{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:01:17Z","timestamp":1788415277050,"version":"build-2803163510"},"reference-count":43,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:00:00Z","timestamp":1647216000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016374","name":"Cures Within Reach","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016374","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013589","name":"Research England","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013589","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["220531"],"award-info":[{"award-number":["220531"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Snakebites affect over 5 million people each year, and over 100,000 per year die as a result. The only available treatment is antivenom, which has many shortcomings including high cost, intravenous administration, and high risk of adverse events. One of the most abundant and harmful components of viper venoms are the zinc-dependent snake venom metalloproteinases (SVMPs). Unithiol is a chelating agent which is routinely used to treat heavy metal poisoning.\n                    <ns4:italic>In vivo<\/ns4:italic>\n                    experiments in small animal models have demonstrated that unithiol can prevent local tissue damage and death caused by a certain viper species. This phase I clinical trial will assess the safety of ascending doses of unithiol with a view for repurposing for snakebite indication.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    This open label, single agent, phase I clinical trial of a repurposed drug has a primary objective to evaluate the safety of escalating doses of unithiol, and a secondary objective to describe its pharmacokinetics. In total, 64 healthy Kenyan volunteers from Kilifi County will be dosed in consecutive groups of eight, with dose escalation decisions dependent on review of safety data by an independent data safety monitoring board. Four groups will receive ascending single oral doses, two will receive multiple oral doses, and two will receive single intravenous doses. Follow-up will be for 6-months and includes full adverse event reporting. Pharmacokinetic analysis will define the Cmax, Tmax, half-life and renal elimination.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    This clinical trial will assess the safety and tolerability of a promising oral therapeutic in a relevant setting where snakebites are prevalent. Unithiol is likely to be safer than antivenom, is easier to manufacture, has activity against diverse snake species, and can be administered orally, and thus shows promise for repurposing for tropical snakebite.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Pan African Clinical Trials Registry:<\/ns4:bold>\n                    PACTR202103718625048 (3\/3\/2021)\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.17682.1","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T10:20:14Z","timestamp":1647253214000},"page":"90","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["TRUE-1: Trial of Repurposed Unithiol for snakebite Envenoming phase 1 (safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Kenyan adults)"],"prefix":"10.12688","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4856-4334","authenticated-orcid":false,"given":"Michael","family":"Abouyannis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"FitzGerald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mwanajuma","family":"Ngama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1166-8965","authenticated-orcid":false,"given":"Hope","family":"Mwangudzah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne K.","family":"Nyambura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samson","family":"Ngome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Riako","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Babu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frida","family":"Lewa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Else","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujan","family":"Dily Penchala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedict","family":"Orindi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3531-8823","authenticated-orcid":false,"given":"Noni","family":"Mumba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Kalama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8977-0030","authenticated-orcid":false,"given":"Francis M.","family":"Ndungu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2556-9407","authenticated-orcid":false,"given":"Ifedayo","family":"Adetifa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saye","family":"Khoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7680-2200","authenticated-orcid":false,"given":"David G.","family":"Lalloo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-4719","authenticated-orcid":false,"given":"Nicholas R.","family":"Casewell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0266-1414","authenticated-orcid":false,"given":"Mainga","family":"Hamaluba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2022,3,14]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"e218","DOI":"10.1371\/journal.pmed.0050218","article-title":"The Global Burden of Snakebite: A Literature Analysis and Modelling Based on Regional Estimates of Envenoming and Deaths.","volume":"5","author":"A Kasturiratne","year":"2008","journal-title":"PLoS Med."},{"key":"ref-2","first-page":"515-524","article-title":"Snake-bites: appraisal of the global situation.","volume":"76","author":"J Chippaux","year":"1998","journal-title":"Bull World Health 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Lavonas, Department of Emergency Medicine, Denver Health, Denver, CO, USA, 28 Mar 2022, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-90\/v1#referee-response-49208","order":0,"name":"referee-response-49208","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Michael Abouyannis<\/b>; \n<i>Posted: 06 Oct 2022<\/i>; We thank Prof Lavonas for his considered review of our trial protocol.  We agree that including vulnerable groups such as children is important given these populations are at risk of snakebite. We would envisage that these groups would be included in later stage clinical trials: potentially at phase III once safety and an early efficacy signal have been established.  We agree it will be important to measure serum levels of various minerals, including calcium, magnesium, and zinc. Stored serum samples will be available to measure these.  Regarding genotyping for CYP450, unfortunately the current ethical approval and consent forms do not allow sequencing of participant DNA. It would be interesting to include a pharmacogenetic analysis in any future clinical trial of unithiol.  The comments on the stability of samples for the pharmacokinetic analysis are discerning. As highlighted, unithiol is unstable and is prone to oxidation, even when stored at -80&deg;C. Various steps have been taken to overcome this. Blood samples destined for pharmacokinetic analysis are collected in Acid Citrate Dextrose tubes, which have a low pH and thus inhibit \n<i>ex vivo <\/i>oxidation. Urine samples are treated with formic acid for the same reason. Prior to freezing, the plasma samples are split in triplicate. The first sample is stored as it is. The second is treated with a reducing agent so that any oxidised unithiol is converted back to its original reduced form (to measure \u2018total circulating unithiol\u2019). The third is treated with an alkylating agent, which reacts with the unithiol and prevents oxidation \n<i>ex vivo<\/i> (to measure \u2018reduced circulating unithiol\u2019). It is hoped that these samples can be measured individually using liquid chromatography\u2013mass spectrometry to quantify the amount of circulating reduced, oxidised, and total unithiol. These techniques are novel and whether all components of this pharmacokinetic analysis will be successful is uncertain.  The frequency and dose used in the multiple dosing stage will be guided by emerging pharmacokinetic and safety data. The aim will be to identify a dosing frequency that avoids accumulation whilst maintaining consistent plasma concentrations.  The decision not to include a placebo group was based on the small sample size of this clinical trial, and the safety threshold for a snakebite therapeutic. On sample size, it is unlikely that a placebo group would identify, with statistical confidence, that a given adverse event is or is not associated to exposure to the investigational product (this review article explains this concept in more detail: Doi: 10.1111\/bcpt.12352). On safety threshold, given that unithiol is proposed as a treatment for a disease with a high risk of morbidity and mortality, most patients would be willing to receive an effective medication with a risk of mild or moderate severity adverse events. The main concern for this trial is to establish whether escalating doses of unithiol are associated with severe or serious adverse events, and these events are unlikely to occur due to a placebo effect. Although there may be some benefit in including a placebo group, it was felt that the complexity and cost this would add was not worthwhile.  We agree with the suggestion that longer periods of follow-up may be needed if \n<i>in utero<\/i> exposure were to occur. In such an instance, expert independent advice from a paediatrician, as well as from the data safety monitoring board, would be followed.  Regarding the pharmacokinetic analysis and assessing for mixed kinetics, we plan to analyse by non-compartmental analysis (NCA), which may not elucidate mixed kinetics, but will allow us to address key pharmacokinetic parameters for clinical decision making. We are not necessarily intending to develop and validate a model, and it is anticipated that we may not be able to determine structural characteristic such as number of compartments and order of elimination kinetics.  Ideally, we would like to describe the fate of unithiol metabolites and sample collection is planned in a way that supports this. However, the inherent instability of the analyte and the difficulties in sourcing reference standards do pose significant challenges. It is anticipated that an understanding of the pharmacokinetics of total unithiol alone will be adequate to guide an appropriate dosing regimen.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-90\/v1#referee-comment-5136","order":1,"name":"referee-comment-5136","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.19564.r49206, Matthew Lewin, California Academy of Sciences, San Francisco, CA, USA, 28 Mar 2022, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-90\/v1#referee-response-49206","order":2,"name":"referee-response-49206","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Michael Abouyannis<\/b>; \n<i>Posted: 06 Oct 2022<\/i>; We thank Dr Lewin for his supportive review of this trial protocol.  Regarding safety of unithiol in people with sickle cell diseases or sickle cell trait, we are not aware of any existing data. Although iron chelating agents are often recommended to prevent accumulation in people who receive frequent blood transfusions, unithiol is not used for this purpose. We agree that areas with a high prevalence of sickle cell trait and sickle cell disease also have a high burden of snakebite disease, and assessing safety in this group will be important, although this would probably occur at a later stage in drug development: potentially \u2018post-marketing.\u2019  Regarding the duration of the multiple dosing stage, the shorter of a two- or three-day period that is predicted to achieve steady state (based on the interim pharmacokinetic analysis), will be used. Unithiol has a short half-life and therefore steady state is anticipated to develop within this timeframe.  The CIV2 dosing cohort (5-10 mg\/kg intravenous single dose) will be included in the second stage of the trial, with the multiple dosing cohorts (CM1 and CM2), so that the higher intravenous dose can be guided by interim safety and pharmacokinetic data. We agree that the layout of Table 2 is somewhat confusing: this will be made clearer in future publications.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-90\/v1#referee-comment-5137","order":3,"name":"referee-comment-5137","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.19564.r49209, Matthew Coldiron, Epicentre - M\u00e9dicins Sans Fronti\u00e8res, Paris, France, 31 Mar 2022, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-90\/v1#referee-response-49209","order":4,"name":"referee-response-49209","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Michael Abouyannis<\/b>; \n<i>Posted: 06 Oct 2022<\/i>; We thank Dr Coldiron for his detailed review of this trial protocol.  Regarding the wide variations in the published rates of allergic reaction caused by snake antivenom, we agree that this is partly due to different definitions being used between studies. This is also pertinent to clinical trial design, where standardised and reproducible outcome measures should be used to assess efficacy and safety.  On the point of how reserve participants are selected, they are not randomly allocated. There will initially be random allocation of 64 participants to the 8 dosing cohorts. However, this is not a randomised controlled trial, and randomisation to dosing cohorts is being undertaken so that participants feel they are being treated equally in terms of their chances of receiving a lower or higher dose, and to reduce potential bias that may occur if the study team were allocating doses. As it is uncertain how many reserve participants will be required, and further reserves may need to be screened as the study progresses, it will not be pragmatic to have a random sample of reserve participants available for each dosing cohort.  Although there may be some value in repeating the electrocardiogram (ECG) at day -1, the baseline ECG should be sufficient for screening out participants with evidence of cardiac disease, and to calculate a baseline QTc interval. Additional ECGs can be conducted at the discretion of the study team based on clinical need.  Further details on the process for collecting and storing clinical samples for the pharmacokinetic and pharmacodynamic analysis will be uploaded to the trial repository (on the Harvard Dataverse: https:\/\/dataverse.harvard.edu\/dataset.xhtml?persistentId=doi:10.7910\/DVN\/LJOYSO).  Wheeze was not included as a solicited AE as it is not expected to occur in people without a diagnosis of asthma. The study only includes healthy adults, and the screening process should be robust enough to exclude volunteers with asthma. Wheeze will be recorded as an unsolicited AE if it were to occur.  The section of the TRUE-1 trial protocol on reporting pregnancies suggesting there will be follow-up of pregnancies linked to male trial participants is a typographical error. It is stated correctly on the approved Patient Information Leaflet that: \u201c(For female participants only) If you become pregnant during study follow-up after receiving unithiol, you will be referred to antenatal services and your pregnancy will be followed-up until delivery. You would be asked to bring your baby to be examined by a paediatrician 6 weeks after delivery, to check for any abnormalities that may be associated with receiving unithiol. Future pregnancies occurring after this trial are at no additional risk and will not require any specialist follow-up.\u201d Thank you for identifying this error on the protocol which we will arrange to be corrected via a protocol amendment.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/7-90\/v1#referee-comment-5138","order":5,"name":"referee-comment-5138","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [109105, <a href=https:\/\/doi.org\/10.35802\/109105>https:\/\/doi.org\/10.35802\/109105<\/a>; a Wellcome Trust fellowship to Michael Abouyannis]. Co-funding for this trial was provided by a ReGRoW Repurposing Research Grant from Cures Within Reach (CWR), and Research England\u2019s Bloomsbury SET Impact Connector Programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}