Clinical trial NCT03519425: A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi
Official title: A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Tuberculosis
Hiv
Tuberculosis, Pulmonary
Keywords: Tuberculosis
HIV
Randomised controlled trial
Africa
Public Health
Screening
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Malawi-Liverpool-Wellcome Trust Clinical Research Programme
name: London School of Hygiene and Tropical Medicine
name: University of Liverpool
name: McGill University
name: Kamuzu University of Health Sciences
First posted: 2018-05-09
Enrollment: 1455
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A pragmatic open, three-arm individually-randomised controlled trial and economic evaluation
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to tuberculosis treatment initiation
timeFrame: Measured at 56 days after randomisation
Secondary outcomes:
measure: Same day TB treatment initiation
timeFrame: Measured at 56 days after randomisation
measure: Undiagnosed/untreated microbiologically-confirmed pulmonary tuberculosis
timeFrame: Measured at 56 days after randomisation
measure: Undiagnosed/untreated HIV
timeFrame: Measured at 56 days after randomisation
measure: Time to antiretroviral therapy initiation
timeFrame: Measured at 56 days after randomisation
measure: Mortality
timeFrame: Measured at 56 days after randomisation
measure: TB treatment outcome
timeFrame: Measured at 6-months after randomisation
measure: Quality of life (EQ5D utility score)
timeFrame: Measured at 56 days after randomisation
measure: Quality of life (EQ5D visual analogue scale)
timeFrame: Measured at 56 days after randomisation
measure: Cost-effectiveness
timeFrame: Measured at 56 days after randomisation
Other outcomes:
measure: Sex-and microbiological TB status-stratified analysis
timeFrame: Measured at 56 days after randomisation
measure: Exploratory Bayesian analysis
timeFrame: Measured at 56 days after randomisation
Locations:
city: Blantyre
country: Malawi
facility: Malawi-Liverpool-Wellcome Trust Clinical Research Programme
state: Chichiri
Study officials:
References:
citation: MacPherson P, Webb EL, Kamchedzera W, Joekes E, Mjoli G, Lalloo DG, Divala TH, Choko AT, Burke RM, Maheswaran H, Pai M, Squire SB, Nliwasa M, Corbett EL. Computer-aided X-ray screening for tuberculosis and HIV testing among adults with cough in Malawi (the PROSPECT study): A randomised trial and cost-effectiveness analysis. PLoS Med. 2021 Sep 9;18(9):e1003752. doi: 10.1371/journal.pmed.1003752. eCollection 2021 Sep.
citation: MacPherson P, Webb EL, Lalloo DG, Nliwasa M, Maheswaran H, Joekes E, Phiri D, Squire B, Pai M, Corbett EL. Design and protocol for a pragmatic randomised study to optimise screening, prevention and care for tuberculosis and HIV in Malawi (PROSPECT Study). Wellcome Open Res. 2018 Nov 21;3:61. doi: 10.12688/wellcomeopenres.14598.3. eCollection 2018.