Xpert Active Case-finding Trial 3 (XACT-3) (XACT-3)

• ClinicalTrials.gov Identifier: NCT04303104
• Recruitment Status: Recruiting
• First Posted: March 10, 2020
• Last Update Posted: July 14, 2022
• Sponsor: University of Cape Town
• Collaborators: Zambart (University of Zambia), Zambia; Instituto Nacional de Saúde, Mozambique; Biomedical Research and Training Institute, Zimbabwe; Radboud University Medical Center; London School of Hygiene and Tropical Medicine; University of Cape Town Lung Institute
• Information provided by (Responsible Party): Keertan Dheda, University of Cape Town

Study Description

Brief Summary:

TB remains the foremost infectious disease killer globally. A startling statistic is that two out of every five TB cases globally (40%) remain undiagnosed and untreated. These 'missed' or undiagnosed cases are disproportionately concentrated in large peri-urban 'slums' and informal settlements of large cities in Africa and Asia (they are frequently minimally symptomatic but remain infectious).

The lack of a sensitive low cost same-day test represented a major challenge to active community-based case finding (ACF) compared to the current model where patients 'self-seek' care (passive case finding). More recently, sensitive TB DNA-detection tests called Gene Xpert (Xpert) have become available. This is a nucleic acid amplification test-based technology which can rule-in a diagnosis of TB in two thirds of smear negative pulmonary TB cases. GeneXpert® has now been rolled out in many African countries and is the frontline TB test in primary care clinics in South Africa. The investigators recently showed that GeneXpert® significantly reduced the time to treatment initiation in the setting of passive case finding (elaborated in next section). The investigators further showed that GeneXpert® can be performed by a minimally trained healthcare worker. However, historically technical and logistical demands meant that the GeneXpert® MTB-RIF assay was not ideally suited to use at point of care and in South Africa it is still centrally located.

Small portable battery-operated versions of these tests are now available (EDGE, GeneXpert two-module mobile platform). The investigators conducted a large study in South Africa and Zimbabwe (published in 2016) that showed that using the old non-portable version of Xpert on a mini-truck equipped with a generator was feasible and highly effective for ACF. A subsequent study funded by the American government (XACT II), showed that using the portable version of Xpert on the back of a small low-cost scalable panel van (in effect a mobile mini-clinic) was feasible and had a very high pick-up rate of TB in peri-urban communities (~10% of those undergoing targeted screening). In this study, the investigators will test the hypothesis that community-based active case finding (ACF) using Gene Xpert Edge (in a low cost scalable mini-mobile clinic) performed at point-of-care (POC) is feasible and more effective (lower proportion of TB cases failing to initiate treatment especially if they are 'super-spreaders' i.e. highly infectious) than Xpert performed in a centralised laboratory.

Condition or disease	Intervention/treatment	Phase
Tuberculosis	Other: GeneXpert Edge; Other: GeneXpert Ultra	Not Applicable

Detailed Description:

In the proposed study (XACT III) the investigators will use the same approach (as for XACT II), but it remains to be shown that such a strategy is scalable and feasible in different settings where the challenges and conditions vary. More importantly, the investigators need to methodologically optimize the ACF model. Thus, the investigators aim to determine where Xpert (the diagnostic test) should be optimally placed from a physical location point-of-view, i.e. does it really need to be installed in the mobile mini clinic, or, can it be located in centralized laboratories (as it is now) with samples being sent to these laboratories? This is a very important question: it is known that sending collected sputum samples to centralized laboratories will be much easier as it uses existing infrastructure, however, the downside is between 20 and 40% of patients fail to come back to collect their results (pre-treatment loss to follow-up; PTLF). Using the diagnostic in the mobile mini van (at point-of-care; POC) dramatically reduces this PTLF enabling quick diagnosis and interrupting transmission. To definitively settle the question, a study is needed using the two different strategies to find out which strategy is most cost-effective yet can rapidly pick up the most cases and minimize transmission.

There are two other important sub-questions that the study will answer. Chest X-rays, which can identify people at high risk of having TB, can now be automatically read by a computer algorithm (called computer-assisted diagnosis of TB; CAD-TB). It will be very important to know whether mass screening using CAD-TB can triage individuals i.e. narrow the net so that the investigators target the ACF only to those at high risk of having TB. This could save even more money yet be just as effective.

Secondly, a fundamental unanswered question is why individuals with minimal or no symptoms can be highly infectious (transmit disease)? The investigators need to study this phenomenon in greater detail using cough aerosol readouts, chest X-rays, and looking at the TB strains. In addition the investigators would like to screen contacts of individuals with confirmed tuberculosis This might provide medical science with the information it needs to design diagnostic or therapeutic interventions to address this important problem.

However, the key priority now is to show that the XACT approach is feasible in different settings and to clarify how the molecular diagnostics should be optimally located. Answering these questions will allow the initiation of ACF programmes in many countries and will contribute critical data to policy makers so that guidelines on ACF can be disseminated and implemented.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 3375 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Screening
• Official Title: A Randomized Controlled Trial to Evaluate a Scalable Active Case Finding Intervention for TB Using a Point-of-care Molecular Tool (Gene Xpert)
• Actual Study Start Date: March 26, 2021
• Estimated Primary Completion Date: July 1, 2023
• Estimated Study Completion Date: December 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Mobile ACF; Xpert Edge performed at point-of-care employing a low-cost panel van that is staffed by three health care workers. Patients identified with active TB will be initiated on TB treatment on the same day at the nearest clinic. On site HIV testing will also be offered. Thus, the interventional package is one of ACF + POC TB testing (TB testing by Xpert will occur on site at the van).	Other: GeneXpert Edge; Screening intervention: novel diagnostic for Active Case Finding (GeneXpert MTB/RIF) for TB on sputum collected and performed at point-of-contact in a mobile van
Placebo Comparator: Centralised ACF; Similar to active arm but Xpert Ultra will be performed at a centralized laboratory (samples will be transported to the laboratory with results being available in a few days). Thus, the standard of care package is ACF + distant TB testing (TB testing by Xpert will occur at a distant laboratory site).	Other: GeneXpert Ultra; Screening intervention: novel diagnostic test for Active Case Finding (GeneXpert MTB/RIF) for TB on sputum collected at point-of-contact in a mobile van but sent to laboratory

Outcome Measures

Primary Outcome Measures :

1. Proportion with PTLF (defined as test positive patients failing to initiate treatment by 60 days) and/ or the proportion of infectious TB patients (smear positive and/ or with cavitatory disease) not initiating treatment within 14 days of diagnosis. [ Time Frame: Within 2 months of enrollment, up to 24 months ]
   The proposed primary outcome measure is a surrogate of transmission and disease amplification (especially of the 'missed' highly infectious cases). Thus, the composite outcome serves as a surrogate of those who will experience a poor outcome (the missing cases) and disease amplification (transmission of TB).

Secondary Outcome Measures :

1. Proportion of culture-positive patients failing to initiate treatment in each study arm within 14 days of diagnosis. [ Time Frame: Within 2 months of enrolment, up to 26 months ]
   Proportion of culture-positive participants not initiating treatment as confirmed by TB Clinic attendance register.
2. Time to TB treatment initiation [ Time Frame: Within 2 months of enrollment, up to 24 months ]
   Time (in days) as determined by difference between enrollment date and date that treatment is commenced in local TB Clinic as per attendance register.
3. Time-specific proportion of patients initiated on TB treatment up to 60 days. [ Time Frame: Within 2 months of enrolment, up to 26 months ]
   Proportion of culture-positive participants initiating treatment as confirmed by TB Clinic attendance register.
4. Feasibility of Xpert being performed by minimally trained health care workers at point-of-care using. [ Time Frame: Through study completion, up to 48 months ]
   Number of study days lost to operational problems with machine or van (recorded daily by study team in daily register). Furthermore, user adherence to test protocol, operator knowledge of the testing procedure, and confidence in the test and satisfaction with its ease of use will be tested by two standardized questionnaires employed and validated in our previous study on active case-finding using lab-based Xpert.
5. Cost effectiveness analysis in each of the four countries. [ Time Frame: Through study completion, up to 48 months ]
   Cost-effectiveness analysis to be performed at study conclusion.
6. Turn-around-time for Xpert testing in both arms. [ Time Frame: Within 2 months of enrolment, up to 26 months ]
   Number of days wait until dispatch of result to patient.
7. Transmission impact using modelling based on exposure scores, imaging and CASS. [ Time Frame: Within 2 months of enrolment, up to 26 months ]
   This is a composite outcome determined by individual score for each of the mechanisms (contact, imaging and CASS) used to investigate transmission.
8. Household contact tracing yield from TB positive patients (active TB and QFT conversion). [ Time Frame: Within 2 months of enrolment, up to 26 months ]
   Captured as number of TB positive contacts for an enrolled participant with active TB.
9. The time-specific proportion of culture-positive TB cases initiating TB treatment in each study arm. [ Time Frame: Through study completion, up to 48 months ]
   Number of culture confirmed cases who initiate treatment in each arm.
10. The proportion of culture-positive TB cases completing 6-months of TB treatment in each study arm. [ Time Frame: Within 8 months of enrolment, up to 48 months ]
    Number of culture confirmed cases who initiate treatment in each arm and finish the course as per TB clinic register.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Community participant willing to complete community-based symptom screening, finger-prick blood testing, and/or undergo TB diagnostic testing.
2. Provision of informed consent.
3. Has documentation of, or willingness to be tested for HIV infection. HIV testing does not need to be repeated if there is written documentation of a confirmed positive test at any time in the past.
4. HIV-negative adults (older than 18 years) with 1 or more of the following:• cough ≥ 2 weeks• loss of weight• Fever• night sweats• generalized fatigue• haemoptysis• chest pain.
5. Any HIV+ve adult (older than 18 years).
6. Agrees to the collection and storage of blood, urine, sputum specimens for use for future research. (The participant may decline collection of specimens for human genetic research and still be eligible for the study).

Exclusion Criteria:

1. Inability to provide informed consent (e.g. mentally impaired).
2. Patients who have completed TB treatment in the last 2 months, or who have self-presented to their local TB clinic and are currently being worked up for suspected TB.
3. Patients already diagnosed with active TB.
4. Patients unable to commit to a two month follow up or who do not wish to be followed up.

Inclusion criteria for Household contacts (HHC)

1. Adult (> 18 years old) with significant recent exposure (within the past 6 months) to an adult with untreated or inadequately treated pulmonary TB.
2. No clinical signs or symptoms of active TB that include, but are not limited to: persistent cough, haemoptysis, fever, unintended weight loss or failure to thrive (children), fatigue or lethargy, night sweats, pleuritic chest pain, draining lymph node, or other evidence of extra-pulmonaryTB. If clinical signs or symptoms of TB are present, Chest X-Ray and/or sputum culture results must be included in the overall evaluation to rule out active TB.
3. Has signed a written consent or witnessed oral consent in the case of illiteracy, prior to his/her first sample or other study-specific data being collected.
4. Agrees to the collection and storage of blood, urine, saliva and sputum specimens for use for future research. (The participant may decline collection of specimens for human genetic research and still be eligible for the study.)

Exclusion Criteria for Household contacts

1. Plans to move from his/her current residence, which would interfere with the participant's ability to complete all study visits (through the Month 24Visit).
2. Has an active psychiatric condition, or alcohol or drug dependence that, in the opinion of the site investigator or designee, might interfere with the ability to give true informed consent and to adhere to the study requirements.

Contacts and Locations

Contacts

Contact: Aliasgar Esmail, MBChB; 2721 406 6119; a.esmail@uct.ac.za

Contact: Shameem Jaumdally, PhD; 2721 406 6119; shameem.jaumdally@uct.ac.za

Locations

Mozambique

Khosa Celso; Recruiting

Maputo, Mozambique

Contact: Khosa Celso, MBChB

South Africa

University of Cape Town; Recruiting

Cape Town, Western Cape, South Africa, 7925

Contact: Keertan Dheda, MBChB, PhD +27214067650 keertan.dheda@uct.ac.za

Contact: Aliasgar Esmail, MBChB +27214066119 a.esmail@uct.ac.za

Sub-Investigator: Suzette Oelofse, MBChB

Sub-Investigator: Anil Pooran, PhD

Sub-Investigator: Tahlia Perumal, MBChB

Zambia

Helen Ayles; Recruiting

Lusaka, Zambia

Contact: Helen Ayles, MBChB helen.ayles@lshtm.ac.uk

Zimbabwe

Junior Mutsvangwa; Recruiting

Harare, Zimbabwe

Contact: Junior Mutsvangwa, MBChB

Sponsors and Collaborators

University of Cape Town

Zambart (University of Zambia), Zambia

Instituto Nacional de Saúde, Mozambique

Biomedical Research and Training Institute, Zimbabwe

Radboud University Medical Center

London School of Hygiene and Tropical Medicine

University of Cape Town Lung Institute

Investigators

• Principal Investigator: Keertan Dheda, MBChB, PhD; Lung Infection and Immunity Unit and Division of Pulmonology

More Information

• Responsible Party: Keertan Dheda, Principal Investigator, University of Cape Town
• ClinicalTrials.gov Identifier: NCT04303104
• Other Study ID Numbers: XACT-3
• First Posted: March 10, 2020
• Last Update Posted: July 14, 2022
• Last Verified: July 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Keertan Dheda, University of Cape Town:

TB Screening; Active Case Finding; Mobile versus Centralized

Additional relevant MeSH terms:

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections