Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-associated Severe Immune Suppression (DATURA)

ANRS, Emerging Infectious Diseases

Status and phase: Completed; Phase 3

Conditions: Immuno-Deficiency; HIV-1-infection; Tuberculosis

Treatments: Drug: WHO standard TB treatment (initial phase); Drug: Intensified TB treatment (initial phase)

Study type: Interventional

Funder types: Other

Identifiers

NCT04738812

ANRS 12424 DATURA

Details and patient eligibility

About

DATURA trial is a phase III, multicenter, two-arm, open-label, randomized superiority trial to compare the efficacy and the safety of an intensified tuberculosis (TB) regimen versus standard TB treatment in HIV-infected adults and adolescents hospitalized for TB with CD4 ≤ 100 cells/μL over 48 weeks:

• Intensified TB treatment regimen: increased doses of rifampicin and isoniazid together with standard-dose of pyrazinamide and ethambutol for 8 weeks in addition to prednisone for 6 weeks and albendazole for 3 days
• WHO standard TB treatment regimen.

The continuation phase of TB treatment will be identical in the two arms: 4 months of rifampicin and isoniazid at standard doses.

Full description

Settings: 5 African (Cameroon, Guinea, Uganda, Zambia, Mozambique) and 1 South-East Asian (Cambodia) countries.

Sample size : 1330 patients (665 in each arm). Follow-up : 48 weeks after entry in the trial (TB treatment initiation).

All participants will initiate antiretroviral therapy (ART) 2 weeks after starting TB treatment. In each country, the chosen ART regimen will be the same in both arms. According to the first-line regimen recommended in each country, the ART combination will be TDF/3TC/EFV 600 mg, or TDF/3TC + double-dose DTG.

The primary objective is to estimate the impact of an intensified initial phase of TB treatment on mortality at 48 weeks among HIV-infected adults and adolescents hospitalized for TB with CD4 ≤ 100 cells/μL in comparison with standard TB treatment.

The secondary objectives are to estimate the impact of an intensified initial phase of TB treatment, in comparison with the standard TB regimen, on:

• Mortality at weeks 8 and 24

• Adverse events, including

  • All grade 3 and 4 events
  • Selected grade 2 events of interest
  • Drug-related adverse events
  • AIDS-defining illnesses
  • Paradoxical TB-associated immune reconstitution inflammatory syndrome (IRIS)

• TB treatment success

• TB recurrence

• ART response in terms of virological success and immunological response

• Adherence to TB treatment and ART

• Peak plasma concentrations of rifampicin and isoniazid (and its N-acetyl-metabolite) at day 3, day 7 and week 2

• Plasma concentrations of efavirenz and dolutegravir at week 4 (i.e. 2 weeks after the onset of ART).

A pharmacokinetic sub-study of rifampicin and isoniazid will be carried out in 72 voluntary patients (6 patients/arm/country) at the second week of the main study.

Enrollment: 1,330 patients

Sex: All

Ages: 15+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

INCLUSION CRITERIA

• Patient (and legally designed representative of minor patient) able to correctly understand the trial and to sign the informed consent

• Aged ≥ 15 years

• Confirmed HIV-1 infection as documented at any time prior to trial entry per national HIV testing procedures

• CD4 count ≤ 100 cells/μL

• Hospitalized for a newly diagnosed TB, defined by:

  • Any positive Xpert® MTB/RIF specimen (sputum, urine, pus, other),
  • Or a positive urine lipoarabinomannan (LAM) test,
  • Or an abnormal chest X-ray compatible with active TB

EXCLUSION CRITERA

• Initiation of TB drugs for more than 7 days
• History of TB treatment during the last 6 months
• Central neurological symptoms, including but not restrictive to TB meningitis
• Suspected TB pericarditis
• Documented Mycobacterium tuberculosis strain resistant to rifampicin using rapid molecular testing (Xpert® MTB/RIF)
• Any concomitant medication or known hypersensitivity contraindicating any component of the TB treatment
• HIV-2 co-infection
• Current treatment with ART containing protease inhibitors
• Any contraindication to efavirenz and dolutegravir
• Severe associated diseases requiring corticosteroids or for which corticosteroids are contra-indicated
• Impaired hepatic function with ALT (SGPT) > 5 times the upper limit of normal (ULN) value
• Creatinine clearance < 30 mL/min/1.73m2 (according to either the MDRD or the CKD-EPI formula)
• Pregnancy or breastfeeding

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,330 participants in 2 patient groups

Intensified TB treatment

Experimental group

Description:

* Increased doses of rifampicin (R) to 35±5 mg/kg daily and isoniazid (H) 10±2 mg/kg daily together with standard-dose of pyrazinamide (Z) 20-30 mg/kg daily + ethambutol (E) 15-20 mg/kg daily for 8 weeks (initial phase of TB treatment). * Prednisone 40 to 80 mg once a day (OD) according to weight bands for 2 weeks, followed by 20 to 40 mg OD according to weight bands for 2 weeks, then 10 to 20 mg OD according to weight bands for the last 2 weeks (total duration: 6 weeks). Because of the corticosteroid treatment, albendazole 400 mg OD will be given to participants for 3 days. * Continuation phase: 16 weeks of RH.

Treatment:

Drug: Intensified TB treatment (initial phase)

WHO standard TB treatment

Active Comparator group

Description:

* Standard-dose of R 8-12 mg/kg daily + H 4-6 mg/kg daily + Z 20-30 mg/kg daily + E 15-20 mg/kg daily for 8 weeks. * Continuation phase: 16 weeks of RH.

Treatment:

Drug: WHO standard TB treatment (initial phase)