The safety of combined triple drug therapy with ivermectin, diethylcarbamazine and albendazole in the neglected tropical diseases co-endemic setting of Fiji: A cluster randomised trial

Myra Hardy; Josaia Samuela; Mike Kama; Meciusela Tuicakau; Lucia Romani; Margot J Whitfeld; Christopher L King; Gary J Weil; Anneke C Grobler; Leanne J Robinson; John M Kaldor; Andrew C Steer

doi:10.1371/journal.pntd.0008106

The safety of combined triple drug therapy with ivermectin, diethylcarbamazine and albendazole in the neglected tropical diseases co-endemic setting of Fiji: A cluster randomised trial

PLoS Negl Trop Dis. 2020 Mar 16;14(3):e0008106. doi: 10.1371/journal.pntd.0008106. eCollection 2020 Mar.

Authors

Myra Hardy^{1

2}, Josaia Samuela³, Mike Kama³, Meciusela Tuicakau³, Lucia Romani⁴, Margot J Whitfeld⁵, Christopher L King⁶, Gary J Weil⁷, Anneke C Grobler^{1

2}, Leanne J Robinson⁸, John M Kaldor⁴, Andrew C Steer^{1

2}

Affiliations

¹ Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
² Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
³ Fiji Ministry of Health and Medical Services, Suva, Fiji.
⁴ Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.
⁵ St Vincent's Hospital, University of New South Wales, Sydney, New South Wales, Australia.
⁶ Centre for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, United States of America.
⁷ Washington University, St. Louis, Missouri, United States of America.
⁸ Vector-borne Diseases and Tropical Public Health, Burnet Institute, Melbourne, Victoria, Australia.

Abstract

Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Albendazole / administration & dosage
Albendazole / adverse effects*
Antiparasitic Agents / administration & dosage
Antiparasitic Agents / adverse effects*
Child
Child, Preschool
Community-Acquired Infections / drug therapy
Diethylcarbamazine / administration & dosage
Diethylcarbamazine / adverse effects*
Drug Therapy, Combination / adverse effects
Drug Therapy, Combination / methods
Drug-Related Side Effects and Adverse Reactions / epidemiology
Drug-Related Side Effects and Adverse Reactions / pathology
Elephantiasis, Filarial / drug therapy
Female
Fiji
Helminthiasis / drug therapy
Humans
Infant
Insecticides / administration & dosage
Insecticides / adverse effects*
Ivermectin / administration & dosage
Ivermectin / adverse effects*
Male
Middle Aged
Neglected Diseases / drug therapy
Rural Population
Scabies / drug therapy
Treatment Outcome
Young Adult

Substances

Antiparasitic Agents
Insecticides
Ivermectin
Albendazole
Diethylcarbamazine

Grants and funding

This study was supported in part by grant OPPGH5342 from the Bill & Melinda Gates Foundation to Washington University. The study was also supported in part by the Coalition for Operational Research on Neglected Tropical Diseases, which is funded at the Task Force for Global Health primarily by the Bill & Melinda Gates Foundation, by the United Kingdom Department for International Development, and by the United States Agency for International Development through its Neglected Tropical Diseases Program. Albendazole (produced and donated by GlaxoSmithKline) and diethylcarbamazine (produced and donated by Eisai Co., Ltd.) were obtained from Ministry of Health stocks in Fiji. Ivermectin was purchased from Merck Sharp Dohme (Australia) Pty. Ltd. and permethrin cream 5% was purchased from Pharmatec Wholesale Company Ltd. Fiji and manufactured by Glenmark Pharmaceuticals Ltd. The funders and drug donors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.