Clinical trial NCT05671718: Bring BPaL2Me Trial Comparing Nurse-Led RR-TB Treatment to Physician-Led RR-TB Treatment
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Drug Resistant Tuberculosis
Keywords: nurse-led
non-inferiority cluster randomized trial
primary care
drug resistant tuberculosis
rifampicin resistant tuberculosis
human immunodeficiency virus
task sharing
South Africa
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: University of Witwatersrand, South Africa
name: University of Cape Town
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2023-01-05
Enrollment: 2944
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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)
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: 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 \[H3\].

Detailed description: 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.

Primary outcomes:
measure: RR-TB treatment outcome
timeFrame: 6 months
measure: Severe Adverse Events as assessed by the Division of AIDS (DAIDS) AE grading table
timeFrame: 12 months
measure: Patient associated catastrophic costs
timeFrame: 12 months
Secondary outcomes:
measure: Time to RR-TB treatment initiation
timeFrame: 60 days from trial screening
measure: Time to smear/culture conversion
timeFrame: 120 days after treatment initiation
measure: Time to HIV treatment initiation
timeFrame: 120 days after treatment initiation
measure: Time to HIV viral suppression
timeFrame: 6 months
measure: RR-TB dosing changes based on AE and SAE events
timeFrame: 12 months
measure: Time to adverse (AE) and severe (SAE) treatment related adverse event resolution
timeFrame: 12 months
measure: Time to initiation of HIV prevention
timeFrame: 6 months
measure: Provider adherence to dosing requirements, treatment initiation
timeFrame: 1 month
measure: AE and SAE adjuvant medication management strategy
timeFrame: 12 months
measure: Programmatic cost effectiveness evaluation
timeFrame: 12 months
Other outcomes:
Locations:
city: Pietermaritzburg
country: South Africa
facility: Doris Goodwin Hospital
state: KwaZulu-Natal
city: Port Shepstone
country: South Africa
facility: Murchison Hospital
state: KwaZulu-Natal
city: East London
country: South Africa
facility: King Dinuzulu TB Hospital
city: East London
country: South Africa
facility: Nkquebela TB Hospital
city: Port Elizabeth
country: South Africa
facility: Jose Pearson Hospital
Study officials:
affiliation: The Center for Infectious Disease and Nursing Innovation (CIDNI)
name: Jason Farley, PhD, MPH, ANP-BC
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Witwatersrand, South Africa
name: Denise Evans, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cape Town
name: Norbert Ndjeka, MBChB
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Rensburg C, Berhanu R, Hirasen K, Evans D, Rosen S, Long L. Cost outcome analysis of decentralized care for drug-resistant tuberculosis in Johannesburg, South Africa. PLoS One. 2019 Jun 6;14(6):e0217820. doi: 10.1371/journal.pone.0217820. eCollection 2019.
citation: Ho J, Byrne AL, Linh NN, Jaramillo E, Fox GJ. Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis. Bull World Health Organ. 2017 Aug 1;95(8):584-593. doi: 10.2471/BLT.17.193375.
citation: Masuku SD, Berhanu R, Van Rensburg C, Ndjeka N, Rosen S, Long L, Evans D, Nichols BE. Managing multidrug-resistant tuberculosis in South Africa: a budget impact analysis. Int J Tuberc Lung Dis. 2020 Apr 1;24(4):376-382. doi: 10.5588/ijtld.19.0409.
citation: Laurence YV, Griffiths UK, Vassall A. Costs to Health Services and the Patient of Treating Tuberculosis: A Systematic Literature Review. Pharmacoeconomics. 2015 Sep;33(9):939-55. doi: 10.1007/s40273-015-0279-6.
citation: Uebel KE, Fairall LR, van Rensburg DH, Mollentze WF, Bachmann MO, Lewin S, Zwarenstein M, Colvin CJ, Georgeu D, Mayers P, Faris GM, Lombard C, Bateman ED. Task shifting and integration of HIV care into primary care in South Africa: the development and content of the streamlining tasks and roles to expand treatment and care for HIV (STRETCH) intervention. Implement Sci. 2011 Aug 2;6:86. doi: 10.1186/1748-5908-6-86.
citation: Crowley T, Mokoka E, Geyer N. Ten years of nurse-initiated antiretroviral treatment in South Africa: A narrative review of enablers and barriers. South Afr J HIV Med. 2021 Mar 11;22(1):1196. doi: 10.4102/sajhivmed.v22i1.1196. eCollection 2021.