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 not yet open for participant recruitment. (see Contacts and Locations)
Verified February 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: February 18, 2014
Last verified: February 2014
  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
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


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 ] [ 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


Secondary Outcome Measures:
  • 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 ]

Other Outcome Measures:
  • 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 ]

Estimated Enrollment: 1050
Study Start Date: May 2014
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: December 2016 (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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
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

Contacts
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

Locations
Cambodia
Sihanouk Hospital Center of Hope Not yet recruiting
Phnom Penh, Cambodia, 2318
Contact: Laurence Borand, PharmD       lborand@pasteur-kh.org   
Principal Investigator: Didier Laureillard, MD         
Côte D'Ivoire
CePReF Centre de Prise en charge de Recherche et de Formation Not yet recruiting
Abidjan, Yopougon, Côte D'Ivoire, 1954
Contact: Eugene Messou, MD PhD    +225 21 75 59 60    messou_eugene@yahoo.fr   
Principal Investigator: Christine Danel, MD, PhD         
Uganda
ISS ImmunoSuppression Service Not yet recruiting
Mbarara, Uganda, 1956
Contact: Conrad MUZOORA, MD    +256 772 547 175    conradmuzoora@yahoo.com   
Principal Investigator: Maryline Bonnet, MD, PhD         
Vietnam
Pham Ngoc Thach Hospital Not yet recruiting
Ho Chi Minh City, Vietnam
Contact: Didier Laureillard, MD    +84 169 7 061 034    didier.laureillard@yahoo.fr   
Principal Investigator: Didier Laureillard, MD         
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

No publications provided

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: February 18, 2014
Health Authority: Cambodia: Ministry of Health (National Ethics Committee for Health Research)
Cote d'Ivoire: National Research and Ethics Committee
Uganda: Ministry of Health
Vietnam: Ministry of Health

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:
Rifampin
Efavirenz
Isoniazid
Pyrazinamide
Ethambutol
Antibiotics, Antitubercular
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Reverse Transcriptase Inhibitors
Anti-Retroviral Agents
Antiviral Agents

ClinicalTrials.gov processed this record on October 01, 2014