The Bring BPaL2Me Trial - Comparing Nurse-Led RR-TB Treatment in Primary Care to Physician-Led, Hospital-Based RR-TB Treatment: A Cluster Randomized, Non-Inferiority Trial

In South Africa (SA), Mycobacterium tuberculosis (TB) is managed within primary care clinics (PCCs), where nurses treat drug-susceptible TB and TB/HIV coinfection with treatment outcomes rivaling the best in the world. A PCC management strategy offers a more convenient, patient-centered, differentiated model of care that

integrates TB and HIV treatment within the same setting. A diagnosis of rifampicin-resistant TB (RR-TB), however, upends this model, requiring referral to a hospital-based, physician-led outpatient treatment center. Hospital-based, physician-led models add significant patient-associated costs, with estimates suggesting 81% of

RR-TB patients experience catastrophic costs even in a decentralized outpatient model. There is hope, however, to move RR-TB care into PCCs and in many settings this involves nurse-led management. The BringBPaL2Me Trial is a multi-principal investigator, multi-site, cluster randomized, non-inferiority trial (CR-NIT), to compare

nurse-led RR-TB treatment in PCCs to standard of care physician-led RR-TB treatment at district hospitals in the provinces of KwaZulu-Natal (KZN), Gauteng (GP) and Eastern Cape (EC), SA. Clusters include 10 PCCs affiliated with 5 decentralized outpatient programs at RR-TB district hospitals (n=50 clusters). We estimate the

need to screen 3,800 RR-TB positive patients to enroll 2,944, or 64 RR-TB participants per PCC cluster. We estimate 60-70% will be HIV co-infected. The interclass correlation is 0.024 based on our prior CRT enrolling 3,000 patients in KZN and EC. The non-inferiority margin is set at 5% with the assumption of 90% treatment

success in the physician-led arm. Treatment will include either a 6-month RR-TB regimen (i.e., bedaquiline, pretomanid, linezolid and moxifloxacin, or BPaLM) or fluroquinolone-resistant TB (i.e., BPaL) regimen. The BringBPaL2Me primary aim is to conduct a 5-year, analyst and clinical safety review committee blinded, multi-

site, CR-NIT to evaluate 1) treatment outcome; 2) safety; and 3) patient associated catastrophic costs with the following hypotheses: 1) Outpatient nurse-led treatment in PCCs will be non-inferior to outpatient physician-led treatment at hospital-based outpatient sites among RR-TB patients, regardless of HIV co-infection, as

determined by a successful treatment outcome [H1]; 2) The proportion of severe adverse events (SAEs) identified will not significantly differ by blinded, independent review [H2]; 3) Patient associated catastrophic costs (i.e., costs 20% or more of household income) will be lower in nurse-led treatment [H3]. Our secondary aims include:

1) time to event analysis for a) RR-TB treatment initiation; b) smear/culture conversion; and, as applicable, c) HIV treatment initiation; d) HIV viral suppression; and e) AE and SAE symptom resolution; 2) characterization of provider adherence to guidelines for: a) dosing requirements; b) RR-TB dosing changes based on AE and SAE

events; and c) AE and SAE adjuvant medication management strategy; 3) programmatic cost-effectiveness evaluation of PCC management. Bring BPaL2Me has strong multi-PI collaborations with support from the national/provincial department of health teams and a rigorous design to evaluate effectiveness, safety and costs.