TuberculosisPROSPECTNCT03519425
A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi
A study testing Optimised HIV screening and linkage to care and Optimised tuberculosis screening and linkage to care in people with Tuberculosis and Hiv, run by Liverpool School of Tropical Medicine at 1 site in Malawi.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis, Hiv, Tuberculosis, Pulmonary
- What is being tested?
- Optimised HIV screening and linkage to care and Optimised tuberculosis screening and linkage to care
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,455 participants
- Where
- 1 siteMalawi
- Study dates
- 15 Nov 2018to Jun 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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 locations and contacts
1 site in 1 country.
Malawi1 site
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Blantyre, Chichiri, 3
About this study
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.
Read more
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.
Read the 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.
- Conditions
- Tuberculosis, Hiv, Tuberculosis, Pulmonary
- Being tested
- Optimised HIV screening and linkage to care, Optimised tuberculosis screening and linkage to care
- Keywords
- Tuberculosis, HIV, Randomised controlled trial, Africa, Public Health, Screening
- Medical subject headings
- Tuberculosis, Acquired Immunodeficiency Syndrome, Tuberculosis, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Optimised HIV screening and linkage to careOther
As described in group descriptions
Optimised tuberculosis screening and linkage to careOther
As described in group descriptions
| Study group | Role | What they receive |
|---|---|---|
| Group 1 (Standard of care) | No intervention | 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 | 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. Receives: Other: Optimised HIV screening and linkage to care |
| Group 3 (Optimised HIV and TB screening and linkage to care) | Active comparator | 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. Receives: Other: Optimised HIV screening and linkage to care; Other: Optimised tuberculosis screening and linkage to care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to tuberculosis treatment initiation
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).
Measured: Measured at 56 days after randomisation
Secondary outcomes (9)
Same day TB treatment initiation
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.
Measured: Measured at 56 days after randomisation
Undiagnosed/untreated microbiologically-confirmed pulmonary tuberculosis
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.
Measured: Measured at 56 days after randomisation
Undiagnosed/untreated HIV
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.
Measured: Measured at 56 days after randomisation
Time to antiretroviral therapy initiation
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.
Measured: Measured at 56 days after randomisation
Mortality
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.
Measured: Measured at 56 days after randomisation
TB treatment outcome
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.
Measured: Measured at 6-months after randomisation
Quality of life (EQ5D utility score)
Mean difference in EuroQoL EQ5D utility score at Day 56, adjusting for participants' EQ5D utility score measured at Day 0.
Measured: Measured at 56 days after randomisation
Quality of life (EQ5D visual analogue scale)
Mean difference in EuroQoL EQ5D visual analogue scale score, adjusting for participants' EQ5D visual analogue scale score measured at Day 0.
Measured: Measured at 56 days after randomisation
Cost-effectiveness
Incremental cost-effectiveness per QALY gained
Measured: Measured at 56 days after randomisation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2018
- Study start15 Nov 2018
- Primary completionDec 2019 (estimated)
- Study completionJun 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A pragmatic open, three-arm individually-randomised controlled trial and economic evaluation
- Masking
- Double blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 1,455 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Liverpool School of Tropical Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, London School of Hygiene and Tropical Medicine, University of Liverpool, McGill University, Kamuzu University of Health Sciences
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03519425
- Sponsor's protocol ID
- 17-050
- Acronym
- PROSPECT
- Status last verified
- Dec 2019
- First submitted
- 26 Apr 2018
- Last updated
- 10 Dec 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: We are strongly committed to ensuring that the trial datasets are made openly available, and that all code used in the analysis are published to allow fully reproducible research. The data collected by this research will be of importance to other researchers and the public, and could for example be used by other researchers conducting meta-analysis, or by policymakers modelling the potential return on investment of implementing interventions within their settings. Therefore, we will establish a public online GitHub repository, where the final anonymised individual participant trial dataset and code to allow reproduction of all analysis will be published.
Publications
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.
PubMed 34499665MacPherson 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.
PubMed 30542662
Study at a glance
From the registry record, last updated by the sponsor on 10 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pragmatic Randomised Study to Optimise Screening, Prevention and Care for Tuberculosis in Malawi
- ClinicalTrials.gov ID
- NCT03519425
- Acronym / sponsor ID
- PROSPECT / 17-050
- Conditions
- Tuberculosis, Hiv, Tuberculosis, Pulmonary
- Keywords
- Tuberculosis, HIV, Randomised controlled trial, Africa, Public Health, Screening
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 1,455 participants (estimated)
- Lead sponsor
- Liverpool School of Tropical MedicineUniversity, hospital or other
- Collaborators
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, London School of Hygiene and Tropical Medicine, University of Liverpool, McGill University, Kamuzu University of Health Sciences
- Study start
- 15 Nov 2018 (actual)
- Primary completion
- Dec 2019 (estimated)
- Study completion
- Jun 2020 (estimated)
- First posted
- 9 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- A pragmatic open, three-arm individually-randomised controlled trial and economic evaluation
| Arm | Type | Receives |
|---|---|---|
| Group 1 (Standard of care) | No intervention | –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 | Other: Optimised HIV screening and linkage to careParticipants 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. |
| Group 3 (Optimised HIV and TB screening and linkage to care) | Active comparator | Other: Optimised HIV screening and linkage to care, Other: Optimised tuberculosis screening and linkage to careParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Optimised HIV screening and linkage to careAs described in group descriptions | Other | Group 2 (Optimised HIV screening and linkage to care), Group 3 (Optimised HIV and TB screening and linkage to care) |
| Optimised tuberculosis screening and linkage to careAs described in group descriptions | Other | Group 3 (Optimised HIV and TB screening and linkage to care) |
Primary outcome
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).
9 secondary outcomes
Same day TB treatment initiation
Time frame: Measured at 56 days after randomisation
Undiagnosed/untreated microbiologically-confirmed pulmonary tuberculosis
Time frame: Measured at 56 days after randomisation
Undiagnosed/untreated HIV
Time frame: Measured at 56 days after randomisation
Time to antiretroviral therapy initiation
Time frame: Measured at 56 days after randomisation
Mortality
Time frame: Measured at 56 days after randomisation
TB treatment outcome
Time frame: Measured at 6-months after randomisation
Quality of life (EQ5D utility score)
Time frame: Measured at 56 days after randomisation
Quality of life (EQ5D visual analogue scale)
Time frame: Measured at 56 days after randomisation
Cost-effectiveness
Time frame: Measured at 56 days after randomisation
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Dec 2019.
- Derived from this study: PubMed 34499665MacPherson 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.
- Derived from this study: PubMed 30542662MacPherson 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.
- Individual participant dataSharing planned: Yes. We are strongly committed to ensuring that the trial datasets are made openly available, and that all code used in the analysis are published to allow fully reproducible research. The data collected by this research will be of importance to other researchers and the public, and could for example be used by other researchers conducting meta-analysis, or by policymakers modelling the potential return on investment of implementing interventions within their settings. Therefore, we will establish a public online GitHub repository, where the final anonymised individual participant trial dataset and code to allow reproduction of all analysis will be published.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Optimised HIV screening and linkage to care and Optimised tuberculosis screening and linkage to care in people with Tuberculosis and Hiv, run by Liverpool School of Tropical Medicine at 1 site in Malawi.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Malawi. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to tuberculosis treatment initiation (time frame: Measured at 56 days after randomisation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03519425, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2019.