Title: Reintroduction of anti-tuberculosis therapy following drug-induced liver injury: a randomised controlled trial
Funder: Department of Health and Social Care

Abstract: Background_x000D_ The standard four-drug treatment for active TB is very effective if the full six month course is completed. However, there can be side effects. An important side effect is drug-induced liver injury (DILI). Around 1 in 14 patients may be affected. For patients experiencing these complications, treatment is usually stopped for a time to allow their liver to recover. Once their liver has recovered treatment will need to be started again - ‘reintroduced’. However, there is only limited evidence to guide clinicians to do this safely. The research question is: What is the safest and most effective way to reintroduce TB drugs?_x000D_ _x000D_ NICE TB guidelines recommend that all four drugs are reintroduced. The American Thoracic Society guidelines differ. These recommend that the drug pyrazinamide (Z) is left out, as it is thought to make DILI more likely. Though this three-drug treatment is still effective it needs to be taken over nine months. This is more difficult for patients and more costly to the NHS. Currently, clinicians in the UK and globally choose between the two guidelines; some reintroduce Z whilst others do not. _x000D_ _x000D_ Research questions_x000D_ This research will review the costs and benefits of using three-drugs rather than four-drugs to reintroduce TB treatment. In particular, whether it:_x000D_ a) leads to fewer patients experiencing DILI?_x000D_ b) results in a better quality of life for patients?_x000D_ c) offers better use of limited NHS resources?_x000D_ _x000D_ How the research is organised_x000D_ The research will be held over four years across a number of hospital clinics in the UK. The research will include 350 adults who experience DILI whilst on standard TB treatment, with 75-90 enrolled for each year of the study. Patients will be selected at random to be in either one of two groups for the study. One group will have four drugs reintroduced (i.e. including Z). The other group will have only three drugs reintroduced, (i.e. excluding Z). Patients and clinicians will know which treatment they are getting. The trial outcome will be a laboratory-based measure of the number of patients that experience the return of DILI (known as ‘recurrence’)._x000D_ _x000D_ Patients will be checked regularly for DILI recurrence. Their quality of life will be measured using the “EQ-5D” questionnaire at specified times. The questionnaire can be completed on paper, online or by telephone and takes around 10 minutes. No additional clinic visits are required._x000D_ _x000D_ Research support_x000D_ This study is supported by the Nottingham Respiratory Infections Patient and Public Involvement (PPI) Group, patients with personal experience of TB, TB Alert (the UK’s national TB charity) and national respiratory and liver specialist societies. _x000D_ _x000D_ PPI members helped to shape the research calls and proposals on this topic, informed the design of the study, and advised on the dissemination plan for study results. PPI members agreed this study is appropriate and would provide clinically valuable information. No ethical objections were identified. _x000D_ _x000D_ Impact and knowledge sharing_x000D_ The trial will inform national (through NICE) and international clinical guidelines thereby influencing clinical practice. Results will be shared in high-impact medical journals, in conference reports, through clinical and research networks (such as PHE TB Control Boards and specialist advisory committees) and through appropriate charities (such as TB Alert). Social media platforms and news releases will also be used, as appropriate.

Lay abstract: Following the occurrence of anti-TB drug-induced liver injury (DILI), there are currently two reintroduction regimens that are recommended with no consensus as regards which regimen is more beneficial. Both regimens are accepted as standard of care in the NHS and globally. Based on weak evidence, one regimen may be associated with a lower DILI recurrence frequency but entails a longer total duration of treatment (9 months vs 6 months). The Research Aim is to compare the relative safety and effectiveness, including cost, of the two different drug reintroduction regimens in adults with TB following an episode of anti-TB DILI._x000D_ _x000D_ Objectives_x000D_ 1. To determine if reintroduction of a non-pyrazinamide (Z)-containing regimen results in a lower DILI recurrence rate compared to a Z-containing regimen in adults who have experienced an episode of DILI when being treated for active TB._x000D_ 2. To determine the cost-effectiveness of reintroducing a non-Z-containing versus Z-containing regimen._x000D_ 3. To determine a) the frequency and b) quality of life impacts of DILI episodes in adults being treated for latent TB infection._x000D_ _x000D_ This is a pragmatic multi-centre open randomised superiority trial with economic analysis. The target population comprises adults treated within the NHS for active TB with standard 4-drug anti-TB therapy (ATT) who have experienced an episode of DILI requiring these drugs to be stopped. Participants (n=350) will be randomly assigned by concealed individual allocation (1:1) to reintroduction of either (A) Intervention arm - Sequential full-dose non-Z-containing 3-drug ATT (comprising EHR), as recommended by the American Thoracic Society TB Guideline or (B) Control arm - Sequential full-dose Z-containing 4-drug ATT (comprising EHRZ), as recommended by the NICE TB Guideline. Participant follow up will be to 12 months post-randomisation. The primary outcome is DILI recurrence within 12 months of randomisation. Secondary outcomes include a) severity of DILI, b) physician-rated clinical cure, c) total number of days on ATT, d) adverse event rate, e) ATT adherence rate, f) mortality, g) QoL using the EQ-5D tool, and healthcare resource use._x000D_ _x000D_ Health economic analysis will take the NHS perspective, considering patient health impacts (measured in QALYs) and healthcare resource costs, following methods recommended by NICE.This is essential for an informed understanding of the trial results; the 3-drug ATT regimen may benefit from a lower DILI recurrence rate but at the cost of a longer duration of treatment, incurring increased NHS costs and potentially having a lower treatment completion rate, with associated health detriment._x000D_ _x000D_ An observational cohort study of adults treated for latent TB infection (LTBI) who experience a DILI event will be conducted alongside the clinical trial. Reintroduction of treatment will be at the discretion of attending clinicians. Follow up will be to the end of treatment. Primary outcome: DILI recurrence at the end of treatment.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;ORAL AND GASTROINTESTINAL