Shortened Regimen for Drug-susceptible TB in Children

Overview

While drug-susceptible tuberculosis (TB) disease in children currently requires four to six months of treatment, most children may be able to be cured with a shorter treatment of more powerful drugs. Shorter treatment may be easier for children to tolerate and finish as well as ease caregiver strain from managing treatment side effects and supporting children over many months. The primary objective of this study is to evaluate if a 2-month regimen (including isoniazid (H), rifapentine (P), pyrazinamide (Z) and moxifloxacin (M)) is as safe and effective as a 4- to 6-month regimen (isoniazid, rifampicin (R), pyrazinamide, ethambutol (E)) in curing drug-susceptible TB disease in children under 10 years old. The study is also evaluating the safety of the HPZM in children with and without HIV.

Detailed description

In previously untreated individuals with presumed drug-susceptible pulmonary and or peripheral lymph node TB treated with eight weeks of rifapentine, isoniazid, pyrazinamide and moxifloxacin (2HPZM), all given daily throughout, the proportion of participants who experience absence of cure (unsuccessful outcome) will not be inferior to that observed in participants who are treated with the standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide, with or without ethambutol followed by 8 to 16 weeks of rifampin plus isoniazid depending on disease severity) all given daily throughout.

Interventions

• Drug Isoniazid
  Once daily weight-based dose
• Drug Rifampin
  Once daily weight-based dose
• Drug Pyrazinamide
  Once daily weight-based dose
• Drug Ethambutol
  Once daily weight-based dose
• Drug Rifapentine
  Once daily weight-based dose
• Drug Moxifloxacin
  Once daily weight-based dose

Primary outcome measures

• TB disease-free survival at 48-weeks [Time frame: Measured from study entry through week 48]
• Proportion of participants with grade 3 or higher adverse events over 28 weeks [Time frame: Measured from study entry through Week 28]

Secondary outcome measures (12)

• TB disease-free survival at 48-weeks [Time frame: Measured from study entry through Week 48]
• TB disease-free survival at 72-weeks [Time frame: Measured from study entry through Week 72]
• Adherence to treatment regimens [Time frame: Measured from study entry through Week 48]
• Tolerability as assessed by proportion of participants who discontinue treatment [Time frame: Week 8 (intervention/HPZM) or Week 16 or Week 24 (control/HRZ(E))]
• Rifapentine Area under the curve (AUC0-24) [Time frame: Measured from study entry through Week 8]
• Rifapentine minimal concentration (Cmin) [Time frame: Measured from study entry through Week 8]
• Rifapentine peak concentration (Cmax) [Time frame: Measured from study entry through Week 8]
• Moxifloxacin AUC0-24 [Time frame: Measured from study entry through Week 8]
• Moxifloxacin Cmin [Time frame: Measured from study entry through Week 8]
• Moxifloxacin Cmax [Time frame: Measured from study entry through Week 8]
• Parent/guardian and/or participant reported palatability and acceptability of study regimen [Time frame: Baseline, Week 4, Week 8 (Regimens 1 and 2) and at Weeks 16 and 24 (Regimen 1 only)]
• Adherence as assessed by proportion of participants who have taken at least 90% of their doses [Time frame: Baseline through Week 8 for HPZM, Week 16 for HRZ(E) with non-severe disease, or Week 24 for HRZ(E) with severe disease]

Eligibility criteria

Inclusion criteria

• Parent or guardian is willing and able to provide written informed consent for potential participant's study participation; in addition, when applicable per Ethics Committee/Institutional Review Board (EC/IRB) policies and procedures, potential participant is willing and able to provide assent for study participation.
• At Entry, age of less than 10 years.
• At Entry, weight 3 kilograms (kg) or greater.
• At Entry, diagnosed with TB disease, defined as:

• Pulmonary (including pleural effusion) and/or lymph node (extra-thoracic and/or intra-thoracic) TB with or without bacteriologic confirmation;
• Clinician has decided to treat with standard first-line drug-susceptible TB regimen.
• Known HIV status or HIV testing in progress based on meeting testing requirements.
• Has normal, Grade 1 or 2 test results for all of the following done at or within 14 days of Entry (including the most recent):

• Alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal;
• Total bilirubin less than or equal to 2.5 times the upper limit of normal;
• Potassium level of 3.0 milliequivalent/L or greater;
• Hemoglobin level of 7.0 g/dL or greater;
• Platelet count of 100,000/mm3 or greater;
• Estimated glomerular filtration rate (eGFR; bedside Schwartz formula) 60 mL/min/1.73m2 or higher.
• For children living with HIV:

• On antiretroviral therapy (ART) at Entry: Must be on, or able to be switched to a dolutegravir-based regimen at or prior to Entry;
• Not on ART at Entry: Planned initiation of dolutegravir before or at study Week 4.
• For participants who have reached menarche or who are engaging in sexual activity (self-reported): negative serum or urine pregnancy test within 7 days of Entry.
• For participants who are engaging in sexual activity that could lead to pregnancy (self-reported): agrees to practice at least one non-hormonal method of contraception or abstain from heterosexual intercourse during study drug treatment and for 30 days after stopping study medications. Non-hormonal methods include:

• Male or female condoms
• Diaphragm or cervical cap (with spermicide, if available)
• Non-hormonal intrauterine device (IUD) or intrauterine system (IUS)
• At Entry, intends to remain in the catchment area of the study site for the duration of study follow-up or willingness to be followed up beyond the catchment area if/when applicable, as determined by the site investigator based on participant/parent/guardian report.

Exclusion criteria

• Presumed or documented extra-pulmonary TB involving the central nervous system and/or bones and/or joints, and/or miliary TB, and/or pericardial TB and/or TB of the gastrointestinal (GI) tract and/or renal TB.
• Premature infant (born less than 37-weeks gestation) who is less than 3 months of age at Entry.
• Any known contraindication to taking any study drug:

• Known allergy or intolerance to any of the study drugs or drugs in the same class as the study drugs;
• Any prohibited medications within three days prior to Entry or planned use within the following 6 months;
• Unable to take oral medications;
• Known history of prolonged QT syndrome not caused by electrolyte derangements.
• Received more than 10 days of treatment directed against TB disease within 6 months preceding initiation of study drugs.
• M. tuberculosis isolate known or suspected to be resistant to isoniazid, rifampin, pyrazinamide, ethambutol, and/or fluoroquinolones.
• Known exposure to an infectious adult with drug-resistant TB, including resistance to isoniazid, rifampin, pyrazinamide, ethambutol, and/or fluoroquinolones.
• Has any other documented or suspected clinically significant medical condition or any other condition that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
• Previously enrolled in this study.

Late Exclusions:

• M. tuberculosis cultured or detected through World Health Organization (WHO) approved molecular assays (e.g., Cepheid Xpert MTB/RIF, Xpert XDR, sequencing or Hain MTB-DR plus assays) from sputum, swallowed sputum, nasopharyngeal aspirates, stool, or lymph node aspirate obtained around the time of study entry is determined to be resistant to isoniazid and/or rifampin and/or pyrazinamide and/or ethambutol and/or fluoroquinolones.
• Any child with a clinical TB diagnosis who is found to have a definitive alternative diagnosis for their presenting signs and symptoms whose TB treatment is discontinued prior to completion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

India · 2 centers

• Indian Council of Medical Research - National Institute for Research in Tuberculosis — Chennai
• Dr. D.Y. Patil Medical College, Hospital and Research Center — Pune

Zambia · 2 centers

• University of Zambia, School of Medicine — Lusaka
• Arthur Davison Children's Hospital — Ndola

Indonesia · 1 center

• Faculty of Medicine, Universitas Padjadjaran — Bandung

Mozambique · 1 center

• Instituto Nacional de Saúde (INS) — Maputo

South Africa · 1 center

• Africa Health Research Institute (AHRI) — Durban

Uganda · 1 center

• MU-JHU Care Ltd — Kampala

Zimbabwe · 1 center

• Harare Health and Research Consortium (HHRC) — Harare

Publications

• Avelox package insert. U.S. Food and Drug Administration. (2016). Label: Avelox (moxifloxacin hydrochloride) tablets. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021085s063lbl.pdf
• Baciewicz AM, Self TH. Isoniazid interactions. South Med J. 1985 Jun;78(6):714-8. doi: 10.1097/00007611-198506000-00025. PMID 3890202
• Ball P. Moxifloxacin (Avelox): an 8-methoxyquinolone antibacterial with enhanced potency. Int J Clin Pract. 2000 Jun;54(5):329-32. PMID 10954961
• Berg A, Clary J, Hanna D, Nuermberger E, Lenaerts A, Ammerman N, Ramey M, Hartley D, Hermann D. Model-Based Meta-Analysis of Relapsing Mouse Model Studies from the Critical Path to Tuberculosis Drug Regimens Initiative Database. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0179321. doi: 10.1128/AAC.01793-21. Epub 2022 Jan 31. PMID 35099274
• Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, O'Brien RJ, Reves RR, Reichman LB, Simone PM, Starke JR, Vernon AA; American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society. American Thoracic Society/Centers for Disease Control and Prevention/Inf PMID 12588714
• Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, Choudhri S, Daley CL, Munsiff SS, Zhao Z, Vernon A, Chaisson RE. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006 Aug 1;174(3):331-8. doi: 10.1164/rccm.200603-360OC. Epub 2006 May 4. PMID 16675781
• Centers for Disease Control and Prevention. (2023, March 22). Tuberculosis (TB) Treatment, Treatment for TB Disease. https://www.cdc.gov/tb/topic/treatment/tbdisease.htm
• Combs DL, O'Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med. 1990 Mar 15;112(6):397-406. doi: 10.7326/0003-4819-76-3-112-6-397. PMID 2155569

Identifiers

NCT: NCT06253715 · IRB00388853

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗