A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi (PROSPECT)
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|ClinicalTrials.gov Identifier: NCT03519425|
Recruitment Status : Not yet recruiting
First Posted : May 9, 2018
Last Update Posted : May 9, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Tuberculosis Hiv Tuberculosis, Pulmonary||Other: Optimised HIV screening and linkage to care Other: Optimised tuberculosis screening and linkage to care||Not Applicable|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||1455 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||A pragmatic open, three-arm individually-randomised controlled trial and economic evaluation|
|Masking:||Double (Investigator, Outcomes Assessor)|
|Primary Purpose:||Health Services Research|
|Official Title:||A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi|
|Estimated Study Start Date :||August 2018|
|Estimated Primary Completion Date :||December 2019|
|Estimated Study Completion Date :||June 2020|
No Intervention: Group 1 (Standard of care)
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:
Active Comparator: Group 2 (Optimised HIV screening and linkage to care)
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.
Other: Optimised HIV screening and linkage to care
As described in group descriptions
Active Comparator: Group 3 (Optimised HIV and TB screening and linkage to care)
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:
Other: Optimised HIV screening and linkage to care
As described in group descriptions
Other: Optimised tuberculosis screening and linkage to care
As described in group descriptions
- Time to tuberculosis treatment initiation [ Time Frame: Measured at 56 days after randomisation ]
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.
Analysis of the primary outcome will be done on an intention to treat basis, with all participants analysed according to the group to which they were randomised. Time to TB treatment outcome analysis will be right censored at Day 56 from randomisation if TB treatment is not initiated, or at day of loss to follow-up. We will make three pair-wise comparisons (Group 2 vs. Group 1; Group 3 vs. Group 2; and Group 3 vs. Group 1).
- Same day TB treatment initiation [ Time Frame: Measured at 56 days after randomisation ]The proportion of randomised participants initiated onto tuberculosis treatment on the same day as randomisation, with the numerator being participants who were initiated on tuberculosis treatment on Day 0, and the denominator being all randomised participants.
- Undiagnosed/untreated microbiologically-confirmed pulmonary tuberculosis [ Time Frame: Measured at 56 days after randomisation ]The proportion of randomised participants with undiagnosed/untreated microbiologically-confirmed pulmonary TB at Day 56, with the numerator being participants with microbiologically-confirmed tuberculosis (either sputum culture, or sputum Xpert, or sputum smear microscopy positive on a sample taken on Day 56) and who are confirmed not to be taking tuberculosis treatment on Day 56 (including participants who have previously initiated tuberculosis treatment, but have defaulted or stopped treatment - regardless of reason - for at least one week). The denominator will be all randomised participants.
- Undiagnosed/untreated HIV [ Time Frame: Measured at 56 days after randomisation ]The proportion of randomised participants with undiagnosed/untreated HIV at Day 56, with the numerator being participants with positive confirmatory HIV test results at Day 56 and who are not taking antiretroviral therapy (regardless of previous HIV test results during or before the study period), and the denominator being all randomised participants.
- Time to antiretroviral therapy initiation [ Time Frame: Measured at 56 days after randomisation ]
Time in days - from Day 0 up to but not including Day 56 - to initiation of antiretroviral therapy among participants with positive confirmatory HIV test results at Day 56 and who were not taking antiretroviral therapy at Day 0.
Initiation of antiretroviral therapy will be defined by:
A participant in whom there is documented evidence of commencement of combination antiretroviral therapy treatment, either by: inspection of the participant-carried national HIV programme treatment card; or inspection of the facility antiretroviral therapy treatment register; or inspection of antiretroviral therapy medication bottles or pill boxes.
- Mortality [ Time Frame: Measured at 56 days after randomisation ]The proportion of randomised participants reported to have died by Day 56, with the numerator being participants confirmed to have died through home tracing visits or TB treatment records, and the denominator being all randomised participants.
- TB treatment outcome [ Time Frame: Measured at 6-months after randomisation ]The proportion of TB cases with a successful TB treatment outcome. The numerator will be participants who were initiated onto tuberculosis treatment (either microbiologically-confirmed or clinically-diagnosed tuberculosis) up to, but not including Day 56, and who have a successful TB treatment outcome (either cured or completed treatment) at 6-months after starting treatment. The denominator will be all participants confirmed to have initiated tuberculosis treatment between Day 0 and up to, but not including Day 56.
- Quality of life (EQ5D utility score) [ Time Frame: Measured at 56 days after randomisation ]Mean difference in EuroQoL EQ5D utility score at Day 56, adjusting for participants' EQ5D utility score measured at Day 0.
- Quality of life (EQ5D visual analogue scale) [ Time Frame: Measured at 56 days after randomisation ]Mean difference in EuroQoL EQ5D visual analogue scale score, adjusting for participants' EQ5D visual analogue scale score measured at Day 0.
- Cost-effectiveness [ Time Frame: Measured at 56 days after randomisation ]Incremental cost-effectiveness per QALY gained
- Sex-and microbiological TB status-stratified analysis [ Time Frame: Measured at 56 days after randomisation ]
Although not statistically powered for comparison, in pre-specified exploratory sub-group analysis, we will stratify analysis of comparisons between pairs of groups for the primary outcome of time to tuberculosis treatment initiation (stratified by sex, and by microbiological TB status), and for the secondary outcomes of the proportion of participants with undiagnosed/untreated microbiologically-confirmed TB (stratified by sex), and undiagnosed/untreated HIV (stratified by sex).
These pre-specified exploratory analyses will be done for hypothesis-generating purposes and to support the case for future research, as our previous studies have shown that men fare considerable worse than women throughout the TB and HIV diagnostic and care pathways.
- Exploratory Bayesian analysis [ Time Frame: Measured at 56 days after randomisation ]
We will additionally undertake a Bayesian analysis of the primary trial outcome. Prior distributions for the proportion of participants initiating TB treatment will be elicited from key stakeholder groups, including community members, clinicians, researchers, TB experts, and policymakers.
Key stakeholders will be invited to attend workshop meetings, where they will be introduced to the study design and interventions through presentations and group discussions. To elicit prior beliefs for effect of interventions, we will use a "bin-and-chip" method, implemented within an interactive web application.
Using Bayes' theorem, we will combine elicited stakeholder group-specific log hazard ratio prior distributions with log-likelihood hazard ratio distributions from each pairwise comparison being made in the PROSPECT Study to construct posterior probability distributions.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03519425
|Contact: Peter MacPherson, MBChB MPH MRes PhD||+265 email@example.com|
|Contact: Marriott Nliwasa, MBChB PhD||+265 firstname.lastname@example.org|
|Malawi-Liverpool-Wellcome Trust Clinical Research Programme||Not yet recruiting|
|Blantyre, Chichiri, Malawi, 3|
|Contact: Peter MacPherson, MBChB MPH MRes PhD +265 191 9304 email@example.com|
|Contact: Marriott Nliwasa, MBChB PhD +265 191 9304 firstname.lastname@example.org|
|Principal Investigator: Peter MacPherson, MBChB MPH|
|Sub-Investigator: Elizabeth L Corbett, PhD|
|Sub-Investigator: Emily L Webb, PhD|
|Sub-Investigator: Elizabeth Joekes|
|Sub-Investigator: Madhukar Pai|
|Sub-Investigator: Marriott Nliwasa, PhD|
|Sub-Investigator: Hendramoorthy Maheswaran|
|Sub-Investigator: S Bertel Squire|
|Sub-Investigator: David G Lalloo|