Shortened Regimen for Drug-susceptible TB in Children (SMILE-TB)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Tuberculosis; Tuberculosis, Pulmonary; Mycobacterium Tuberculosis; Tuberculosis, Lymph Node
• Intervention / Treatment: Drug: Isoniazid; Drug: Rifampin; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Rifapentine; Drug: Moxifloxacin

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.

• Study Type: Interventional
• Enrollment (Estimated): 860
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kisten Nolan, MPH, BSN; Phone Number: +14435403993; Email: knolan2@jh.edu
• Study Contact Backup: Name: Andrea Deluca, MHS; Phone Number: +14434872217; Email: adeluca@jhu.edu

Study Locations

• Indonesia
  • Bandung, Indonesia
    • Faculty of Medicine, Universitas Padjadjaran
    • Contact: Rovina Ruslami, MD, PhD; Phone Number: +62895328254920; Email: n.ruslami@gmail.com
    • Principal Investigator: Rovina Ruslami, MD, PhD
• Mozambique
  • Maputo, Mozambique
    • Instituto Nacional de Saúde (INS)
    • Contact: Celso Khosa, MD PhD; Phone Number: +25821311038; Email: celso.khosa@ins.gov.mz
    • Principal Investigator: Celso Khosa, MD, PhD
• South Africa
  • Durban, South Africa
    • Africa Health Research Institute (AHRI)
    • Principal Investigator: Moherndran Archary, MBChB, PhD
    • Contact: Moherndran Archary, MBChB PhD; Phone Number: +270312604318; Email: mo.archary@ahri.org
• Uganda
  • Kampala, Uganda
    • MU-JHU Care Ltd
    • Contact: Eric Wobudeya, MD; Phone Number: +256708162351; Email: ewobudeya@mujhu.org
    • Principal Investigator: Eric Wobudeya, MBChB MMed MSc
• Zambia
  • Lusaka, Zambia
    • University of Zambia, School of Medicine
    • Contact: Chishala Chabala, MBChB MMed MSc; Phone Number: +260977849537; Email: cchabala@gmail.com
    • Principal Investigator: Chishala Chabala, MBChB MMed MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E); 8 weeks of daily HRZ(E) followed by either 16 or 24 weeks of daily HR, per local standard of care	Drug: Isoniazid; Once daily weight-based dose; Other Names: H; Drug: Rifampin; Once daily weight-based dose; Other Names: R; Drug: Pyrazinamide; Once daily weight-based dose; Other Names: Z; Drug: Ethambutol; Once daily weight-based dose; Other Names: E
Experimental: Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M); 8 weeks of daily HPZM	Drug: Isoniazid; Once daily weight-based dose; Other Names: H; Drug: Pyrazinamide; Once daily weight-based dose; Other Names: Z; Drug: Rifapentine; Once daily weight-based dose; Other Names: Priftin; P; Drug: Moxifloxacin; Once daily weight-based dose; Other Names: Avelox; M

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TB disease-free survival at 48-weeks	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.	Measured from study entry through week 48
Proportion of participants with grade 3 or higher adverse events over 28 weeks	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.	Measured from study entry through Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TB disease-free survival at 48-weeks	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.	Measured from study entry through Week 48
TB disease-free survival at 72-weeks	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.	Measured from study entry through Week 72
Adherence to treatment regimens	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.	Measured from study entry through Week 48
Tolerability as assessed by proportion of participants who discontinue treatment	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.	Week 8 (intervention/HPZM) or Week 16 or Week 24 (control/HRZ(E))
Rifapentine Area under the curve (AUC0-24)	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.	Measured from study entry through Week 8
Rifapentine minimal concentration (Cmin)	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.	Measured from study entry through Week 8
Rifapentine peak concentration (Cmax)	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.	Measured from study entry through Week 8
Moxifloxacin AUC0-24	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.	Measured from study entry through Week 8
Moxifloxacin Cmin	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.	Measured from study entry through Week 8
Moxifloxacin Cmax	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.	Measured from study entry through Week 8
Parent/guardian and/or participant reported palatability and acceptability of study regimen	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.	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	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.	Baseline through Week 8 for HPZM, Week 16 for HRZ(E) with non-severe disease, or Week 24 for HRZ(E) with severe disease
Risk Stratification Algorithm	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.	Measured from study entry through Week 48
Cost-effectiveness of the HPZM regimen compared with the HRZ(E) regimen	Comparison of the cost-effectiveness of 8-week HPZM and 16- or 24-week HRZ(E) using a societal approach, modeling the incremental cost-effectiveness of HPZM vs 16- or 24-week HRZ(E), 24-week HRZ(E) and no treatment. Data will include two cost surveys developed by the study team, per participant at Week 4 and at treatment completion (Week 8, 16 or 24).	Measured from study entry through Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dolutegravir AUC0-24	Area under the curve from start of dose to 24 hours post-dose. Measured at Week 4 or 8 and at between Weeks 12-28. Blood samples drawn at 0, 1 hour, 4 hours and 6 hours post dose.	Measured from study entry through Week 28
Dolutegravir Cmin	Minimal concentration from start of dose to 24 hours post-dose. Measured at Week 4 or 8 and at between Weeks 12-28. Blood samples drawn at 0, 1 hour, 4 hours and 6 hours post dose.	Measured from study entry through Week 28
Dolutegravir Cmax	Peak concentration from start of dose to 24 hours post-dose. Measured at Week 4 or 8 and at between Weeks 12-28. Blood samples drawn at 0, 1 hour, 4 hours and 6 hours post dose.	Measured from study entry through Week 28
Proportion of children living with HIV	Among participants living with HIV, the proportions of participants in each study arm who achieve or maintain virologic control (< 200 copies/mL) at Weeks 24 and 48 will be presented in aggregate, as well as broken down by weight bands (if the sample sizes are sufficient) bounded by 95% confidence intervals.	Week 24 and Week 48

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: United States Agency for International Development (USAID)
• Investigators: Principal Investigator: Nicole Salazar-Austin, MD, ScM, Johns Hopkins University

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2024
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: January 26, 2024
• First Submitted That Met QC Criteria: February 2, 2024
• First Posted (Actual): February 12, 2024

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 2, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: pediatric; rifapentine; infections; child; TB; lung diseases; respiratory tract diseases; tuberculosis; dolutegravir; pulmonary; paediatric; moxifloxacin; respiratory tract infections; stratified medicine; shortened regimen; lymph node; drug-susceptible; mycobacterium infections; antitubercular agents
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Tuberculosis, Extrapulmonary; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Lymph Node; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Moxifloxacin; Rifapentine; Rifampin; Isoniazid; Pyrazinamide; Ethambutol
• Other Study ID Numbers: IRB00388853

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No