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

Primary Purpose

Drug Resistant Tuberculosis

Status
Recruiting
Phase
Not Applicable
Locations
South Africa
Study Type
Interventional
Intervention
Nurse-Led Treatment in Primary Care
Sponsored by
Johns Hopkins University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional health services research trial for Drug Resistant Tuberculosis focused on measuring nurse-led, non-inferiority cluster randomized trial, primary care, drug resistant tuberculosis, rifampicin resistant tuberculosis, human immunodeficiency virus, task sharing, South Africa

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Jose Pearson HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Nurse-Led Treatment in Primary Care

Physician-Led Treatment Hospital Based

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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
Patient associated catastrophic costs
Costs 20% or more of household income) will be lower in nurse-led treatment

Secondary Outcome Measures

Time to RR-TB treatment initiation
Time to event analysis between diagnosis and treatment initiation
Time to smear/culture conversion
Time to event analysis between treatment initiation and smear and culture conversion
Time to HIV treatment initiation
Time to event analysis between enrollment and Antiretroviral therapy (ART) initiation
Time to HIV viral suppression
Time to event analysis between enrollment and HIV viral load < 200 copies
Time to adverse (AE) and severe (SAE) treatment related adverse event resolution
Time to event analysis for adverse and severe treatment related adverse events
Provider adherence to dosing requirements, treatment initiation
Accuracy of regimen dosing based on treatment guidelines
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
AE and SAE adjuvant medication management strategy
Provider appropriately manages AE and SAE events, as determined by blinded safety review
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.

Full Information

First Posted
December 20, 2022
Last Updated
September 5, 2023
Sponsor
Johns Hopkins University
Collaborators
University of Witwatersrand, South Africa, University of Cape Town, National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT05671718
Brief Title
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

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 4, 2023 (Actual)
Primary Completion Date
June 30, 2028 (Anticipated)
Study Completion Date
December 31, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University
Collaborators
University of Witwatersrand, South Africa, University of Cape Town, National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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: 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Health Services Research
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
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
InvestigatorOutcomes Assessor
Masking Description
We will mask the investigators, statistician and safety review committee to treatment assignment.
Allocation
Randomized
Enrollment
2944 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nurse-Led Treatment in Primary Care
Arm Type
Experimental
Arm Description
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.
Arm Title
Physician-Led Treatment Hospital Based
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Nurse-Led Treatment in Primary Care
Intervention Description
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.
Primary Outcome Measure Information:
Title
RR-TB treatment outcome
Description
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.
Time Frame
6 months
Title
Severe Adverse Events as assessed by the Division of AIDS (DAIDS) AE grading table
Description
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
Time Frame
12 months
Title
Patient associated catastrophic costs
Description
Costs 20% or more of household income) will be lower in nurse-led treatment
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Time to RR-TB treatment initiation
Description
Time to event analysis between diagnosis and treatment initiation
Time Frame
60 days from trial screening
Title
Time to smear/culture conversion
Description
Time to event analysis between treatment initiation and smear and culture conversion
Time Frame
120 days after treatment initiation
Title
Time to HIV treatment initiation
Description
Time to event analysis between enrollment and Antiretroviral therapy (ART) initiation
Time Frame
120 days after treatment initiation
Title
Time to HIV viral suppression
Description
Time to event analysis between enrollment and HIV viral load < 200 copies
Time Frame
6 months
Title
Time to adverse (AE) and severe (SAE) treatment related adverse event resolution
Description
Time to event analysis for adverse and severe treatment related adverse events
Time Frame
12 months
Title
Provider adherence to dosing requirements, treatment initiation
Description
Accuracy of regimen dosing based on treatment guidelines
Time Frame
1 month
Title
RR-TB dosing changes based on AE and SAE events
Description
Provider appropriately manages RR-TB regimen based on AE and SAE events, as determined by blinded safety review
Time Frame
12 months
Title
AE and SAE adjuvant medication management strategy
Description
Provider appropriately manages AE and SAE events, as determined by blinded safety review
Time Frame
12 months
Title
Programmatic cost effectiveness evaluation
Description
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.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kelly Lowensen, MSN, RN
Phone
4104091372
Email
klowens1@jhu.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason Farley, PhD, MPH, ANP-BC
Organizational Affiliation
The Center for Infectious Disease and Nursing Innovation (CIDNI)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Denise Evans, PhD
Organizational Affiliation
University of Witwatersrand, South Africa
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Norbert Ndjeka, MBChB
Organizational Affiliation
University of Cape Town
Official's Role
Principal Investigator
Facility Information:
Facility Name
Jose Pearson Hospital
City
Port Elizabeth
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jason Farley, PhD

12. IPD Sharing Statement

Citations:
PubMed Identifier
31170207
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.
Results Reference
background
PubMed Identifier
28804170
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.
Results Reference
background
PubMed Identifier
32317060
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.
Results Reference
background
PubMed Identifier
25939501
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.
Results Reference
background
PubMed Identifier
21810242
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.
Results Reference
result
PubMed Identifier
33824736
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.
Results Reference
result

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

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