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Evaluating Accuracy, Impact, and Operational Challenges of GeneXpert Use for TB Case Finding Among HIV-infected Persons (XPRES)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02538952
Recruitment Status : Completed
First Posted : September 2, 2015
Last Update Posted : June 25, 2019
Sponsor:
Collaborators:
Botswana Ministry of Health
University of Pennsylvania
Information provided by (Responsible Party):
Centers for Disease Control and Prevention

Brief Summary:

Background: In Botswana, as in the rest of sub-Saharan Africa, undiagnosed TB or TB diagnosed late in the course of disease is thought to be the most common cause of death among HIV-infected persons.

Interventions for Evaluation: The Xpert MTB/RIF assay for the GeneXpert platform (Xpert) has a TB diagnostic sensitivity of 82.4%, significantly superior to that of smear microscopy (44.6%). In line with WHO guidelines, the Botswana Ministry of Health (MOH) and CDC rapidly rolled out the Xpert device and a new Xpert-based diagnostic algorithm in service of 22 HIV care and treatment clinics. To maximize impact of the Xpert device in improving detection of active TB, Xpert rollout was preceded by strengthening of TB screening procedures by: (1) adopting the WHO-recommended 4-symptom TB screen for adults; (2) situating trained TB case-finding nurses in facilities; and (3) training health facility personnel in TB diagnostic algorithms. The combination of these strengthened TB screening procedures and rollout of the Xpert device is referred to as the "Xpert package" in this protocol.

Key Evaluation Objectives: The protocol has two key objectives: (1) to evaluate whether the new MOH-recommended Xpert-based TB diagnostic algorithm for new adult HIV clinic enrollees is more sensitive than the pre-Xpert smear-microscopy-based algorithm in diagnosing culture-positive TB disease; and (2) to evaluate the impact of the whole "Xpert package" on all-cause mortality during the first 6 months of ART, among adult patients.

Design: Stepped-wedge cluster randomized trial. Sample Size: 6,136 patients were prospectively enrolled to meet the first primary objective. A retrospective cohort of 10,131 persons was also enrolled to meet the second objective. Projected power to meet both objectives is >80%.

Time line: Prospective cohort enrollment started in July 2012 and was complete by March 2014. Retrospective cohort enrollment was complete by March 2015. Patient follow-up and data entry will be complete in March 2016 at which time analysis to answer the first two primary study questions will be possible.


Condition or disease Intervention/treatment Phase
Tuberculosis Human Immunodeficiency Virus Device: Xpert device Other: Intensified TB Case Finding (ICF) Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18696 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Evaluating Performance, Impact, and Operational Challenges of GeneXpert Use for TB Case Finding Among HIV-infected Persons in Botswana During 2012-2013: The Xpert Package Rollout Evaluation Study (XPRES)
Actual Study Start Date : August 1, 2012
Actual Primary Completion Date : July 1, 2017
Actual Study Completion Date : July 1, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Xpert package
There are three phases to this stepped-wedge trial: (1) the retrospective cohort (standard of care) phase, (2) the active comparator phase, where intensified TB case finding (ICF) interventions are in place but no Xpert device, and (3) the "experimental phase" of full Xpert package implementation that includes both ICF interventions and Xpert device activation. Interventions in the experimental phase therefore include: (a) adoption of the WHO-recommended 4-symptom TB screen for adults; (b) situating trained TB case-finding nurses in the 22 facilities; (c) training health facility personnel in TB diagnostic algorithms; and (d) Xpert device activation. The combination of the ICF interventions and rollout of the Xpert device is referred to as the "Xpert package" in this protocol.
Device: Xpert device
Interventions in the "Experimental phase" of this stepped-wedge trial include: (a) ensuring WHO-recommended TB screening adopted, (b) situating trained TB case finding nurses in the clinics, (c) training clinic personnel in the TB diagnostic algorithms, and (d) activation of the Xpert diagnostic device.

Other: Intensified TB Case Finding (ICF)
Interventions in the active comparator phase of this stepped wedge trial only include: (a) adoption of the WHO-recommended 4-symptom TB screen for adults; (b) situating trained TB case-finding nurses in the 22 facilities; and (c) training health facility personnel in TB diagnostic algorithms. There is no Xpert device activation in this phase. Only the standard of care microscopy algorithm (smear microscopy and chest x-ray) are available during this phase.

Active Comparator: Active comparator
There are three phases to this stepped-wedge trial: (1) the retrospective cohort (standard of care) phase, (2) the active comparator phase, where intensified TB case finding (ICF) interventions are in place but no Xpert device, and (3) the "experimental phase" of full Xpert package implementation that includes both ICF interventions and Xpert device activation. Interventions in the active comparator phase therefore include only: (a) adoption of the WHO-recommended 4-symptom TB screen for adults; (b) situating trained TB case-finding nurses in the 22 facilities; and (c) training health facility personnel in TB diagnostic algorithms. There is no Xpert device activation in this phase. Only standard of care microscopy-based TB diagnostic algorithms are available during this phase.
Other: Intensified TB Case Finding (ICF)
Interventions in the active comparator phase of this stepped wedge trial only include: (a) adoption of the WHO-recommended 4-symptom TB screen for adults; (b) situating trained TB case-finding nurses in the 22 facilities; and (c) training health facility personnel in TB diagnostic algorithms. There is no Xpert device activation in this phase. Only the standard of care microscopy algorithm (smear microscopy and chest x-ray) are available during this phase.

No Intervention: Standard of Care
There are three phases to this stepped-wedge trial: (1) the retrospective cohort (standard of care) phase, (2) the active comparator phase, where intensified TB case finding (ICF) interventions are in place but no Xpert device, and (3) the "experimental phase" of full Xpert package implementation that includes both ICF interventions and Xpert device activation. There are no interventions in the standard of care arm (retrospective cohort). There are no ICF interventions and no Xpert device activations in this phase. Only the standard of care TB case finding procedures and microscopy-based TB diagnostic algorithm are available during this phase.



Primary Outcome Measures :
  1. TB diagnostic sensitivity among adults (>12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below). [ Time Frame: Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months. ]
    TB diagnostic algorithm sensitivity will be estimated in the pre-Xpert and post-Xpert time periods of this stepped wedge design, among adults (>12 years old). Sensitivity is the proportion of culture-positive TB cases correctly diagnosed with TB using the relevant diagnostic algorithm. The denominator is all culture-confirmed TB cases and the numerator the number of culture-confirmed TB cases that were correctly identified as positive by the relevant TB diagnostic algorithm.

  2. All-cause mortality [ Time Frame: Patients will be followed for an average of about 6 months each, with vital status assessed across the 6 month follow-up period. ]
    All-cause 6-month mortality among adult antiretroviral therapy enrollees will be compared between the pre-Xpert retrospective cohort and the post-Xpert package cohorts.


Secondary Outcome Measures :
  1. Clinician TB screening compliance. Compliance proportions will be estimated using data from study questionnaires (see "Description" below). [ Time Frame: Patients will be followed for an average of about 6 months each, with clinician TB screening compliance assessed at each clinic visit, which should occur every one to 3 months. ]
    Clinician TB screening compliance will be compared between the pre-Xpert and post-Xpert cohorts. This is the proportion of clinic visits that the TB screening algorithm for adults was correctly administered by the attending clinician. The denominator is the number of clinic visits and the numerator is the number of occasions that the TB screening algorithm was completely and correctly administered.

  2. The proportion of patients screening positive for TB at the HIV clinic enrollment visit. Proportions screening positive will be estimated using data from study questionnaires (see "Description" below). [ Time Frame: Patients will be followed for an average of about 6 months each, and the proportion screening positive for TB will be estimated at each clinical visit, including the first clinic visit, with clinic visits occuring every one to 3 months. ]
    The proportion of HIV clinic enrollees, who screen positive for TB, will be compared between the pre-Xpert and post-Xpert cohorts. The denominator of the proportion will be the number of patients screened for TB at the HIV clinic enrollment visit, and the numerator will be the number of patients screening positive for TB at the HIV clinic enrollment visit.

  3. The proportion of patients diagnosed with TB at HIV clinic enrollment. Proportions diagnosed with TB will be estimated using data from study questionnaires and laboratory tests. [ Time Frame: Patients will be followed for an average of about 6 months each, and the proportion diagnosed with TB will be estimated at each clinical visit, with clinic visits occuring every one to 3 months. ]
    The proportion of HIV clinic enrollees, who are diagnosed with TB following tests conducted at the enrollment visit, will be compared between the pre-Xpert and post-Xpert cohorts. The denominator will be the number of patients attending the HIV clinic enrollment visit, and the numerator will be the number of patients diagnosed with TB at the HIV clinic enrollment visit.

  4. TB diagnostic sensitivity among children (<=12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below). [ Time Frame: Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months. ]
    TB diagnostic algorithm sensitivity will be estimated in the pre-Xpert and post-Xpert time periods of this stepped wedge design, among children (<=12 years old). Sensitivity is the proportion of culture-positive TB cases among children correctly diagnosed with TB using the relevant diagnostic algorithm. The denominator is all culture-confirmed TB cases among children and the numerator the number of culture-confirmed TB cases that were correctly identified as positive by the relevant TB diagnostic algorithm.

  5. TB screening algorithm sensitivity among children (<=12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses and questionnaire data on the screening algorithm (see "Description" below). [ Time Frame: Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months. ]
    MOH-recommended TB screening algorithm sensitivity will be estimated among children (<=12 years old). Sensitivity is the proportion of culture-positive TB cases correctly identified as potentially having TB using the MOH-recommended, 6-symptom, TB screening algorithm for children. The denominator is all culture-confirmed TB cases among children, and the numerator is the number of culture-confirmed TB cases that were correctly identified as potentially having TB by the 6-symptom, TB screening algorithm for children.

  6. Diagnostic sensitivity of Xpert in diagnosing culture-positive drug resistant TB. [ Time Frame: Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for drug resistant TB, with clinic visits occuring every one to 3 months. ]
    The study will estimate the sensitivity of the Xpert-based TB diagnostic algorithm in identifying drug resistant TB. The denominator is all culture-confirmed TB cases with genotypic or phenotypic drug resistance, and the numerator is the number of culture-confirmed drug resistant TB cases that were correctly identified as rifampicin resistant by the Xpert-based diagnostic algorithm.

  7. TB incidence [ Time Frame: Patients will be followed for an average of about 6 months each, and TB incidence will be estimated at each clinical visit, with clinic visits occuring every one to 3 months. ]
    TB incidence among adult antiretroviral therapy enrollees will be compared between the pre-Xpert cohorts and the post-Xpert package cohorts.

  8. TB treatment outcomes. The incidence rate will be estimated using data from study questionnaires (see "Description" below). [ Time Frame: Patients will be followed for an average of about 6 months each, and TB treatment outcomes will be estimated at each clinical visit, with clinic visits occuring every one to 3 months. ]
    TB treatment outcomes among HIV clinic enrollees will be compared between the pre-Xpert cohorts and the post-Xpert package cohorts. Possible treatment outcomes include "Cured", "Completed Treatment", "Died", "Treatment failure", "Defaulted/Lost-to-follow-up/missing", "Transferred out", and "Treatment ongoing".

  9. Hospitalization rates. Incidence of hospitalization rates will be estimated from study questionnaires. [ Time Frame: Patients will be followed for an average of about 6 months each, and the hospitalization outcome will be measured at each clinical visit, with clinic visits occuring every one to 3 months. ]
    Hospitalization rates among adult antiretroviral therapy enrollees in the first 6 months of ART will be compared between the pre-Xpert cohorts and the post-Xpert package cohorts.

  10. Xpert diagnostic sensitivity. Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below). [ Time Frame: Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months. ]
    Variations in Xpert diagnostic accuracy by location (point of care versus lab-based), and over time, will be explored. Sensitivity is the proportion of culture-positive TB cases correctly diagnosed with TB using the relevant diagnostic algorithm. The denominator is all culture-confirmed TB cases and the numerator the number of culture-confirmed TB cases that were correctly identified as positive by the relevant TB diagnostic algorithm.

  11. The proportion of attempts to use Xpert where Xpert was considered inoperable. These data will be obtained from study questionnaires. [ Time Frame: Patients will be followed for an average of about 6 months each, and Xpert fuctionality be estimated at each clinical visit where the patient screens positive for TB and provides a sputum sample, with clinic visits occuring every one to 3 months. ]
    The study will estimate what proportion of attempts to use Xpert where Xpert was considered inoperable for any duration of time.

  12. Median turnaround time for sputum samples from the time of sample collection to the time the patient was initiated on TB treatment. These data will be obtained from study questionnaires. [ Time Frame: Patients will be followed for an average of about 6 months each, and turnaround times for sputum samples will be estimated at each clinical visit where the patient provides a sputum sample, with clinic visits occuring every one to 3 months. ]
    The median time from the time of sputum sample collection to the time of TB treatment initiation will be estimated using study questionnaires.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Prospective cohorts:

Inclusion Criteria:

  • All new HIV clinic enrollees who meet consent requirements.

Exclusion Criteria:

  • Prisoners

Retrospective cohort:

Inclusion Criteria:

  • All patients starting antiretroviral therapy at a study clinic in the 24 months before study start.

Exclusion Criteria:

  • Prisoners

Information from the National Library of Medicine

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): NCT02538952


Locations
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Botswana
22 HIV care and Treatment clinics in Botswana
Multiple Locations, Multiple, Botswana
Sponsors and Collaborators
Centers for Disease Control and Prevention
Botswana Ministry of Health
University of Pennsylvania
Investigators
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Principal Investigator: Alyssa Finlay, MD CDC Botswana
Principal Investigator: Tedd V Ellerbrock, MD CDC Atlanta
Principal Investigator: Andrew F Auld, MBChB, MSc CDC Atlanta
Principal Investigator: Tefera Agizew, MD, MPhil CDC Botswana
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier: NCT02538952    
Other Study ID Numbers: CDC-CGH-6294
First Posted: September 2, 2015    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: IRB-approved protocols and CDC regulations will be followed.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centers for Disease Control and Prevention:
GeneXpert
Tuberculosis
Human immunodeficiency virus
Diagnostic accuracy
Impact
Additional relevant MeSH terms:
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Tuberculosis
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases