Ivermectin 2025: Why the Largest RCTs (MATAMAL and RIMDAMAL II) Have Failed to Fight Malaria

by

The Origins of the Endectocide Concept

The idea of using ivermectin as a tool in malaria control didn’t emerge from traditional antiparasitic research-it came from an observation that was both simple and striking: mosquitoes feeding on individuals recently treated with ivermectin died. (Has Anyone Died from Ivermectin Overdose? Separating Fact from Fear)

This unexpected entomological side effect led to the concept of an “endectocide”-a drug that not only kills internal parasites but also affects ectoparasites and vectors like mosquitoes. Since ivermectin has a well-established safety profile and is already used in mass drug administration (MDA) campaigns for diseases like onchocerciasis and lymphatic filariasis, researchers hypothesized it could be repurposed as a vector-control tool in regions where insecticide resistance threatens traditional malaria interventions.

The logic was compelling: reduce mosquito survival by treating humans, thereby lowering the probability that a mosquito would live long enough to transmit Plasmodium parasites. This strategy seemed especially promising for seasonal malaria transmission settings, and pilot studies showed encouraging results. But two of the largest and most rigorous randomized trials to date-MATAMAL and RIMDAMAL II-have now cast doubt on the strategy’s real-world effectiveness.

What MATAMAL and RIMDAMAL II Found

In 2024 and early 2025, two landmark cluster-randomized controlled trials-MATAMAL and RIMDAMAL II-were published, representing the most ambitious efforts to evaluate ivermectin mass drug administration (MDA) for malaria control. Despite high expectations, neither trial demonstrated a statistically significant reduction in malaria transmission or infection rates.

The MATAMAL trial, conducted on the Bijagós Archipelago in Guinea-Bissau, enrolled 25,883 residents aged ≥5 years across 32 clusters. Participants received a single oral dose of 400 µg/kg ivermectin, co-administered with dihydroartemisinin-piperaquine (DHA-PPQ). The intervention was delivered in three monthly rounds, spaced 28 days apart.

In RIMDAMAL II, carried out in Burkina Faso, the strategy was more intensive: six 3-day regimens of 300 µg/kg ivermectin administered on days 1, 2, and 3 of each monthly cycle, across two consecutive rainy seasons (4,089 participants in 14 clusters).

Both studies were powered to detect changes in parasitemia prevalence, clinical malaria incidence, and entomological inoculation rates (EIR) among children.

  • MATAMAL: absolute risk difference for malaria infection = +1.67 percentage points (p = 0.28)
  • RIMDAMAL II: IRR = 0.95 (95% CI: 0.63–1.42; p = 0.79)

Entomological impact was strong but short-lived: Anopheles gambiae 7-day mortality averaged 91–94% during post-MDA periods (see supplemental appendix), but did not translate into reductions in malaria transmission or case incidence.

“Despite high coverage and compliance, we observed no significant difference in malaria infection between arms.”

London School of Hygiene & Tropical Medicine press release, 24 January 2025

Possible Reasons for Failure

The disappointing outcomes of the MATAMAL and RIMDAMAL II trials have prompted a critical question: Why did ivermectin-based mass drug administration fail to reduce malaria transmission under trial conditions? Several interrelated factors-pharmacological, demographic, programmatic, and ecological-may explain this lack of efficacy.

Short Half-Life of Ivermectin

Ivermectin has a relatively short plasma half-life of 18 to 36 hours, and its mosquitocidal concentrations in human blood typically fall below effective levels within 7 days after administration. This pharmacokinetic limitation is a fundamental challenge when the goal is to suppress mosquito populations over weeks or months of transmission season.

Even with frequent administration, as in RIMDAMAL II, maintaining consistently lethal concentrations between doses was biologically difficult. This makes it unlikely that vector populations could be significantly reduced using oral ivermectin alone in its current form.

Excluded Populations: Children and Pregnant Women

Both trials excluded children under 5 years of age and pregnant women-groups at highest risk of malaria complications and major contributors to the transmission reservoir. These exclusions, though ethically and clinically justified, meant that a substantial share of the community remained untreated, undermining the potential for herd-level transmission reduction.

Parallel Use of Effective Malaria Interventions

In both trials, participants also received high-coverage insecticide-treated nets (ITNs), and in eligible groups, seasonal malaria chemoprevention (SMC). These interventions are themselves highly effective, and may have masked any incremental benefits of ivermectin.

In such settings, where baseline malaria control is already strong, demonstrating additional impact from novel tools becomes methodologically and statistically difficult.

Mosquito Ecology and Timing

Vector behavior may also have played a role. In some study regions, Anopheles mosquitoes exhibited partial zoophily, meaning they feed on both humans and animals. As a result, not all mosquitoes were exposed to drug-treated blood, limiting the community-level impact of ivermectin.

Additionally, if the timing of MDA rounds does not precisely align with the peak mosquito season, the window for suppressing transmission may be missed. Even modest temporal mismatches could significantly reduce intervention efficacy.

What’s Next: Long-Acting Ivermectin Formulations

Given the short duration of mosquitocidal blood levels following oral ivermectin, researchers are now turning their attention to long-acting formulations capable of maintaining effective concentrations throughout an entire malaria transmission season.

IVM-BEPO: Innovation and Environmental Risk

One of the most advanced candidates is IVM-BEPO-a biodegradable injectable formulation that creates a subcutaneous depot, slowly releasing ivermectin over a period of more than six months. Preclinical models show that it can sustain blood levels above the threshold lethal to Anopheles mosquitoes, potentially offering season-long vector suppression from a single injection.

However, this innovation raises new concerns. Because ivermectin is excreted largely unchanged in feces, long-term release increases the risk of environmental contamination. In particular, dung beetles, aquatic insect larvae, and soil microbiota may be adversely affected if ivermectin residues accumulate in livestock dung or latrine runoff.

A 2024 study published in Nature Sustainability (Pooda et al.) emphasized that localized ecotoxicological modeling is essential before deploying such formulations. The risk to non-target species could vary significantly depending on local ecosystems, livestock density, and sanitation infrastructure.

The mdc-STM Project: MedinCell and Unitaid

In parallel, the mdc-STM project, developed by MedinCell in partnership with Unitaid, is pursuing a once-per-season injectable formulation based on the company’s BEPO® delivery technology. Clinical development progressed rapidly in 2024, and first-in-human trials began in late 2024.

The goal is to produce an affordable, low-volume injectable that delivers mosquitocidal plasma levels for up to six months-sufficient to cover the entirety of the rainy season in most endemic settings.

If proven safe and effective, these long-acting agents could revive the endectocide strategy, making it operationally viable for integrated vector control. Still, success will depend not only on clinical efficacy, but also on regulatory approval, cost-effectiveness, supply chain logistics, and above all, environmental stewardship.

Current Applications of Ivermectin in 2025: Limits and Legitimate Uses

Although ivermectin has not met expectations as a malaria control tool, it remains a globally essential antiparasitic, with established uses and new applications being recognized in global health policy.

COVID-19: Limited to Research Contexts

Despite widespread interest early in the COVID-19 pandemic, multiple large-scale randomized trials have failed to demonstrate clinical benefit of ivermectin for prevention or treatment of SARS-CoV-2 infection. As of November 11, 2023, the World Health Organization (WHO) reaffirmed its position:

Ivermectin should only be used for COVID-19 in the context of well-designed clinical trials. – who.int

This recommendation remains current in 2025. The drug is not approved or recommended for routine clinical use in COVID-19, and no new pivotal trials are underway. Its role in COVID-19 has largely been relegated to historical debate and ongoing meta-analytical reappraisals.

Strongyloidiasis: A Major Step Forward in Mass Drug Administration

In contrast, ivermectin’s role in controlling Strongyloides stercoralis infection has been significantly expanded. In August 2024, the WHO issued updated guidelines recommending:

  • Annual mass drug administration (MDA) of ivermectin at 200 µg/kg
  • In communities with ≥5% prevalence of strongyloidiasis
  • Particularly in areas with limited diagnostic access and poor sanitation

This marks the first global endorsement of ivermectin MDA for strongyloidiasis and reflects a shift in WHO policy toward preventive chemotherapy for neglected soil-transmitted helminthiases.

The recommendation is especially relevant for countries in Southeast Asia, Latin America, and sub-Saharan Africa, where infection is common but often underdiagnosed. Unlike its use for malaria, ivermectin’s impact here is individual and community-protective, well supported by pharmacokinetics and real-world programmatic feasibility.

Takeaways for the Practicing Clinician

The case of ivermectin and malaria control illustrates how even biologically promising strategies can fail to deliver real-world impact. While the endectocide concept remains theoretically attractive, the most robust evidence to date does not support the use of ivermectin-based MDA as an effective public health tool against malaria.

What This Means in Practice:

  • Mass ivermectin administration for malaria is not ready for implementation. The MATAMAL and RIMDAMAL II trials, involving slightly more than 30,000 participants (~25,900 in MATAMAL and ~4,100 in RIMDAMAL II), found no statistically significant reduction in malaria infection or incidence-despite high adherence and strong entomological effects.
  • Entomological impact does not guarantee transmission reduction. In both trials, mean 7-day mortality for Anopheles gambiae reached 91–94% during post-MDA periods. However, this transient mosquitocidal activity did not translate into lower EIR or clinical cases.
  • Ivermectin retains high therapeutic value in the treatment of onchocerciasis, lymphatic filariasis, strongyloidiasis, scabies, and lice. These indications remain well-supported by evidence and global health policy.
  • New WHO guidance (2024) recommends annual MDA of ivermectin at 200 µg/kg in regions with strongyloidiasis prevalence ≥5%-a major step forward in addressing neglected helminth infections.
  • Long-acting injectable formulations like IVM-BEPO and mdc-STM may still offer future potential for vector control, but require further validation regarding efficacy, safety, environmental impact, and operational feasibility.
  • As of 2025, WHO recommendations are clear:
    • Use ivermectin for COVID-19 only within clinical trials (guideline of 11 November 2023)
    • Do not use ivermectin MDA for malaria outside of research settings
    • Support ivermectin MDA for strongyloidiasis in eligible endemic areas

In sum, the path forward lies in innovation combined with caution. Ivermectin’s role in malaria control may yet evolve, but for now, it remains a question of formulation, timing, ecological context, and realistic expectations.

References

© 2025 website-pace

We use cookies to personalise content and ads, to provide social media features and to analyse our traffic. We also share information about your use of our site with our social media, advertising and analytics partners.
Cookies settings
Accept
Privacy & Cookie policy
Privacy & Cookies policy
Cookies list
Cookie name Active
Save settings
Cookies settings