Therapeutics

DRAMATIC Phase 2 Duration Randomized MDR-TB Treatment Trial

  • Investigator: C. Robert Horsburgh
  • Funding Source: National Institute of Allergy and Infectious Diseases

Multidrug-resistant tuberculosis (MDR-TB) was estimated to occur in 600,000 people in 2017. The roll-out of the GeneXpert™ test has generated a substantial increase in the demand for MDR-TB treatment. However, current MDR-TB treatment regimens take 9 months or longer to complete and have substantial toxicity. Therefore, a shorter, less toxic treatment regimen is needed. We have developed an innovative Phase 2 study design (“duration-randomization”) to identify the shortest effective treatment duration. In this design, participants are randomized to four durations of treatment from the shortest to the longest likely effective duration. The results are then analyzed together to determine the optimal treatment duration. In the proposed multicenter, randomized, partially blinded, four-arm, phase 2 DRAMATIC Trial (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical Trial) we will examine the efficacy and safety of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine given for 16, 24, 32 or 40 weeks. Aim 1: To identify the optimal duration of an experimental MDR-TB treatment regimen consistent with a successful treatment outcome. Aim 2: To describe the relationship between baseline prognostic risk strata and successful treatment outcome. Aim 3: To establish that the rRNA synthesis ratio, a novel biologic marker based on M. tb precursor rRNA, is associated with relapse at the individual-level across the range of durations studied in the trial. Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability of TB control programs to treat the growing number of patients.

    Necrosis in Pulmonary TB Granulomas: Dynamics, Mechanisms, and Therapies

    • Investigator: Igor Kramnik
    • Funding Source: National Heart, Lung, and Blood Institute

    The Kramnik laboratory at the National Emerging Infectious Diseases Laboratory (NEIDL) uses mouse models to address mechanistic questions that are central for understanding Mycobacterium tuberculosis pathogenesis and host immunity:

    • What makes lungs the most permissive organ for tuberculosis?
    • What are mechanisms of the formation of organized TB lesions and lung damage during TB progression?
    • What are the mechanisms of increased TB susceptibility due to aging and viral co-infections?
    • How to develop mechanistic interventions to prevent the pulmonary TB progression in susceptible hosts?

    We have developed unique mouse models of pulmonary tuberculosis and demonstrated that TB develops in the lungs of susceptible hosts despite active T cell-mediated immunity. We found that aberrant macrophage activation due to inadequate anti-oxidant defense may be a common trait underlying susceptibility to pulmonary tuberculosis in immunocompetent individuals. We use mouse genetics and genomics to dissect macrophage states associated with host resistance and susceptibility to TB and to develop therapies that direct macrophages to resistant states. We believe that these interventions will prevent lung damage triggered by tuberculosis infection and act synergistically with antibiotics and vaccines to overcome a major obstacle to the sterilization of TB lesions.

    Predictors of Resistance Emergence Evaluation in MDR-TB Patients on Treatment (PREEMPT)

    • Investigator: C. Robert Horsburgh
    • Funding Source: National Institute of Allergy and Infectious Diseases

    Tuberculosis (TB) is a leading causes of global mortality. Nearly one-third of the world’s population is infected with M. tuberculosis, an estimated 10.4 million new cases of TB develop annually, and 1.4 million persons die from the disease. The emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB has exacerbated the threat to public health and created a renewed sense of urgency to control the disease. Treatment of MDR-TB leads to emergence of additional drug resistance in 6-20% of patients on treatment. We propose to investigate the causes of emergence of mycobacterial drug resistance in an observational cohort study, the Predictors of Resistance Emergence Evaluation in MDR-TB Patients on Treatment (PREEMPT) Study. In the PREEMPT study, we will enroll 400 patients with MDR-TB in India and Brazil over a 24-month period and follow them prospectively for 3 years. The proposal has the following Specific Aims: Aim 1: To determine whether low serum antimycobacterial drug concentrations contribute to the emergence of drug resistance in MDR TB patients, and whether HIV seropositivity is a risk factor for low serum drug concentrations and/or the emergence of resistance. Aim 2: To determine the contribution of increased DNA mutation (caused either by an intrinsic property of the M. tuberculosis strain or by FQ treatment) to clinical emergence of drug resistance in patient isolates. Aim 3: To determine whether mutations responsible for drug resistance can be detected early during treatment, when an intervention to prevent XDR-TB might be possible.

      URBAN ARCH (3/5) Uganda Cohort – TB Prevention Therapy for HIV-Infected Alcohol Drinkers in Uganda

      • Investigator: Karen Jacobson
      • Funding Source: National Institute on Alcohol Abuse and Alcoholism