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A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi (PROSPECT)

L

Liverpool School of Tropical Medicine

Status

Unknown

Conditions

Tuberculosis
Tuberculosis, Pulmonary
Hiv

Treatments

Other: Optimised tuberculosis screening and linkage to care
Other: Optimised HIV screening and linkage to care

Study type

Interventional

Funder types

Other

Identifiers

Details and patient eligibility

About

A pragmatic open, three-arm individually-randomised controlled trial and economic evaluation will be conducted in one primary health care centre in Blantyre, Malawi, where HIV and TB are major contributors to early mortality.

Participants will be adults with symptoms of tuberculosis (cough of any duration) attending the primary clinic with an acute care episode. We will exclude adults who have taken treatment for TB within the previous 6-months, who are taking isoniazid preventive therapy, who are not resident of Blantyre, or who plan to move out of Blantyre in the following 6-months.

Participants will be randomly allocated into one of three groups:

Group 1: Standard of care: Participants will be seen by facility health workers and receive clinician-directed screening for HIV and TB according to Malawi national guidelines.

Group 2: Optimised HIV testing and treatment linkage: Participants will be offered testing for HIV using rapid oral fluid kits by research assistants. Those with confirmed HIV infection will be linked to the HIV care clinic where facility healthworkers will screen for TB using standard sputum-based diagnostics.

Group 3: Optimised TB diagnosis, HIV screening and treatment linkage: Participants will receive a high-throughput and high-sensitivity TB screening intervention, in addition to the HIV testing intervention. This will comprise of an initial digital chest x-ray classified by the CAD4TB image-recognition software as either "high probability of TB", or "low probability of TB". Participants whose x-rays are suggestive of TB will receive confirmatory sputum testing with Xpert MTB/Rif Ultra cartridges, whilst participants whose x-rays have a low probability of TB will be referred to facility healthworkers for routine care.

All participants will be seen at the health facility at day 56, where they will be tested for HIV (if not on ART) and screened for TB.

The Primary Trial Outcome will compare between groups the time to tuberculosis treatment initiation by day 56. The trial is sufficiently powered to permit 3 pairwise comparisons between groups (i.e. Group 1 vs. 2; Group 2 vs. 3; and Group 1 vs. 3).

This three-arm pragmatic trial design allows us to efficiently answer two separate, important public health questions: firstly, by comparing Group 2 to Group 1, we should be able to determine whether HIV care should be prioritised for adults with TB symptoms. Additionally, by comparing Group 3 to Group 2, we will provide strong evidence for the effectiveness of an optimised and integrated HIV and TB diagnostic and treatment linkage approach.

Full description

Ambitious global targets have been set to eliminate tuberculosis as a public health problem by 2035. However, in Africa, where HIV has driven extremely high incidence rates, progress in reducing new infections and TB deaths remains too slow.

We have previously demonstrated that adults seeking diagnosis and treatment for TB and HIV face considerable barriers, and have long delays in starting treatment with high pre-treatment mortality.

Efforts to reduce TB mortality have been hampered by limitations in TB diagnostics, with considerable uncertainty about how available and new tests can be best implemented.

The aim of the PROSPECT Study is therefore to investigate the effectiveness and cost-effectiveness of optimised TB/HIV diagnosis and treatment linkage interventions on TB and HIV case detection, treatment initiation and mortality.

Study design A pragmatic open, three-arm individually-randomised controlled trial and economic evaluation will be conducted in one primary health care centre in Blantyre, Malawi.

Study site and participants The study will be conducted at one primary health clinic in Blantyre Malawi, where we have established HIV and TB research facilities and previously demonstrated high need for improved TB and HIV diagnosis. Sputum-based TB diagnostics (smear microscopy, and Xpert MTB/Rif) and treatment, and comprehensive HIV care (including provider-initiated HIV testing and antiretroviral therapy) are available free-to-cost to patients through the Malawi national TB and HIV programmes.

Participants will be adults with symptoms of pulmonary tuberculosis (cough of any duration) attending the primary clinic with an acute care episode. We will exclude adults who have taken treatment for TB within the previous 6-months, or who are taking isoniazid preventive therapy, or who do not live in Blantyre, or plan to move out of Blantyre.

Interventions

Participants will be randomly allocated into one of three groups:

Group 1 - Standard of care: Participants will be seen by facility health workers and receive clinician-directed screening for HIV and TB according to Malawi national guidelines without further study input.

Group 2 - Optimised HIV testing and treatment linkage: Participants will be offered testing for HIV using rapid oral fluid kits by research assistants. Those with confirmed HIV infection will be linked to the HIV care clinic where facility healthworkers will screen for TB using standard sputum-based diagnostics without further study input.

Group 3 - Optimised TB diagnosis, HIV screening and treatment linkage: Participants will receive a high-throughput and high-sensitivity TB screening intervention, in addition to the HIV testing intervention. This will comprise of an initial digital chest x-ray classified by the CAD4TB image-recognition software as either "high probability of TB", or "low probability of TB". Participants whose x-rays are classified as having high probability of TB will receive confirmatory sputum testing with Xpert MTB/Rif cartridges, whilst participants whose x-rays have a low probability of TB will be referred to facility healthworkers for routine care.

All participants will be seen at the health facility at day 56, where they will be assessed to determine whether they are taking treatment for tuberculosis by inspection of medication, inspection of treatment cards, and inspection of facility TB registers. They will also be offered testing for HIV (if not on ART) and screened for TB, including by sputum culture, Xpert and smear microscopy.

Outcomes The primary trial outcome will be time in days - from Day 0 up to but not including Day 56 - to tuberculosis treatment initiation, evaluated at Day 56 following randomization. The trial is sufficiently powered to permit 3 pairwise comparisons between groups (i.e. Group 1 vs. 2; Group 2 vs. 3; and Group 1 vs. 3).

This three-arm pragmatic trial design allows us to efficiently answer two separate, important public health questions: firstly, by comparing Group 2 to Group 1, we should be able to determine whether HIV care should be prioritised for adults with TB symptoms. Additionally, by comparing Group 3 to Group 2, we will provide strong evidence for the effectiveness of an optimised and integrated HIV and TB diagnostic and treatment linkage approach.

Statistical considerations Assuming 17% of participants in Group 1 initiate TB treatment by 8-weeks, and 5% loss to-follow-up, a sample size of n=1455 participants randomised in a 1:1:1 ratio across the three groups provides at least 80% power to detect a hazard ratio of 1.5 comparing Group 2 to Group 1, and a hazard ratio of 1.41 comparing Group 3 to Group 2.

Enrollment

1,455 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

  • Attends Study Clinic with an acute care episode
  • 18 years of age or older on the day of clinic attendance
  • Has symptoms of tuberculosis (cough of any duration)
  • Is resident within urban Blantyre
  • Provides informed consent to participate

Exclusion criteria

  • Taking treatment for tuberculosis on the day of clinic attendance
  • Has taken any treatment for tuberculosis in the 6-months prior to clinic attendance
  • Is taking isoniazid preventive therapy
  • Plans to move out of Blantyre to live elsewhere in the following 6-months

Trial design

Primary purpose

Health Services Research

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Double Blind

1,455 participants in 3 patient groups

Group 1 (Standard of care)
No Intervention group
Description:
Participants will be directed to the clinic waiting area to be seen by facility health workers who will direct all further care without any further input from the study team. Available to facility health workers will be: * Routine HIV testing and counselling, provided by Facility HIV Testers using a rapid fingerprick kit-based algorithm. * Routine TB screening, with both sputum smear microscopy and Xpert MTB/Rif testing available onsite. * Routine linkage to the onsite HIV clinic, where patients are registered and assessed for initiation onto antiretroviral therapy by facility HIV Care Clinic health workers. Malawi guidelines recommend universal treatment for HIV. HIV Care Clinic health workers will additionally have access to TB screening tests as described above. * Routine linkage to the onsite TB clinic, where patients are registered and initiated onto anti-TB treatment. Malawi guidelines recommend universal HIV testing for all patients with confirmed TB.
Group 2 (Optimised HIV screening and linkage to care)
Active Comparator group
Description:
Participants will be directed to the study room located in a separate building. After identity validation participants will be offered a supervised HIV self-testing intervention. Participants will be given brief pre-test instructions and will be asked to self-test in a private area using the OraQuick 1/2 (OraSure Technologies) oral fluid HIV kit. Participants will be supported to read their HIV test result by study Research Assistants, and provided with confirmatory HIV testing by the trained Research Assistants. * HIV-positive participants will be supported by Research Assistants to register at the onsite HIV care clinic, and all further care (including TB screening) will be directed by facility health workers without any further study input. * HIV-negative participants will be referred to the clinic waiting area (with a copy of their HIV test results) to be seen by the facility health workers who will direct all further investigations without further study input.
Treatment:
Other: Optimised HIV screening and linkage to care
Group 3 (Optimised HIV and TB screening and linkage to care)
Active Comparator group
Description:
Participants will be directed to the Study Room. After identity validation, they will be offered the HIV self-testing and linkage intervention as described above for Group 2. Additionally, they will be offered a TB screening intervention comprising of: * A digital chest x-ray using the study MinXray unit. * Chest x-rays will be immediately classified by the CAD4TB software running on the MinXray unit laptop as either "high probability of TB", or "low probability of TB". * Participants whose chest x-rays have a low probability of TB will be referred to facility health workers (at either the onsite HIV care clinic if HIV-positive, or the clinic waiting area), with copies of their results for further routine care, and without further study input. * Participants whose chest x-ray x-ray show a high probability of TB will submit a single spot sputum sample for Xpert testing (done in the clinic). Those with confirmed TB will be linked to register at the onsite TB clinic.
Treatment:
Other: Optimised tuberculosis screening and linkage to care
Other: Optimised HIV screening and linkage to care

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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