Evaluating a Shorter, Rifampicin-Based Treatment for People With Less Severe Tuberculosis Disease

Official title

Shortening TB Treatment With Optimised Rifampicin-Based Therapy and Disease Stratification: A Pragmatic Phase 3 Double-Blind Placebo-Controlled Randomised Trial (RIFAstrat)

Overview

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

• Drug Extra 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.
• Drug Placebo
  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).

Primary outcome measures

• 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. [Time frame: From enrollment through to Week 48.]

Secondary outcome measures (11)

• Death [Time frame: 72 weeks]
• Treatment-emergent adverse events [Time frame: 14 days after end of randomised treatment]
• Proportion of participants experiencing symptoms of interest during assigned treatment (tolerability) [Time frame: 14 days after end of randomised treatment]
• Proportion of participants temporarily discontinuing assigned treatment (tolerability) [Time frame: 14 days after end of randomised treatement]
• Proportion of participants permanently discontinuing assigned treatment (tolerability) [Time frame: 14 days after end of randomised treatment]
• Percentage of treatment doses taken (adherence) [Time frame: 48 weeks]
• Total Time on Treatment [Time frame: 72 weeks]
• Proportion of participants with acquired (post-baseline) drug resistance [Time frame: 72 weeks]
• Scores on 5-level EQ-5D questionnaire [Time frame: 72 weeks]
• Catastrophic costs and cost-effectiveness ratios, calculated using the adapted WHO patient costs survey [Time frame: 72 weeks]
• Respiratory disability measured by Medical Research Council (MRC) Dyspnea scale [Time frame: 72 weeks]

Eligibility criteria

Inclusion criteria

• Aged 12 years and over
• Clinical and/or radiological evidence of pulmonary TB
• At least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF or Ultra within 30 days of screening confirming rifampicin-sensitive TB
• 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)
• Documentation of HIV status from a validated test performed within 30 days of screening or known to be HIV-positive
• Well enough to be treated as an outpatient

Exclusion criteria

• Received more than 7 days treatment for index TB episode
• Previous treatment for active TB disease in past 12 months
• M. tuberculosis with known resistance to rifampicin or isoniazid
• Weight < 30 kg at screening
• 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)
• 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)
• For participants living with HIV:

• Urinary lipoarabinomannan test positive at screening
• Requires protease inhibitor-based antiretroviral therapy, and/or long acting antiretrovirals cabotegravir/rilpivirine
• 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
• Clinical evidence of acute hepatitis or advanced chronic liver disease (e.g. jaundice, signs of portal hypertension)
• Known end stage renal failure
• Active malignancy not in remission or had systemic chemotherapy within 2 years (except for non-melanomatous skin cancer)
• Contraindication to study medications because of known allergy or intolerance or unavoidable drug-drug interaction
• Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest
• Inability to attend follow up visits

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07118696 · 18513

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗