Shortened Regimen for Drug-susceptible TB in Children

Tuberculosis Clinical Trial

— SMILE-TB  

Official title:

Shortened Regimen for Drug-susceptible TB in Children

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06253715
• Other study ID #: IRB00388853
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: September 30, 2024
• Est. completion date: September 30, 2027

Study information

• Verified date: June 2024
• Source: Johns Hopkins University
• Contact: Kisten Nolan, MPH, BSN
• Phone: +14435403993
• Email: knolan2[@]jh.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 860
• Est. completion date: September 30, 2027
• Est. primary completion date: September 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Days to 9 Years

Eligibility

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.

Related Conditions & MeSH terms

• Mycobacterium Infections
• Mycobacterium Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

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

Locations

Country	Name	City	State
Indonesia	Faculty of Medicine, Universitas Padjadjaran	Bandung
Mozambique	Instituto Nacional de Saúde (INS)	Maputo
South Africa	Africa Health Research Institute (AHRI)	Durban
Uganda	MU-JHU Care Ltd	Kampala
Zambia	University of Zambia, School of Medicine	Lusaka

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins University	United States Agency for International Development (USAID)

Countries where clinical trial is conducted

Indonesia,  Mozambique,  South Africa,  Uganda,  Zambia, 

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Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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))
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	Cost effectiveness as assessed by the incremental cost-effective ratio (ICER)	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.	Measured from study entry through Week 24