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

Study Overview
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Brief Summary
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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: 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]. The proportion of SAEs identified will not significantly differ by blinded, independent review [H2]. Patient associated catastrophic costs (i.e., costs 20% or more of household income) will be lower in nurse-led treatment [H3].

Detailed Description
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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: 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. 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. Programmatic cost-effectiveness evaluation.

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

Conditions
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Drug Resistant Tuberculosis

Intervention / Treatment
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* Other: Nurse-Led Treatment in Primary Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cluster Inclusion Criteria: Primary Care Clinics (PCCs) (i.e., clusters) are eligible if they meet the following: within one of the selected hospital treatment catchment areas in Kwazulu-Natal, Gauteng and Eastern Cape Provinces; willingness of provincial TB program managers and hospital leadership to participate; willingness of PCC nurse manager to participate; diagnosis of 15 or more RR-TB patients per year; and 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: any clinical presentation requiring hospital referral (e.g., severe weakness, confusion, severe mental illness); laboratory or clinical evidence of myelosuppression (hemoglobin < 8mg/dL; absolute neutrophil count <1800/microL; platelet count < 150,000/microL), renal (eGFR<60mL/min) or liver disease (ALT > 2 times upper limit of normal); prolonged QTc>500ms; pregnancy; evidence of extrapulmonary disease; any condition (social or medical), which in the opinion of the investigators, would make participation unsafe.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Nurse-led primary care management for patients newly diagnosed with rifampicin-resistant tuberculosis (i.e. intervention) will be compared to physician-led, hospital-based management (i.e. standard of care)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nurse-Led Treatment in Primary Care<br>At a primary care clinic intervention site, a nurse will be available once or twice weekly. The days/times will be dependent on clinic volume (i.e., cluster size), with scheduled rotations between PCCs. This rotation between PCC sites will mimic the physician's responsibilities/availability at a district hospital and creates parity between the trial arms. In this trial, we will have nurses dedicated to the management of RR-TB treatment, yet the volume at each site will not require the presence of a full-time nurse. | Other: Nurse-Led Treatment in Primary Care<br>* At a primary care clinic intervention site, a nurse will be available once or twice weekly. The days/times will be dependent on clinic volume (i.e., cluster size), with scheduled rotations between PCCs. This rotation between PCC sites will mimic the physician's responsibilities/availability at a district hospital and creates parity between the trial arms. In this trial, we will have nurses dedicated to the management of RR-TB treatment, yet the volume at each site will not require the presence of a full-time nurse.<br>|
| No Intervention: Physician-Led Treatment Hospital Based<br>Representing standard of care, primary care clinics will refer to hospital-based, physician-led care who will provide outpatient treatment. The typical clinical operations involve initiation of new patients once or twice weekly and PCCs are required to schedule a clinic day/time for the patient prior to referral (generally < 72 hours from the time of referral). All individuals receiving care at this site will receive care at the district RR-TB treatment program for the catchment area. For HIV co-infected persons, their HIV treatment is also transferred to the RR-TB physician with details about the HIV treatment communicated in the transfer of care letter. Physicians often cover multiple clinics and routinely take on call sessions on the weekend, due to staffing limitations, thus preventing their sole focus on the RR-TB program and limiting the number of days the RR-TB clinic offers new patient visits and, in most cases, days for follow-up visits. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RR-TB treatment outcome | defined by the WHO will include the following: treatment success - the sum of cure and treatment completion; non-success - composite of each of the following negative outcomes: death, for any reason, while enrolled in RR-TB treatment (all-cause mortality); treatment failure - treatment terminated or need for permanent regimen change of at least two drugs because of: lack of culture conversion, bacterial reversion, worsening resistance profile, adverse events; and loss to follow-up interruption of 2 or more consecutive months of missed treatment. | 6 months | 
| Severe Adverse Events as assessed by the Division of AIDS (DAIDS) AE grading table | The following will be classified as an SAE using the DAIDS AE grading table for the purposes of this protocol: Lab abnormalities demonstrating grade 3 or higher: Myelosuppression (White blood cells (WBC), Red blood cells (RBC), Platelets); hepatotoxicity (Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin); renal impairment (serum creatinine and creatinine clearance) Peripheral neuropathy, grade 3 or higher QT prolongation (Frederica's QTc), grade 3 or higher New onset seizure, regardless of grade Hospitalization, regardless of identified cause Mortality, regardless of identified cause All grade 4 AEs not listed above as an SAE | 12 months | 
| Patient associated catastrophic costs | Costs 20% or more of household income) will be lower in nurse-led treatment | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to RR-TB treatment initiation | Time to event analysis between diagnosis and treatment initiation | 60 days from trial screening | 
| Time to smear/culture conversion | Time to event analysis between treatment initiation and smear and culture conversion | 120 days after treatment initiation | 
| Time to HIV treatment initiation | Time to event analysis between enrollment and Antiretroviral therapy (ART) initiation | 120 days after treatment initiation | 
| Time to HIV viral suppression | Time to event analysis between enrollment and HIV viral load < 200 copies | 6 months | 
| Time to adverse (AE) and severe (SAE) treatment related adverse event resolution | Time to event analysis for adverse and severe treatment related adverse events | 12 months | 
| Provider adherence to dosing requirements, treatment initiation | Accuracy of regimen dosing based on treatment guidelines | 1 month | 
| RR-TB dosing changes based on AE and SAE events | Provider appropriately manages RR-TB regimen based on AE and SAE events, as determined by blinded safety review | 12 months | 
| AE and SAE adjuvant medication management strategy | Provider appropriately manages AE and SAE events, as determined by blinded safety review | 12 months | 
| Programmatic cost effectiveness evaluation | For the health system costs, we will use standard approaches outlined in Value TB costing guidelines for TB interventions. If the costs averted are found to be greater than the cost of the nurse-led PCC so that intervention saves money and is non-inferior, then it can be described as dominating (a more effective, less expensive choice) and it is economically the correct choice. In contrast, if the nurse-led PCC is non-inferior and yet more expensive, then we will calculate an incremental cost-effectiveness ratio (i.e., (CostNurse-CostUsual care)/(EffectNurse-EffectUsualCare)) that describes the extra costs necessary for each additional cured case. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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South Africa, nurse-led, non-inferiority cluster randomized trial, primary care, drug resistant tuberculosis, rifampicin resistant tuberculosis, human immunodeficiency virus, task sharing