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

Tuberculosis Clinical Trial

— DATURA  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04738812
• Other study ID #: ANRS 12424 DATURA
• Status: Recruiting
• Phase: Phase 3
• Start date: April 21, 2022
• Est. completion date: March 2025

Study information

• Verified date: September 2022
• Source: ANRS, Emerging Infectious Diseases
• Contact: BLANC François-Xavier, MD, PhD
• Phone: +33 240 165 545
• Email: xavier.blanc[@]chu-nantes.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Settings: 4 African (Cameroon, Guinea, Uganda, Zambia) and 2 South-East Asian (Cambodia, Vietnam) 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1330
• Est. completion date: March 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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 3 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

• History of ART, unless if stopped for more than 1 year

• Current treatment with ART for more than 1 week

• Any contraindication to efavirenz and dolutegravir

• Severe associated diseases requiring specific treatment (including all specific AIDS defining illnesses other than TB and any severe sepsis)

• Impaired hepatic function with ALT (SGPT) > 5 times the upper limit of normal (ULN) value

• Creatinine clearance < 50 mL/min (according to the Cockcroft-Gault formula)

• Pregnancy or breastfeeding

Related Conditions & MeSH terms

• HIV-1-infection
• Immuno-Deficiency
• Immunologic Deficiency Syndromes
• Tuberculosis

Intervention

Drug:
• Intensified TB treatment (initial phase)
8 weeks of RHEZ with high dose of rifampicin (R) and isoniazid (H). Fixed dose combination (FDC) of RHZE with the addition of FDC of RH and single caps of R. 6 weeks of prednisone with tapering doses. 3 days of albendazole 400 mg.
• WHO standard TB treatment (initial phase)
8 weeks of RHEZ with FDC.

Locations

Country	Name	City	State
Cambodia	National Center for HIV/AIDS, Dermatology and STD (NCHADS)	Phnom Penh
Cameroon	Jamot Hospital	Yaoundé
Guinea	Ignace Deen Hospital	Conakry
Uganda	Mbarara Regional Referral hospital	Mbarara
Vietnam	Pham Ngoc Thach Hospital	Ho Chi Minh City
Zambia	University Teaching Hospital	Lusaka

Sponsors (3)

Lead Sponsor	Collaborator
ANRS, Emerging Infectious Diseases	European and Developing Countries Clinical Trials Partnership (EDCTP), European Union

Countries where clinical trial is conducted

Cambodia,  Cameroon,  Guinea,  Uganda,  Vietnam,  Zambia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of all causes death	Number of deaths between the inclusion visit and week 48, divided by the total person-years of follow-up until week 48	Up to 48 weeks
Secondary	Rate of all causes death	Death for any cause at week 8 will be calculated as the number of deaths between the inclusion visit and week 24, divided by the total person-years of follow-up during the same period	Up to 8 weeks
Secondary	Rate of all causes death	Death for any cause at week 24 will be calculated as the number of deaths between the inclusion visit and week 24, divided by the total person-years of follow-up during the same period	Up to 24 weeks
Secondary	Rate of adverse events	Number of serious adverse events, all grade 3-4 adverse events (using the DAIDS tables), and any grade 2 adverse events of interest (e.g., hepatotoxicity, rash, peripheral neuropathy, thrombocytopenia, neuropsychiatric disorders), between the inclusion visit and week 48, divided by the total person-years of follow-up during that period	Up to 48 weeks
Secondary	Rate of AIDS-defining illnesses	Number of AIDS-defining illnesses according to the WHO clinical staging table	Up to 48 weeks
Secondary	Rate of paradoxical TB-associated IRIS	Number of paradoxical TB-associated IRIS according to the definition of the international network for the study of HIV-associated (INSHI) consensus case definition	Up to 14 weeks
Secondary	Rate of TB treatment success	The percentage of patients with TB success will be calculated as the number of patients who are cured or who have completed TB treatment, as defined by WHO, divided by the total number of randomized patients	Up to 24 weeks
Secondary	Rate of TB recurrence	The number of patients with TB recurrence divided by the total number of randomized patients with TB treatment success at week 24	Up to 48 weeks
Secondary	Rate of virological success	The percentage will be calculated as the number of patients with HIV RNA <50 copies/mL divided by the total number of randomized patients.	Week 24
Secondary	Rate of virological success	The percentage will be calculated as the number of patients with HIV RNA <50 copies/mL divided by the total number of randomized patients.	Week 48
Secondary	Adherence to TB and ART treatment	The proportion of days with perfect adherence divided by the total number of days of treatment	up to 24 weeks
Secondary	Immunological response	The mean CD4 cell count gain (with 95% confidence interval) will be calculated as the difference of CD4 cell count between pre-inclusion and week 48	Up to 48 weeks
Secondary	Plasma concentrations of rifampicin and isoniazid	Determined 2 hours after the TB drugs intake at day 3, day 7 and week 2 in a subset of 20 patients per arm per country	Up to 2 weeks
Secondary	Plasma concentrations of efavirenz and dolutegravir	Determined 12 hours after the drugs intake at week 4 (i.e. 2 weeks after the onset of ART) in a subset of 60 patients per arm for efavirenz and 60 patients per arm for dolutegravir	Week 4