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| ID | Type | Description | Link |
|---|---|---|---|
| Protocol Version 2/10/26 | Other Identifier | UW Madison | |
| SMPH | Pediatrics - GPAM | Other Identifier | UW Madison | |
| 1U01AI192041-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
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Current tuberculosis (TB) treatment is effective (works well), but it takes a long time to cure TB. This study will evaluate if TB treatment with a higher dose of rifampicin, one of the TB medicines, and shorter TB treatment duration is as effective and safe as the standard, TB treatment (with the usual rifampicin dose and usual duration). This study hopes to find a better shorter treatment that works as well as the current treatment (standard of care). This could benefit children worldwide who are getting TB treatment.
Children 3 months to less than 10 years of age who have drug-susceptible TB (can be successfully treated with standard TB medicines) are eligible for this study.
This is a multi-arm open-label phase IIc trial with duration randomization, with a lead-in pharmacokinetics (PK) study. Children 3 months to less than 10 years of age with routinely diagnosed clinical or confirmed drug-susceptible TB will be screened and if eligible randomly assigned 1:1:1:1:1 to one of five arms (durations of TB treatment and control arm). Randomization will be stratified by age (3 months to less than 5 years of age vs 5 to less than 10 years of age).
A total of 200 participants will be enrolled in the main trial (Step 2), with 40 per study arm, with an additional 30 participants enrolled in a Lead-in PK study (Step 1).
Step 1 - Lead-in PK study participants will be on treatment for 8 weeks, complete their trial participation in up to 9 weeks, and will not contribute to the main trial endpoints.
Step 2 - Main trial participants will be on study for 48 weeks.
Primary Objective:
In children with drug-susceptible tuberculosis, with and without HIV:
• To characterize the relationship between treatment duration of the experimental regimen and the proportion of participants with unfavorable treatment outcome at 48 weeks after randomization (i.e., the duration-response curve)
Secondary Objectives:
The secondary objectives of the Lead-In PK study are to
The secondary objectives of the Main Study are to:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1: 8 week duration | Experimental | N = 40, 8 weeks of odRHZE |
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| Arm 2: 11 week duration | Experimental | N = 40, 8 weeks of odRHZE followed by 3 weeks of odRH |
|
| Arm 3: 14 week duration | Experimental | N = 40, 8 weeks of odRHZE followed by 6 weeks of odRH |
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| Arm 4: 17 week duration | Experimental | N = 40, 8 weeks of odRHZE followed by 9 weeks of odRH |
|
| Arm 5: Control (17 or 24 week duration) | Active Comparator | N = 40, 8 week of RHZ(E) followed by 9 weeks (5a - non-severe TB) or 16 weeks (5b - severe TB) of RH |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifampicin | Drug | odR for main trial determined from Lead-in PK study 75 mg tablet, and 150 or 300 mg capsule, dosed by weight and age |
|
| Measure | Description | Time Frame |
|---|---|---|
| Step 2: Unfavorable TB treatment outcome | A participant has unfavorable treatment outcomes if they fail to meet either of the following criteria:
| 48 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Step 1: Safety measured by occurrence of Grade 3 to 5 Adverse Events after the first dose of study treatment by period in Lead-in PK study | Occurrence of at least one new or worsened Grade 3-5 Adverse Event (AE) after the first dose of study treatment by period. | data collected from individual participants for 2 regimens of 4 weeks each, up to 8 weeks total |
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Inclusion Criteria:
3 months to less than 10 years of age
Body weight greater than or equal to 3 kilograms (kg) and less than 45 kg at study entry
Confirmed or clinically diagnosed intrathoracic (pulmonary) and/or some forms of extrathoracic (extrapulmonary) drug-susceptible TB:
Confirmed intrathoracic (pulmonary) TB, based on chest radiograph and/or symptoms consistent with TB, and/or some forms of extrathoracic TB, with all of the following as determined by the site investigator:
Clinically diagnosed intrathoracic (pulmonary) TB, based on chest radiograph and/or symptoms consistent with TB, and/or some forms of extrathoracic TB, with all of the following as determined by the site investigator:
HIV positive or negative
For participants living with HIV, they must be on a dolutegravir-based antiretroviral therapy regimen at the time of study entry
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| UW Clinical Trials Institute | Contact | 608.265.3132 | info@clinicaltrials.wisc.edu |
| Name | Affiliation | Role |
|---|---|---|
| Anthony Garcia-Prats, MD, MSc, PhD | UW School of Medicine and Public Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Socios en Salud Sucursal Peru | Lima | Peru |
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| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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| ID | Term |
|---|---|
| D012293 | Rifampin |
| D007538 | Isoniazid |
| D011522 | Protons |
| D011718 | Pyrazinamide |
| D004977 | Ethambutol |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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This is a multi-arm open-label phase IIc trial with duration randomization, with a lead-in PK study. Children 3 months to less than 10 years of age with routinely diagnosed clinical or confirmed drug-susceptible TB will be screened and if eligible randomly assigned 1:1:1:1:1 to one of five arms (durations of TB treatment and control arm). Randomization will be stratified by age (3 months to less than 5 years of age vs 5 to less than 10 years of age). A total of 200 participants will be enrolled in the main trial, with 40 per study arm, with an additional 30 participants enrolled in a Lead-in PK study that has a crossover trial design.
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| Step 1: PK - Dosing Schedule A > B | Experimental | N = 15
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg) |
|
| Step 1: PK - Dosing Schedule B > A | Experimental | N = 15
Dosing schedules are by weight and age, with Schedule A a higher dose of RIF (totaling 250 - 1650mg) than Schedule B (totaling 200 - 1350mg) |
|
|
| Isoniazid | Drug | 50 mg tablet, dosed by weight and age |
|
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| Pyrazinamide | Drug | 150 mg tablet, dosed by weight and age |
|
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| Ethambutol | Drug | 100 mg tablet, dosed by weight and age |
|
|
| Rifampicin | Drug | standard of care and only the 75 mg tablet will be used |
|
|
| Step 1: Tolerability Measured by discontinuation of at least one drug in Lead-in PK study | Permanent discontinuation of at least one drug in the study regimen during each treatment period due to an AE of any grade that is either safety- or tolerability-related, death due to toxicity (probably/possibly/certainly) related to one or more of the study drugs, or participant/parent/guardian request. | data collected from individual participants for 2 regimens of 4 weeks each, up to 8 weeks total |
| Step 1: Pharmacokinetics of optimized-dose rifampicin: (AUC0-24) | Area under the concentration time curve over 24 hours (AUC0-24) | data collected at week 4 (and week 8) visit lead-in PK study; pre-dose (0 hour), 1, 2, 4, 8 and 24 hour post dose |
| Step 1: Pharmacokinetics of optimized-dose rifampicin: (Cmax) | Maximum concentration (Cmax) | data collected at week 4 (and week 8) visit lead-in PK study; pre-dose (0 hour), 1, 2, 4, 8 and 24 hour post dose |
| Step 1: Acceptability of optimized-dose rifampicin summarized by participant count | Participant and/or parent/guardian responses to rifampicin acceptability question of "Overall, how did you/your child feel about taking this medicine?", scored on a likert scale from 1-5 with higher scores being more acceptable. Summarized by number of responses per score. | baseline (at dose 1), week 4, week 8 |
| Step 2: Safety Measured by Occurrence of at least one new or worsened Grade 3-5 adverse event after the first dose of study treatment in Main Trial | Occurrence of at least one new or worsened Grade 3-5 adverse event after the first dose of study treatment and during the 28 weeks following randomization, where 28 weeks is 4 weeks beyond the longest scheduled treatment duration of 24 weeks. | up to 28 weeks |
| Step 2: Tolerability Measured by discontinuation of at least one drug in Main Trial | Permanent discontinuation of at least one drug in the study regimen prior to the end of the assigned treatment period due to an AE of any grade that is either safety- or tolerability-related, death due to toxicity (probably/possibly/certainly) related to one or more of the study drugs, or participant/parent/guardian request. | up to 24 weeks |
| Step 2: Lung function post-TB treatment | The outcome of interest is abnormal lung function classified as having at least one of the following physiological findings based on results of spirometry and oscillometry (FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity):
| week 48 |
| Step 2: Acceptability of optimized-dose rifampicin summarized by participant count | Participant and/or parent/guardian responses to rifampicin acceptability question of "Overall, how did you/your child feel about taking this medicine?", scored on a likert scale from 1-5 with higher scores being more acceptable. Summarized by number of responses per score. | baseline (at dose 1), week 4, week 8 |
| Step 2: Acceptability of overall TB treatment regimen summarized by participant count | Participant and/or parent/guardian responses to overall TB treatment regimen acceptability question of "In the last 4 weeks, how did you/your child feel about taking this TB treatment regimen, considering all of the TB medicines in the regimen together?", scored on a likert scale from 1-5 with higher scores being more acceptable. Summarized by number of responses per score. | week 4, week 8 |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D006834 | Hydrazines |
| D009930 | Organic Chemicals |
| D007539 | Isonicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D002414 | Cations, Monovalent |
| D002412 | Cations |
| D007477 | Ions |
| D004573 | Electrolytes |
| D007287 | Inorganic Chemicals |
| D006859 | Hydrogen |
| D004602 | Elements |
| D005740 | Gases |
| D000071940 | Nucleons |
| D004601 | Elementary Particles |
| D055585 | Physical Phenomena |
| D011719 | Pyrazines |
| D005029 | Ethylenediamines |
| D003959 | Diamines |
| D011073 | Polyamines |
| D000588 | Amines |