Safety of single-dose bedaquiline combined with rifampicin for leprosy post-exposure prophylaxis: A Phase 2 randomized non-inferiority trial in the Comoros Islands
To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double d...
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| Veröffentlicht in: | PLoS medicine Jg. 21; H. 10; S. e1004453 |
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Public Library of Science
21.10.2024
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| Abstract | To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP).
From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group.
In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros.
ClinicalTrials.gov NCT05406479. |
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| AbstractList | BackgroundTo reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP).Methods and findingsFrom July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc.Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI −1.8, 5.3, p = 0.41). No individual’s QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; −1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group.ConclusionsIn this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros.Trial RegistrationClinicalTrials.gov NCT05406479. Bouke C. de Jong and team assess the safety of a Bedaquiline enhanced post-exposure prophylaxis regimen in the Comoros Islands. To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP).BACKGROUNDTo reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP).From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group.METHODS AND FINDINGSFrom July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group.In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros.CONCLUSIONSIn this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros.ClinicalTrials.gov NCT05406479.TRIAL REGISTRATIONClinicalTrials.gov NCT05406479. To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. ClinicalTrials.gov NCT05406479. To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3x the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a 50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. Background To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). Methods and findings From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI −1.8, 5.3, p = 0.41). No individual’s QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; −1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. Conclusions In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. Trial Registration ClinicalTrials.gov NCT05406479. BackgroundTo reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP).Methods and findingsFrom July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group.ConclusionsIn this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros.Trial registrationClinicalTrials.gov NCT05406479. Background To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). Methods and findings From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3x the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a 50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. Conclusions In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. Trial Registration ClinicalTrials.gov NCT05406479. |
| Audience | Academic |
| Author | Grillone, Silahi Halifa Braet, Sofie Marijke Assoumani, Younoussa Mzembaba, Aboubacar Hasker, Epco Ronse, Maya Tsoumanis, Achilleas Ortuño-Gutiérrez, Nimer Snijders, Rian Nourdine, Said Hoof, Carolien Bergeman, Auke Thomas Piubello, Alberto Salim, Zahara de Jong, Bouke Catherine Wirdane Abdou, Mohamed der Werf, Christian van |
| AuthorAffiliation | 5 Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium University of Glasgow, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND 1 Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium 2 National Tuberculosis and Leprosy control Program, Moroni, Union of the Comoros 3 Heart Centre, Department of Cardiology, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, the Netherlands 6 Damien Foundation, Brussels, Belgium 4 Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium |
| AuthorAffiliation_xml | – name: 1 Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium – name: 3 Heart Centre, Department of Cardiology, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, the Netherlands – name: 5 Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium – name: University of Glasgow, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND – name: 2 National Tuberculosis and Leprosy control Program, Moroni, Union of the Comoros – name: 6 Damien Foundation, Brussels, Belgium – name: 4 Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium |
| Author_xml | – sequence: 1 givenname: Bouke Catherine orcidid: 0000-0002-1017-4675 surname: de Jong fullname: de Jong, Bouke Catherine – sequence: 2 givenname: Said surname: Nourdine fullname: Nourdine, Said – sequence: 3 givenname: Auke Thomas orcidid: 0000-0002-3881-9105 surname: Bergeman fullname: Bergeman, Auke Thomas – sequence: 4 givenname: Zahara surname: Salim fullname: Salim, Zahara – sequence: 5 givenname: Silahi Halifa surname: Grillone fullname: Grillone, Silahi Halifa – sequence: 6 givenname: Sofie Marijke orcidid: 0000-0003-3291-8257 surname: Braet fullname: Braet, Sofie Marijke – sequence: 7 givenname: Mohamed surname: Wirdane Abdou fullname: Wirdane Abdou, Mohamed – sequence: 8 givenname: Rian orcidid: 0000-0002-2432-9818 surname: Snijders fullname: Snijders, Rian – sequence: 9 givenname: Maya orcidid: 0000-0001-7182-6940 surname: Ronse fullname: Ronse, Maya – sequence: 10 givenname: Carolien surname: Hoof fullname: Hoof, Carolien – sequence: 11 givenname: Achilleas surname: Tsoumanis fullname: Tsoumanis, Achilleas – sequence: 12 givenname: Nimer surname: Ortuño-Gutiérrez fullname: Ortuño-Gutiérrez, Nimer – sequence: 13 givenname: Christian van orcidid: 0000-0001-8703-8527 surname: der Werf fullname: der Werf, Christian van – sequence: 14 givenname: Alberto orcidid: 0000-0002-6937-3126 surname: Piubello fullname: Piubello, Alberto – sequence: 15 givenname: Aboubacar surname: Mzembaba fullname: Mzembaba, Aboubacar – sequence: 16 givenname: Younoussa surname: Assoumani fullname: Assoumani, Younoussa – sequence: 17 givenname: Epco surname: Hasker fullname: Hasker, Epco |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39432509$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1016/S2666-5247(22)00117-3 10.1093/jac/dku171 10.1016/S2214-109X(24)00062-7 10.1186/s40249-016-0140-y 10.1136/bmj.39500.885752.BE 10.1183/13993003.02338-2020 10.1186/s12879-019-4649-0 10.1128/AAC.00722-09 10.1016/j.ebiom.2023.104649 10.47276/lr.88.3.334 10.1128/AAC.50.4.1558-1560.2006 10.1128/AAC.02243-12 10.1186/s12879-023-08290-0 10.1128/AAC.01474-06 10.1164/rccm.201407-1264OC |
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| Copyright | Copyright: © 2024 de Jong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. COPYRIGHT 2024 Public Library of Science 2024 de Jong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2024 de Jong et al 2024 de Jong et al 2024 de Jong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| DOI | 10.1371/journal.pmed.1004453 |
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| Notes | new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3 The trial was funded by Janssen Pharmaceuticals, manufacturer of bedaquiline used in the study, awarded to the Institute of Tropical Medicine, Principal Investigator EH, as an investigator-initiated collaboration. Financial support included the expenses related to training for and conduct of the trial, laboratory analyses, data analysis, and trial monitoring. The role of Janssen Pharmaceuticals was limited to support for regulatory duties and to deliver the study product. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLoS policies. The authors declare to have no other conflicts relevant to this trial. |
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| References | RP van Heeswijk (pmed.1004453.ref013) 2014; 69 N Ortuno-Gutierrez (pmed.1004453.ref017) 2019; 19 E Hasker (pmed.1004453.ref009) 2017; 88 MJ Boeree (pmed.1004453.ref006) 2015; 191 WHO (pmed.1004453.ref019) 2014 E Hasker (pmed.1004453.ref008) 2024; 12 J. Pharmaceutica (pmed.1004453.ref012) 2023 RC Johnson (pmed.1004453.ref015) 2023 L Mieras (pmed.1004453.ref004) 2016; 5 R Gelber (pmed.1004453.ref010) 2009; 53 WHO (pmed.1004453.ref002) 2018 Y Assoumani (pmed.1004453.ref016) 2023; 23 AH Diacon (pmed.1004453.ref014) 2013; 57 SM Braet (pmed.1004453.ref005) 2022; 3 AH Diacon (pmed.1004453.ref007) 2007; 51 FJ Moet (pmed.1004453.ref003) 2008; 336 WHO (pmed.1004453.ref018) 2020 B Ji (pmed.1004453.ref011) 2006; 50 A Jouet (pmed.1004453.ref020) 2021; 57 pmed.1004453.ref001 pmed.1004453.ref021 |
| References_xml | – year: 2023 ident: pmed.1004453.ref015 article-title: Pilot trial of the treatment of multibacillary leprosy with bedaquiline for two months followed by WHO MDT in adults in Mali: preliminary results. publication-title: European Congress on Tropical Medicine and International Health – year: 2018 ident: pmed.1004453.ref002 article-title: Guidelines for the diagnosis publication-title: treatment and prevention of leprosy – volume: 3 start-page: e693 issue: 9 year: 2022 ident: pmed.1004453.ref005 article-title: Investigating drug resistance of Mycobacterium leprae in the Comoros: an observational deep-sequencing study publication-title: Lancet Microbe doi: 10.1016/S2666-5247(22)00117-3 – volume: 69 start-page: 2310 issue: 9 year: 2014 ident: pmed.1004453.ref013 article-title: Bedaquiline: a review of human pharmacokinetics and drug-drug interactions publication-title: J Antimicrob Chemother doi: 10.1093/jac/dku171 – volume: 12 start-page: e1017 issue: 6 year: 2024 ident: pmed.1004453.ref008 article-title: Post-exposure prophylaxis in leprosy (PEOPLE): a cluster randomised trial. publication-title: Lancet Glob Health doi: 10.1016/S2214-109X(24)00062-7 – volume: 5 start-page: 46 issue: 1 year: 2016 ident: pmed.1004453.ref004 article-title: Negligible risk of inducing resistance in Mycobacterium tuberculosis with single-dose rifampicin as post-exposure prophylaxis for leprosy publication-title: Infect Dis Poverty doi: 10.1186/s40249-016-0140-y – start-page: 1 volume-title: Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. year: 2014 ident: pmed.1004453.ref019 – volume: 336 start-page: 761 issue: 7647 year: 2008 ident: pmed.1004453.ref003 article-title: Effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial publication-title: BMJ doi: 10.1136/bmj.39500.885752.BE – volume: 57 issue: 3 year: 2021 ident: pmed.1004453.ref020 article-title: Deep amplicon sequencing for culture-free prediction of susceptibility or resistance to 13 anti-tuberculous drugs publication-title: Eur Respir J doi: 10.1183/13993003.02338-2020 – volume: 19 start-page: 1033 issue: 1 year: 2019 ident: pmed.1004453.ref017 article-title: Protocol, rationale and design of PEOPLE (Post ExpOsure Prophylaxis for LEprosy in the Comoros and Madagascar): a cluster randomized trial on effectiveness of different modalities of implementation of post-exposure prophylaxis of leprosy contacts. publication-title: BMC Infect Dis doi: 10.1186/s12879-019-4649-0 – volume: 53 start-page: 3989 issue: 9 year: 2009 ident: pmed.1004453.ref010 article-title: The diarylquinoline R207910 is bactericidal against Mycobacterium leprae in mice at low dose and administered intermittently publication-title: Antimicrob Agents Chemother doi: 10.1128/AAC.00722-09 – ident: pmed.1004453.ref021 doi: 10.1016/j.ebiom.2023.104649 – volume: 88 start-page: 334 issue: 3 year: 2017 ident: pmed.1004453.ref009 article-title: Leprosy on Anjouan (Comoros): persistent hyper-endemicity despite decades of solid control efforts. publication-title: Lepr Rev. doi: 10.47276/lr.88.3.334 – volume: 50 start-page: 1558 issue: 4 year: 2006 ident: pmed.1004453.ref011 article-title: Bactericidal activities of R207910 and other newer antimicrobial agents against Mycobacterium leprae in mice publication-title: Antimicrob Agents Chemother doi: 10.1128/AAC.50.4.1558-1560.2006 – ident: pmed.1004453.ref001 – volume: 57 start-page: 2199 year: 2013 ident: pmed.1004453.ref014 article-title: Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis. publication-title: Antimicrob Agents Chemother doi: 10.1128/AAC.02243-12 – year: 2023 ident: pmed.1004453.ref012 article-title: Summary of Product Characteristics – volume: 23 start-page: 310 issue: 1 year: 2023 ident: pmed.1004453.ref016 article-title: Protocol, rationale and design of BE-PEOPLE (Bedaquiline enhanced exposure prophylaxis for LEprosy in the Comoros): a cluster randomized trial on effectiveness of rifampicin and bedaquiline as post-exposure prophylaxis of leprosy contacts. publication-title: BMC Infect Dis doi: 10.1186/s12879-023-08290-0 – volume: 51 start-page: 2994 year: 2007 ident: pmed.1004453.ref007 article-title: Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears publication-title: Antimicrob Agents Chemother doi: 10.1128/AAC.01474-06 – year: 2020 ident: pmed.1004453.ref018 article-title: Leprosy/Hansen disease: Contact tracing and post-exposure prophylaxis. publication-title: Technical guidance – volume: 191 start-page: 1058 year: 2015 ident: pmed.1004453.ref006 article-title: A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis publication-title: Am J Respir Crit Care Med doi: 10.1164/rccm.201407-1264OC |
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| Snippet | To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis... Background To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure... BackgroundTo reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure... Bouke C. de Jong and team assess the safety of a Bedaquiline enhanced post-exposure prophylaxis regimen in the Comoros Islands. Background To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure... |
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| SubjectTerms | Children Collaboration Data collection Diarrhea Disease prevention Dosage and administration Drug dosages Drug therapy Drug therapy, Combination EKG Electrocardiogram Electrocardiography Enzymes Heart rate Leprosy Liver Medicine and Health Sciences Pediatrics Pharmaceuticals Pharmacology, Experimental Physiological aspects Prophylaxis Research and Analysis Methods Rifampin Testing Tuberculosis |
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| Title | Safety of single-dose bedaquiline combined with rifampicin for leprosy post-exposure prophylaxis: A Phase 2 randomized non-inferiority trial in the Comoros Islands |
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