What is the problem/background?

Every year over 80,000 people die following a snakebite.  In Kilifi County Hospital alone, there have been 1,500 snakebites requiring hospital admission since 2007. The only treatment available (antivenom – a product made by repeatedly exposing mammals, such as horses, to sub-lethal doses of venom) is expensive and can cause allergic reactions. Many snake venoms require zinc to function. Drugs that stick to and remove zinc (‘chelators’, including unithiol) have been shown to deactivate these snake venoms in laboratory experiments.

Unithiol is a treatment for heavy metal poisoning (such as arsenic or mercury poisoning) and has been in use as an established therapy for a number of decades. It is known to bind to zinc. This drug is available as an oral capsule as well as a solution for intravenous injection into the blood-stream. As far as we are aware, unithiol is not routinely available in Kenya, and it is not registered with the pharmacy and poisons board (PPB). For many years, safety data has been collected for unithiol elsewhere and overall it is a safe drug with minimal risk of serious side effects. When unithiol is used as a treatment for snakebite, laboratory experiments suggest that higher doses may be needed, compared to doses normally used for treating heavy metal poisoning.

Unlike antivenom, unithiol is available as a capsule and could be stocked in rural clinics, which would reduce delays to accessing snakebite treatment. Unithiol has been used for the treatment of metal poisoning for many years and there is a reasonable amount of reassuring safety data.

In this study, groups of healthy Kenyan people will be given increasing amounts of unithiol and closely monitored to check if this is safe.

What questions are we trying to answer?

1) Can higher doses of unithiol be safely given?

2) What are the drug levels of unithiol and how long are drug levels maintained after each dose?

3) Can a new method of measuring the activity of unithiol in blood samples, to inhibit the actions of venom, produce reliable results?

Where is the study taking place, how many people does it involve and how are they selected?

Healthy volunteers will be invited from Ngerenya, Chasimba or Kilifi township and will attend the study at a KEMRI-CGMRC staffed clinic. Only adults aged 18 to 64 years (inclusive) will be eligible. Healthy people will be selected, rather than victims of snakebite, as the main aim of this study is to understand the safety of this drug, which is more easily understood in people without symptoms due to snakebite.

Initially, groups of 8 people will be given increasing amounts of unithiol as a single dose. A minimum of 4 groups (32 people) will be given the drug until the maximum dose is reached. A further 2 groups (16 people) will be given unithiol as an injection into a vein. Then, a minimum of two groups of 8 people will be given unithiol four times a day for 2 or 3 days (the number of days depends on the time it takes for drug levels to stabilize, and this is estimated to be 2-3 days). In total 64 people are expected to be given unithiol, although more may receive it if smaller dose increases are required.

Awareness will be raised with permission of community leaders at the community level, using our standard community engagement activities; barazas, health talks, mobilizing community health volunteers and fieldworkers. Volunteers for the study will be required to be healthy, non-pregnant, non-breastfeeding and willing to attend the required visits.

What does the study involve for those who are in it?

Once individuals have been given verbal and written information about the study they will be asked if they would like to proceed. The decision to proceed will be made in writing on the consent form and can be reversed at any time by the individual. The individual will then be screened to check they are eligible to participate. Screening tests will include: pregnancy test, full blood count (for anaemia and other blood disorders), kidney function test, liver function test, HIV test, hepatitis virus test, blood sugar level, malaria test and a heart tracing. Individuals that can proceed following screening will be randomly allocated to a treatment group. A minimum of four treatment groups will receive increasing single oral doses of the study drug. More than 8 groups may be needed if adverse events occur which warrant redosing or smaller dose increases.

The starting dose will be 300 mg oral, which is the dose normally used for treating acute heavy metal poisoning. The maximum oral dose that will be given is 1,500 mg. Dose levels equivalent to 1,500 mg have been previously given to people with heavy metal poisoning and were well tolerated. In experiments conducted at the Liverpool School of Tropical Medicine, doses equivalent to 1,500 mg oral were needed to stop venom from causing blood clotting abnormalities in the laboratory (in vitro).

A minimum of two study groups will receive the oral drug four times per day for between 2 and 3 days. At least two groups will receive an intravenous dose of the drug. The starting intravenous dose will be 3 mg/kg. The normal intravenous dose used in acute heavy metal poisoning is 3-5 mg/kg, so this is expected to be safe. The second intravenous dose will be planned based on data emerging from the first group, but is expected to be a dose of 5 mg/kg (a higher dose of up to 10 mg/kg may be used if there is evidence that higher levels offer better activity to inhibit the damaging effects of venom). Intravenous doses are being evaluated in addition to oral doses, as it expected that the drug may work better if given as an injection (as this results in higher blood levels of the drug). Oral doses will also be important as many rural clinic settings are not able to give injections into the blood stream but could offer an oral capsule.

Each treatment group contains 8 individuals. Individuals will be admitted to an inpatient  facility the day before they receive the drug. After final safety checks the drug will be given to each individual. When higher oral doses (900mg or above) are given, one individual will receive the drug before the other 7 individuals – as a safety measure. After the study drug has been given, individuals will be closely monitored as an inpatient until at least 24 hours after they last received the study drug – then they will be discharged home. Frequent blood and urine samples will be collected (at least every hour initially). When possible, blood tests will be taken through a cannula (a small rubber tube placed into a vein in the arm), to minimize discomfort. After discharge from the inpatient facility, individuals will have planned visits to the study clinic on day 2, day 5 and day 42 after receiving the study drug, and will undergo telephone follow-up at 6 months. Individuals will be encouraged to attend the study site if they feel unwell. Participants that remain well after the 6-month follow up, will not require any further follow-up or study activities. If an individual becomes unwell during the trial, appropriate treatment will be offered (including referral to an appropriate facility) and funding for this will be provided through the trial insurance.

What are the benefits and risks/costs of the study for those involved?

There are limited direct benefits to those involved. The screening process may identify health conditions that would otherwise have gone unnoticed (such as high blood pressure or diabetes), and thus allow for earlier treatment. Referrals will be made to appropriate specialist clinics for further review, management and follow-up of such conditions. There may be some perceived benefits, although this will just be close clinical monitoring during the trial.

Unithiol is a drug that has been used in humans for treating certain types of poisoning for many years. It is a safe drug with minimal serious risks. Skin reactions occur in less than 1 in 100 people. Severe skin reactions that would require hospitalization, and could be life-threatening, are very rare and occur in less than 1 in 10,000. It is not known whether the risk of skin reactions increases with higher doses of unithiol, however there does appear to be an association with repeated doses. Initially, participants will only receive a single dose of unithiol, which should minimise the risk of skin reactions. It is planned for 16 participants to receive multiple doses over a period of 2-3 days, which is still a significantly shorter period of time than unithiol is given for heavy metals poisoning. Any illness occurring during this study will be treated at an appropriate government health facility with all costs of care being provided by the study insurance. The trial procedures will involve frequent blood sampling and this will cause some discomfort. When possible, a cannula (small plastic tube) will be inserted into an arm vein, to allow blood samples to be collected without repeatedly inserting needles. There is a risk of introducing infection when using cannulas, although procedures to keep the device clean will be undertaken to minimize this risk. All financial costs (travel, out of pocket expenses, accommodation) will be met by the study according to institutional guidelines, as follows (these guidelines are reviewed regularly and costs may change in order to match updated guidance):

1) Per day of work missed: 500 KES (includes days at inpatient facility and clinic visits).

2) Compensation for each overnight stay at inpatinet facility: 2,000 KES

3) Meals: included whilst resident at inpatient facility

4) Travel costs: included based on actual amounts spent through public means

How will the study benefit society?

There may be benefit to the local community if this drug were found to be effective in treating snakebite. This drug has the potential to protect people bitten by a range of viper species, including the puff adder and Kenyan carpet viper. Unithiol may provide a safe, effective and affordable therapy for these patients. As well as protecting people from death, unithiol may reduce the development skin damage, which can cause long lasting morbidity.This study builds on a programme of work in Kenya that, in collaboration with the Centre for Snakebite Research and Interventions (CSRI LSTM) will improve our understanding of how to improve the management of snakebite. Novel therapeutics for snakebite are being screened at CSRI LSTM, and this trial in Kilifi will provide a platform for further trials.

Snakebite affects over 5 million people each year, and over 100,000 per year die as a result. Children and young people bear the greatest burden, and the majority of bites occur in remote rural settings with limited access to medical services. The only available treatment is antivenom, an animal product produced through a process of exposing large mammals to repeated sublethal doses of snake venom. Antivenom has many shortcomings, including high cost, intravenous administration, high risk of adverse events and narrow species specificity. The venom of vipers predominantly consists of Snake Venom Metalloproteinases (SVMPs), which are zinc dependent enzymes. SVMPs cause blood vessel breakdown, consumption coagulopathy and skin necrosis. Pre-clinical research, including use of the same in vivo experiments that are the gold standard for assessing antivenom, have shown that metal chelators can potently inhibit the activity of viper venom, by deactivating SVMPs. Through systematic screening of a range of chelating agents, unithiol has been identified as the most promising chelating agent and needs further evaluation in clinical trials. As well as preventing skin damage and death in vivo, unithiol is a safe and well tolerated drug that has been is use as a treatment for heavy metal poisoning for many decades. We propose a phase I clinical trial to assess unithiol as a treatment for snakebite.

The primary outcome will be to determine safety and tolerability of a dosing regimen that is relevant to snakebite. The pharmacokinetic and pharmacodynamic profile of unithiol will also be described. Healthy Kenyan volunteers will be invited to enroll from Kilili County. Volunteers will be randomized into dosing cohorts of 8. The first dosing cohort will receive 300 mg of oral unithiol, which is the dose normally used for heavy metal poisoning. With review of safety, single ascending dose escalations will be made with the aim of giving a maximum dose of 1,500 mg oral. A minimum of two further cohorts will receive intravenous doses of unithiol, as this route may be useful for rapidly achieving therapeutic levels. Following review of the emerging data, two cohorts will receive multiple doses of unithiol for up to 72 hours, which will be the anticipated regimen for snakebite treatment.Pharmacokinetic analysis will be undertaken to calculate the half-life, Cmax and to define the elimination of unithiol in the urine. Pharmacodynamic analysis will include application of a novel ex vivo assay for quantifying the inhibition of SVMP associated pathology.