Principal Investigator - Dr. Shahin Lockman MD, MPH

Study Objectives

Primary Objectives

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.

Secondary Objectives

• To compare the efficacy and safety of DLM versus INH for preventing confirmed or probable TB 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; LTBI test positive 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.

Study Design: A Phase III, open-label, multi-center trial with a cluster-randomized superiority design (eligible contacts in the same household [HH] are a cluster), to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for  preventing confirmed or probable active TB during 96 weeks of follow-up among high- risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR- TB). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years.

Study Population: An index case is defined as an adult (18 years and older) with pulmonary MDR-TB who has started MDR-TB treatment within the past 90 days. 

An HHC is defined as a person who currently lives or lived in the same dwelling unit or plot of land and shares or has shared the same housekeeping arrangements as the index case and who reports exposure within 90 days prior to the index case starting MDR-TB treatment. Also, shared >4 hours of indoor airspace with the index case during any one-week period prior to the index case starting MDR-TB treatment. Following enrolment of an eligible index case with permission to complete an HH visit, HHCs will be screened for eligibility. 

Only HHCs of index cases who are at high risk of developing TB will be enrolled into the study:

• Children 0 to <5 years of age regardless of tuberculin skin test (TST)/interferon gamma release assay (IGRA), or HIV status;
• Adults, adolescents, and children ≥5 years of age who are LTBI test positive {either TST-positive (≥5 mm) or IGRA-positive} and whose HIV status is negative, indeterminate, or unknown and who are not non-HIV immunosuppressed;
• Adults, adolescents, and children ≥5 years of age who are HIV-infected or are non-HIV immunosuppressed (defined as receiving anti-tumor necrosis factor (TNF) treatment, or being solid organ or hematologic transplant recipients), regardless of LTBI test status.

Study duration: 96 weeks for each participating HHC and index case.5 years 

Study Results: Study ongoing

Sponsor: National Institute of Allergy and Infectious Diseases and National Institute of Child Health and Human Development