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

Primary Purpose

Tuberculosis

Status

Recruiting

Phase

Not Applicable

Locations

International

Study Type

Interventional

Intervention

GeneXpert Edge

GeneXpert Ultra

About this trial

This is an interventional screening trial for Tuberculosis focused on measuring TB Screening, Active Case Finding, Mobile versus Centralized

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Community participant willing to complete community-based symptom screening, finger-prick blood testing, and/or undergo TB diagnostic testing.
Provision of informed consent.
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.
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.
Any HIV+ve adult (older than 18 years).
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:

Inability to provide informed consent (e.g. mentally impaired).
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.
Patients already diagnosed with active TB.
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)

Adult (> 18 years old) with significant recent exposure (within the past 6 months) to an adult with untreated or inadequately treated pulmonary TB.
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.
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.
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

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).
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.

Sites / Locations

Khosa CelsoRecruiting
University of Cape TownRecruiting
Helen AylesRecruiting
Junior MutsvangwaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Mobile ACF

Centralised ACF

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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.

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

Proportion of culture-positive patients failing to initiate treatment in each study arm within 14 days of diagnosis.

Proportion of culture-positive participants not initiating treatment as confirmed by TB Clinic attendance register.

Time to TB treatment initiation

Time (in days) as determined by difference between enrollment date and date that treatment is commenced in local TB Clinic as per attendance register.

Time-specific proportion of patients initiated on TB treatment up to 60 days.

Proportion of culture-positive participants initiating treatment as confirmed by TB Clinic attendance register.

Feasibility of Xpert being performed by minimally trained health care workers at point-of-care using.

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.

Cost effectiveness analysis in each of the four countries.

Cost-effectiveness analysis to be performed at study conclusion.

Turn-around-time for Xpert testing in both arms.

Number of days wait until dispatch of result to patient.

Transmission impact using modelling based on exposure scores, imaging and CASS.

This is a composite outcome determined by individual score for each of the mechanisms (contact, imaging and CASS) used to investigate transmission.

Household contact tracing yield from TB positive patients (active TB and QFT conversion).

Captured as number of TB positive contacts for an enrolled participant with active TB.

The time-specific proportion of culture-positive TB cases initiating TB treatment in each study arm.

Number of culture confirmed cases who initiate treatment in each arm.

The proportion of culture-positive TB cases completing 6-months of TB treatment in each study arm.

Number of culture confirmed cases who initiate treatment in each arm and finish the course as per TB clinic register.

Full Information

NCT ID

NCT04303104

First Posted

March 6, 2020

Last Updated

July 12, 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

1. Study Identification

Unique Protocol Identification Number

NCT04303104

Brief Title

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

Acronym

XACT-3

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)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Recruiting

Study Start Date

March 26, 2021 (Actual)

Primary Completion Date

July 1, 2023 (Anticipated)

Study Completion Date

December 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Cape Town

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

Keywords

TB Screening, Active Case Finding, Mobile versus Centralized

7. Study Design

Primary Purpose

Screening

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

3375 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Mobile ACF

Arm Type

Active Comparator

Arm Description

Arm Title

Centralised ACF

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Other

Intervention Name(s)

GeneXpert Edge

Intervention Description

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

Intervention Type

Other

Intervention Name(s)

GeneXpert Ultra

Intervention Description

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

Primary Outcome Measure Information:

Title

Description

Time Frame

Within 2 months of enrollment, up to 24 months

Secondary Outcome Measure Information:

Title

Proportion of culture-positive patients failing to initiate treatment in each study arm within 14 days of diagnosis.

Description

Proportion of culture-positive participants not initiating treatment as confirmed by TB Clinic attendance register.

Time Frame

Within 2 months of enrolment, up to 26 months

Title

Time to TB treatment initiation

Description

Time (in days) as determined by difference between enrollment date and date that treatment is commenced in local TB Clinic as per attendance register.

Time Frame

Within 2 months of enrollment, up to 24 months

Title

Time-specific proportion of patients initiated on TB treatment up to 60 days.

Description

Proportion of culture-positive participants initiating treatment as confirmed by TB Clinic attendance register.

Time Frame

Within 2 months of enrolment, up to 26 months

Title

Feasibility of Xpert being performed by minimally trained health care workers at point-of-care using.

Description

Time Frame

Through study completion, up to 48 months

Title

Cost effectiveness analysis in each of the four countries.

Description

Cost-effectiveness analysis to be performed at study conclusion.

Time Frame

Through study completion, up to 48 months

Title

Turn-around-time for Xpert testing in both arms.

Description

Number of days wait until dispatch of result to patient.

Time Frame

Within 2 months of enrolment, up to 26 months

Title

Transmission impact using modelling based on exposure scores, imaging and CASS.

Description

This is a composite outcome determined by individual score for each of the mechanisms (contact, imaging and CASS) used to investigate transmission.

Time Frame

Within 2 months of enrolment, up to 26 months

Title

Household contact tracing yield from TB positive patients (active TB and QFT conversion).

Description

Captured as number of TB positive contacts for an enrolled participant with active TB.

Time Frame

Within 2 months of enrolment, up to 26 months

Title

The time-specific proportion of culture-positive TB cases initiating TB treatment in each study arm.

Description

Number of culture confirmed cases who initiate treatment in each arm.

Time Frame

Through study completion, up to 48 months

Title

The proportion of culture-positive TB cases completing 6-months of TB treatment in each study arm.

Description

Number of culture confirmed cases who initiate treatment in each arm and finish the course as per TB clinic register.

Time Frame

Within 8 months of enrolment, up to 48 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Community participant willing to complete community-based symptom screening, finger-prick blood testing, and/or undergo TB diagnostic testing. Provision of informed consent. 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. 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. Any HIV+ve adult (older than 18 years). 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: Inability to provide informed consent (e.g. mentally impaired). 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. Patients already diagnosed with active TB. 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) Adult (> 18 years old) with significant recent exposure (within the past 6 months) to an adult with untreated or inadequately treated pulmonary TB. 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. 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. 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 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). 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Aliasgar Esmail, MBChB

Phone

2721 406 6119

a.esmail@uct.ac.za

First Name & Middle Initial & Last Name or Official Title & Degree

Shameem Jaumdally, PhD

Phone

2721 406 6119

shameem.jaumdally@uct.ac.za

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Keertan Dheda, MBChB, PhD

Organizational Affiliation

Lung Infection and Immunity Unit and Division of Pulmonology

Official's Role

Principal Investigator

Facility Information:

Facility Name

Khosa Celso

City

Maputo

Country

Mozambique

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Khosa Celso, MBChB

Facility Name

University of Cape Town

City

Cape Town

State/Province

Western Cape

ZIP/Postal Code

7925

Country

South Africa

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Keertan Dheda, MBChB, PhD

Phone

+27214067650

keertan.dheda@uct.ac.za

First Name & Middle Initial & Last Name & Degree

Aliasgar Esmail, MBChB

Phone

+27214066119

a.esmail@uct.ac.za

First Name & Middle Initial & Last Name & Degree

Suzette Oelofse, MBChB

First Name & Middle Initial & Last Name & Degree

Anil Pooran, PhD

First Name & Middle Initial & Last Name & Degree

Tahlia Perumal, MBChB

Facility Name

Helen Ayles

City

Lusaka

Country

Zambia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Helen Ayles, MBChB

helen.ayles@lshtm.ac.uk

Facility Name

Junior Mutsvangwa

City

Harare

Country

Zimbabwe

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Junior Mutsvangwa, MBChB

12. IPD Sharing Statement

Learn more about this trial

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

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