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

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

An Open Label, Randomized Controlled Trial to Establish 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 Tuberculosis (RR-TB)

Regents of the University of California, University of Cape Town, Perinatal HIV Research Unit of the University of the Witswatersrand

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.

Tuberculosis, Pre-XDR-TB, Extensively Drug-Resistant Tuberculosis, Multi Drug Resistant Tuberculosis, Rifampicin Resistant Tuberculosis

Tuberculosis, Drug-resistant Tuberculosis, Randomized Controlled Trial, Rifampicin Resistant Tuberculosis, Multi Drug Resistant Tuberculosis, Extensively Drug-Resistant Tuberculosis, Pre-XDR-TB (fluoroquinolone resistant), Open label, South Africa

Weight Group 16 - 29.9kg: 200mg daily for two weeks; followed by 100mg three times weekly for weeks 3 - 24 Weight Group: 30 - >50kg: 400mg once daily for 14 days followed by 200mg three times weekly for weeks 3 - 24

Weight Group 16 - 23kg: 180 - 210mg (crush 1 tab and mix in 10ml water, administer 3-3.5ml. Discard rest) Weight Group 23.1 - 29.9kg: 300mg daily Weight Group 30 - 33.9kg: 450mg daily Weight Group 34 - >50kg: 600mg daily

Weight Group 16 - 23kg: 25mg twice daily for 24 weeks Weight Group 23.1 - 33.9kg: 50mg twice daily for 24 weeks Weight Group 34 - >50kg: 100mg twice daily for 8 weeks followed by 200 mg daily for 16 weeks

Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - >50kg: 100mg daily

Weight Group 16 - 23kg: 375 - 500mg daily Weight Group 23.1 - 33.9kg: 500mg once daily Weight Group 34 - 50kg: 750mg daily Weight Group >50kg:1000mg daily

Weight Group 16 - 23kg: 300mg daily Weight Group 23.1 - 50kg: 400mg daily Weight Group >50kg: 600mg daily

Weight Group 16 - 23kg: 400mg daily Weight Group 23.1 - 29.9kg: 600mg daily Weight Group 30 - 50kg: 800mg daily Weight Group >50kg: 1200mg daily

Weight Group 16 - 23kg: 750mg daily Weight Group 23.1 - 29.9kg: 1000mg daily Weight Group 30 - 33.9kg: 1250mg daily Weight Group 34 - 50kg: 1500mg daily Weight Group >50kg: 2000mg daily

Weight Group 16 - 23kg: 180 - 210mg (crush 1 tab and mix in 10ml water, administer 3-3.5ml. Discard rest) Weight Group 23.1 - 29.9kg: 300mg daily Weight Group 30 - 33.9kg: 450mg daily Weight Group 34 - >50kg: 600mg daily

Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - >50kg: 100mg daily

Weight Group 16 - 23kg: 375 - 500mg daily Weight Group 23.1 - 33.9kg: 500mg once daily Weight Group 34 - 50kg: 750mg daily Weight Group >50kg:1000mg daily

A successful treatment outcome measured at the end of treatment is defined as either Cured or Treatment Completed. Cured: Adequate treatment adherence (at least 80% of doses taken) as per protocol without evidence of failure and the last two negative sputum specimens at the end of treatment being culture negative. These specimens must be separated by at least 14 days. Treatment completed: Adequate treatment adherence (at least 80% of doses taken) as per protocol without evidence of failure but no record that two or more consecutive cultures taken at least 14 days apart are negative.

The proportion of participants with a successful outcome at the end of follow up at 76 weeks post treatment initiation

A successful end of follow up outcome measured at 76 weeks post treatment initiation is defined as either Cured or Culture negative when last seen. Cured: Sputum Culture negative at the end of follow up at 76 weeks post treatment initiation. Culture negative when last seen: if the participant is lost before the end of follow up at 76 weeks and provided they have a successful treatment outcome at the last study visit attended.

The proportion of participants who experience grade 3 or greater adverse events during treatment and up to 30 days following the end of treatment

Adverse events are graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events

The proportion of participants with a successful composite outcome at 76 weeks post treatment initiation

A successful composite outcome is defined as a successful end of follow up outcome at 76 weeks post treatment initiation and no grade 3 or higher adverse events during treatment. A successful end of follow up outcome is either Cured or Culture negative when last seen.

To link PK/PD measure of Maximum Plasma Concentration (Cmax) to time to culture conversion (efficacy ) clofazimine

To link PK/PD measure of Area Under the Plasma Concentration-time to the time to sputum culture (efficacy) conversion for clofazimine

To link PK/PD measure of Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to sputum culture (efficacy ) conversion for clofazimine

To link PK/PD measure of Elimination Half-life (t1/2) to the time to sputum culture (efficacy ) conversion for clofazimine

To link PK/PD measure of Maximum Plasma Concentration (Cmax), to culture conversion(efficacy) for bedaquiline, delamanid, levofloxacin, linezolid

To link PK/PD measure of Time to Reach Minimum Plasma Concentration (Cmin) to the time to sputum culture (efficacy) conversion for bedaquiline, delamanid, levofloxacin, linezolid

To link PK/PD measure of Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to sputum culture (efficacy) conversion for bedaquiline, delamanid, levofloxacin, linezolid

To link PK/PD measure of the Elimination Half-life (t1/2) to the time to sputum culture (efficacy) conversion for bedaquiline, delamanid, levofloxacin, linezolid

PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin)

To link PK/PD measure of Maximum Plasma Concentration (Cmax) to the time to toxicity of increased QTcF prolongation for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin)

To link PK/PD measure of Time to Reach Maximum Plasma Concentration (Tmax),increased QTcF for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin)

To link PK/PD measure of Minimum Plasma Concentration (Cmin) to the time to toxicity of increased QTcF for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin)

To link PK/PD measure of the Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to toxicity of increased QTcF conversion for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

To link PK/PD measures of Maximum Plasma Concentration (Cmax) to the time to toxicity of bone marrow toxicity and neuropathy

To link PK/PD measure of Time to Reach Maximum Plasma Concentration (Tmax) to the time to toxicity of bone marrow toxicity and neuropathy

To link PK/PD measure of Plasma Concentration (Cmin) to the time to toxicity of bone marrow toxicity and neuropathy

To link PK/PD measure of the Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to toxicity of bone marrow toxicity and neuropathy

Inclusion Criteria: Willing and able to give informed consent to be enrolled in the research study prior to any study related procedures (signed or witnessed consent if the participant is unable to read and understand the informed consent document; signed or witnessed consent from a child's biological parent, legal guardian or primary caregiver) and if the participant is a child (6-17 years) is willing to sign assent Willing and able to adhere to the complete follow-up schedule and to study procedures Male or female, aged 6 years or older, including breastfeeding and/or pregnant women Weigh more than or equal to 16kg Participants above the age of 12 years, must have confirmed pulmonary TB with initial laboratory result of resistance to at least rifampicin as confirmed by genotypic or phenotypic susceptibility testing in the last three months Willing to use effective contraception for females of childbearing potential if sexually active; must be willing to use either an intrauterine contraceptive device or a hormonal method for the duration of the treatment regimen and for three months thereafter Willing to have an HIV test, and if positive, is willing to be treated with appropriate antiretroviral therapy Participants between the ages of 6 - 12 years, must have either confirmed pulmonary RR-TB or probable pulmonary RR-TB and a decision has been made by the referring clinician or investigator to treat the child for RR-TB Participants who are pregnant, should have an ultrasound done to confirm a viable intrauterine pregnancy prior to enrolment Exclusion Criteria: Had taken more than 28 days but less than 24 weeks of second line TB drugs including BDQ, LNZ, CFZ, fluoroquinolones or DLM. Please note: Participants with prior successfully treated episodes of DR TB are permitted to enroll. Has complicated or severe extra-pulmonary manifestations of TB, including osteo-articular, pericardial and central nervous system infection as per investigators opinion Is unable to take oral medication Is taking any prohibited medications as referred to in the protocol Has a known allergy or hypersensitivity to any of the medicines in the regimens Is currently taking part in another clinical trial of any medicinal product Has a QTcF interval of greater than 480 ms. Please note: If the QTcF interval is greater than 480 ms, it may be repeated if participant has reversible contributory factors, i.e. low potassium or to allow washout of previous QT prolonging drugs. Has clinically significant ECG abnormality in the opinion of the site investigator within 60 days prior to entry, including but not limited to second or third degree atrioventricular (AV) block or clinically important arrhythmia Participants with the following laboratory abnormality at screening. Haemoglobin level of < 8.0 g/dL Platelet count < 75,000/mm^3 Absolute neutrophil count (ANC) < 1000/ mm^3 An estimated creatinine clearance (CrCl) less than 30 mL/min as calculated by the National Health Laboratory Service (NHLS) equation Alanine aminotransferase (ALT) ≥3 x upper limit of normal (ULN) Total bilirubin grade 3 or greater (>2.0 x ULN, or >1.50 x ULN when accompanied by any increase in other liver function test) Serum potassium less than 3.2 mmol/l Peripheral neuropathy of grade 3 or 4 using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events If in the investigator's opinion, the participant is unable to commit to study related procedures or it is unsafe for the participant to take part in the study

We plan to share the de-identified individual participant data set to national and international policy makers, including the World Health Organization.

There will be controlled access to the data/documents with the gatekeepers being the Principal Investigator (PI) and the chair of the Trial Steering Committee (TSC), who will be responsible for deciding who may have access. Access to the data/documents must include prior ethical approval for secondary data analysis and the statistical methods for secondary data analysis must be vetted by a statistician. If access is requested during the conduct of the trial, it must be directed to all the members of the TSC via the chair.

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Bedaquiline- and delamanid- containing regimens achieve excellent interim treatment response without safety concerns