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 currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
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)
ClinicalTrials.gov Identifier:
NCT02057796
First received: February 5, 2014
Last updated: October 7, 2014
Last verified: October 2014

February 5, 2014
October 7, 2014
September 2014
April 2017   (final data collection date for primary outcome measure)
All-cause mortality and incidence of invasive bacterial infections [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
The primary endpoint is the composite of (i) 24-week all-cause mortality and (ii) 24-week incidence of invasive bacterial infections
Same as current
Complete list of historical versions of study NCT02057796 on ClinicalTrials.gov Archive Site
  • Incidence of confirmed/probable/possible TB [ Time Frame: 24 Weeks and 48 weeks ] [ Designated as safety issue: No ]
  • Incidence of grade 3 or 4 adverse events [ Time Frame: 24 Weeks and 48 weeks ] [ Designated as safety issue: Yes ]
Same as current
  • Incidence of TB-associated IRIS [ Time Frame: 24 Weeks and 48 Weeks ] [ Designated as safety issue: No ]
  • Incidence of AIDS-defining diseases other than TB [ Time Frame: 24 Weeks and 48 Weeks ] [ Designated as safety issue: No ]
Same as current
 
Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3
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

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.

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%).

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
HIV-1 Infection
  • 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: 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
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1050
October 2017
April 2017   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Contact: François-Xavier Blanc, MD, PhD +33 240 165 545 xavier.blanc@chu-nantes.fr
Contact: Didier Laureillard, MD +84 169 7 061 034 didier.laureillard@yahoo.fr
Côte D'Ivoire,   Uganda,   Vietnam,   Cambodia
 
NCT02057796
ANRS 12290
Yes
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Not Provided
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
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
October 2014

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