Effect of a single dose of 8 mg moxidectin or 150 μg/kg ivermectin on O. volvulus skin microfilariae in a randomized trial: Differences between areas in the Democratic Republic of the Congo, Liberia and Ghana and impact of intensity of infection

Abstract

Background Our study in CDTI-naïve areas in Nord Kivu and Ituri (Democratic Republic of the Congo, DRC), Lofa County (Liberia) and Nkwanta district (Ghana) showed that a single 8 mg moxidectin dose reduced skin microfilariae density (microfilariae/mg skin, SmfD) better and for longer than a single 150μg/kg ivermectin dose. We now analysed efficacy by study area and pre-treatment SmfD (intensity of infection, IoI). Methodology/Principal findings Four and three IoI categories were defined for across-study and by-study area analyses, respectively. We used a general linear model to analyse SmfD 1, 6, 12 and 18 months post-treatment, a logistic model to determine the odds of undetectable SmfD from month 1 to month 6 (UD1-6), month 12 (UD1-12) and month 18 (UD1-18), and descriptive statistics to quantitate inter-interindividual response differences. Twelve months post-treatment, treatment differences (difference in adjusted geometric mean SmfD after moxidectin and ivermectin in percentage of the adjusted geometric mean SmfD after ivermectin treatment) were 92.9%, 90.1%, 86.8% and 84.5% in Nord Kivu, Ituri, Lofa and Nkwanta, and 74.1%, 84.2%, 90.0% and 95.4% for participants with SmfD 10–20, ≥20-<50, ≥50-<80, ≥80, respectively. Ivermectin’s efficacy was lower in Ituri and Nkwanta than Nord Kivu and Lofa (p≤0.002) and moxidectin’s efficacy lower in Nkwanta than Nord Kivu, Ituri and Lofa (p<0.006). Odds ratios for UD1-6, UD1-12 or UD1-18 after moxidectin versus ivermectin treatment exceeded 7.0. Suboptimal response (SmfD 12 months post-treatment >40% of pre-treatment SmfD) occurred in 0%, 0.3%, 1.6% and 3.9% of moxidectin and 12.1%, 23.7%, 10.8% and 28.0% of ivermectin treated participants in Nord Kivu, Ituri, Lofa and Nkwanta, respectively. Conclusions/Significance The benefit of moxidectin vs ivermectin treatment increased with pre-treatment IoI. The possibility that parasite populations in different areas have different drug susceptibility without prior ivermectin selection pressure needs to be considered and further investigated. Clinical Trial Registration Registered on 14 November 2008 in Clinicaltrials.gov (ID: NCT00790998).

O. volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: Results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia

“…As previously reported [20,60], the protocol, information documents for potential participants, participant consent and assent forms and study conduct were approved by the Ghana Food and Drugs Authority and the Ghana Health Service Ethics Review Committee, the Liberia Ministry of Health and Social Welfare and the Ethics Committee of the Liberia Institute for Biomedical Research, the Ministère de la Santé Publique of DRC and the Ethics Committee of the Ecole de la Santé Publique Université de Kinshasa in DRC, and the WHO Ethics Review Committee.…”

“…Expert consultations and data reviews by the African Programme for Onchocerciasis Control (APOC, 1995(APOC, -2015 concluded that alternative treatment strategies (ATS) are required for onchocerciasis elimination in many areas in Africa [17]. Potential strategies identi ed include those based on moxidectin which was approved in 2018 for treatment of O. volvulus infected individuals ≥ 12 years of age by the US Food and Drug Administration (FDA) [19,20,21,22,23,24,25,26,27]. Discovery, development and implementation research for other ATS [28] is also ongoing including for new or repurposed drugs [10,29,30,31,32], for effective, affordable, and sustainable complementary vector control strategies [33,34] and for approaches to safe use of ivermectin in loiasis coendemic areas (drugs for safe reduction of Loa loa micro laraemia [35,36,37] and 'test-and-not-treat' or 'test-and-treat' strategies [38,39,40,41,42]).…”

“…We have previously reported results of our randomized, double blind Phase 3 trial comparing the e cacy and safety of a single oral dose of 8 mg moxidectin and 150 µg/kg ivermectin in ivermectin-naïve individuals with ≥ 10 mf/mg skin with or without ocular involvement. The data showed that 1, 6, 12 and 18 months after treatment, skin micro lariae density (mf/mg skin, SmfD) was signi cantly lower among moxidectin than ivermectin treated participants [20,60]. In contrast, there was no statistically signi cant difference between the treatment arms in the level of live micro lariae in the anterior chamber (mfAC) 12 months after treatment among participants with > 10 mfAC pre-treatment [60].…”

Efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole coadministration in adolescents infected with Trichuris trichiura in Tanzania: an open-label, non-inferiority, randomised, controlled, phase 2/3 trial

“…Further studies in other settings might reveal useful insights as T trichiura might have different drug susceptibility depending on geographical location, which has been suggested in an onchocerciasis study 33 and observed with albendazole and ivermectin against T trichiura . 12 …”

The pipeline for drugs for control and elimination of neglected tropical diseases: 1. Anti-infective drugs for regulatory registration

“…are of economic interest, face the additional hurdle of the willingness of pharmaceutical company partners to continue the development/collaboration and/or the willingness or ability of donors to continue financial support to complete all activities required for a submission for regulatory approval. As described above, a case in point for this hurdle is moxidectin development, which was put in jeopardy, and regulatory registration delayed by several years, because Pfizer withdrew from the collaboration agreement with WHO [ 29 , 30 ].…”