Health Trials

Shortened Regimen for Drug-susceptible TB in Children

ConditionsTuberculosisTuberculosis, PulmonaryTuberculosis, Lymph NodeMycobacterium Tuberculosis
Trial statusRecruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
Age0-9
SponsorJohns Hopkins University

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Pulmonary (including pleural effusion) and/or lymph node (extra-thoracic and/or intra-thoracic) TB with or without bacteriologic confirmation;

Disqualifiers

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.

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;

Trial design

Design model

Parallel

Treatments tested in this trial

  • Isoniazid

    Drug

    Once daily weight-based dose

  • Rifampin

    Drug

    Once daily weight-based dose

  • Pyrazinamide

    Drug

    Once daily weight-based dose

  • Ethambutol

    Drug

    Once daily weight-based dose

  • Rifapentine

    Drug

    Once daily weight-based dose

  • Moxifloxacin

    Drug

    Once daily weight-based dose

Treatment groups

860 Participants
are divided into 2 treatment groups
Group A: Regimen 1: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)Active comparator 4 interventions
Group B: Regimen 2: Isoniazid (H), Rifapentine (P), Pyrazinamide (Z), Moxifloxacin (M)Experimental treatment 4 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
Measured from study entry through week 48
2

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.

Time frame
Measured from study entry through Week 28

Secondary outcomes

1

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.

Time frame
Measured from study entry through Week 48
2

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.

Time frame
Measured from study entry through Week 72
3

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.

Time frame
Measured from study entry through Week 48
4

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.

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

Other outcomes

1

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.

Time frame
Measured from study entry through Week 28
2

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.

Time frame
Measured from study entry through Week 28
3

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.

Time frame
Measured from study entry through Week 28
4

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.

Time frame
Week 24 and Week 48

Sponsors and contacts

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Johns Hopkins University

Lead sponsor

United States Agency for International Development (USAID)

Collaborator

Source ClinicalTrials.gov
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