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→‎The problem with clinical trials: Removed this entire section from this location for addition to the Research page.
(→‎The problem with clinical trials: Removed this entire section from this location for addition to the Research page.)
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Larvae that have been cleaned by any method will have a shorter shelf life than those that have not been cleaned.
Larvae that have been cleaned by any method will have a shorter shelf life than those that have not been cleaned.

== The problem with clinical trials ==

Many independent lines of evidence, including epidemiologic studies, clinical observations and investigations using animal models, have pointed to the idea that humans need exposure to helminths in order to enjoy optimal immune function, and the many hundreds of reports by self-treaters featured elsewhere in this wiki attest to the therapeutic benefits of reworming. The fact that these benefits have not been confirmed by the majority of clinical trials is due to a number of factors.
{{Quote|indent}}Unfortunately, for a variety of economic, regulatory, and practical issues surrounding the conduct of clinical trials, main stream 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. [https://helminthictherapywiki.org/wiki/images/9/94/Socio-medical_studies_of_individuals_self-treating_with_helminths_suggest_that_most_clinical_trials_assessing_helminth_therapy_may_be_designed_to_fail.pdf]{{Quote|/indent}}
=== Trials of pig whipworm ova (TSO) ===

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. [https://pubmed.ncbi.nlm.nih.gov/14499784/] [https://pubmed.ncbi.nlm.nih.gov/15591509/] [https://pubmed.ncbi.nlm.nih.gov/15825065/] [https://pubmed.ncbi.nlm.nih.gov/21372112/] 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 different diseases, produced such universally lacklustre results that all but three of them were discontinued prematurely. [https://www.clinicaltrials.gov/ct2/show/NCT00645749] [https://pubmed.ncbi.nlm.nih.gov/25698173/] [https://www.clinicaltrials.gov/ct2/show/NCT01040221] [https://www.clinicaltrials.gov/ct2/show/NCT01279577] [https://www.clinicaltrials.gov/ct2/show/NCT01413243] [https://www.clinicaltrials.gov/ct2/show/NCT01433471] [https://www.clinicaltrials.gov/ct2/show/NCT01836939] [https://clinicaltrials.gov/ct2/show/NCT01948271] [https://clinicaltrials.gov/ct2/show/NCT01953354] [https://pubmed.ncbi.nlm.nih.gov/27707789/] [https://www.clinicaltrials.gov/ct2/show/NCT02140112] [https://pubmed.ncbi.nlm.nih.gov/33572978/]
The researchers involved in this unprecedented project made two critical 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, which only begin to produce consistent effects after 12 weeks, and, in some cases may produce no indication of benefit whatsoever during the first two years. [https://helminthictherapywiki.org/wiki/index.php/Hookworm_dosing_and_response#Consistent_improvement_can_begin_anytime_from_3_to_24_months]
Arguably the most critical mistake was to insist 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, which was the formulation used in the earlier, more successful trials.
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, and poor subject selection, which is revealed by the high rate of improvement in the placebo group in some cases.
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.
Other researchers began referencing these trials in support of assertions that TSO is ineffective. 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. [https://pubmed.ncbi.nlm.nih.gov/30142867/] 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. 

This glut of poorly designed trials, and consequently flawed meta-analyses, by researchers who clearly had not fully understood the therapy they were investigating, also appears to have dissuaded other researchers from investigating helminthic therapy. This may explain why, after increasing steadily for around 50 years, the annual number of published papers in which “helminthic therapy” is mentioned plateaued from 2014 onwards. (Data from [https://pubmed.ncbi.nlm.nih.gov PubMed].)
=== Trials of the human hookworm (NA) ===
TSO is not the only living helminth to have failed to reveal its true colours when tested using methods developed to assess the performance of pharmaceutical products. 

In 2007, Correale and Farez had revealed that patients with multiple sclerosis who were hosting helminths experienced a reduced number of disease exacerbations compared with patients who were helminth-free. [https://helminthictherapywiki.org/wiki/images/e/ec/Association_Between_Parasite_Infection_and_Immune_Responses_in_Multiple_Sclerosis_.pdf] 

However, when researchers at Nottingham University published the results for a randomized double-blinded placebo-controlled trial in which patients with RRMS were colonised by hookworms [https://pubmed.ncbi.nlm.nih.gov/32539079/] they reported that the statistical endpoint determined for the trial had not been reached, so concluded this helminth appeared to be ineffective against RRMS. Yet closer examination of the data revealed that more than half the patients given hookworms had not developed any new lesions. [https://www.sciencedaily.com/releases/2020/06/200618150223.htm] 

And socio-medical research has shown that NA is extremely effective at treating MS, with a success rate of approximately 50% for the progressive form of the disease and more than 90% for relapsing-remitting MS. [http://www.yourwildlife.org/wp-content/uploads/2015/05/galley-proof-v2.pdf]  

=== Self-treaters provide the most reliable data ===
Unless the scientists conducting trials to assess the effects of hosting living helminths cease treating these organisms as pharmaceutical products and take into account the unique and dynamic nature of each individual helminth/host relationship when designing formal studies, clinical trials will continue to fail to demonstrate the benefits offered by reworming.
Until this reality is understood, accepted and acted upon by researchers, the best evidence for the benefits of helminth replacement will continue to come from the collated experience of self-treaters.
{{Quote|indent}}… 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. [https://helminthictherapywiki.org/wiki/images/9/94/Socio-medical_studies_of_individuals_self-treating_with_helminths_suggest_that_most_clinical_trials_assessing_helminth_therapy_may_be_designed_to_fail.pdf]{{Quote|/indent}}


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