| Protocol No: | ECCT/21/04/01 | Date of Protocol: | 23-09-2020 |
| Study Title: |
Diagnostic performance of a novel lipoarabinomannan test (FujiLAM) to detect tuberculosis in HIV-positive patients in Kenya
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| Study Objectives: | Objectives
The aim of this study is to investigate the diagnostic performance of FujiLAM in ambulatory HIV290
Primary objective
Secondary objectives |
| Laymans Summary: |
Tuberculosis (TB) is the leading cause of death among individuals living with HIV. Many cases of TB are missed each year for various reasons including lack of appropriate tools for the diagnosis of tuberculosis in specific populations at risk. This hinders the efforts to combat the disease. A test called the GeneXpert is a standard in the diagnosis of TB in Kenya and many similar settings. The test looks for the genetic material of the bacteria causing tuberculosis and requires individuals with suspected tuberculosis to produce phlegm for testing. While this test shows good performance, it is not always available and some categories of individuals such as HIV patients who are very sick are unable to cough up the phlegm required for testing.
The purpose of this study is to assess the performance of a new test called the Fujifilm SILVAMP TB LAM or simply the Fuji-LAM test. The Fuji-LAM test is a test that can be done on urine to look for specific proteins that are produced by the bacteria that causes tuberculosis. This test offers an advantage over the tests that are based on phlegm because most patients can produce urine for testing even when they are very sick. Additionally, this test does not require a complex laboratory set up and it can therefore be used by health workers as they interact with the patient. This study will also look at how the new test compares with an existing test - AlereLAM - that is based on similar technology. Initial laboratory-based studies conducted on frozen urine samples show that the new test has better performance than the existing test. This study is different from the first studies because it is being conducted in real life settings rather than in a laboratory.
Tuberculosis shares certain symptoms with the ongoing COVID-19 pandemic and patients who have both diseases may experience worse outcomes. Because it might be difficult to accurately differentiate between early Tuberculosis and COVID19, individuals who agree to participate will be also offered COVID 19 tests to help distinguish between the two diseases and offer those with COVID19 appropriate treatment. This will also help us understand how COVID19 is affecting patients living with HIV and TB.
The study will be conducted at the Homa Bay County Hospital in Kenya. Individuals living with HIV with and without signs and symptoms of TB will be invited to take part. Individuals who agree to participate will be seen by the health workers in the study and will provide samples for testing using the FujiLAM test and other standard tests used to investigate individuals for suspected tuberculosis. We are also conducting similar studies in other African countries including Uganda, Mozambique and South Africa. This will enable us to assess the performance of the test in diverse settings.
Should the study find that the performance of the Fuji-LAM test is good, it will make recommendations on the use of the test. The use of the test may allow faster identification of TB particularly among persons living with HIV. This faster identification will allow earlier treatment and likely to reduce the deaths that are associated with TB among persons living with HIV.
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| Abstract of Study: |
Background
Tuberculosis (TB) is the leading cause of death in HIV-positive individuals. Underdiagnosis of TB is a principal barrier to combatting the disease. In resource-limited settings, molecular diagnoses such as Xpert MTB/RIF are still not widely available and sputum samples can be difficult to produce, especially for very ill HIV-positive patients.
The Fujifilm SILVAMP TB LAM (FujiLAM; Fujifilm, Tokyo, Japan) is a novel (not commercialised) urine107 based point-of-care assay to diagnose TB in HIV-positive patients. A first study using urine frozen samples has reported a higher sensitivity of this test over the currently commercialised Alere Determine TB LAM Ag assay (AlereLAM).
At the time of the study preparations, a pandemic caused by a new coronavirus (SARS-CoV-2), is ongoing. Symptoms of coronavirus disease (CoViD-19) are similar to those of TB and people with suppressed immune systems may be particularly vulnerable to this disease.
Objectives
The aim of this study is to investigate the diagnostic performance of FujiLAM in ambulatory HIV positive patients from fresh urine samples.
Primary objective: To assess the sensitivity of FujiLAM among patients with microbiological confirmed TB in two groups of HIV-positive patients: 1) ambulatory adult HIV-positive patients with signs and symptoms of TB regardless of their CD4 count (Group 1), and 2) ambulatory adult patients with advanced HIV disease and no signs and symptoms of TB (Group 2).
Secondary objectives: To assess the sensitivity of FujiLAM and AlereLAM in urine by level of CD4 among patients with microbiologically confirmed TB and among patients with probable TB or microbiologically confirmed TB, the diagnostic performance of algorithms including FujiLAM, the mortality at 6 months according to the FujiLAM result and the feasibility of using the FujiLAM at point-of-care and the test acceptability by test users, clinic managers and patients. To assess the prevalence of CoViD-19 among HIV-positive ambulatory patients with symptoms of TB, to describe the clinical features, the severity and the outcomes of the patients diagnosed with CoViD-19, and the proportion of patients co-infected with CoViD-19 and TB, to assess the proportion of HIV-positive patients exposed to SARS-CoV-2
Methods
This prospective diagnostic study, will include two groups of ambulatory adult patients: 1) HIV positive patients with signs and symptoms of TB (Group 1), and 2) patients with advanced HIV disease (CD4 < 200 cells/μL or WHO Stage III/IV) and no signs and symptoms of TB (Group 2). In addition, a mix-methods approach will be used to assess the feasibility and acceptability of the test. Quantitative and qualitative methods using an exploratory design will be used for this purpose.
The study will take place in Homa Bay County Hospital in Kenya. This study is part of a multicentric study that includes other sites: the Mbarara Regional Reference Hospital in Uganda, Alto Maé Health Centre in Mozambique, and Eshowe Gateway Clinic (EGC) in Eshowe, KwaZulu-Natal, South Africa.
Patients will be assessed for signs and symptoms of TB (cough, fever, weight loss, 138 night sweats). HIV139
positive patients with signs and symptoms of TB and fulfilling other eligibility criteria will be invited to participate in the study as Group 1. HIV-positive patients with no signs and symptoms of TB, and with CD4 <200 cells/μL within the month prior to the consultation or in clinical Stage III/IV at the time of the consultation, and fulfilling other eligibility criteria will be invited to participate in the study as Group 2. All eligible patients will be proposed to sign an informed consent. For patients with no signs and symptoms of TB who are on clinical stage I/II and do not have a CD4 result within the month prior to the consultation, CD4 monitoring will be done by the study. In such case, patients will sign an informed consent before screening for eligibility.
Patients will receive a clinical exam, FujiLAM and AlereLAM in urine, Xpert MTB/RIF and MTB culture on sputum samples, and chest X-ray. The treating clinician will decide to treat for TB or not according to the clinical exam and the test results available except the Fuji LAM test results. Patients with signs and symptoms of TB not started on TB treatment will be re-assessed at a second consultation no later than 7 days (earlier if laboratory results are available earlier or if the patient requires a consultation earlier). In some cases a third consultation may be needed due to the clinical situation or to the delay in receiving some test results. Patient’s outcomes whether on TB treatment or not, will be assessed at 3 months and 6 months.
In addition to the TB investigations, patients with signs and symptoms of TB will be proposed optional CoViD-19 testing using conventional PCR or point-of-care PCR (GeneXpert SARS-CoV-2) at the first consultation and during follow-up if COVID-19 symptoms arise. Patients diagnosed with Covid-19 will be referred to the Homa Bay Ministry of Health Covid-19 centre for their management. All patients (symptomatic and asymptomatic) will be also proposed optional SARS-CoV-2 antibody testing at the first and last consultation.
The primary endpoint will be the sensitivity of FujiLAM calculated as the proportion of patients with a positive test result among patients with microbiological confirmed TB.
Secondary endpoints will be:
- Sensitivity of FujijLAM and AlereLAM by level of CD4 among patients with microbiologically confirmed TB and among patients with probable TB or microbiologically confirmed TB
- Specificity, positive and negative predictive values of FujiLAM
- Diagnostic performance of algorithms combining AlereLAM or FujiLAM in urine with Xpert MTB/RIF in sputum
- Median time to FujiLAM, AlereLAM and Xpert MTB/RIF test results
- Mortality at 6 months according to the FujiLAM result.
- Feasibility and acceptability of the FujiLAM test at point of care by test users, managers and patients.
- Proportion of TB symptomatic patients diagnosed with CoViD-19 overall, by TB diagnosis, by severity of disease and by outcome.
- Proportion of patients exposed to SARS-CoV-2.
A total of 200 HIV-positive patients with signs and symptoms of TB (Group 1) and 250 HIV-positive patients with no signs and symptoms of TB and CD4<200 or in stage III/IV (Group 2) will be recruited in Homa Bay.
Patients’ informed consent will be obtained before enrolment in the study. The study 180 protocol, the information sheets, the consent forms and any other relevant documents will be submitted for approval to the National Ethics Committees in each country where the study will be conducted and to Médecins Sans Frontières (MSF) Ethics Review Board.
Expected results
This research study would be among the first to provide evidence through a prospective study on the performance of FujiLAM, a novel point-of-care test to diagnose TB in HIV-positive patients in programmatic conditions. If the diagnostic performance of this test is proven to be good, the use of the test would allow rapid TB diagnosis and would potentially decrease mortality in HIV-positive patients.
The study will also inform WHO and the international scientific community on the diagnostic performance and other implementation aspects of using the test. The study will also provide additional evidence on CoViD-19 among HIV-positive patients.
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