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A5300B/I2003B: Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx)
Dr. Amita Gupta is Protocol Co-chair for this multinational clinical trial.
The World Health Organization (WHO) estimates that there were 480,000 incident cases of MDR-TB globally in 2015. MDR-TB has been shown to be almost twice as common in TB patients living with HIV compared with TB patients without HIV infection. Very high mortality rates reported among HIV-infected patients with MDR or extensively drug-resistant tuberculosis (XDR-TB) are also a major concern. Of the MDR-TB cases reported globally in 2014, 90% received appropriate treatment. For those who started treatment in 2012, only 50% had documented successful treatment outcomes. With the rollout of rapid molecular diagnostic tools, including Xpert MTB/RIF (Cepheid), the number of adult MDR-TB cases diagnosed is growing, with an associated increase in the numbers of child and adult household contacts (HHCs) identified. For every case of MDR-TB, the majority of HHCs are likely to become infected HHCs of MDR-TB patients who become infected have a high risk of progressing to active disease, and in the absence of effective therapy, possibly death. While precise data are not available, HIV-infected HHCs are likely to be at much higher risk of TB disease progression, based on their known susceptibility to TB infection, reinfection, and reactivation.
Among HHCs in high-burden settings, the vast majority of MDR-TB in children arises from transmission within the HH, whereas TB among adolescents and adults is equally likely to be from infections acquired within the HH or in the community. No randomized controlled trials have been conducted to guide the management of adults or children exposed to MDR-TB. As a result, there are inconsistent international guidelines for the management of MDR-TB contacts. The US Centers for Disease Control and Prevention (CDC) 2000 guidelines recommend pyrazinamide and ethambutol or pyrazinamide plus a fluoroquinolone for persons at high risk of developing TB. As it is not clear how these infected individuals should be managed, the 1992 CDC and WHO 2015 guidelines recommend not treating MDR-TB-exposed contacts for presumed latent TB infection (LTBI) with MDR-TB, to follow contacts for up to 2 years, and to only treat those who progress to disease . Some high-burden countries have local guidelines for treating young and HIV-infected child contacts of MDR-TB cases, including using INH (up to 20 mg/kg/day) in combination with a fluoroquinolone and ethambutol. However, none of these guidelines are based on high-quality evidence.
Despite newly updated WHO treatment guidelines in 2016 allowing for certain MDR-TB cases to be treated for 9-12 months, this shortened regimen still includes 4-6 months of highly toxic injectable drugs (e.g., amikacin), and this regimen does not apply to all MDR-TB cases (http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/). Most persons who develop MDR-TB disease still require treatment for up to 24 months with existing second-line TB therapies that are often poorly tolerated, highly toxic, poorly efficacious, frequently require hospital admission for administration, and carry a high risk of mortality, particularly in persons who are HIV-infected or malnourished. Under these uncertain and unacceptable circumstances, it is essential to re-examine the current strategy for MDR-TB prevention in high-risk contacts. There have never been randomized controlled trials in this population for MDR-TB prevention. A WHO expert committee recently identified treatment of MDR-TB contacts as an important policy gap that urgently requires randomized controlled trials to inform policy.
Among HIV-infected and other child, adolescent, and adult HHCs of MDR-TB patients at high risk of developing TB:
- To compare the efficacy of 26 weeks of DLM versus 26 weeks of INH for preventing confirmed or probable active TB during 96 weeks of follow-up.
- To compare the safety (permanently stopping study drug due to treatment-related adverse events) of 26 weeks of DLM versus 26 weeks of INH for the treatment of presumed latent TB infection (LTBI) with MDR-TB.
- To compare the efficacy and safety of DLM versus INH for preventing confirmed or probable TB in HHCs of MDR-TB patients by their HIV status (i.e., HIV-infected vs HIV-negative, indeterminate, or have unknown HIV status).
- To compare the efficacy and safety of DLM versus INH for preventing confirmed or probable TB in each of the three high risk populations of HHCs enrolled (i.e., children aged <5 years; HIV-infected or non-HIV immunosuppressed adults, adolescents, and children ≥5 years; TST+ and/or IGRA+ adults, adolescents, and children aged ≥5 years who are HIV-negative, indeterminate, or have unknown HIV status and are not non-HIV immunosuppressed).
- To compare the efficacy of DLM versus INH for preventing confirmed active MDR-TB.
- To compare the efficacy of DLM versus INH in reducing all-cause mortality.
- To compare the efficacy of DLM versus INH for reducing the composite outcome of confirmed or probable TB and all-cause mortality.
- To compare the proportions of Grades 3 or higher events among HHCs receiving DLM versus INH.
- To compare the drug-susceptibility pattern and whole genome sequence of the index case to that of confirmed incident TB cases among HHCs.
- To evaluate factors, including index case characteristics, index case TB status at the end of HHC study treatment, household characteristics, and characteristics of HHCs, HHC medication adherence, and pharmacokinetic (PK) measures, as predictors of the risk of confirmed or probable TB among HHCs or possible modifiers of the difference in risk between randomized arms.
- To describe the PK and safety of DLM administered once daily in children, 0 to <5 years old.