Clinical trial NCT04738812: Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-associated Severe Immune Suppression
Official title: ANRS 12424: Determination of Adequate Tuberculosis Regimen in Adults and Adolescents Hospitalized With HIV-associated Severe Immune Suppression (CD4 ≤ 100 Cells/µL): the DATURA Trial.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Tuberculosis
HIV-1-infection
Immuno-Deficiency
Keywords: Tuberculosis
HIV-1
Mortality
Immuno-deficiency
Isoniazid
Rifampicin
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: European Union
name: European and Developing Countries Clinical Trials Partnership (EDCTP)
First posted: 2021-02-04
Enrollment: 1330
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: DATURA trial is a phase III, multicenter, two-arm, open-label, randomized superiority trial.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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

Primary outcomes:
measure: Rate of all causes death
timeFrame: Up to 48 weeks
Secondary outcomes:
measure: Rate of all causes death
timeFrame: Up to 8 weeks
measure: Rate of all causes death
timeFrame: Up to 24 weeks
measure: Rate of adverse events
timeFrame: Up to 48 weeks
measure: Rate of AIDS-defining illnesses
timeFrame: Up to 48 weeks
measure: Rate of paradoxical TB-associated IRIS
timeFrame: Up to 14 weeks
measure: Rate of TB treatment success
timeFrame: Up to 24 weeks
measure: Rate of TB recurrence
timeFrame: Up to 48 weeks
measure: Rate of virological success
timeFrame: Week 24
measure: Rate of virological success
timeFrame: Week 48
measure: Adherence to TB and ART treatment
timeFrame: up to 24 weeks
measure: Immunological response
timeFrame: Up to 48 weeks
measure: Plasma concentrations of rifampicin and isoniazid
timeFrame: Up to 2 weeks
measure: Plasma concentrations of efavirenz and dolutegravir
timeFrame: Week 4
Other outcomes:
Locations:
city: Phnom Penh
country: Cambodia
facility: National Center for HIV/AIDS, Dermatology and STD (NCHADS)
city: Yaoundé
country: Cameroon
facility: Jamot Hospital
city: Conakry
country: Guinea
facility: Ignace Deen Hospital
city: Maputo
country: Mozambique
facility: MACHAVA Hospital
city: Mbarara
country: Uganda
facility: Mbarara Regional Referral hospital
city: Lusaka
country: Zambia
facility: University Teaching Hospital
Study officials:
affiliation: University Hospital of Nantes, France
name: BLANC François-Xavier, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Nimes, France
name: LAUREILLARD Didier, MD
role: PRINCIPAL_INVESTIGATOR
References: