title: Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial.
abstract: BACKGROUND
  Existing anthelmintic drugs (eg, albendazole and mebendazole) have low efficacy against the intestinal nematode species Trichuris trichiura and the drug pipeline is exhausted. We aimed to investigate the strategy of combination chemotherapy with existing drugs to establish whether their efficacy could be enhanced and broadened.
  
  
  METHODS
  In this randomised controlled trial, we compared three drug combinations and one standard drug alone in children aged 6-14 years in two schools on Pemba Island, Tanzania infected with T trichiura and concomitant intestinal nematodes. We assigned children, via a randomisation list with block sizes of either four or eight, to orally receive albendazole (400 mg) plus ivermectin (200 μg/kg); albendazole (400 mg) plus mebendazole (500 mg); albendazole (400 mg) plus oxantel pamoate (20 mg/kg); or mebendazole (500 mg) alone. The primary endpoints were the proportion of children cured of T trichiura infection and the reduction of T trichiura eggs in stool based on geometric means, both analysed by available case. This study is registered with ISRCTN, number ISRCTN80245406.
  
  
  RESULTS
  We randomly assigned 440 eligible children infected with T trichiura between Sept 2, and Oct 18, 2013, to one of the four treatment groups (110 children per group). Data for 431 children were included in the analysis for the primary endpoints. Albendazole plus oxantel pamoate (74 of 108 children cured [68·5%, 95% CI 59·6-77·4]; egg reduction 99·2%, 98·7-99·6) and albendazole plus ivermectin (30 of 109 cured [27·5%, 19·0-36·0]; egg reduction 94·5%, 91·7-96·3) were significantly more effective against T trichiura than mebendazole alone (nine of 107 cured [8·4%, 3·1-13·8]; egg reduction 58·5%, 45·2-70·9). Albendazole plus mebendazole had similar low efficacy (nine of 107 cured [8·4%, 3·1-13·8; egg reduction 51·6%, 35·0-65·3) to mebendazole alone. About a fifth of the children reported adverse events, which were mainly mild. Abdominal cramps and headache were the most common adverse events after treatment; abdominal cramps were reported by 13 (12·0%) children for albendazole plus ivermectin, 10 (9·3%) for albendazole plus mebendazole, 20 (18·2%) for albendazole plus oxantel pamoate, and 16 (14·5%) for mebendazole; headaches were reported by 5 (4·6%) children for albendazole plus ivermectin, 6 (5·6%) for albendazole plus mebendazole, 12 (10·9%) for albendazole plus oxantel pamoate, and 7 (6·4%) for mebendazole.
  
  
  CONCLUSIONS
  Our head-to-head comparison of three combination chemotherapies showed the highest efficacy for albendazole plus oxantel pamoate for the treatment of infection with T trichiura. Further studies should investigate the combination of albendazole plus oxantel pamoate so that it can be considered for soil-transmitted helminthiasis control programmes.
  
  
  BACKGROUND
  Medicor Foundation and Swiss National Science Foundation.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Speich
authors.affiliation: Laboratory Division, Public Health Laboratory-Ivo de Carneri, Chake Chake, Tanzania.
authors.forename: Said M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Laboratory Division, Public Health Laboratory-Ivo de Carneri, Chake Chake, Tanzania.
authors.forename: Shaali M
authors.initials: SM
authors.lastname: Ame
authors.affiliation: Divisions of Internal Medicine and Infectious Diseases, Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Isaac I
authors.initials: II
authors.lastname: Bogoch
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Alles
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.affiliation: Ivo de Carneri Foundation, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Albonico
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Hattendorf
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Utzinger
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland. Electronic address: jennifer.keiser@unibas.ch.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D015766:Albendazole / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000871:Anthelmintics / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D005243:Feces / Q000469:parasitology; D005260:Female; D006373:Helminthiasis / Q000188:drug therapy*; D006801:Humans; D007411:Intestinal Diseases, Parasitic / Q000188:drug therapy*; D007559:Ivermectin / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008463:Mebendazole / Q000009:adverse effects / Q000627:therapeutic use*; D010270:Parasite Egg Count; D011716:Pyrantel Pamoate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013636:Tanzania; D016896:Treatment Outcome; D014257:Trichuriasis / Q000188:drug therapy*; D014258:Trichuris / Q000302:isolation & purification
chemical_list: D000871:Anthelmintics; D007559:Ivermectin; D011716:Pyrantel Pamoate; D008463:Mebendazole; D015766:Albendazole; C037225:oxantel pamoate