Pulmonary TB
Conditions
Keywords
Rifampicin, Treatment Shortening
Brief summary
RIFAstrat is a Phase 3, double-blind, placebo-controlled, non-inferiority trial to compare the 6-month standard treatment for DS-TB with a 4-month optimised- rifampicin based regimen provided to individuals with limited disease severity.
Detailed description
RIFAstrat is a Phase 3, double-blind, placebo-controlled, non-inferiority trial to compare the 6-month standard treatment for DS-TB with a 4-month optimised-rifampicin based regimen provided to individuals with limited disease severity. Participants are eligible for the study if they are ≥12 years old with newly diagnosed rifampicin-susceptible pulmonary TB confirmed by rapid molecular testing (Xpert MTB/RIF or ultra) with a limited disease phenotype, defined as a cycle threshold on sputum Xpert MTB/RIF or Ultra corresponding to 'medium' or below for bacterial burden at screening. Broad eligibility criteria allow for enrolment of people living with HIV, diabetes, other common comorbidities.
Interventions
DRUGExtra 600mg of Rifampicin
Intervention group participants will receive standard treatment (RHZE), plus an optimised regimen consisting of RIfampicin at 20 mg/kg (additional 600mg rifampicin in each weight band) during a shortened treatment period of 16 weeks.
DRUGPlacebo
The standard treatment regimen for DS-TB (rifampicin at 10 mg/kg and isoniazid for 6 months, plus pyrazinamide and ethambutol for the first 2 months; 2RHZE/4RH), with additional placebo for the first 4 months (16 weeks).
Sponsors
St George's, University of London
McMaster University
Hamilton Health Sciences Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants will be randomised to the control or experimental arm in 1:1 ratio, stratified by site and HIV status. Intervention (experimental arm): an optimised regimen consisting of rifampicin at 20 mg/kg and isoniazid for 4 months (16 weeks), plus pyrazinamide and ethambutol for the first 2 months (2R20HZE/2R20H). Delivered as local standard of care (RHZE) plus 600mg (2 additional tablets) of rifampicin. Control: The standard treatment regimen for DS-TB (rifampicin at 10 mg/kg and isoniazid for 6 months, plus pyrazinamide and ethambutol for the first 2 months; 2RHZE/4RH), with additional placebo for the first 4 months (16 weeks).
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Aged 12 years and over 2. Clinical and/or radiological evidence of pulmonary TB 3. At least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF or Ultra within 30 days of screening confirming rifampicin-sensitive TB 4. Have limited TB disease defined as having a cycle threshold on sputum Xpert MTB/RIF or Ultra corresponding to 'medium' or below for bacterial burden at screening (where results from more than one test are available at screening, eligibility will be determined by the highest grade) 5. Documentation of HIV status from a validated test performed within 30 days of screening or known to be HIV-positive 6. Well enough to be treated as an outpatient
Exclusion criteria
1. Received more than 7 days treatment for index TB episode 2. Previous treatment for active TB disease in past 12 months 3. M. tuberculosis with known resistance to rifampicin or isoniazid 4. Weight \< 30 kg at screening 5. Sick with one or more WHO 'danger signs' at screening (respiratory rate \> 30 breaths per minute, temperature \> 39 ˚C, heart rate \> 120 bpm, inability to walk unaided) 6. Suspected or confirmed extra-pulmonary TB involving the central nervous system, bones, joints, abdomen, and/or pericardium (coexistent pleural or lymph node TB are not exclusions) 7. For participants living with HIV: * Urinary lipoarabinomannan test positive at screening * Requires protease inhibitor-based antiretroviral therapy, and/or long acting antiretrovirals cabotegravir/rilpivirine 8. For participants of child-bearing potential: currently pregnant or not currently pregnant but unwilling to practice an effective method of contraception during study drug treatment 9. Clinical evidence of acute hepatitis or advanced chronic liver disease (e.g. jaundice, signs of portal hypertension) 10. Known end stage renal failure 11. Active malignancy not in remission or had systemic chemotherapy within 2 years (except for non-melanomatous skin cancer) 12. Contraindication to study medications because of known allergy or intolerance or unavoidable drug-drug interaction 13. Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest 14. Inability to attend follow up visits
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of participants with an unfavourable efficacy outcome (treatment failure, recurrence or re-treatment for poor treatment response) through week 48 in the intention to treat population. | From enrollment through to Week 48. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent adverse events | 14 days after end of randomised treatment | Any adverse event leading to premature, permanent discontinuation of a study drug. Treatment-related adverse events of special interest. Treatment-related SAEs. |
| Proportion of participants experiencing symptoms of interest during assigned treatment (tolerability) | 14 days after end of randomised treatment | Proportion of participants experiencing symptoms of interest during assigned treatment (tolerability) |
| Proportion of participants temporarily discontinuing assigned treatment (tolerability) | 14 days after end of randomised treatement | Proportion of participants temporarily discontinuing assigned treatment (tolerability) |
| Proportion of participants permanently discontinuing assigned treatment (tolerability) | 14 days after end of randomised treatment | Proportion of participants permanently discontinuing assigned treatment (tolerability) |
| Percentage of treatment doses taken (adherence) | 48 weeks | Percentage of treatment doses taken (adherence) |
| Death | 72 weeks | — |
| Proportion of participants with acquired (post-baseline) drug resistance | 72 weeks | Proportion of participants with acquired (post-baseline) drug resistance |
| Scores on 5-level EQ-5D questionnaire | 72 weeks | Scores on 5-level EQ-5D questionnaire |
| Catastrophic costs and cost-effectiveness ratios, calculated using the adapted WHO patient costs survey | 72 weeks | Catastrophic costs and cost-effectiveness ratios, calculated using the adapted WHO patient costs survey |
| Respiratory disability measured by Medical Research Council (MRC) Dyspnea scale | 72 weeks | Respiratory disability measured by Medical Research Council (MRC) Dyspnea scale |
| Total Time on Treatment | 72 weeks | Total Time on Treatment |
Contacts
Primary ContactSarah Karampatos, BASc, MSc
Backup ContactSteven Agapay, BSc
Outcome results
None listed