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

Primary Purpose

Tuberculosis, HIV-1-infection, Immuno-Deficiency

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Intensified TB treatment (initial phase)
WHO standard TB treatment (initial phase)
Sponsored by
ANRS, Emerging Infectious Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring Tuberculosis, HIV-1, Mortality, Immuno-deficiency, Isoniazid, Rifampicin

Eligibility Criteria

15 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • National Center for HIV/AIDS, Dermatology and STD (NCHADS)Recruiting
  • Jamot HospitalRecruiting
  • Ignace Deen HospitalRecruiting
  • Mbarara Regional Referral hospitalRecruiting
  • Pham Ngoc Thach Hospital
  • University Teaching HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intensified TB treatment

WHO standard TB treatment

Arm 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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
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
Rate of AIDS-defining illnesses
Number of AIDS-defining illnesses according to the WHO clinical staging table
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
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
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
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.
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.
Adherence to TB and ART treatment
The proportion of days with perfect adherence divided by the total number of days of treatment
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
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
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

Full Information

First Posted
February 1, 2021
Last Updated
September 20, 2022
Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
European Union, European and Developing Countries Clinical Trials Partnership (EDCTP)
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1. Study Identification

Unique Protocol Identification Number
NCT04738812
Brief Title
Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-associated Severe Immune Suppression
Acronym
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.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 21, 2022 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
European Union, European and Developing Countries Clinical Trials Partnership (EDCTP)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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: 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, HIV-1-infection, Immuno-Deficiency
Keywords
Tuberculosis, HIV-1, Mortality, Immuno-deficiency, Isoniazid, Rifampicin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
DATURA trial is a phase III, multicenter, two-arm, open-label, randomized superiority trial.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1330 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intensified TB treatment
Arm Type
Experimental
Arm 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.
Arm Title
WHO standard TB treatment
Arm Type
Active Comparator
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Intensified TB treatment (initial phase)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
WHO standard TB treatment (initial phase)
Intervention Description
8 weeks of RHEZ with FDC.
Primary Outcome Measure Information:
Title
Rate of all causes death
Description
Number of deaths between the inclusion visit and week 48, divided by the total person-years of follow-up until week 48
Time Frame
Up to 48 weeks
Secondary Outcome Measure Information:
Title
Rate of all causes death
Description
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
Time Frame
Up to 8 weeks
Title
Rate of all causes death
Description
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
Time Frame
Up to 24 weeks
Title
Rate of adverse events
Description
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
Time Frame
Up to 48 weeks
Title
Rate of AIDS-defining illnesses
Description
Number of AIDS-defining illnesses according to the WHO clinical staging table
Time Frame
Up to 48 weeks
Title
Rate of paradoxical TB-associated IRIS
Description
Number of paradoxical TB-associated IRIS according to the definition of the international network for the study of HIV-associated (INSHI) consensus case definition
Time Frame
Up to 14 weeks
Title
Rate of TB treatment success
Description
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
Time Frame
Up to 24 weeks
Title
Rate of TB recurrence
Description
The number of patients with TB recurrence divided by the total number of randomized patients with TB treatment success at week 24
Time Frame
Up to 48 weeks
Title
Rate of virological success
Description
The percentage will be calculated as the number of patients with HIV RNA <50 copies/mL divided by the total number of randomized patients.
Time Frame
Week 24
Title
Rate of virological success
Description
The percentage will be calculated as the number of patients with HIV RNA <50 copies/mL divided by the total number of randomized patients.
Time Frame
Week 48
Title
Adherence to TB and ART treatment
Description
The proportion of days with perfect adherence divided by the total number of days of treatment
Time Frame
up to 24 weeks
Title
Immunological response
Description
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
Time Frame
Up to 48 weeks
Title
Plasma concentrations of rifampicin and isoniazid
Description
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
Time Frame
Up to 2 weeks
Title
Plasma concentrations of efavirenz and dolutegravir
Description
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
Time Frame
Week 4

10. Eligibility

Sex
All
Minimum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
BLANC François-Xavier, MD, PhD
Phone
+33 240 165 545
Email
xavier.blanc@chu-nantes.fr
First Name & Middle Initial & Last Name or Official Title & Degree
LAUREILLARD Didier, MD
Phone
+33 466 684 149
Email
didier.laureillard@chu-nimes.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
BLANC François-Xavier, MD, PhD
Organizational Affiliation
University Hospital of Nantes, France
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
LAUREILLARD Didier, MD
Organizational Affiliation
University Hospital of Nimes, France
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Center for HIV/AIDS, Dermatology and STD (NCHADS)
City
Phnom Penh
Country
Cambodia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
SAMRETH Sovannarith, MD
Facility Name
Jamot Hospital
City
Yaoundé
Country
Cameroon
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
KOUANFACK Charles, MD
Facility Name
Ignace Deen Hospital
City
Conakry
Country
Guinea
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
DIALLO B. Djelo, MD
Facility Name
Mbarara Regional Referral hospital
City
Mbarara
Country
Uganda
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
MUZOORA Conrad, MD
Facility Name
Pham Ngoc Thach Hospital
City
Ho Chi Minh City
Country
Vietnam
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
DANG TM Ha, MD
First Name & Middle Initial & Last Name & Degree
NGUYEN D Bang, MD
Facility Name
University Teaching Hospital
City
Lusaka
Country
Zambia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
MATEYO Kondwelani, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
All coded IPD will be available upon researchers request.
IPD Sharing Time Frame
Data will be available after the princeps paper has been published and for at least 2 years.
IPD Sharing Access Criteria
After the analysis and publication of the trial results, a clear process for data access will be developed with the sponsor to ensure transparency and accountability of data requestors.

Learn more about this trial

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

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