Bring BPaL2Me Trial Comparing Nurse-Led RR-TB Treatment to Physician-Led RR-TB Treatment

The goal of the BringBPaL2Me Trial, a multi-principal investigator, multi-site, cluster randomized, non-inferiority trial is to compare nurse-led RR-TB treatment in primary care clinics to standard of care physician-led RR-TB treatment at district hospitals in the provinces of KwaZulu-Natal, Gauteng, and Eastern Cape.

The main aim is to conduct a 5-year, analyst and clinical safety review committee blinded, multi-site, cluster randomized trial to evaluate 1) treatment outcome; 2) safety; 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 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 \[H3\].

In South Africa (SA), nurses manage drug-susceptible Mycobacterium tuberculosis (TB) and TB/HIV coinfection within primary care clinics (PCCs); the TB treatment outcomes in this care model rival the best in the world. A primary care management strategy offers a convenient, patient-centered, model of care that integrates TB and HIV treatment within the same setting. However, a diagnosis of rifampicin-resistant TB (RR-TB), upends this model, requiring referral to a hospital-based, physician-led outpatient treatment center.

Hospital-based models add significant costs to patients, with estimates suggesting more than 80% of RR-TB patients experience catastrophic costs. Such added costs may decrease access to care, delay treatment receipt and contribute to loss to follow-up. One testable solution to this problem, however, is to move RR-TB care to primary care clinics led by nurses. The World Health Organization (WHO) released recommendations for RR-TB treatment earlier this year endorsing 6-month regimens and calling for decentralized, patient-centered models of care closer to the patient's home.

Although SA has long been a leading implementer of nurse-led models of care for TB and HIV due to large physician shortages and the National Department of Health's (NDoH) RR-TB Treatment Guidelines recommend integration of RR-TB within PCCs supporting both physician- and nurse-led models, utilization has been limited. While the team has spent the last decade building observational evidence around outcomes and safety, no randomized controlled trial evaluates nurse-led RR-TB treatment.

Secondary Aims: To evaluate clinical and cost-associated differentiators by arm:

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.

Eligibility Criteria:
Inclusion Criteria:

Cluster Inclusion Criteria:

Primary Care Clinics (PCCs) (i.e., clusters) are eligible if they meet the following:

1. within one of the selected hospital treatment catchment areas in Kwazulu-Natal, Gauteng and Eastern Cape Provinces;
2. willingness of provincial TB program managers and hospital leadership to participate;
3. willingness of PCC nurse manager to participate;
4. diagnosis of 10 or more RR-TB patients per year; and
5. have access to necessary labs, X-ray and electrocardiogram (ECG) equipment.

Participant Inclusion Criteria:

Adult participants aged 18 years of age and older, regardless of HIV status, who have a new RR-TB diagnosis, deemed willing and able to provide informed consent in one of the four most common SA languages \[Zulu, Xhosa, Afrikaans, and English\] will be eligible.

Participant Exclusion Criteria:

1. any clinical presentation requiring hospital admission or, in other words, the participant is not a candidate for outpatient primary care initiation (e.g., severe weakness, confusion, severe mental illness, symptomatic low blood pressure, severe shortness of breath, and temp \>39.0);
2. Hemoglobin \< 8mg/dL (from National Health Laboratory Service (NHLS) or point of care)) or liver disease (ALT \> 120 U/L);
3. prolonged QTc\>470ms, confirmed by 2 or more ecg;
4. rapid heartrate, tachycardia (HR \>140); confirmed after 5 minutes of rest;
5. pregnancy;
6. evidence of extrapulmonary disease;
7. enrolled in another clinical trial that changes BPaL-L regimen, duration or symptom management process.