High-Dose Rifampicin Plus Albendazole Rapidly Clears Lymphatic Filariasis Circulating Filarial Antigen in a Randomised Clinical Trial: A Promising Step Toward Short-Course Macrofilaricidal Therapy

<b>Background</b>: The lack of a short-course of safe and effective macrofilaricidal therapy for lymphatic filariasis (LF) hinders elimination efforts, especially in the endgame scenario. Preclinical studies in mice demonstrated that high-dose rifampicin (RIF) plus albendazole (ALB) produced macrofilaricidal effects within seven days, prompting this randomised, open-label, parallel-group, interventional phase II pilot trial to determine the efficacy of high-dose RIF plus ALB against LF in humans. <b>Methods</b>: In three LF-endemic districts of Ghana's Upper East Region, circulating filarial antigen (CFA)-positive individuals aged 18 to 55 years identified using the Alere Filariasis Test Strip were enrolled into the study. The participants were randomised through a centralized computer-generated randomisation into four treatment arms. They were treated according to the arm they were assigned to and followed up at 4-, 6-, 12-, and 18-months post-treatment to monitor changes in CFA status and levels, as well as adverse events. Outcome assessors were blinded to minimize assessment bias. <b>Results</b>: A total of 69 eligible participants were randomised into four treatment arms: RIF (35 mg/kg/day) + ALB (400 mg/day) for 7 days (<i>n</i> = 17), RIF (35 mg/kg/day) + ALB (400 mg/day) for 14 days (<i>n</i> = 18), ALB alone for 14 days (<i>n</i> = 17), and an untreated controlled group participating in standard mass drug administration (<i>n</i> = 17). All regimens were well tolerated, with no serious adverse events. Even though CFA positivity declined across all groups, with maximal reductions at 18 months, the RIF + ALB 7-day regimen consistently showed the highest decline, while ALB alone was the least effective. RIF + ALB groups exhibited early antigen decline by 4 months, unlike comparator groups, where reductions occurred from 12 months. <b>Conclusions</b>: These findings suggest macrofilaricidal activity of high-dose RIF plus ALB, supporting further trials in larger, microfilaraemic populations. The trial was registered in the Pan African Clinical Trials Registry on 9 September 2020 under the code PACTR202009704006025.Funding was by the European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), with grant code TMA2018SF-2451-ASTAWOL, and by the German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung-BMBF) under agreement with Gesellschaft für Internationale Zusammenarbeit (GIZ) through agreement number: 81204851.