster dressing.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Patients will receive 25 live hookworm larvae. Receives: Biological: Live Hookworm Larvae |
| 2 | Placebo comparator | Patients will receive 0.01 % histamine solution. Receives: Other: Histamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary outcome measure is an increase in the percentage from total CD4+ T cells of CD4+CD25+foxp3+ cells.
Measured: End of study
Secondary outcomes (4)
The expression of foxp3 mRNA from peripheral blood mononuclear cells (PBMC).
Measured: End of study
The percentage from total PBMC of NK and NKT cells (CD3-CD56+ and CD3+CD56+ respectively).
Measured: End of study
The percentage from total CD3+ T cells of Tr1 cells (CD3+IL10+ T cells).
Measured: End of study
The percentage from total PBMC of B regulatory cells (CD20+IL-10+).
Measured: End of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Mar 2008 (estimated)
- Study startFeb 2008
- Primary completionMay 2008
- Study completionMay 2008
Why it stopped: superceded by another similar study
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by University of NottinghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Nottingham
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Cris Constantinescu, MD PhD, Principal investigator, University of Nottingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00630383
- Sponsor's protocol ID
- 08025
- Other IDs
- WIRMS-Pilot
- Acronym
- WIRMS-1
- Status last verified
- Jun 2012
- First submitted
- 27 Feb 2008
- Last updated
- 14 Jun 2012
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002 Sep 19;347(12):911-20. doi: 10.1056/NEJMra020100. No abstract available.
PubMed 12239261Edwards LJ, Constantinescu CS. A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Mult Scler. 2004 Oct;10(5):575-81. doi: 10.1191/1352458504ms1087oa.
PubMed 15471376Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007 Feb;13(2):139-45. doi: 10.1038/nm1551.
PubMed 17290272Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004 Apr 5;199(7):971-9. doi: 10.1084/jem.20031579.
PubMed 15067033Fleming JO, Cook TD. Multiple sclerosis and the hygiene hypothesis. Neurology. 2006 Dec 12;67(11):2085-6. doi: 10.1212/01.wnl.0000247663.40297.2d. No abstract available.
PubMed 17159130Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol. 2007 Feb;61(2):97-108. doi: 10.1002/ana.21067.
PubMed 17230481Sewell D, Qing Z, Reinke E, Elliot D, Weinstock J, Sandor M, Fabry Z. Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization. Int Immunol. 2003 Jan;15(1):59-69. doi: 10.1093/intimm/dxg012.
PubMed 12502726Mortimer K, Brown A, Feary J, Jagger C, Lewis S, Antoniak M, Pritchard D, Britton J. Dose-ranging study for trials of therapeutic infection with Necator americanus in humans. Am J Trop Med Hyg. 2006 Nov;75(5):914-20.
PubMed 17123987Compston A, Coles A. Multiple sclerosis. Lancet. 2002 Apr 6;359(9313):1221-31. doi: 10.1016/S0140-6736(02)08220-X.
PubMed 11955556Hotez PJ, Pritchard DI. Hookworm infection. Sci Am. 1995 Jun;272(6):68-74. doi: 10.1038/scientificamerican0695-68.
PubMed 7761817Falcone FH, Pritchard DI. Parasite role reversal: worms on trial. Trends Parasitol. 2005 Apr;21(4):157-60. doi: 10.1016/j.pt.2005.02.002.
PubMed 15780835Raine T, Zaccone P, Dunne DW, Cooke A. Can helminth antigens be exploited therapeutically to downregulate pathological Th1 responses? Curr Opin Investig Drugs. 2004 Nov;5(11):1184-91.
PubMed 15573869Quinnell RJ, Bethony J, Pritchard DI. The immunoepidemiology of human hookworm infection. Parasite Immunol. 2004 Nov-Dec;26(11-12):443-54. doi: 10.1111/j.0141-9838.2004.00727.x.
PubMed 15771680
Study at a glance
From the registry record, last updated by the sponsor on 14 Jun 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Immunoregulation by Controlled Parasite Exposure in Multiple Sclerosis.
- ClinicalTrials.gov ID
- NCT00630383
- Acronym / sponsor ID
- WIRMS-1 / 08025
- Conditions
- Multiple Sclerosis
- Keywords
- Parasite, Necator, immune regulation, regulatory T cells, foxp3, cytokines, multiple sclerosis, hygiene hypothesis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: superceded by another similar study
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of NottinghamUniversity, hospital or other
- Study start
- Feb 2008
- Primary completion
- May 2008 (actual)
- Study completion
- May 2008 (actual)
- First posted
- 7 Mar 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of the study is to determine whether controlled infection with a clinically safe number of larvae of hookworm results in an immune response that is protective in relapsing MS.
Detailed description
Studies have shown that there may be an inverse relationship between infections with worms including hookworms and inflammatory diseases including multiple sclerosis (MS). This has been explained by a protective immune reaction that is triggered by the hookworm in the body that dampens inflammation. In mice with MS, infections with some mouse worms reduced the inflammation and damage to their brain. The primary purpose of this study is to determine whether people with MS who are exposed to a small number of hookworms will develop this protective immune reaction that may reduce MS disease activity. We also plan to determine the effect of the hookworms on relapses during 1 year study.
A study of people with MS naturally infected with intestinal parasites did show significant protection over 5 years, and the levels of biological markers of the infection and some immune substances triggered by it were similar to the ones we obtained with controlled infection in normal volunteers, allergic and asthmatic peoples. We think the study has a genuine potential to benefit people with MS, and there is known interest in the MS patient community. At the therapeutic doses proposed here, this is an innocuous infection. Natural hookworm infection affects 1 billion people worldwide, often without symptoms unless the parasite load is very high. Our controlled exposure studies have shown good tolerability and safety; the risk of infecting others and auto-infection virtually is nil in Western standard hygiene conditions. Many people with MS when asked stated they would prefer an innocuous infection with microscopic larvae to a man-made product that may have more side effects. If the protective mechanisms are determined these studies may also lead to new ways of treating MS, possibly by selecting only the specific chemical components of the worms and the immune response to them that confer protection.
The increase in MS in the Western world, along with other autoimmune inflammatory diseases and asthma may be attributed to decreased exposure to infections such as gut parasites due to improved hygiene ('the hygiene hypothesis'). In animal models, controlled parasite infections including hookworms and related worms protect against MS-like disease. Parasites have evolved host-specific molecular mechanisms to dampen or condition the excessive immune responses against them and thus survive. These parasites induce regulatory mechanisms including Treg and a novel class of B cells that also dampen immune responses called Breg and were recently shown to improve MS in natural infection. They may suppress a class of lymphocytes that cause most damage in MS, Th17 cells. We will produce, with controlled exposure, a similar response to those associated with protective natural exposure in MS. We have the unique combination of expertise in hookworm biology, controlled parasite exposure and immunology of MS and MS trials and our data from our other human studies indicate this is a safe and tolerable intervention of significant potential.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Biological: Live Hookworm LarvaePatients will receive 25 live hookworm larvae. |
| 2 | Placebo comparator | Other: HistaminePatients will receive 0.01 % histamine solution. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Patients with documented multiple sclerosis relapsing remitting or secondary progressive with relapses, according to McDonald's criteria, and an MRI scan consistent with MS according to Fazekas criteria
- Patients with at least 1 relapse in the last 12 months
- Patients with EDSS score in the range of 0 to 5.5 at the baseline visit
- Patients of both genders, age >18 years and < 60 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.
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Live Hookworm LarvaeAlso: Hookworm, Necator Americanus25 live hookworm will be applied to the arm and will infect transdermally. They will be eradicated after 48 weeks. | Biological | 1 |
| Histamine0.01% histamine solution is pipetted onto a plaster dressing. | Other | 2 |
Primary outcome
Primary outcome measure is an increase in the percentage from total CD4+ T cells of CD4+CD25+foxp3+ cells.
Time frame: End of study
4 secondary outcomes
The expression of foxp3 mRNA from peripheral blood mononuclear cells (PBMC).
Time frame: End of study
The percentage from total PBMC of NK and NKT cells (CD3-CD56+ and CD3+CD56+ respectively).
Time frame: End of study
The percentage from total CD3+ T cells of Tr1 cells (CD3+IL10+ T cells).
Time frame: End of study
The percentage from total PBMC of B regulatory cells (CD20+IL-10+).
Time frame: End of study
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jun 2012.
- Background: PubMed 12239261Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002 Sep 19;347(12):911-20. doi: 10.1056/NEJMra020100. No abstract available.
- Background: PubMed 15471376Edwards LJ, Constantinescu CS. A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Mult Scler. 2004 Oct;10(5):575-81. doi: 10.1191/1352458504ms1087oa.
- Background: PubMed 17290272Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007 Feb;13(2):139-45. doi: 10.1038/nm1551.
- Background: PubMed 15067033Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004 Apr 5;199(7):971-9. doi: 10.1084/jem.20031579.
- Background: PubMed 17159130Fleming JO, Cook TD. Multiple sclerosis and the hygiene hypothesis. Neurology. 2006 Dec 12;67(11):2085-6. doi: 10.1212/01.wnl.0000247663.40297.2d. No abstract available.
- Background: PubMed 17230481Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol. 2007 Feb;61(2):97-108. doi: 10.1002/ana.21067.
- Background: PubMed 12502726Sewell D, Qing Z, Reinke E, Elliot D, Weinstock J, Sandor M, Fabry Z. Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization. Int Immunol. 2003 Jan;15(1):59-69. doi: 10.1093/intimm/dxg012.
- Background: PubMed 17123987Mortimer K, Brown A, Feary J, Jagger C, Lewis S, Antoniak M, Pritchard D, Britton J. Dose-ranging study for trials of therapeutic infection with Necator americanus in humans. Am J Trop Med Hyg. 2006 Nov;75(5):914-20.
- Background: PubMed 11955556Compston A, Coles A. Multiple sclerosis. Lancet. 2002 Apr 6;359(9313):1221-31. doi: 10.1016/S0140-6736(02)08220-X.
- Background: PubMed 7761817Hotez PJ, Pritchard DI. Hookworm infection. Sci Am. 1995 Jun;272(6):68-74. doi: 10.1038/scientificamerican0695-68.
- Background: PubMed 15780835Falcone FH, Pritchard DI. Parasite role reversal: worms on trial. Trends Parasitol. 2005 Apr;21(4):157-60. doi: 10.1016/j.pt.2005.02.002.
- Background: PubMed 15573869Raine T, Zaccone P, Dunne DW, Cooke A. Can helminth antigens be exploited therapeutically to downregulate pathological Th1 responses? Curr Opin Investig Drugs. 2004 Nov;5(11):1184-91.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Cris Constantinescu, MD PhD principal investigator
University of Nottingham
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Live Hookworm Larvae and Histamine in people with Multiple Sclerosis, run by University of Nottingham at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 14 Jun 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Primary outcome measure is an increase in the percentage from total CD4+ T cells of CD4+CD25+foxp3+ cells. (time frame: End of study). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00630383, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2012.