Building Evidence for Advancing New Treatment for Rifampicin Resistant Tuberculosis (RR-TB) Comparing a Short Course of Treatment (Containing Bedaquiline, Delamanid and Linezolid) With the Current South African Standard of Care

Overview

BEAT Tuberculosis is a phase 3, open label, multi-centre, randomized controlled trial. The purpose of this trial is to compare the efficacy and safety of a Study Strategy consisting of 6 months of bedaquiline (BDQ), delamanid (DLM), and linezolid (LNZ), with levofloxacin (LVX) and clofazimine (CFZ) compared to the current South African Standard of Care (Control Strategy) for 9 months for the treatment of rifampicin resistant (RR-TB) Tuberculosis.

In 2016, the World Health Organization (WHO) issued guidelines for the use of a shorter treatment regimen (STR) for eligible patients with RR and multidrug-resistant tuberculosis (MDR-TB) which was adopted by the South African National Tuberculosis Program (SANTP) in 2017. The WHO then released guidelines in September 2018 regrouping the medicines for the treatment of MDR/RR-TB into three categories and ranking them based on the latest evidence about the balance of effectiveness to safety. BDQ, LNZ and fluoroquinolones were moved to Category A and should be included in all regimens as core drugs. CFZ and terizidone as Category B drugs, should be added to all regimens. The current short injectable-free treatment regimen for RR-TB in South Africa is based on these WHO recommendations. This South African standard of care, referred to as the Control Strategy, is given for a duration of 40 to 48 weeks and consists of BDQ, LNZ, Isoniazid (high dose), LVX, ethambutol, pyrazinamide and CFZ. Should a patient have resistance to the fluoroquinolones and/or the injectable, the patient is started on a strengthened regimen that may include BDQ, LNZ and DLM with other added agents depending on prior exposure and any other available resistance testing. In addition to the shorter RR-TB regimen recommended by the WHO, there are other shorter regimens currently being evaluated in clinical trials. Many of these regimens employ new or re-purposed medicines such as BDQ, DLM, and LNZ, which have each been shown to be effective in clinical trials. Some of the regimens forgo the use of a second-line injectable, which is associated with a high rate of adverse events and is programmatically difficult to administer. Although these regimens are currently undergoing testing in clinical trials, the programmatic use of these regimens under operational and pragmatic research conditions can also provide important data to the global TB community about their effectiveness and safety, while also providing more information about programmatic implementation and expanding access to their potential benefits. For this reason, BEAT Tuberculosis aims to be as pragmatic as possible, with broad eligibility criteria including almost all participants diagnosed with RR-TB. It aligns itself with the SANTP's goal to investigate an effective treatment regimen for RR-TB, while strictly adhering to the high standards of ethical conduct in clinical research. The primary objective of the trial is to evaluate the efficacy and safety of the Study Strategy, specifically to demonstrate that the intervention or Study Strategy has non-inferior efficacy to the Control Strategy. The principle behind the Study Strategy is to "hit early and to hit hard" with the agents most likely to be effective- it is common that upon the diagnosis of RR-TB, fluoroquinolone resistance is unknown. Therefore, the Study Strategy contains three novel agents as core drugs -BDQ, LNZ, and DLM against which there is no expected Mtb resistance in the community. In addition, there are two other support medications- LVX and CFZ. Treatment will be changed on receipt of the second-line line probe assay (LPA) results. The Study Strategy has been designed to cover all possible eventualities from rifampicin mono resistant TB to Extensively Drug Resistant (XDR-TB) with an all oral regimen. The Study Strategy is given for 24 weeks but if culture conversion has not occurred by week 16, the full treatment duration can be extended to 36 weeks. Participants include children from 6 years of age and adults diagnosed with RR-TB with or without resistance to isoniazid (INH) and/or fluoroquinolones. A total of 400 participants will be enrolled into the clinical trial. Participants will be randomized in a 1:1 ratio to receive either the Study Strategy or Control Strategy, with a stratification by clinical site and HIV status. All participants will be followed up for 76 weeks from randomization. All patients in South Africa who are diagnosed with RR-TB are managed by the SANTP. All study tests will therefore be performed by the National Health Laboratory Services, including mycobacteriology, blood screening and safety testing and point of contact testing. These tests will be done in line with the national programme's schedule of events. The trial will be open label, as blinding is not feasible. It is not possible to formulate placebos with multiple drugs and durations of treatment. However, the trial will be treated as if it were a blinded trial in all ways other than the physician and the participant having knowledge of the treatment assignment. Individuals assessing x-rays, cultures, ECGs and other participant information will be blinded to treatment assignment. BEAT Tuberculosis will be conducted in Port Elizabeth in the Eastern Cape, and in Durban, KwaZulu Natal, where there is a high burden of drug resistant TB (DR TB). The clinical trial sites are established DR-TB initiation and treating sites and have been approved by the national, provincial and district TB program with the capacity for long term follow up for safety evaluation. This trial will strengthen the drug resistant TB research capacity in an under-researched area such as the Eastern Cape. All participants will be offered an HIV test, as is standard in South Africa, and must be willing to take antiretroviral treatment, should they test positive. Wherever possible, participants who are co-infected with HIV will be managed in a joint treatment clinic to ensure close co-ordination of management of the two conditions, and to ensure that appropriate decisions can be made concerning the management of drug interactions and side effects. Additionally, there is a pharmacokinetics/pharmacodynamics (PK-PD) aspect to the trial. There are limited data describing the association of drug concentrations with efficacy and treatment related toxicities of many of the anti-TB drugs used in the treatment of RR-TB. Understanding these PK-PD relationships can result in dose optimization to improve outcomes in the relevant patient populations. BEAT Tuberculosis is a unique opportunity to explore these relationships.