A randomized controlled trial has found that a single, mango-flavored tablet combining two of the most widely used treatments for neglected tropical diseases could help control an intestinal worm infection that affects an estimated 1.5 billion people a year, researchers reported late last week in The Lancet Infectious Diseases.
The trial, conducted in school-aged children in Ethiopia, Kenya, and Mozambique, found that a fixed-dose combination (FDC) of ivermectin and albendazole was more effective in treating Trichuris trichiura (whipworm) and other worms that cause soil-transmitted helminth (STH) infections than albendazole alone, with a similar safety profile. The treatment was also well-accepted in children.
STH infections are caused primarily by ingestion of eggs laid by whipworms, roundworms (Ascaris lumbricoides), and hookworms (Necator americanus and Ancylostoma duodenale) in the intestine and passed to the soil and water through feces. They occur primarily in countries with tropical or subtropical climates and where sanitation is poor. Although most STH infections are asymptomatic, they can lead to anemia and chronic protein deficiency, particularly in children and pregnant women.
Preventive drug therapy with a single dose of albendazole or mebendazole for at-risk populations has been the World Health Organization (WHO)-recommended STH control strategy for decades. But concerns have been raised about its efficacy against T trichiura and the development of resistance. In addition, another intestinal worm that causes STH infections, Strongyloides stercoralis, does not respond to either drug but has shown high susceptibility to ivermectin. Previous research has also shown that ivermectin is more effective against T trichiura when combined with albendazole.
The aim of the phase 2/3 trial, which was conducted by researchers with the STOP (Stop Transmission of Intestinal Parasites) consortium, was to see if a novel, orodispersible tablet combining ivermectin and albendazole, with ivermectin given at fixed doses, is safe and might produce better results.
Higher cure rates
From January 20, 2022, through March 24, 2023, trial investigators enrolled 1,001 children ages 5 to 18 from 15 schools in the three countries; 636 (64%) were infected with T trichiura, 360 (36%) with hookworm, and 104 (10%) with S stercoralis. They randomly assigned participants to receive either one dose of the FDC (FDCx1), three FDC doses over 3 days (FDCx3), or a single dose of albendazole.Â
The primary outcome of the phase 2 study (conducted only in Kenya) was safety during the first 3 hours after intervention and for 7 days. The primary outcome of the phase 3 study was efficacy against T trichiura, defined as the proportion of participants cured at day 21.
A total of 360 adverse events were recorded in 256 participants, mostly gastrointestinal disorders that resolved within 48 hours. The frequency of adverse events was similar between the three treatment groups. No serious adverse events were reported.
Efficacy analysis showed that both FDC treatment groups had much higher cures rates for T trichiura: 97.2% (95% confidence interval [CI], 95.2% to 99.3%) for FDCx3 and 82.9% (95% CI, 78.2% to 87.5%) for FDCx1, compared with 35.9% (95% CI, 27.2% to 44.1%) for albendazole alone. For hookworm, FDCx3 (95.0%; 95% CI, 91.1% to 98.9%) also had a higher cure rate than albendazole (65.1%; 95% CI, 56% to 74.2%), but FDCx1 was similar to albendazole (79.8%; 95% CI, 72.8% to 86.9%).
The sample size for S stercoralis was too small to assess efficacy. But the investigators say the existing evidence suggests the FDC would work against S stercoralis, given the known efficacy of ivermectin against the parasite.
A palatability and acceptability analysis conducted in phase 2 participants also found that most found the FDC to be good or very good in terms of taste (93%), smell (82%), and texture (86%).
Expanding control efforts
The investigators say the results, along with the easy-to-administer, child-friendly formulation, open up new possibilities for efforts to tackle STH infections and other tropical diseases. The current WHO strategy for controlling STH infections is to reduce illness through periodic de-worming of at-risk people living in endemic areas. The investigators suggest the single-dose regimen could be used for mass de-worming programs, while the more effective 3-day dose could be used for individual treatments.
“This is a pivotal trial that opens up the possibility of controlling all species of STH, including Strongyloides, and may lead to reconsider elimination goals that were deemed unattainable with albendazole alone,” Alejandro Krolewiecki, MD, clinical trial coordinator and first author, said in a press release from the Barcelona Institute for Global Health.
Krolewiecki and his colleagues say the next steps will be to evaluate the FDC in larger studies in other endemic countries and to assess the feasibility of widespread implementation.
