Mycobacterium Tuberculosis, Tuberculosis, Tuberculosis, Lymph Node, Tuberculosis, Pulmonary
Conditions
Keywords
tuberculosis, pediatric, stratified medicine, shortened regimen, rifapentine, moxifloxacin, dolutegravir, drug-susceptible, lymph node, pulmonary, infections, TB, mycobacterium infections, respiratory tract infections, lung diseases, antitubercular agents, respiratory tract diseases, child, paediatric
Brief summary
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
DRUGIsoniazid
Once daily weight-based dose
DRUGRifampin
Once daily weight-based dose
DRUGPyrazinamide
Once daily weight-based dose
DRUGEthambutol
Once daily weight-based dose
DRUGRifapentine
Once daily weight-based dose
DRUGMoxifloxacin
Once daily weight-based dose
Sponsors
Johns Hopkins University
United States Agency for International Development (USAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
International, multicenter, randomized, controlled, open-label, non-inferiority
Eligibility
Sex/Gender
ALL
Age
0 Days to 9 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| TB disease-free survival at 48-weeks | Measured from study entry through week 48 | Non-inferiority will be assessed by comparing the upper bound of a 95%, 2-sided confidence interval for the difference between the proportion of participants who are classified as having an unsuccessful outcome on the control regimen (HRZ(E)) and the intervention regimen (HPZM) to the predefined non-inferiority margin of 6% at 48 weeks. |
| Proportion of participants with grade 3 or higher adverse events over 28 weeks | Measured from study entry through Week 28 | The proportion of participants with a Grade 3 or higher adverse event and the corresponding 95% confidence intervals will be generated. An exact test for equality of proportions will be used to compare safety outcomes between the arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TB disease-free survival at 48-weeks | Measured from study entry through Week 48 | Non-inferiority will be assessed by comparing the upper bound of a 95%, 2-sided confidence interval for the difference between the proportion of participants who are classified as having an unsuccessful outcome on the control regimen (HRZ(E)) and the intervention regimen (HPZM) to the predefined non-inferiority margin of 6% at 48 weeks. |
| TB disease-free survival at 72-weeks | Measured from study entry through Week 72 | Non-inferiority will be assessed by comparing the upper bound of a 95%, 2-sided confidence interval for the difference between the proportion of participants who are classified as having an unsuccessful outcome on the control regimen (HRZ(E)) and the intervention regimen (HPZM) to the predefined non-inferiority margin of 6% at 72 weeks. |
| Adherence to treatment regimens | Measured from study entry through Week 48 | The per-protocol analysis will account for variations in adherence to the treatment regimens. Inverse probability of treatment weighting (IPTW) using propensity scores will be applied and the net difference in treatment failure rates between the two treatment regimens and the 95% confidence interval around this will be calculated to determine non-inferiority. |
| Tolerability as assessed by proportion of participants who discontinue treatment | Week 8 (intervention/HPZM) or Week 16 or Week 24 (control/HRZ(E)) | Tolerability will be assessed as discontinuation of the assigned treatment for a reason other than microbiological ineligibility (AEs assessed as related to the study regimen that led to permanent discontinuation of the regimen, participant refusal, parent/guardian prematurely discontinues, etc.) among the modified intention-to-treat population. Proportion of participants who discontinue the assigned study regimen and the corresponding 95% confidence intervals will be generated. The control regimen (HRZ(E)) will be compared against the intervention regimen (HPZM) using an exact test for equality of proportions. |
| Rifapentine Area under the curve (AUC0-24) | Measured from study entry through Week 8 | Area under the curve from start of dose to 24 hours post-dose. Measured at Week 4 or Week 8. Blood samples drawn at 0, 1 minute, 2 minutes, 4 hours and 6 hours post dose. |
| Rifapentine minimal concentration (Cmin) | Measured from study entry through Week 8 | Minimal concentration from start of dose to 24 hours post-dose. Measured at Week 4 or Week 8. Blood samples drawn at 0, 1 minute, 2 minutes, 4 hours and 6 hours post dose. |
| Rifapentine peak concentration (Cmax) | Measured from study entry through Week 8 | Peak concentration from start of dose to 24 hours post-dose. Measured at Week 4 or Week 8. Blood samples drawn at 0, 1 minute, 2 minutes, 4 hours and 6 hours post dose. |
| Moxifloxacin AUC0-24 | Measured from study entry through Week 8 | Area under the curve from start of dose to 24 hours post-dose. Measured at Week 4 or Week 8. Blood samples drawn at 0, 1 minute, 2 minutes, 4 hours and 6 hours post dose. |
| Moxifloxacin Cmin | Measured from study entry through Week 8 | Minimal concentration from start of dose to 24 hours post-dose. Measured at Week 4 or Week 8. Blood samples drawn at 0, 1 minute, 2 minutes, 4 hours and 6 hours post dose. |
| Moxifloxacin Cmax | Measured from study entry through Week 8 | Peak concentration from start of dose to 24 hours post-dose. Measured at Week 4 or Week 8. Blood samples drawn at 0, 1 minute, 2 minutes, 4 hours and 6 hours post dose. |
| Parent/guardian and/or participant reported palatability and acceptability of study regimen | Baseline, Week 4, Week 8 (Regimens 1 and 2) and at Weeks 16 and 24 (Regimen 1 only) | Based on questionnaire developed by study team, data will be aggregated to measure acceptability at Entry, Week 4, and Week 8 (all participants), and Weeks 16 and 24 (for those who continue on HRZ(E) only). Scoring based on a likert or likert-like scale for each question. Each question is scored 1 to 5 with higher scores reflecting increased acceptability. |
| Adherence as assessed by proportion of participants who have taken at least 90% of their doses | Baseline through Week 8 for HPZM, Week 16 for HRZ(E) with non-severe disease, or Week 24 for HRZ(E) with severe disease | Adherence measures will be documented by a treatment supporter on a TB treatment card (as per local practice), by pill count and by an adherence questionnaire and descriptively summarized for all participants. Participants are considered adherent who have taken at least 90% of their doses within the 8 week, 16 week or 24-week time frame of their regimen. |
| Risk Stratification Algorithm | Measured from study entry through Week 48 | If the study outcome is not non-inferior, pragmatic, programmatically available data will be considered for inclusion in a risk stratification algorithm that would aim to identify children at high risk of unsuccessful TB treatment outcome who may benefit from a longer duration of therapy. The efficacy endpoint will be analyzed using mixed-effects logistic regression models to identify predictors. The models will be adjusted for World Bank country income categories and by site using random intercepts. Univariable and multivariable analysis will be performed. The association between baseline clinical predictors and unsuccessful treatment outcomes will be analyzed, Treatment characteristics will then be added to the models to determine if treatment helped in the description of the primary efficacy endpoint. |
| Cost effectiveness as assessed by the incremental cost-effective ratio (ICER) | Measured from study entry through Week 24 | ICER: Total costs of HPZM minus the total costs 16 or 24 week HRZE, divided by the total number of disability-adjusted life-year (DALY) averted for HPZM minus the total DALYs averted for 16- or 24-week HRZE. |
Countries
India, Indonesia, Mozambique, South Africa, Uganda, Zambia, Zimbabwe
Contacts
CONTACTKisten Nolan, MPH, BSN
PRINCIPAL_INVESTIGATORNicole Salazar-Austin, MD, ScM
Johns Hopkins University
Outcome results
None listed