Clinical Trials

MainTitle

Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3 (STATIS)

This study is ongoing, but not recruiting participants.
Sponsor
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)


Information provided by (Responsible Party)
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier
NCT02057796

First received: February 5, 2014
Last updated: July 10, 2017
Last Verified: July 2017
History of Changes
Purpose

Purpose

In countries with a high tuberculosis (TB) prevalence, TB and invasive bacterial infections are leading causes of early death in patients who initiate antiretroviral therapy (ART) with advanced immunodeficiency.

We hypothesize that a systematic 6-month empirical TB treatment initiated 2 weeks before the introduction of ART in HIV-infected adults with severe immunosuppression (CD4<100/mm3) and no overt evidence of TB will reduce the risk of death and invasive bacterial infections. This strategy will be compared to one of extensive TB testing using point-of-care tests (Xpert MTB/RIF® and urine lipoarabinomanan LAM) and chest X-ray to identify and treat only patients with at least one positive test suggestive of TB.

Condition Intervention Phase
HIV-1 Infection

Device : Xpert MTB/RIF®, Determine TB LAM, Chest X-ray
Drug : ART (Atripla, Truvada, Efavirenz, Combivir)
Drug : Rifampin, isoniazid, pyrazinamide, ethambutol
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Systematic Empirical vs. Test-guided Anti-tuberculosis Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating Antiretroviral Therapy With CD4 Cell Counts <100/mm3: the STATIS Randomized Controlled Trial

Further study details as provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

Primary Outcome Measures

  • All-cause mortality and incidence of invasive bacterial infections [ Time Frame: 24 weeks ]
    The primary endpoint is the composite of (i) 24-week all-cause mortality and (ii) 24-week incidence of invasive bacterial infections
Secondary Outcome Measures:
  • Incidence of confirmed/probable/possible TB [ Time Frame: 24 Weeks and 48 weeks ]
  • Incidence of grade 3 or 4 adverse events [ Time Frame: 24 Weeks and 48 weeks ]
Other Outcome Measures:
  • Incidence of TB-associated IRIS [ Time Frame: 24 Weeks and 48 Weeks ]
  • Incidence of AIDS-defining diseases other than TB [ Time Frame: 24 Weeks and 48 Weeks ]

Estimated Enrollment: 1050
Study Start Date: September 2014
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray
Arm1 Extensive TB screening: In this arm, point-of-care tests for TB will be used at randomization (in all patients) and at each scheduled or unscheduled follow-up visit (in patients with signs or symptoms suggestive of TB and no clear alternative diagnosis); TB treatment will only be prescribed to patients with a diagnosis of TB
Device: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray
    The following point-of-care TB tests will be systematically performed:
    • Xpert MTB/RIF® on sputum (in all patients able to provide sputum; no sputum induction will be requested in others), Urine LAM (all patients). Depending on clinical presentation, Xpert MTB/RIF® will also be performed on any relevant extra-pulmonary specimen.
    TB treatment will depend on the result of the tests:
    • Criteria met for confirmed or probable TB : TB treatment will be initiated immediately (Visit 1) followed by ART initiation 2 weeks later (Visit 2); No evidence of confirmed or probable TB: ART will be started immediately (Visit 1).

    Drug: ART (Atripla, Truvada, Efavirenz, Combivir)
    • ART (TDF-3TC/FTC or AZT-3TC + efavirenz) will be started immediately after randomization in patients not put on TB treatment, and 2 weeks after initiation of TB treatment in others.
    • ART will be initiated 2 weeks after the onset of TB treatment (V2) for Arm 2

    Other Name: ART
    Drug: Rifampin, isoniazid, pyrazinamide, ethambutol

    Arm 1: Only patients who meet standardized criteria for TB at inclusion or during follow-up will receive a standard TB treatment (2ERHZ/4RH); Arm 2: • All patients will start a 6-month standard TB treatment (2ERHZ/4RH) at randomization

    Other Name: Systematic Empiric treatment
    Experimental: Rifampin, isoniazid, pyrazinamide, ethambutol
    Arm 2: Systematic Empiric treatment (Rifampicin,isoniazid, pyrazinamide, ethambutol) ART In this arm, all patients will start a systematic 6-month TB treatment at randomization. TB screening tests will not systematically be used neither at randomization nor while patients are on TB treatment.
    Drug: ART (Atripla, Truvada, Efavirenz, Combivir)
    • ART (TDF-3TC/FTC or AZT-3TC + efavirenz) will be started immediately after randomization in patients not put on TB treatment, and 2 weeks after initiation of TB treatment in others.
    • ART will be initiated 2 weeks after the onset of TB treatment (V2) for Arm 2

    Other Name: ART
    Drug: Rifampin, isoniazid, pyrazinamide, ethambutol

    Arm 1: Only patients who meet standardized criteria for TB at inclusion or during follow-up will receive a standard TB treatment (2ERHZ/4RH); Arm 2: • All patients will start a 6-month standard TB treatment (2ERHZ/4RH) at randomization

    Other Name: Systematic Empiric treatment

    Detailed Description:

    Settings: Cambodia, Côte d'Ivoire, Uganda, Vietnam. Design: Multicentre, two-arm, unblinded randomized controlled superiority trial.
    Objective: To compare the 24-week risk of death and occurrence of invasive bacterial infection between two experimental strategies in HIV-1 infected adults who start ART with a CD4 count <100/mm3: (i) continuous extensive TB screening during follow-up each time the patient present with symptoms, versus (ii) systematic empirical TB treatment started 2 weeks before ART initiation.
    Trial strategies:
    At inclusion, participants will be randomized 1:1 in two strategies of TB testing and treatment: extensive TB screening, or systematic empirical TB treatment.
    Extensive TB screening (arm 1): In this arm:

    • TB screening point-of-care tests (Xpert MTB/RIF®, urine LAM) and chest X-ray will be used extensively at randomisation (in all patients) and during follow-up (in patients with signs or symptoms suggestive of TB);
    • Only patients who meet standardized criteria for TB at inclusion or during follow-up will receive a standard TB treatment (2ERHZ/4RH);
    • ART (tenofovir(TDF)-lamivudine (3TC)/emtricitabine(FTC) or zidovudine (AZT)-lamivudine+ efavirenz) will be started immediately after randomization in patients not put on TB treatment, and 2 weeks after initiation of TB treatment in others.

    Systematic empirical TB treatment (arm 2): In this arm:
  • TB screening point-of-care tests will not be used;
  • All patients will start a 6-month standard TB treatment (2ERHZ/4RH) at randomization; ART (tenofovir-lamivudine/emtricitabine or zidovudine-lamivudine+ efavirenz) will be started 2 weeks after TB treatment initiation.

  • Both strategies will apply to the first 24 weeks in the trial (intervention period).
    From week-24 to week-48, the choice of TB tests and the prescription of TB treatment will be left upon the decision of the investigator in both trial arms.
    Inclusion time: 24 months. Follow-up: each patient will be followed 48 weeks. Statistical analysis: the primary analysis will be intention to treat. It will compare the 24-week probability of death or invasive bacterial infection between arms.
    Sample size: 1050 participants. This will allow demonstration of a 40% reduction in the 24-week probability of death or invasive bacterial infection in arm 2, compared to arm 1 (α 5%; 1-β 80%).

    Eligibility

    Eligibility

    Ages Eligible for Study: 18 Years and older  
    Sexes Eligible for Study: All  
    Accepts Healthy Volunteers: No  

    Criteria

    Inclusion Criteria:

    • Age ≥18 years;
    • HIV-1 infection as documented at any time prior to trial entry, as per national testing procedures;
    • CD4 <100 cells/mm3;
    • No history of antiretroviral drug use (except transient ART for PMTCT);
    • Able to correctly understand the trial and to sign the informed consent.


    Exclusion Criteria:
    • HIV-2 co-infection;
    • Contra-indication to efavirenz;
    • Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >5 times the upper limit of normal;
    • Creatinine clearance <50 ml/min;
    • Overt evidence that TB treatment should be started immediately;
    • History of TB treatment in the past 5 years;
    • Ongoing TB chemoprophylaxis (isoniazid preventive therapy);
    • Any condition that would lead to differ ART initiation (e.g. acute condition requiring investigations and/or treatment prior to ART initiation);
    • Current pregnancy or breastfeeding.

    contacts and locations

    Contacts and Locations

    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, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT02057796

    Locations

    Cambodia
    Sihanouk Hospital Center of Hope
    Phnom Penh, Cambodia, 2318
    Côte D'Ivoire
    CePReF Centre de Prise en charge de Recherche et de Formation
    Abidjan, Yopougon, Côte D'Ivoire, 1954
    Uganda
    ISS ImmunoSuppression Service
    Mbarara, Uganda, 1956
    Vietnam
    Pham Ngoc Thach Hospital
    Ho Chi Minh City, Vietnam

    Sponsors and Collaborators

    French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)

    Investigators

    Principal Investigator: François-Xavier Blanc, MD, PhD Université de Nantes, Institut du thorax, CHU Nantes, France
    Principal Investigator: Kouao Médard Serge Domoua, MD Service de Pneumologie, CHU de Treichville, Abidjan, Côte d'Ivoire
    More Information

    More Information


    Responsible Party: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)  
    ClinicalTrials.gov Identifier: NCT02057796   History of Changes  
    Other Study ID Numbers: ANRS 12290  
    Study First Received: February 5, 2014  
    Last Updated: July 10, 2017  

    Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

    HIV-1
    Tuberculosis
    Systematic empiric TB treatment
    ART
    TB diagnosis
    Xpert MTB/RIF®
    Urine LAM

    Additional relevant MeSH terms:
    Efavirenz
    Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
    Lamivudine, zidovudine drug combination
    Rifampin
    Isoniazid
    Pyrazinamide
    Ethambutol

    ClinicalTrials.gov processed this data on December 15, 2017
    This information is provided by ClinicalTrials.gov.