Dora Buonfrate1, Joaquin Salas-Coronas2, José Muñoz3, Begoña Trevino Maruri4, Paola Rodari5, Francesco Castelli6, Lorenzo Zammarchi7, Leila Bianchi8, Federico Gobbi5, Teresa Cabezas-Fernández2, Ana Requena-Mendez3, Gauri Godbole9, Ronaldo Silva5, Marilena Romero10, Peter L Chiodini11, Zeno Bisoffi12. 1. Department of Infectious Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. Electronic address: dora.buonfrate@sacrocuore.it. 2. Unidad de Medicina Tropical, Hospital de Poniente, El Ejido, Almería, Spain. 3. Barcelona Institute for Global Health, ISGlobal-CRESIB, Universitat de Barcelona, Barcelona, Spain. 4. Unitat de Medicina Tropical Vall d'Hebron-Drassanes, Programa de Salut Internacional de l'ICS (PROSICS), Barcelona, Spain. 5. Department of Infectious Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. 6. Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili General Hospital, Brescia, Italy. 7. Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Florence, Italy; SOD Malattie Infettive e Tropicali, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. 8. Department of Health Sciences, University of Florence, Anna Meyer Children's University Hospital, Florence, Italy. 9. Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust London, UK. 10. Department of Medical and Oral Sciences and Biotechnologies, Università degli Studi "G d'Annunzio", Chieti, Italy. 11. Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust London, UK; London School of Hygiene and Tropical Medicine, London, UK. 12. Department of Infectious Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy; Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
Abstract
BACKGROUND:Strongyloides stercoralis infection is a neglected condition that places people who are immunocompromised at risk of hyperinfection and death. Ivermectin is the drug of choice for the treatment of S stercoralis infection, but there is no definitive evidence on the optimal dose. This trial aimed to assess whether multiple doses of ivermectin were superior to a single dose for the treatment of non-disseminated strongyloidiasis. METHODS: Our study was designed as a multicentre, open-label, phase 3, randomised controlled superiority trial. Participants were enrolled in four centres in Italy, three in Spain, and two in the UK, and recruiting sites were predominantly hospitals. Eligible patients were older than 5 years, weighed more than 15 kg, were residents in an area not endemic for S stercoralis, and either were positive for S stercoralis in faecal tests and on serology (any titre) or had a positive serological test with high titres, irrespective of the result of faecal tests. Patients were randomly assigned (1:1) using a computer-generated, blinded allocation sequence (with randomly mixed block sizes of six, eight, and ten participants) to receive either one dose of ivermectin 200 μg/kg or four doses of ivermectin 200 μg/kg (given on days 1, 2, 15, and 16). The primary endpoint was the proportion of participants with clearance of S stercoralis infection at 12 months, which was assessed in all randomly assigned participants who were not lost to follow-up (modified full-analysis set) and in participants in the modified full-analysis set who did not deviate from the assigned treatment regimen (per-protocol set). All participants were included in the safety analysis. The trial was registered with ClinicalTrials.gov, NCT01570504, and is now closed for recruitment. FINDINGS: Of the 351 patients assessed for eligibility, 309 recruited between March 26, 2013, and May 3, 2017, were randomly assigned to one dose (n=155) or four doses (n=154) of ivermectin. At 12 months in the modified full-analysis set, 86% (95% CI 79 to 91; 102 of 118 participants) had responded to treatment in the single-dose group compared with 85% (77 to 90; 96 of 113 participants) in the four-dose group (risk difference 1·48%, 95% CI -7·55 to 10·52; p=0·75); similar results were observed in the per-protocol set. Adverse events were generally of mild intensity and more frequent in the multiple-dose than in the single-dose group. The trial was terminated early due to futility. INTERPRETATION: Multiple doses of ivermectin did not show higher efficacy and was tolerated less than a single dose. A single dose should therefore be preferred for the treatment of non-disseminated strongyloidiasis. FUNDING: There was no funding source for this study.
RCT Entities:
BACKGROUND:Strongyloides stercoralis infection is a neglected condition that places people who are immunocompromised at risk of hyperinfection and death. Ivermectin is the drug of choice for the treatment of S stercoralis infection, but there is no definitive evidence on the optimal dose. This trial aimed to assess whether multiple doses of ivermectin were superior to a single dose for the treatment of non-disseminated strongyloidiasis. METHODS: Our study was designed as a multicentre, open-label, phase 3, randomised controlled superiority trial. Participants were enrolled in four centres in Italy, three in Spain, and two in the UK, and recruiting sites were predominantly hospitals. Eligible patients were older than 5 years, weighed more than 15 kg, were residents in an area not endemic for S stercoralis, and either were positive for S stercoralis in faecal tests and on serology (any titre) or had a positive serological test with high titres, irrespective of the result of faecal tests. Patients were randomly assigned (1:1) using a computer-generated, blinded allocation sequence (with randomly mixed block sizes of six, eight, and ten participants) to receive either one dose of ivermectin 200 μg/kg or four doses of ivermectin 200 μg/kg (given on days 1, 2, 15, and 16). The primary endpoint was the proportion of participants with clearance of S stercoralis infection at 12 months, which was assessed in all randomly assigned participants who were not lost to follow-up (modified full-analysis set) and in participants in the modified full-analysis set who did not deviate from the assigned treatment regimen (per-protocol set). All participants were included in the safety analysis. The trial was registered with ClinicalTrials.gov, NCT01570504, and is now closed for recruitment. FINDINGS: Of the 351 patients assessed for eligibility, 309 recruited between March 26, 2013, and May 3, 2017, were randomly assigned to one dose (n=155) or four doses (n=154) of ivermectin. At 12 months in the modified full-analysis set, 86% (95% CI 79 to 91; 102 of 118 participants) had responded to treatment in the single-dose group compared with 85% (77 to 90; 96 of 113 participants) in the four-dose group (risk difference 1·48%, 95% CI -7·55 to 10·52; p=0·75); similar results were observed in the per-protocol set. Adverse events were generally of mild intensity and more frequent in the multiple-dose than in the single-dose group. The trial was terminated early due to futility. INTERPRETATION: Multiple doses of ivermectin did not show higher efficacy and was tolerated less than a single dose. A single dose should therefore be preferred for the treatment of non-disseminated strongyloidiasis. FUNDING: There was no funding source for this study.
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