Treatment for preventing tuberculosis in children and adolescents

A randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and Isoniazid

International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC)

Research output: Contribution to journalArticleResearchpeer-review

73 Citations (Scopus)

Abstract

Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited. Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.Design, Setting, And Participants: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.Interventions: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.Main Outcomes And Measures: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.Results: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95%CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74%and an upper bound of the 95%CI of the difference of +0.32%, which met the noninferiority criterion.Conclusions And Relevance: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.Trial Registration: clinicaltrials.gov Identifier: NCT00023452.

Original languageEnglish
Pages (from-to)247-255
Number of pages9
JournalJAMA Pediatrics
Volume169
Issue number3
DOIs
StatePublished - 1 Mar 2015

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rifapentine
Isoniazid
Tuberculosis
Randomized Controlled Trials
Latent Tuberculosis
Group Psychotherapy
Therapeutics
Drug Combinations

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International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC) (2015). Treatment for preventing tuberculosis in children and adolescents: A randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and Isoniazid. JAMA Pediatrics, 169(3), 247-255. https://doi.org/10.1001/jamapediatrics.2014.3158
International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC). / Treatment for preventing tuberculosis in children and adolescents : A randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and Isoniazid. In: JAMA Pediatrics. 2015 ; Vol. 169, No. 3. pp. 247-255.
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abstract = "Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited. Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.Design, Setting, And Participants: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.Interventions: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.Main Outcomes And Measures: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5{\%}. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75{\%}.Results: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1{\%}) completed treatment vs 351 of 434 (80.9{\%}) in the isoniazid-only group (P = .003). The 95{\%}CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6{\%}) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2{\%}) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74{\%}) in the isoniazid-only group, for a difference of -0.74{\%}and an upper bound of the 95{\%}CI of the difference of +0.32{\%}, which met the noninferiority criterion.Conclusions And Relevance: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.Trial Registration: clinicaltrials.gov Identifier: NCT00023452.",
author = "{International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC)} and Villarino, {M. Elsa} and Scott, {Nigel A.} and Stephen Weis and Marc Weiner and Conde, {Marcus B.} and Brenda Jones and Sharon Nachman and Ricardo Oliveira and Moro, {Ruth N.} and Nong Shang and Goldberg, {Stefan V.} and Sterling, {Timothy R.}",
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International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC) 2015, 'Treatment for preventing tuberculosis in children and adolescents: A randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and Isoniazid', JAMA Pediatrics, vol. 169, no. 3, pp. 247-255. https://doi.org/10.1001/jamapediatrics.2014.3158

Treatment for preventing tuberculosis in children and adolescents : A randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and Isoniazid. / International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC).

In: JAMA Pediatrics, Vol. 169, No. 3, 01.03.2015, p. 247-255.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Treatment for preventing tuberculosis in children and adolescents

T2 - A randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and Isoniazid

AU - International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC)

AU - Villarino, M. Elsa

AU - Scott, Nigel A.

AU - Weis, Stephen

AU - Weiner, Marc

AU - Conde, Marcus B.

AU - Jones, Brenda

AU - Nachman, Sharon

AU - Oliveira, Ricardo

AU - Moro, Ruth N.

AU - Shang, Nong

AU - Goldberg, Stefan V.

AU - Sterling, Timothy R.

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N2 - Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited. Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.Design, Setting, And Participants: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.Interventions: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.Main Outcomes And Measures: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.Results: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95%CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74%and an upper bound of the 95%CI of the difference of +0.32%, which met the noninferiority criterion.Conclusions And Relevance: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.Trial Registration: clinicaltrials.gov Identifier: NCT00023452.

AB - Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited. Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.Design, Setting, And Participants: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.Interventions: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.Main Outcomes And Measures: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.Results: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95%CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74%and an upper bound of the 95%CI of the difference of +0.32%, which met the noninferiority criterion.Conclusions And Relevance: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.Trial Registration: clinicaltrials.gov Identifier: NCT00023452.

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International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC). Treatment for preventing tuberculosis in children and adolescents: A randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and Isoniazid. JAMA Pediatrics. 2015 Mar 1;169(3):247-255. https://doi.org/10.1001/jamapediatrics.2014.3158