A Trial of a Triple-Drug Treatment for Lymphatic Filariasis

Abstract

Background: The World Health Organization has targeted lymphatic filariasis for global elimination by 2020 with a strategy of mass drug administration. This trial tested whether a single dose of a three-drug regimen of ivermectin plus diethylcarbamazine plus albendazole results in a greater sustained clearance of microfilariae than a single dose of a two-drug regimen of diethylcarbamazine plus albendazole and is noninferior to the two-drug regimen administered once a year for 3 years.

Methods: In a randomized, controlled trial involving adults from Papua New Guinea with Wuchereria bancrofti microfilaremia, we assigned 182 participants to receive a single dose of the three-drug regimen (60 participants), a single dose of the two-drug regimen (61 participants), or the two-drug regimen once a year for 3 years (61 participants). Clearance of microfilariae from the blood was measured at 12, 24, and 36 months after trial initiation.

Results: The three-drug regimen cleared microfilaremia in 55 of 57 participants (96%) at 12 months, in 52 of 54 participants (96%) at 24 months, and in 55 of 57 participants (96%) at 36 months. A single dose of the two-drug regimen cleared microfilaremia in 18 of 56 participants (32%) at 12 months, in 31 of 55 participants (56%) at 24 months, and in 43 of 52 participants (83%) at 36 months (P=0.02 for the three-drug regimen vs. a single dose of the two-drug regimen at 36 months). The two-drug regimen administered once a year for 3 years cleared microfilaremia in 20 of 59 participants (34%) at 12 months, in 42 of 56 participants (75%) at 24 months, and in 51 of 52 participants (98%) at 36 months (P=0.004 for noninferiority of the three-drug regimen vs. the two-drug regimen administered once a year for 3 years at 36 months). Moderate adverse events were more common in the group that received the three-drug regimen than in the combined two-drug-regimen groups (27% vs. 5%, P<0.001). There were no serious adverse events.

Conclusions: The three-drug regimen induced clearance of microfilariae from the blood for 3 years in almost all participants who received the treatment and was superior to the two-drug regimen administered once and noninferior to the two-drug regimen administered once a year for 3 years. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01975441 .).

Figure 1.. Enrollment and follow-up of participants in the treatment trial.

Figure 2.

Percent of participants with complete Mf clearance at 12 and 24 months post- treatment with DEC/ALB x 1 (hatched bars), DEC/ALB x 2 (light bars), and IVM/DEC/ALB x 1 (dark solid bars). Mf clearance rates were significantly higher for the IVM/DEC/ALB x 1 group compared to the other two groups at both 12 and 24 months (***p<0.001, chi-square). Complete Mf clearance at 24 months was more common in the DEC/ALB x 2 group compared to DEC/ALB x 1, p=0.004.

Figure 3.

Reductions in Mf counts at 12 and 24 months post-treatment. Note the log scale + 1 for Mf counts. A single dose of IVM/DEC/ALB was significantly more effective for reducing Mf counts than either of the two DEC/ALB treatments at 12 and 24 months, p<0.001, Mann- Whitney U test. The DEC/ALB x 2 group had greater reductions in Mf counts than the DEC/ALB x 1 group at 24 months, p=0.004.