Researchers from African, Latin American and European organisations have published the results of the ALIVE study, the phase 2/3 pivotal clinical trial that demonstrates the safety and superior efficacy of our fixed-dose coformulation (FDC) of albendazole and ivermectin in the control of soil-transmitted helminths (STH). The study was successfully carried out by the STOP 1 and 2 projects, funded by EDCTP. As the successor project, the STOP2030 consortium builds upon this work to take the FDC from experimental drug to its mass adoption.
The results of the ALIVE study, published by the journal The Lancet Infectious Diseases, show the improved efficacy of the single dose FDC against T. trichiura when compared to albendazole monotherapy, all while maintaining an equivalent efficacy against hookworm and a similar safety profile. Only mild to moderate adverse events were registered from the over 1,000 thousand individuals treated either with a single dose of the FDC or three consecutive doses in three days.
A combination of drugs and strategies
WHO’s 2021-2030 Roadmap for soil-transmitted helminthiasis (STH) aims for its elimination as a public health problem before the end of the decade. Among other measures, the roadmap recommends periodic mass drug administration (MDA) campaigns in high-prevalence areas, which usually translate to annual or biannual treatment rounds with a single, fixed dose tablet of albendazole or mebendazole, an anthelminthic medicine.
The FDC includes albendazole and ivermectin in a single, fixed-dose pill, so it delivers the simpler logistics of the current one-pill-per-person approach and the improved efficacy of the combination strategy
Albendazole monotherapy has shown high efficacy against two intestinal parasites: Ascaris lumbricoides and hookworm, but is not as efficacious for the other two, Trichuris trichiura and Strongyloides stercoralis. T. trichiura is the second STH species in prevalence, with an estimated 460 million people affected worldwide, while S. stercoralis impacts at least 300 million. Complementing albendazole with ivermectin, an antiparasitic drug considered the treatment of choice for S. stercoralis, significantly improves the outcome against T. trichiura while maintaining efficacy for the rest. Also, using two drugs with different modes of action may lessen the risk of resistance emergence.
Combining albendazole and ivermectin leads to a broader control of the intestinal parasite species considered in the WHO 2021-2030 Roadmap, but it complicates the logistics of MDA campaigns because the latter drug is dosed individually. According to current recommendations, every person’s height or weight is measured before providing them with up to 4 extra tablets, aimed at reaching a dose of 200 µg of ivermectin for every 1 kg of weight. (i.e. a 45 kg person would get 3 tablets of 3 mg ivermectin for a total dose of 9 mg)
“The key innovation behind this coformulation is proving that ivermectin can also be used at fixed doses, like albendazole is”, says Alejandro Krolewiecki, MD, Director of Innovation at Mundo Sano Foundation, who led the clinical trial. Before this pivotal clinical trial, several studies had confirmed the safety of ivermectin at doses significantly higher than 200µg/kg.
The FDC includes albendazole and ivermectin in a single, fixed-dose pill, so it delivers the simpler logistics of the current one-pill-per-person approach and the improved efficacy of the combination strategy. “It provides a tool that can tackle Strongyloides stercoralis and Trichuris trichiura too but is easy to integrate with ongoing programs”, Krolewiecki explains. “It can give endemic countries a chance to aim at STH elimination goals, while albendazole alone can’t”.
Better efficacy against Trichuris trichiura
The clinical trial, named ‘ALIVE study’, took place between 2022 and 2023 in STH endemic areas of Ethiopia, Kenya and Mozambique. It was carried out by the STOP project, a consortium of 8 African and European institutions funded by the European and Developing countries Clinical Trials Partnership (EDCTP) and led by ISGlobal. It started as a phase 2, focused on evaluating safety within a small group of people. After the team verified the absence of any severe adverse effects, they advanced to phase 3. They recruited more people and expanded the aims of the study to evaluate both safety and efficacy.
The researchers treated 1,001 school-aged children (from 5 to 18 years) with an active helminth infection, randomly assigned to one of three groups: a control group treated with the standard albendazole tablet, another treated with a single dose of the FDC, and a third group that received three doses of the FDC in three days.
The ALIVE trial evaluated the efficacy measured as the cure rate (CR, the proportion of individuals infected before treatment and free of infection after treatment) and the egg reduction rate (ERR, the percentage reduction in the number of parasite eggs in faeces after treatment, compared to the number before treatment) for hookworms (Ancylostoma duodenale and Necator americanus) and Trichuris trichiura. The FDC achieved comparable CR and ERR for hookworms and superior CR and ERR for T. trichiura compared to albendazole.
Cure Rate
Egg reduction rate (geometric mean)
A big enough sample size of Strongyloides stercoralis infections was not met for statistically significant results about efficacy, although the STOP researchers are confident in the ample evidence that supports ivermectin as the treatment of choice for this parasite. With regards to the safety of the FDC, the study only found mild to moderate adverse events (AE), and all resolved within 48 hours and without the need of any intervention.
“Innovation plays a crucial role in advancing public health initiatives in countries endemic for Neglected Tropical Diseases”, says José Muñoz, MD, researcher at the Barcelona Institute of Global Health (ISGlobal) and Hospital Clinic Barcelona and the principal investigator of the STOP project. “Furthermore, as a Phase 2/3 study, these results have been pivotal in enabling their submission to regulatory agencies for registration”.
The results of the study have already been submitted to regulators in Africa (Ghana FDA) and Europe (EMA), whose decisions are expected in early 2025.
Next step: taking the FDC to mass adoption
“The FDC has a great potential for improving the health of affected communities in endemic areas, but we still have work to do,” says Stella Kepha, a researcher at Kenya Medical Research Institute (KEMRI) who worked on the ALIVE trial under the STOP project and is also part STOP2030, the successor project –funded by EDCTP and the Swiss Government– that is already working on the next steps. “We need to make a compelling case about the FDC being the better choice to tackle STH as a public health problem worldwide,” she stated.
The STOP2030 consortium, formed by 7 organisations from Africa and Europe, is in the planning stages of a Phase IV clinical trial, the REALISE study, for evaluating the safety of the FDC in large populations (around 20,000 school-age children) as a primary goal, and to gather additional efficacy data as a secondary target. It will be carried out in 2025 in Kenya and Ghana.
Researchers from the STOP2030 project are also working on studies that can provide evidence with regards to important implementation aspects like the cost-effectiveness of the FDC, or its acceptability in comparison with the current standard. It will also monitor the emergence of resistance to treatment through genetic analysis.
“Its approval by regulators is not the finish line,” explains Esteban Gergic, from Liconsa, the pharma company that develops and produces the FDC, and got ivermectin prequalified by WHO in 2021. “We want to build a product that reaches the people that need it and truly makes a difference and improves people’s life.”
“We have come a long way pursuing the apparently simple idea that ivermectin can be given at fixed doses”, explains Krolewiecki. The concept was born from a small research project in northern Argentina in 2010. Since then, it has grown to include public-private partnerships between 18 institutions across Africa, Latin America and Europe and has led to the design and execution of several clinical trials.
