An open label, block randomized, community study of the safety and efficacy of co-administered ivermectin, diethylcarbamazine plus albendazole vs. diethylcarbamazine plus albendazole for lymphatic filariasis in India

Abstract

Background: Better drug regimens for mass drug administration (MDA) could accelerate the Global Programme to Eliminate Lymphatic Filariasis (LF). This community study was designed to compare the safety and efficacy of MDA with IDA (ivermectin, diethylcarbamazine and albendazole) or DA (diethylcarbamazine and albendazole) in India.

Methodology/principal findings: This two-armed, open-labelled, block randomised, community study was conducted in LF endemic villages in Yadgir district, Karnataka, India. Consenting participants ≥5 years of age were tested for circulating filarial antigenemia (CFA) and microfilaremia (Mf) before treatment with a single oral dose of IDA or DA. Adverse events (AEs) were monitored actively for two days and passively for five more days. Persons with positive CFA or Mf tests at baseline were retested 12-months post-treatment to assess treatment efficacy. Baseline CFA and Mf-rates were 26.4% and 6.9% in IDA and 24.5% and 6.4% in DA villages respectively. 4758 and 4160 participants received IDA and DA. Most AEs were mild after both treatments; fewer than 0.1% of participants experienced AEs with severity > grade 1. No serious AEs were observed. Fever, headache and dizziness were the most common AEs. AE rates were slightly higher after IDA than DA (8.3% vs. 6.4%, P<0.01). AEs were more frequent in females and Mf-positives after either treatment, but significantly more frequent after IDA (40.5% vs 20.2%, P < 0.001). IDA was more effective for clearing Mf than DA (84% vs. 61.8%, P < 0.001). Geometric mean Mf counts per 60μl in retested Mf-positives decreased by 96.4% from 11.8 after IDA and by 90.0% from 9.5 after DA. Neither treatment was effective for clearing CFA.

Conclusions/significance: IDA had an acceptable safety profile and was more effective for clearing Mf than DA. With adequate compliance and medical support to manage AEs, IDA has the potential to accelerate LF elimination in India.

Trial registration: Clinical Trial Registry of India (CTRI No/2016/10/007399).

Fig 1. Map showing the study sites by treatment regimen.

Fig 2. CONSORT diagram.

Treatment allocation was by block randomization (DA: Diethyl carbamazine plus albendazole and IDA: ivermectin+DA).

Fig 3. Forest plot showing unadjusted and adjusted odds ratios for factors associated with AE following MDA for filariasis.

Fig 4. No. of persons with the most commonly observed AE by treatment regimen expressed as percentages of participants who were assessed for AE after treatment.

A participant was counted only once for each AE type (e.g., a subject can only have a single headache). But if a participant experienced different AE types he/she was included in the numerator of each AE type (e.g., if a subject experience a headache and fatigue, then they will be included in the numerator for both of these AE categories). AE, adverse event; DA, double-drug therapy (diethylcarbamazine, albendazole); IDA, triple-drug therapy (ivermectin, diethylcarbamazine, albendazole).

Fig 5. CONSORT diagram.

Information on individuals with filarial infections at baseline and who were retested and retreated 1-year post-treatment.

Fig 6. Distribution of subjects who were amicrofilaremic 1 year after treatment by pre-treatment microfilaria count.

Error bars 95% CI based on exact binomial probability distribution.

Fig 7. Percentage of CFA positives tested positive for Mf prior to and 1-year post treatment with IDA in children, adult and for all ages.

Fig 8. Percentage of CFA positives tested positive for Mf prior to and 1-year post treatment with DA in children, adult and for all ages.