Pharmacy and Poisons Board
Protocol No: ECCT/11/07/02 Date of Protocol: 29-10-2010
Study Title:

A5274/REMEMBER "Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens"
Study Objectives:

Primary Objective

 

To compare survival probabilities between the two study arms 24 weeks after randomization.

 

 Secondary Objectives

 

  1. To compare the time to death between the two arms.
  2. To compare the time to AIDS progression or death between the two arms.
  3. To compare the survival without AIDS progression 24 and 48 weeks after randomization between the two arms.
  4. To compare Probabilities of plasma HIV-1 RNA levels of <400 copies/mL at 4, 24, and 48 weeks after randomization between the two arms.
  5. To compare rates of safety and tolerability (including Grades 3 and 4 events, immune reconstitution inflammatory syndrome [IRIS] events, ART and TB treatment changes, and rates/causes of reportable hospitalization) of ART and TB treatment 24 and 48 weeks after randomization between the two arms.
  6. To compare changes in CD4+ cell counts 4, 24, and 48 weeks after randomization between the two arms.
  7. To compare cause of death, including TB-specific mortality, between the two arms through 96 weeks.
  8. To compare ART adherence by self-report 4, 24, and 48 weeks after randomization between the two arms.
  9. To compare TB incidence between the two arms from randomization through week 48 and week 96.
  10. To explore TB incidence by geographic region and by arm.
  11. To compare adherence to TB treatment between the two arms while participants are receiving TB treatment.
  12. To compare resistance to TB drugs at time of incident TB between the two arms.
  13. To compare cost-effectiveness of the treatment strategies between the two arms.
  14. To compare quality of life between the two arms.
  15. To compare cost effectiveness of intervention by intensity of TB evaluation practices.
  16. To evaluate the evolution of plasma HIV-1 drug resistance through week 48.
  17. To evaluate issues related to dietary intake and food insecurity and their relation to early mortality.
  18. To assess the relationship between levels of bacterial and/or fungal DNA in plasma at study entry and during ART treatment and survival at 24 weeks.

 
Laymans Summary:

In this randomized, open-label strategy trial, participants from RLS who present with advanced HIV disease and will be initiating ART but are without evidence of probable or confirmed TB according to criteria in the current ACTG diagnosis appendix (which will be identified on the case report form [CRF]) will be randomized 1:1 to one of two strategy arms: empiric TB treatment (public health approach, Arm A) or local standard of care (individualized TB treatment approach, Arm B) at study entry. At the 48 week visit, participants will transition to a 48-week follow-up period of non-study-provided treatment and care, with total study duration being 96 weeks.

The primary endpoint is survival status at 24 weeks post randomization. AIDS progression, virologic and immunologic response, development of plasma HIV drug resistance, resistance to TB drugs, safety and tolerability of ART and TB drugs, and adherence to ART and TB drugs will also be evaluated as will the relative cost-effectiveness of the two strategies.
Abstract of Study:

DESIGN          In this randomized, open-label, phase IV strategy trial, participants from resource-limited settings (RLS) who present with advanced HIV disease and no probable or confirmed tuberculosis (TB), as defined in the current ACTG diagnosis appendix, and who are initiating antiretroviral treatment (ART) will be randomized to one of two strategy arms: immediate, empiric TB treatment (public health approach) or local standard of care TB treatment (individualized approach). The primary endpoint is survival status in the two arms 24 weeks after randomization. AIDS progression (any new WHO Stage 3 or 4 condition), virologic and CD4+ cell response, HIV and TB drug resistance, AND safety and tolerability of, and adherence to HIV and TB drugs will be evaluated, as will the cost-effectiveness of the two strategies.

DURATION    96 weeks. Participants will transition to locally provided care and treatment at week 48.

SAMPLE SIZE            836 participants

POPULATION            HIV-infected antiretroviral-naïve males and females aged 13 years and older, with CD4+ cell count <50 cells/mm3 who are initiating ART. Participating sites must have a regional TB incidence (i.e., the TB incidence within the site’s expected catchment area) of more than 100 cases/100,000 population per year, a national ART program, and documented high mortality rates among HIV-infected individuals (i.e., at least 5% overall at 6 months post ART initiation). Sites whose regional TB incidence or mortality rates approach but do not meet the requirements stated above may be approved on a case-by-case basis by the study team, following a review of all relevant information. Participants with probable or confirmed TB at screening will be excluded.

RANDOMIZATION    1:1 to empiric or local standard of care TB treatment

Participants will be randomized to initiate TB treatment either at entry (Arm A, empiric) or when indicated according to local practice and the discretion of the site investigator (Arm B, local standard of care).

STRATIFICATION     Randomization will be stratified according to CD4+ cell count (<25 vs. ≥25 cells/mm3) and presence of poor prognostic factors (i.e., absence of all vs. presence of at least one of the following: reportable hospitalization [see section 6.3.5) within the past 30 days, body mass index [BMI] <18.5, or anemia [hemoglobin <8 g/dl]).

REGIMEN      Section 5.1 provides detailed information about treatment options and their provision.

                        All participants will receive efavirenz-(EFV) based ART beginning at study entry.  

The TB treatment described below must be obtained by the sites as described in section 5.3.1.

Pyridoxine will be provided by the sites to all participants while they are receiving isoniazid (INH) to prevent emergence of neuropathy associated with INH use. All participants will be provided Pneumocystis jiroveci pneumonia (PCP) prophylaxis by the sites according to local guidelines.

Regimens by arm:

Arm A (empiric)

EFV-based ART (see section 5.1.1)

Plus  

Full TB treatment course, defined as:

  • rifampin/isoniazid/ethambutol/pyrazinamide (RIF/INH/EMB/PZA) for 8 weeks,

followed by

  • RIF/INH only for 16 weeks

Arm B Regimen (standard of care)

EFV-based ART alone

If TB treatment is subsequently indicated for participants in either arm according to local standard practice and/or discretion of site investigator, then the TB treatment described above should be initiated.