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

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ClinicalTrials.gov Identifier: NCT02057796
Recruitment Status : Unknown
Verified July 2017 by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS).
Recruitment status was:  Active, not recruiting
First Posted : February 7, 2014
Last Update Posted : July 12, 2017
Sponsor:
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)

Tracking Information
First Submitted Date  ICMJE February 5, 2014
First Posted Date  ICMJE February 7, 2014
Last Update Posted Date July 12, 2017
Actual Study Start Date  ICMJE September 2014
Estimated Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2014)
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
Original Primary Outcome Measures  ICMJE
 (submitted: February 6, 2014)
  • 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
  • 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
Change History Complete list of historical versions of study NCT02057796 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 6, 2014)
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 6, 2014)
  • 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 ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3
Official Title  ICMJE 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
Brief Summary

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.

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%).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE HIV-1 Infection
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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

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

    Interventions:
    • Drug: ART (Atripla, Truvada, Efavirenz, Combivir)
    • Drug: Rifampin, isoniazid, pyrazinamide, ethambutol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: February 6, 2014)
1050
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2018
Estimated Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Uganda,   Côte D'Ivoire,   Cambodia,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02057796
Other Study ID Numbers  ICMJE ANRS 12290
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Study Sponsor  ICMJE French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP