Background
Disease setting and context in the study
The spectrum of TB disease in children
TB diagnosis and measuring response to treatment in children
Drug doses and fixed-dose formulations of anti-tuberculosis drugs in children
Anti-TB and antiretroviral treatment interactions in HIV co-infected children
TB treatment-shortening trials in adults
Rationale for the trial
Aims
Methods
Trial design
Setting and population
Inclusion criteria | Exclusion criteria |
---|---|
1. Age 0–16 years 2. Weight ≥ 3 kg 3. Clinician has decided to treat with standard first-line regimen (intensive phase of 4 drugs or 3 drugs as per local practice) 4. Symptomatic but non-severe TB including: a. extrathoracic lymph node TB; intrathoracic uncomplicated (hilar) lymph node TB b. minimal or no parenchymal abnormality on CXR c. smear-negative on gastric aspirate/other respiratory sample Note: GeneXpert may be positive or negative and a negative GeneXpert can be used as a substitute for a negative smear; culture of respiratory sample may be positive or negative; lymph node aspirate may be smear/culture/GeneXpert positive or negative) 5. Not treated for previous TB unless successfully treated > 2 years since last completed treatment 6. Known (or pending confirmation of)HIV status; HIV-infected or HIV-uninfected 7. Willing and likely to adhere to 72 weeks’ follow-up 8. Informed written consent from the parent/legal caregiver(s) and assent in children, as per local Ethics Committee guidance 9. Home address accessible for visiting and intending to remain within the recruitment area for follow-up. | 1. Smear-positive respiratory sample 2. Premature (< 37 weeks) and aged under 3 months 3. Miliary tuberculosis (TB), spinal TB, TB meningitis, osteoarticular TB, abdominal TB, congenital TB 4. Pre-existing non-tuberculous disease likely to prejudice the response to, or assessment of, treatment, e.g. liver or kidney disease, peripheral neuropathy, cavitation 5. Any known contraindication to taking anti-TB drugs 6. Known contact with drug-resistant adult source case (including mono-resistant TB) 7. Known drug resistance in the child 8. Severely ill 9. Pregnancy |
Definition of minimal (non-severe) TB
Endpoints
Primary outcome
Secondary outcomes
Screening and enrolment procedures
Randomisation and allocation
Trial interventions
TB treatment products, dosing schedule and treatment supervision
Weight bands | Intensive phase | Continuation phase | |
---|---|---|---|
50H, 75R, 150Z | 100Eb | 50H, 75R | |
3.0–3.9 kg | 0.75 | 0.75 | 0.75 |
4.0–7.9 kg | 1 | 1 | 1 |
8.0–11.9 kg | 2 | 2 | 2 |
12.0–15.9 kg | 3 | 3 | 3 |
16.0–24.9 kg | 4 | 4 | 4 |
≥ 25.0 kg | Adult formulation and doses | Adult formulation and doses | Adult formulation and doses |
Weight bands | Intensive phase | Continuation phase |
---|---|---|
75H, 150R, 400Z, 275Eb | 75H, 150R | |
25–36.9 kg | 2 | 2 |
37–54.9 kg | 3 | 3 |
55–70.0 kg | 4 | 4 |
Protocol treatment discontinuation
Non-trial treatment
Trial assessments and follow-up
Procedures for assessment of TB diagnosis and treatment response
Procedures for assessing safety
Substudies
Pharmacokinetic (PK) studies
Hair PK sub-study
Health economics
Social science
Statistical considerations
Sample size and power
Non-inferiority margin
Analysis plan
Definition of adequate treatment
Primary efficacy analysis
PK substudies analysis plan
Safety reporting
Adverse events and adverse reactions
Term | Definition |
---|---|
Adverse event (AE)a | Any untoward medical occurrence in a patient or clinical trial subject to whom a medicinal product has been administered including occurrences that are not necessarily caused by or related to that product |
Adverse reaction (AR) | Any untoward and unintended response to an investigational medicinal product related to any dose administered |
Unexpected adverse reaction (UAR) | An adverse reaction, the nature or severity of which is not consistent with the information about the medicinal product in question set out in the Summary of Product Characteristics (SPC) or Investigator Brochure (IB) for that product |
Serious adverse event (SAE) or serious adverse reaction (SAR) or suspected unexpected serious adverse reaction (SUSAR) | Respectively, any adverse event, adverse reaction or unexpected adverse reaction that: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Consists of a congenital anomaly or birth defect Is another important medical condition |