HUNADIA

The challenge

Recent years have seen a resurgence in cholera (acute watery diarrhoea caused by infection with the bacterium Vibrio cholerae). Contamination of water sources can cause explosive outbreaks of diarrhoeal disease that may lead to deaths and place enormous strains on health systems. Globally, up to 4 million cases are estimated to occur each year, leading to tens of thousands of deaths. Sub-Saharan Africa accounts for more than half of all cases and the overwhelming majority of deaths.

Cholera can be prevented by good water, sanitation, and hygiene (WASH) infrastructure and practices, but in many resource-poor settings and during humanitarian emergencies, outbreaks remain common. Although oral cholera vaccine (OCV) can prevent disease, it is in short supply and vaccine protection wanes over time.

Treatment of cholera is mostly based on the use of oral rehydration solution (ORS) and zinc to replace fluids and electrolytes. Antibiotics may also be given, although they have minimal immediate impact on symptoms. 

While beneficial, these treatments do not address the key mechanism underlying the most dangerous symptoms of cholera: massive fluid loss. This is due to a toxin released by V. cholerae (cholera toxin), which acts on a protein, known as CFTR, that regulates fluid flow in the gut. Cholera toxin leads to the persistent activation of CFTR, leading to a massive outflow of water into the gut, generating the acute watery diarrhoea typical of cholera.

The project

The HUNADIA project is carrying out a major international trial to determine whether a newly developed drug, known as VR-AD-1005 (VR), can provide an additional tool for cholera management by directly targeting the action of cholera toxin. 

Developed by a biotech company in Spain, VR inhibits CFTR, which turns off the tap held open by cholera toxin. VR has two components: a compound that inhibits CFTR, and a second component that helps the drug stick to the intestinal wall, preventing it from being washed away (which typically happens with oral anti-diarrhoeal drugs). 

In animal models, VR led to a 70% reduction in stool volume (faecal matter excreted) and 30% reduction in mortality. Furthermore, in a phase II clinical trial in Bangladesh, where cholera outbreaks are seasonal, VR halved the time to hospital discharge, significantly reduced stool volumes, and reduced the need for intravenous fluid infusions. 

To extend these highly promising findings, the HUNADIA project is conducting a larger-scale phase III trial, recruiting 1,200 patients in Cameroon, the Democratic Republic of the Congo (DRC), Malawi, Mozambique, Tanzania, and Zambia, as well as in Bangladesh. Patients will receive local standard of care for cholera plus either VR or a placebo. 

The trial will be a multi-centre adaptive trial, since it is difficult to predict where and when cases of cholera will arise. Recruitment at different sites will be activated when local outbreaks occur. The trial will also include the potential to vary other parameters, such as sample size or dose (under clearly defined circumstances).  A smaller number of cases will be recruited in the community to determine whether VR can be used early to prevent hospitalisation.

The trial will assess multiple aspects of patients' symptoms and use of health system resources. Data will be used to develop a comprehensive impact and health economic assessment that examines the implications for both households and health systems. 

In addition, the trial will use the data collected to explore the impact of climate and environmental variables on the risk of cholera outbreaks. 

Impact

The HUNADIA project could have a transformational impact on the treatment of cholera. It will:

• Reveal what impact a newly developed drug, known as VR-AD-1005 (VR), has on the severity and duration of clinical symptoms of cholera.
• Whether early use of VR can reduce the risk of hospitalisation.
• Identify the potential impacts of VR administration on the use of health resources, including hospital stays, use of intravenous fluids and antibiotics.
• Provide a rigorous assessment of the cost-effectiveness of VR use.

VR has the potential not only to benefit patients by reducing the severity and duration of cholera cases, but also to deliver health system benefits by reducing demand during outbreaks, freeing up hospital beds, and providing savings on medical supplies – to the extent that it may deliver overall cost savings.