Shortened Regimen for Drug-susceptible TB in Children

NCT06253715 | Recruiting Phase 3 DMC

• 1 other identifier: IRB00388853
• Study Type: interventional
• Target: 860
• Locations: 6 countries
• Sites: 7

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.

Conditions

Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Lymph Node; Mycobacterium Tuberculosis

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (14)

• TB disease-free survival at 48-weeks

  Measured from study entry through Week 48

• TB disease-free survival at 72-weeks

  Measured from study entry through Week 72

• Adherence to treatment regimens

  Measured from study entry through Week 48

• Tolerability as assessed by proportion of participants who discontinue treatment

  Week 8 (intervention/HPZM) or Week 16 or Week 24 (control/HRZ(E))

• Rifapentine Area under the curve (AUC0-24)

  Measured from study entry through Week 8

Other Outcomes (4)

• Dolutegravir AUC0-24

  Measured from study entry through Week 28

• Dolutegravir Cmin

  Measured from study entry through Week 28

• Dolutegravir Cmax

  Measured from study entry through Week 28

Study Arms (2)

Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)

ACTIVE COMPARATOR

8 weeks of daily HRZ(E) followed by either 16 or 24 weeks of daily HR, per local standard of care

Drug: Isoniazid; Drug: Rifampin; Drug: Pyrazinamide; Drug: Ethambutol

Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)

EXPERIMENTAL

8 weeks of daily HPZM

Drug: Isoniazid; Drug: Pyrazinamide; Drug: Rifapentine; Drug: Moxifloxacin

Interventions

Isoniazid DRUG

Once daily weight-based dose

Also known as: H

Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E); Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)

Rifampin DRUG

Once daily weight-based dose

Also known as: R

Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)

Pyrazinamide DRUG

Once daily weight-based dose

Also known as: Z

Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E); Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)

Ethambutol DRUG

Once daily weight-based dose

Also known as: E

Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)

Rifapentine DRUG

Once daily weight-based dose

Also known as: P, Priftin

Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)

Moxifloxacin DRUG

Once daily weight-based dose

Also known as: M, Avelox

Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)

Eligibility Criteria

• Age: 0 Days - 9 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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:

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Johns Hopkins University: lead
• United States Agency for International Development (USAID): collaborator

Study Sites (9)

Indian Council of Medical Research - National Institute for Research in Tuberculosis

Chennai, India

NOT YET RECRUITING

Dr. D.Y. Patil Medical College, Hospital and Research Center

Pune, India

NOT YET RECRUITING

Faculty of Medicine, Universitas Padjadjaran

Bandung, Indonesia

RECRUITING

Instituto Nacional de Saúde (INS)

Maputo, Mozambique

NOT YET RECRUITING

Africa Health Research Institute (AHRI)

Durban, South Africa

NOT YET RECRUITING

MU-JHU Care Ltd

Kampala, Uganda

RECRUITING

University of Zambia, School of Medicine

Lusaka, Zambia

RECRUITING

Arthur Davison Children's Hospital

Ndola, Zambia

NOT YET RECRUITING

Harare Health and Research Consortium (HHRC)

Harare, Zimbabwe

RECRUITING

Related Publications (74)

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MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Lymph Node; Infections; Mycobacterium Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Interventions

Isoniazid; Protons; Rifampin; Pyrazinamide; Ethambutol; rifapentine; Moxifloxacin

Condition Hierarchy (Ancestors)

Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Tuberculosis, Extrapulmonary

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Cations, Monovalent; Cations; Ions; Electrolytes; Inorganic Chemicals; Hydrogen; Elements; Gases; Nucleons; Elementary Particles; Physical Phenomena; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring

Study Officials

• Nicole Salazar-Austin, MD, ScM

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kisten Nolan, MPH, BSN

CONTACT

+14435403993; knolan2@jh.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: International, multicenter, randomized, controlled, open-label, non-inferiority

Study Record Dates

• First Submitted: January 26, 2024
• First Posted: February 12, 2024
• Study Start: January 15, 2025
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: April 2, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: After study completion, de-identified data that can be legally released to the public may be released.
• Access Criteria: With whom: Researchers who provide a methodologically sound proposal for the use of the data per USAID's policy on data sharing and in accordance with in-country data sharing agreements. For what types of analysis: To achieve aims specified in the researcher's approved proposal. By what mechanisms will data be available: To be determined.

Locations

ZI (1); UG (1); IN (2); ID (1); ZA (1); MO (1)