A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America..
BACKGROUND: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment.
METHODS: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months.
RESULTS: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective.
CONCLUSIONS: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days.
CLINICAL TRIALS REGISTRATION: NCT02498782.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:76 |
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| Enthalten in: |
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America - 76(2023), 3 vom: 08. Feb., Seite e1186-e1194 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Torrico, Faustino [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.02.2023 Date Revised 20.02.2023 published: Print ClinicalTrials.gov: NCT02498782 Citation Status MEDLINE |
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| doi: |
10.1093/cid/ciac579 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM344451046 |
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| 245 | 1 | 2 | |a A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease |
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| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT02498782 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. | ||
| 520 | |a BACKGROUND: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment | ||
| 520 | |a METHODS: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months | ||
| 520 | |a RESULTS: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective | ||
| 520 | |a CONCLUSIONS: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days | ||
| 520 | |a CLINICAL TRIALS REGISTRATION: NCT02498782 | ||
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