Helminthic therapy clinical trials

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    This page lists clinical, observational, and epidemiological studies concerning helminthic therapy.

    Please note: the most robust clinical studies are based on a defective protocol. They have been grouped together in a separate section.

    See also

    Clinical trials by disease[edit | edit source]

    Allergy[edit | edit source]

    Allergic sensitisation increased following treatment with albendazole.
    "There is a negative association between a chronic helminth infection and skin prick test reactivity even in a developed country."
    "Intestinal parasite infection appears to protect against allergic sensitization".
    "Anthelminthic treatment of chronically infected children results in increased atopic reactivity, which indicates that helminths directly suppress allergic reactions".

    Allergic rhinitis[edit | edit source]

    Alzheimer[edit | edit source]

    Asthma[edit | edit source]

    See also Allergy, above.

    Result: in this trial, experimental infection with ten hookworm larvae (NA) in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control during the 16 week trial period. However, a single dose of 10 larvae is known to be an insufficient number of NA to produce therapeutic benefits in some individuals, and 16 weeks insufficient time to assess the effects of these living organisms which, in most cases, do not even begin to produce consistent benefits until at least 12 weeks and, in some cases, not until 2 years post-inoculation. For more about this, see Problems with clinical trials using live helminths: Trialing the human hookworm (NA), below.
    This study explored the dose of hookworms that would be required to have a therapeutic effect on asthma.

    Autism[edit | edit source]

    • 2012-2018 - TSO pH 2.4 and 5.0 - 11-11-384 - Montefiore NYO - Trichuris Suis Ova in Autism Spectrum Disorders.
    Treatment: T. suis 2500 ova or placebo orally every 2 wks for 12 wks, 4-week washout, then crossover.
    Results: 10 patients. No significant adverse effects. Results: 2016 May - TSO pH 2.4 - Trichuris Suis Ova (TSO) as an immune-inflammatory treatment for repetitive behaviors in autism spectrum disorders (ASD), Second part with pH 5.0 with poor results: Trend for treatment arm to be more beneficial than placebo but did not reach statistical significance. See: Randomized crossover feasibility trial of helminthic Trichuris suis ova versus placebo for repetitive behaviors in adult autism spectrum disorder
    (NB The phase 2 trial was done with a version of TSO at pH 5.0, which is known to be less effective than the commercially available TSO product at pH 2.4. See "Defective clinical trials" below.)

    Cancer[edit | edit source]

    Cardiovascular disease[edit | edit source]

    "In the Ugandan context, living in rural fishing communities may protect against hypertension but worsen glucose metabolism"
    "Helminth infections improve lipid profiles and may lower blood pressure"
    Results: The high level of HDL-C and the low level of LDL-C, VLDL, triglycerides and PON1 activity in alcoholic patients infected with S. stercoralis evidenced an anti-atherogenic pattern

    Coeliac / celiac disease[edit | edit source]

    Conclusion: "Hookworm infection does not restore tolerance to sustained moderate consumption of gluten (2 g/d) but was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.".
    Comment by Mark Davis on a podcast:
    "…an Australian researcher named Croese … did a trial that I did a writeup on where he gave Necator americanus to people with biopsy-proven celiac disease. And then he slowly microdosed gluten and gave them more and more and looked at their tTg, tissue transglutaminase, and their DGP, their deamidated gluten peptidase, the two big blood markers for celiac disease.
    "And he did biopsies of their small bowel over time and kept giving them more and more until they were literally, I think eight out of 11 of them were literally eating a bowl of spaghetti a day, a literal bowl of spaghetti a day as part of this study, people with biopsy proven celiac disease. And of those eight who finished the trial, three dropped out. I think one just moved and two experienced symptoms or something like that. But the eight out of 11 who finished the trial said they had no symptoms, no increase in tTg or DGP, and their marsh scores on their biopsies looked fine. Nothing does that…
    "That was the (study) that got everyone excited. And then maybe two years ago, the same research group, Croese et al, did a follow-up study, which was way messier, way messier, and more confusing and hard to interpret. It was in Australia and New Zealand and the New Zealand group had way worse outcomes. Maybe there was something in the mailing process that damaged (the helminths), but we don't know. So they took the whole group as a whole, and there was not statistical significance between the Necator americanus group and the placebo group, but all sorts of bizarre things happened. Like a substantial number of people in the placebo group started to eat gluten and had no symptoms and no elevated tTg or DGP, and their marsh scores looked fine. What? Then how do you interpret that? Oh my gosh."
    Treatment: Larvae inoculation at weeks 0 (n = 10) and 4 (n = 10), followed by small, incremental gluten challenge in 12 subjects.
    Results: No serious adverse events. Ten subjects successfully completed low-dose gluten challenge.
    Treatment: Larvae inoculation at weeks 0 (n = 7) and 12 (n = 7). Seven subjects challenged at 20 weeks with 16 g gluten orally per day for 5 days.
    Results: No serious adverse events. Duodenal biopsies cultured with gluten antigen produced more IL-10 and IL-5 post-infection
    Treatment: Larvae inoculation at weeks 0 (n = 10) and 12 (n = 5) and placebo (n = 10). Twenty subjects challenged at 20 weeks with 16 g gluten orally per day for 5 days.
    Results: Transient enteritis in five subjects. Hookworm-infected mucosa retained healthy appearance. Infection resulted in no obvious benefit on pathology.

    Crohn's disease[edit | edit source]

    • 2014-2018 - P28GST - Phase 2 - ACROHNEM - Lille, France - Safety Study of P28GST Treatment in Crohn's Disease Patients.
    Treatment: Injections of P28GST protein (100 μg) at 1-month intervals for 3 months (n = 24).
    Results: 2019 Jun 12 Contribution of the Gut Microbiota in P28GST-Mediated Anti-Inflammatory Effects: Experimental and Clinical Insights -- Full text.
    See also 08/12/2021 Compréhension du mécanisme d'action de la P28GST dans le traitement des maladies inflammatoires auto-immunes (Thesis in French). Also reported by Le Figaro (French)
    Treatment: 56 patients randomised to received 10 necator americanus or placebo during 12 weeks.
    Results: "Our preliminary analysis appears to exclude any significant overall benefit from treatment with 10 Necator americanus larvae in active Crohn's Disease".
    NB: The most significant revelation in the abstract is the fact that the trial only lasted for 12 weeks, which, while the standard length for drug trials, is nowhere near adequate for a trial of helminths, which typically don’t begin to deliver consistent benefits until after 12 weeks, and in some cases, not for up to 2 years post initial inoculation
    Investigated whether Crohn’s disease patients would tolerate a hookworm infection, and the practical issues associated with establishing reservoir donors for this species.
    Treatment: Larvae inoculation at week 0 (n = 9). Reinoculation between weeks 27–30 (n = 5).
    Results: No serious adverse events. Five patients from first inoculation were in remission at week 45
    TSO is shown to offer a unique, safe and effective alternative treatment for Crohn's disease, and potentially protection against other immunological disorders.
    This trial showed that pig whipworm ova (TSO) can reduce symptoms of Crohn’s disease without producing side effects.
    Treatment: Oral inoculation (2,500 ova) monitored over 12 weeks in 7 patients (4× Crohn’s disease, 3× UC).
    Results: Clinical improvements observed with no serious adverse events. According to the IBD Quality of Life Index, six of seven patients (86%) achieved remission

    Diabetes type 1[edit | edit source]

    "The present study showed that patients with T1D were significantly less parasitized with intestinal G. lamblia and A. lumbricoides than those with T2D. Helminth infections might protect against T1D diabetes development by disrupting the pathways leading to the Th1-mediated destruction of insulin-producing beta cells mediated by mechanisms related to the capacity of the host to mount a Th2 response to parasites, thus, decreasing the frequency of T1D"

    Diabetes type 2[edit | edit source]

    Results: "In summary, our study reveals that hookworm infestation may confer protection against the pathology associated with T2DM by alleviating the altered levels of glucose indices, pancreatic hormones, incretins, and adipocytokines… Furthermore, our results highlight the potential of worms as a new therapeutic strategy to conquer T2DM by regulating host immunity."
    Results : The present study suggests that experimental infection with low hookworm doses is safe and is associated with improvements in glucose homoeostasis in people with Metabolic Syndrome and at risk of type 2 diabetes mellitus.
    Results : "Our findings suggest that mass deworming has long-term harmful health consequences by significantly increasing the probability of diabetes".

    Eczema[edit | edit source]

    Infectious diseases[edit | edit source]

    Leaky gut[edit | edit source]

    Metabolic syndrome[edit | edit source]

    "Potential long-term effects of PSI (previous schistosome infection) may reduce the risk of metabolic syndrome"

    Migraine[edit | edit source]

    Treatment : Eleven patients with the diagnosis of refractory chronic migraine. After the run-in period, patient ingested TSO every 2 weeks for 5 month.
    Results : Results : 5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month) (...) 4 of 11 patients did not meet the primary endpoint. 1 patient did not supply data, and another discontinued due to diarrhea. So there is 50% of improvement with TSO.

    Multiple sclerosis[edit | edit source]

    (See also the original study proposal from 2011: Worms for Immune Regulation of Multiple Sclerosis (WIRMS)).
    This research was also reported in Science Daily, where it was noted that, “The findings of the research… show that infecting MS patients with a safe dose of… Necator americanus induces immunoregulatory responses and boosts the number of cells which help keep the immune system under control.” [7]
    In fact, the trial data reveal that more than half the patients given hookworms did not develop any new lesions, and the conclusion of the trial's lead researcher was that, "there would be a niche for this approach - for individuals with mild disease who don't want to take immunomodulating drugs for life and would prefer a more natural approach.” [8]
    The conclusion published by this study's authors in their formal report - that NA appeared to be ineffective against MS - and the sceptical tenor of the editorial from Jama Neurology, [9] were based on the fact that the particular statistical endpoint determined for the trial by its designers - the cumulative number of new/enlarging T2 and new enhancing T1 lesions at month 9 - had not been reached. This conclusion is a glaring example of the endemic failure within the mainstream medical research community to understand, and accommodate, the unique requirements of living organisms when they are being trialled as a therapy. To read more about this, see, Problems with clinical trials using live helminths.
    Treatment: Prospective clinical monitoring study of parasite-infected patients with relapsing-remitting disease (n = 12). Four patients received anti-parasitic treatment over the monitoring period.
    Results: After antiparasitic treatment, patients presented with increased numbers of exacerbations. This was met with a decrease in IL-10- and TGFβ-secreting cells
    Treatment: Five subjects with newly diagnosed, treatment-naive relapsing-remitting multiple sclerosis (RRMS) were given 2500 TSO orally every 2 weeks for 3 months in a baseline versus treatment control exploratory trial.
    Results: The mean number of new gadolinium-enhancing magnetic resonance imaging (MRI) lesions (n-Gd+) fell from 6.6 at baseline to 2.0 at the end of TSO administration
    NB HINT2 - see below - was done with a version of TSO at pH 5.0, which is known to be less effective than the TSO product at pH 2.4 that is commercially available and was used in Weinstock's early trials.
    • 2008 - NA - WIRMS-1 - University of Nottingham - Immunoregulation by Controlled Parasite Exposure in Multiple Sclerosis. (WIRMS-1).
    Treatment: Single dermal inoculation (25 larvae) at week 0. Placebo group included.
    Results: Withdrawn prior to enrollment, superceded by similar study
    This was the first study to explore the effect of helminth infection on immune response and the natural course of Relapsing Remitting Multiple Sclerosis. It showed that MS progressed much more slowly in patients who hosted intestinal worms.
    Treatment: Prospective clinical monitoring study of parasite-infected patients (n = 12) and non-infected patients (n = 12).
    Results: Parasite-infected patients presented with fewer numbers of exacerbations. A significant increase in IL-10 and TGFβ and a decrease in IL-12 and IFNγ observed in self-reactive cells

    Obesity[edit | edit source]

    "Our data offer a possible biological mechanism for the protective effect of Strongyloides stercoralis infection on obesity"

    Psoriasis[edit | edit source]

    • 2012-2012 - TTO and TSO pH 1.0 - NCT03079700 - Denmark - Mucosal and Systemic Immune Modulation From Trichuris Suis in a Self-infected Individual.
    "The included volunteer is a researcher within parasitology with main focus on Trichuris trichiura and Trichiura suis. He planned to infect himself and contacted our department with the purpose of being monitored during this infection for safety (medical supervision) and research reasons. The only clinical criterion for his inclusion in the study was that he was healthy."
    Results 2016 Oct 15 for TTO Mucosal and systemic immune modulation by Trichuris trichiura in a self-infected individual -- PDF.
    Results 2017 Jun 8 for TSO - Immune responses and parasitological observations induced during probiotic treatment with medicinal Trichuris suis ova in a healthy volunteer
    Comment by Detlev Goj:
    Quotein.gif
    Strangely, this patient has received TTO (trichiuris trichura, the human whipworm, prior to Trichuris suis from the very same group of authors [12]. It is under very strong doubt that the worms the authors claim to have found in this patient was Trichuris suis rather than from the previous inoculation he had with TTO. Especially because he was only treated with one dose of Mebendazole. TTO is quite difficult to kill and it takes much more than a quick shot of Mebendazole.
    Comment by William Parker:
    Quotein.gif
    The report by Williams and colleagues in the August issue of Immunology Letters describes a case in which a scientist exposed himself/herself to a helminth well-known among the veterinary community, the porcine whipworm. The intention was to observe the effects of exposure to the helminth on the scientist’s immune disorder and to monitor the fate of the organisms following that exposure. The scientist saw improvement in his or her psoriasis (...) Fortunately, Williams used a lower pH formulation (produced in-house using the ParaTech protocol and stored at pH 1). [13] (PDF)
    The authors of this report also claimed that, during their study, they made "the first definitive observations that T. suis can mature to adult size and reproduce in humans". However, patent infection was claimed solely on the basis of colonoscopic examination and the passage of unembryonated whipworm eggs in the subject’s faeces, neither of which provides definitive proof of species. The subject had in fact previously hosted the human whipworm, Trichuris trichiura (TT), which was assumed by those conducting the study to have been eradicated following the administration of mebendazole. However, the use of mebendazole to eradicate TT is not reliable unless 100mg of the drug is taken twice daily for at least 3-5 days (see Terminating a human whipworm infection) so, in spite of the bold claim by the researchers that they were the first to report a patent TS infection in a human volunteer undergoing TSO treatment, it is likely that the adult whipworms observed in this case were TT and not TS, and that the eggs were TTO and not TSO.

    Rheumatoid Arthritis[edit | edit source]

    Ulcerative colitis[edit | edit source]

    Treatment: Oral inoculation (2,500 ova) at 2-week intervals for 12 weeks (n = 30). Placebo group included (n = 24).
    Results: Treatment cohort saw 43% improvement in disease index. No serious adverse events
    This trial showed that pig whipworm ova (TSO) can reduce symptoms of Crohn’s disease without producing side effects.
    Treatment: Oral inoculation (2,500 ova) monitored over 12 weeks in 7 patients (4× Crohn’s disease, 3× UC).
    Results: Clinical improvements observed with no serious adverse events. Three patients experienced remission relapse 12 weeks after the initial dose

    Well people[edit | edit source]

    • 2024-2026 - NA - HiBiSki - Leiden (NLD) - Investigating the Local Immune Responses in the Skin After Repeated Hookworm Infection
    • 2015-2026 - NA - SVI-CH-01 - Leiden (NLD) - An Experimental Infection Study of Dermally-applied Infectious Necator Americanus Hookworm Larvae in Hookworm-naïve Adults
    • 2018-2019 - NA - ITCHHI - Leiden (NLD) - Immunisation, Treatment and Controlled Human Hookworm Infection

    Others[edit | edit source]

    "Natural hookworm infection induces a high frequency of circulating monocytes that present a regulatory profile and promote the downmodulation of the proinflammatory response"

    Defective clinical trials[edit | edit source]

    Due to a number of significant issues with the design of many of the trials using live helminths, specifically those trials the results from which were published between 2011 and 2024, the conclusions drawn by the authors of these studies cannot be relied upon.

    The design flaws in question are elaborated in Problems with clinical trials using live helminths, below.

    Dr. Falk Pharma GmbH / Coronado Biosciences (Fortress Biotech) clinical trials[edit | edit source]

    See Press Release for more details.

    NB. The TSO product used in all the Dr. Falk Pharma / Coronado Biosciences clinical trials was stored in a solution at pH 5.0, whereas all previously successful trials of TSO had used a storage solution at pH 2.4. This change to a much higher pH was insisted upon by Dr. Falk Pharma against the advice of Ovamed, the developer of TSO who had been closely involved in the earlier successful trials and who stressed that the proposed higher pH would be likely to have a negative effect on the product's efficacy by triggering premature hatching of the ova. [15]

    Comment by William Parker:
    Quotein.gif
    ... the field suffered more than a catastrophic failure when Ovamed, the owner of the TSO technology, shut down clinical trials in mid-2015 due to a lack of effectiveness. But failure of a helminth in a clinical trial, more so than failure of a precisely characterized pharmaceutical, is not necessarily a sign that potential is low. Our socio-medical studies (2) suggest that storage of TSO at a pH above 4, the standard used in the Ovamed-sponsored trials, may impede the therapeutic effect of the organisms in humans. [16] (PDF)

    Allergic rhinitis

    Autism

    • 2014-2015 - TSO pH 5 - 0522-12-HMO - Jerusalem, Israel - TSO in Pediatric Autistic Spectrum Disorders (TSO). Treatment: T. suis 2500 or 7500 ova or placebo orally every 2 wks for 16 wks. Results: study terminated due to shut down of supplier Ovamed.
    • 2014-2015 - TSO pH 5 - CNDO 201-101 - Efficacy and Safety of Trichuris Suis Ova (TSO) as Compared to Placebo in Autism Spectrum Disorder. Treatment: T. suis 2500 ova or placebo orally every 2 wks for 4 wks followed by 7500 ova every 2 wks for 12 wks, 4-week washout, then crossover. Results: Study terminated prior to enrollment.

    Crohn's disease

    • 2010-2014 - TSO pH 5 - Phase 2 - TRUST-2 - Trichuris Suis Ova (TSO) Suspension Versus Placebo in Active Crohn's Disease (TRUST-2). Treatment: Oral inoculation (low, medium, and high-dose ova) with placebo group included. Results: study results unknown
    • 2012-2014 - TSO pH 5 - Phase 2 - TRUST-I Phase 2: Efficacy and Safety of Trichuris Suis Ova (TSO) as Compared to Placebo (TRUST-I). Treatment: Oral inoculation (7,500 ova) at 2-week intervals for 10 weeks. Placebo group included. Results: "In the overall patient population, response rate of patients on TSO did not separate from that of placebo" [18]. "The company later canceled a European Phase 2 study due to lack of efficacy, the London School of Hygiene and Tropical Medicine's Helmby wrote in BMC Immunology" [19]
    • 2011-2012 - TSO pH 5 - Phase 1 - CNDO 201-002 - A Sequential Dose-Escalation, Double-Blind, Placebo-Controlled, Phase I Study to Evaluate the Safety and Tolerability of Single Doses of 3 Different Doses of Oral CNDO 201 Trichuris Suis Ova Suspension (Tso) in Patients With Crohn's Disease. Treatment: Sequential dose escalation (500, 2,500, and 7,500 ova) given orally (n = 27). Placebo group included (n = 9). Results: Minor adverse events seen in both placebo and treatment groups. Infection resulted in no obvious benefit to pathology. Seven thousand five hundred ova dose was safe and well tolerated

    Food Allergies

    • 2010-2011 - TSO pH 5 - Phase 1 - 2009P000414 - Boston (USA) - Trichuris Suis Ova Therapy for Mild to Moderate Peanut and Tree Nut Allergy in Adults and Children. According to Detlev Goj "This was a safety study not going for efficacy".

    Relapsing-remitting multiple sclerosis

    Psoriasis

    • 2014-2015 - TSO pH 5 - CNDO 201-201 - TSO for Plaque Psoriasis. Treatment: Three arms. First arm, oral inoculation (7,500 ova) every 2 weeks for 10 weeks. Second arm, oral inoculation (15,000 ova) every 2 weeks for 10 weeks. Third arm, placebo comparator. Results: Withdrawn
    • 2013-2014 - TSO pH 5 - TSOPSO13 - Tufts (USA) - Efficacy Study of Trichuris Suis Ova to Treat Chronic Plaque Psoriasis. Treatment: Oral inoculation (7,500 ova) every 2 weeks for 14 weeks. Results: Lack of efficacy
    • 2013-2014 - TSO pH 5 - GCO 12-188 - Mount Sinai (USA) - Safety and Effectiveness of CNDO 201Trichuris Suis Ova (TSO) for the Treatment of Moderate to Severe Plaque Psoriasis. Treatment: Two arms. First arm, oral inoculation (2,500 ova) every 2 weeks for 10 weeks. Second arm, oral inoculation (7,500 ova) every 2 week for 10 weeks. Total study (n = 8). Resuts: Study results unknown

    Rheumatoid arthritis

    • 2011 - TSO pH 5 - TSORA. Immanuel Krankenhouse in Berlin. Trichuris suis ova (TSO) as a additional therapy for rheumatoid arthritis patients with insufficient response to methotrexate. A prospective, double-blind, randomized, controlled monocenter study. Treatment: Oral inoculation (2,500 ova) every 2 weeks for 24 weeks. Placebo group included. Total study (n = 50). Results: "Prematurely Ended"

    Ulcerative Colitis

    • 2013-2015 - TSO pH 5 - CNDO 201 - A Prospective, Randomized, Double-blind, Placebo-controlled Phase II Clinical Study of Trichuris Suis Ova Treatment in Left-sided Ulcerative Colitis and Its Effects on Mucosal Immune State and Microbiota
    • 2012-2015 - TSO pH 5 - MUCUS - NYU Langone Health (USA) - Mucosal Immunity of Ulcerative Colitis Patients Undergoing Therapy With Trichuris Suis Ova - Treatment: Two arms. First arm, oral inoculation (2,500 ova) at 2-week intervals for 12 weeks followed by placebo for 12 weeks. Second arm, placebo for 12 weeks followed by oral inoculation (2,500 ova) at 2-weeks intervals for 12 weeks. Results: According to Detlev Goj "Because of the small sample size of this study, investigators decided it was not possible to draw meaningful conclusions from the outcome measures and outcome measures were not collected or analyzed as originally planned. Therefore, no outcome measure data is available."

    ParaTech A/S[edit | edit source]

    ParaTech was a company set up by Detlev Goj in association with scientists from Copenhagen University, but the researchers' use of a seriously flawed trial design, about which they had omitted to consult Goj, led to the trial’s failure. The company was subsequently wound up in 2024.

    NB. The TSO product used in ParaTech clinical trial was stored in a solution at pH 5.0, whereas all previously successful trials of TSO had used a storage solution at pH 2.4. This change to a much higher pH was also insisted upon by Dr. Falk Pharma against the advice of Goj, the developer of TSO who had been closely involved in the earlier successful trials and who had stressed that the proposed higher pH would be likely to have a negative effect on the product's efficacy by triggering premature hatching of the ova. [23]

    Ulcerative Colitis

    NB. Subjects in the treatment arm of this trial received a dose of 7,500 TSO every second week for 24 weeks. This was a significant deviation from the much lower level of dosing that had been established empirically by the Tufts Medical Center team involved in the early clinical trials of TSO [24] [25] [26] [27] and which had been further confirmed as the optimal level for dosing with this organism during more than a decade of use by thousands of customers of Ovamed, who marketed the product from 2003 onwards, and, later, Tanawisa.
    This collective experience had shown that a course of 10 fortnightly doses of 2,500 TSO would frequently produce disease remission in ulcerative colitis and that, if remission were not achieved by this means, a further course of 10 fortnightly doses of 2,500 TSO would often prove to be effective. Only in the few cases where this second course of treatment has failed to produce complete remission is there any need to escalate the dosage, first to 5,000 TSO every two weeks, and then, if necessary, to 7,500 TSO fortnightly.
    Starting with 7,500 ova at the outset of treatment, as was done in the PROCTO trial, is not only inadvisable on the grounds of cost, but also pointless from the therapeutic perspective. Moreover, it is possible that commencing with this unnecessarily excessive dose may trigger a more aggressive immune response by the host to the live TSO product, which might result in a greater loss of organisms than would have been the case with a lower dose, potentially resulting in a reduction in therapeutic effect.
    The most critical mistake was the use of a TSO formulation with a pH of 5.0, as in the studies carried out by Dr Falk/Coronado, Not the pH 2.4 recommended by initial creator of the TSO protocol, Ovamed, who knew from his own product development work that TSO is most effective when formulated with a pH of 2.4, the formulation that had been used in the earlier, successful trials and has received consistently high marks from individuals self-treating with TSO. [28] PDF. The issue with the higher pH is thought to be that this triggers hatching of the ova during storage, before appropriate nutrients are available to the hatchlings from a host organism. [29]. (See: Problems with clinical trials using live helminths, below.) The study's supervising author has been approached for clarification on the product's pH, but has never responded.

    Problems with clinical trials using live helminths[edit | edit source]

    Randomised controlled trials] (RCTs) are considered to be the "gold standard" experimental method for assessing medical treatments, but the evidence produced by many of the RCTs that have looked at the efficacy of helminthic therapy has been starkly at odds with the many independent lines of evidence that have converged to demonstrate the significant health benefits of hosting helminths.

    An extensive body of data from epidemiologic studies, clinical observations, and investigations using animal models, has pointed very clearly to the idea that humans need exposure to helminths in order to enjoy optimal immune function, [30] and many hundreds of reports by helminthic therapy self-treaters that are featured in this wiki and elsewhere attest to the therapeutic benefits of re-worming. [31]

    So why is there such a chasmic divergence between the results from the majority of RCTs and the evidence from other sources of data? One possible explanation has been put forward by a team of socio-medical researchers.

    Quotein.gif
    Unfortunately, for a variety of economic, regulatory, and practical issues surrounding the conduct of clinical trials, mainstream trials have thus far been unable to accommodate the nuances of helminth therapy. Foremost among the issues that clinical trials must address before they can effectively test the potential for helminth therapy are (a) details in formulation of the helminth product that affect efficacy, and (b) the very wide range of doses typically needed within a cohort of individuals. [32]

    Trials of pig whipworm ova (TSO)[edit | edit source]

    
The first helminth to be systematically investigated by researchers was TSO, the ova of the pig whipworm, Trichuris suis, and results from early trials of TSO carried out in the first few years of the 21st century were very encouraging. [33] [34] [35] But a raft of twelve trials carried out by a different research team between 2008 and 2017, to investigate the effect of TSO in five diseases, produced such universally lacklustre results that all but three of them were discontinued prematurely. [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47]

    The researchers involved in this unprecedented project made significant errors in their study design, the first of which was to use a trial length of only 12 weeks. While this is the standard trial period used in pharmaceutical research, it is not appropriate for studies of live helminths such as TSO, which typically only begins to deliver benefits after 8 weeks, and remission only after 20 weeks, with even longer waits experienced by some patients with severe or chronic disease.

    Arguably the most critical mistake was insisting on the use of a novel TSO formulation with a pH of 5.0, even though the investigators were advised against this by the product’s manufacturer, who knew from his own product development work that TSO is most effective when formulated with a pH of 2.4, the formulation that had been used in the earlier, successful trials and has received consistently high marks from individuals self-treating with TSO. [48] PDF. The issue with the higher pH is thought to be that this triggers hatching of the ova during storage, before appropriate nutrients are available to the hatchlings from a host organism. [49]

    Other significant errors in the design of these trials included the use of a single dose size for all participants, when it is known that the helminth dosage requirements of individuals can vary by as much as a factor of 10. Poor subject selection was also revealed by the high rate of improvement in the placebo group in some of the trials.

    With so few clinical trials of helminthic therapy having been carried out previously, the sheer number of these “failed” studies overwhelmed the existing helminthic therapy research base to deliver a body blow to the therapy’s reputation that set back progress by at least 20 years. The number of published scientific papers relating to therapy using live helminths, which had climbed steadily from just 5 in 2000 to peak at almost 100 during 2017, fell into a steep decline after this, as scientists lost interest in the use of living worms. (See: Medical researchers abandon therapy with living worms. (PDF))

    Other researchers began referencing the twelve TSO trials in support of assertions that this species is ineffective as a therapeutic agent. For example, four of these trials were included in a meta-analysis of six studies which concluded that TSO therapy showed no statistical benefit for IBD patients. [50] Apart from the issues with the product's pH, only one of the trials reviewed in this analysis had lasted for longer than 12 weeks, and the remit of that particular study was only to assess the safety and tolerability (not efficacy) of a single dose of TSO.

    Trialing the human hookworm (NA)[edit | edit source]

    TSO is not the only living helminth to have failed to impress when tested using methods that were developed to assess the efficacy of pharmaceutical products.

    In 2007, Correale and Farez had revealed that patients with multiple sclerosis who were hosting a variety of helminths, including hookworms, experienced a reduced number of disease exacerbations compared with patients who were helminth-free. [51] And socio-medical research has shown that NA is extremely effective in the treatment of MS, with a success rate of approximately 50% for the progressive form of the disease and more than 90% for relapsing-remitting MS. (PDF)

    However, when researchers at Nottingham University carried out a randomized double-blinded placebo-controlled trial in which patients with RRMS were experimentally colonised by the hookworm, Necator americanus (NA), they concluded that this helminth appeared to be ineffective against this disease because the particular statistical endpoint determined for the trial had not been reached, [52] even though the data revealed that more than half the patients given NA had not developed any new lesions. [53]

    In order to avoid repeating the design errors made by the teams responsible for previous trials, future studies exploring the therapeutic potential of NA need to take into account the following issues.

    1. For any form of helminthic therapy to be effective, it is essential to maintain continuing exposure to the selected organism. Unfortunately, the period of survival of a helminth varies considerably between individual hosts, and the experience of self-treaters has shown that, in the case of NA, survival of the organism ranges from several years to as little as two months. (See Hookworm lifespan.)
    2. There is more than a 10-fold difference in the level of helminth dosing required to achieve disease remission in different human hosts. Until such time as there are tests capable of providing guidance about the extent of dosing that might be required by each individual, determination of the optimum dosing regimen (the number of larvae in, and the intervals between, each dose) will require the employment by each self-treater of an individualised dose-finding protocol, which can be a lengthy process in the case of NA. (See Long-term dosing is based on individual user experience.)
    3. The benefits derived from hosting NA can take a long time to develop in some cases. While some benefits may appear within weeks, these do not become consistent until at least 12 weeks, and more typically only appear between 3 and 6 months after the initial inoculation. In a few cases, benefits can take up to two years before making their first appearance, and there have even been rare cases in which clear benefits only appeared during the third year. (See Consistent improvement can begin anytime from 3 to 24 months.)
    How the above three factors relate to the therapeutic use of NA is explained in detail on the Hookworm dosing and response page of this wiki.
    4. A further factor that can limit the extent of any therapeutic benefit produced by NA is the potential for certain substances to adversely affect, or even kill, this organism in some individuals. Exactly how it is affected in this way is explained in the Human helminth care manual.
    To take the example of oregano, some NA hosts who ingest this herb may experience reduced benefit from their helminths, possibly even losing their entire colony if they eat a sufficiently large quantity of the plant, consume a concentrated extract or tincture of oregano, or take an oregano oil supplement.
    A more complex situation is found with coconut products, some of which are harmless to NA, while others have been reported to have caused varying levels of harm up to, and including, the total eradication of entire colonies.
    Beyond being dependent on the form in which the substance is encountered, and the dose level, the adverse effect of such substances differs widely between hosts. Users of NA are therefore advised to avoid these, and a few other substances, until they are seeing clear and consistent benefits from the therapy, and then to begin gradually to reintroduce them to assess any effects. This way, the hookworm self-treater is able to learn which, if any, of the potentially risky foods, drugs and other substances they might need to avoid in the long term.
    5. The viability of NA larvae has been shown to decrease rapidly over time from a mean of 85% to < 70% within 14 days. [54] Larval age is therefore another crucial variable that needs to be taken into consideration in future clinical trials, and may perhaps explain some of the inconsistencies in previously reported studies.

    Citizen scientists lead the way[edit | edit source]

    Unless the scientists conducting trials to investigate the effects of hosting helminths are able to devise methods to assess them as living organisms rather than pharmaceutical products, and to take into account the unique and dynamic nature of each individual helminth/host relationship, it is likely that clinical trials will continue to fail to reflect the reality regarding helminthic therapy. Until then, the best evidence will continue to come from the collated experience of self-treaters, as documented extensively in this wiki.

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    … at the present time, systematic data gathering from individuals self-treating may be the most practical and effective means of evaluating the effects of helminth therapy. [55]

    The reintroduction to the digestive tract of a controlled number of specially domesticated, mutualistic helminths (intestinal worms) in the form of microscopic eggs or larvae to reconstitute a depleted biome to treat or prevent chronic inflammation, autoimmune disease and other immune-related disorders, including allergy.

    The reintroduction to the digestive tract of a controlled number of specially domesticated, mutualistic helminths (intestinal worms) in the form of microscopic eggs or larvae to reconstitute a depleted biome to treat or prevent chronic inflammation, autoimmune disease and other immune-related disorders, including allergy.

    An intestinal worm which grows large enough to be seen with the naked eye when mature but which is microscopic when administered in helminthic therapy. Wikipedia:Helminths

    An organism that lives in or on another organism (its host) and benefits at the host’s expense. (The organisms used in helminthic therapy are, strictly speaking, not parasites, but mutualists, because they have a mutually beneficial symbiotic relationship with their hosts.)

    A substance capable of eliminating or destroying intestinal worms.

    An intestinal worm which grows large enough to be seen with the naked eye when mature but which is microscopic when administered in helminthic therapy. Wikipedia:Helminths

    the human hookworm, Necator americanus

    the ova (eggs) of the human whipworm, Trichuris trichiura

    A helminth that lives in the small intestine. Necator americanus (NA) is the only hookworm species used in helminthic therapy. Its microscopic larvae are applied periodically to the skin.

    The active immature form of an insect, or an animal such as a helminth, which develops from an egg and eventually transforms again into its adult state.

    The introduction of an infectious agent into an organism. Helminth inoculation

    A helminth that lives in the small intestine. Necator americanus (NA) is the only hookworm species used in helminthic therapy. Its microscopic larvae are applied periodically to the skin.

    a change which is a result or consequence of an action or other cause.

    the ova (eggs) of the porcine (pig) whipworm, Trichuris suis

    An intestinal worm which grows large enough to be seen with the naked eye when mature but which is microscopic when administered in helminthic therapy. Wikipedia:Helminths

    The roundworm that causes strongyloidiasis and is known as 'pinworm' in the UK and 'threadworm' in the US. Infection with S. stercoralis can be fatal.

    A helminth that lives in the small intestine. Necator americanus (NA) is the only hookworm species used in helminthic therapy. Its microscopic larvae are applied periodically to the skin.

    The species of human hookworm used in helminthic therapy. Its microscopic larvae are applied periodically to the skin.

    Also known as regional enteritis, this is an inflammatory disease of the intestines that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms. It primarily causes abdominal pain, diarrhea (which may be bloody if inflammation is severe), vomiting or weight loss, but may also cause complications outside the gastrointestinal tract such as skin rashes, arthritis, inflammation of the eye, tiredness and lack of concentration.

    The species of human hookworm used in helminthic therapy. Its microscopic larvae are applied periodically to the skin.

    Inflammatory bowel disease is a group of conditions affecting the gastrointestinal (GI) tract, particularly the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis (UC).

    A helminth with a tapering whiplike body that lives in the colon. In helminthic therapy, the microscopic eggs of either the human Trichuris trichiura (TTO) or pig Trichuris suis (TSO) are taken in a drink.

    Ulcerative colitis (Colitis ulcerosa, UC) is a form of inflammatory bowel disease (IBD) which specifically affects the large intestine, or colon, causing characteristic ulcers, or open sores. The main symptom of active disease is constant diarrhea mixed with blood, of gradual onset.

    An organism that lives in or on another organism (its host) and benefits at the host’s expense. (The organisms used in helminthic therapy are, strictly speaking, not parasites, but mutualists, because they have a mutually beneficial symbiotic relationship with their hosts.)

    Multiple sclerosis (also known as disseminated sclerosis) is a chronic, typically progressive disease involving damage to the sheaths of nerve cells in the brain and spinal cord, whose symptoms may include numbness, impairment of speech and of muscular coordination, blurred vision and severe fatigue.

    An organism that lives in or on another organism (its host) and benefits at the host’s expense. (The organisms used in helminthic therapy are, strictly speaking, not parasites, but mutualists, because they have a mutually beneficial symbiotic relationship with their hosts.)

    An organism that lives in or on another organism (its host) and benefits at the host’s expense. (The organisms used in helminthic therapy are, strictly speaking, not parasites, but mutualists, because they have a mutually beneficial symbiotic relationship with their hosts.)

    The roundworm that causes strongyloidiasis and is known as 'pinworm' in the UK and 'threadworm' in the US. Infection with S. stercoralis can be fatal.

    The human whipworm used in helminthic therapy and taken periodically as microscopic eggs (TTO) in a drink.

    The porcine (pig) whipworm used in helminthic therapy and taken as microscopic eggs (TSO) in a drink every two weeks.

    the human whipworm, Trichuris trichiura

    the porcine (pig) whipworm, Trichuris suis

    A helminth with a tapering whiplike body that lives in the colon. In helminthic therapy, the microscopic eggs of either the human Trichuris trichiura (TTO) or pig Trichuris suis (TSO) are taken in a drink.

    Ulcerative colitis (Colitis ulcerosa, UC) is a form of inflammatory bowel disease (IBD) which specifically affects the large intestine, or colon, causing characteristic ulcers, or open sores. The main symptom of active disease is constant diarrhea mixed with blood, of gradual onset.

    the ability to produce a desired or intended result.

    the degree to which something is successful in producing a desired result; success.

    Helminth-Induced Immunomodulation Therapy. This term was adopted by researchers investigating the effects of TSO in patients with MS. [56]

    Microorganisms that are believed to provide health benefits when consumed.

    Ulcerative colitis (Colitis ulcerosa, UC) is a form of inflammatory bowel disease (IBD) which specifically affects the large intestine, or colon, causing characteristic ulcers, or open sores. The main symptom of active disease is constant diarrhea mixed with blood, of gradual onset.

    Reintroducing worms to a helminth-deficient biome.

    The reintroduction to the digestive tract of a controlled number of specially domesticated, mutualistic helminths (intestinal worms) in the form of microscopic eggs or larvae to reconstitute a depleted biome to treat or prevent chronic inflammation, autoimmune disease and other immune-related disorders, including allergy.

    Someone who treats their own disease or condition without medical assistance.

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