Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB
Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB
Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis (TB) that is resistant to at least
 isoniazid and rifampicin, the two most important anti-TB drugs. It occurs in 3.6% of newly
 diagnosed TB patients in the world and 17% of patients who have been previously treated. In
 2017, approximately 600,000 people were estimated to have acquired MDR-TB. However, only 25%
 of persons with MDR-TB were diagnosed and started on treatment, reflecting inadequate
 diagnostic capacity and lack of TB treatment capacity.

 In this multicenter, randomized, partially blinded, four-arm, phase 2 study, the
 investigators 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
Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least
 isoniazid and rifampicin, the two most important drugs in treating TB. In 2017, approximately
 558,000 new people were estimated to have developed MDR-TB, and 8.5% of the cases had
 extensively drug-resistant tuberculosis (XDR-TB).(1) Current WHO-endorsed MDR-TB treatment
 regimens take 9-20 months to complete and are associated with substantial toxicity, including
 deafness from injectable agents, hepatitis from pyrazinamide and severe neuropathy from
 linezolid. Given the long duration and toxicities of MDR-TB regimens, it is perhaps not
 surprising that WHO reports that only 25% of patients with MDR-TB are enrolled into
 WHO-endorsed treatment regimens. Thus, there is an urgent need for shorter, less toxic
 treatments for MDR-TB. This proposal will determine the efficacy, safety, tolerability and
 optimal duration of a novel, all oral MDR-TB treatment regimen while addressing three major
 challenges with innovations that have the potential to transform future trials.

 The proposed DRAMATIC (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical)
 Trial is a multicenter, randomized, partially blinded, four-arm, phase 2 trial that will
 examine an injectable- and pyrazinamide-sparing regimen of bedaquiline, delamanid,
 levofloxacin, linezolid, and clofazimine. The DRAMATIC regimen limits the administration of
 linezolid to the initial 8 weeks of treatment, the window before linezolid-related neuropathy
 occurs. Animal and human studies provide evidence for the potential efficacy of this 5-drug
 regimen, but the optimal duration of treatment remains uncertain.(2-4)

 Primary Objectives:

 1. Describe the relationship between the duration of the experimental regimen and the
 proportion of participants with sustained cure at 76 weeks after randomization without
 treatment failure or relapse.

 2. Describe the relationship between baseline prognostic risk strata and sustained cure at
 76 weeks after randomization without treatment failure or relapse.

 3. Evaluate the association between novel biologic markers and sustained cure at 76 weeks
 after randomization without treatment failure or relapse.

 Secondary Objectives:

 4. Identify the shortest duration of the study regimen that has acceptable safety and
 efficacy for a Phase 3 clinical trial of the DRAMATIC regimen for treatment of MDR-TB.

 5. Describe the frequency, magnitude, time course of and risk factors for QTc prolongation
 associated with the study regimen.

 6. Demonstrate the feasibility and efficiency of implementing the new duration-randomized
 design in a multi-centre randomized trial of drug-resistant TB.

 7. Determine if time to sputum culture conversion predicts optimal duration of treatment
 when stratified by extent of disease.

 8. Describe the relationship between the duration of the experimental regimen and the
 proportion of participants with sustained cure at 104 weeks after randomization without
 treatment failure or relapse.

 9. Assess vital status at 132 weeks post randomization.

 Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability
 of TB control programs to treat the growing number of patients. The DRAMATIC Trial will
 employ an innovative and efficient new design to establish a robust, nontoxic MDR-TB
 treatment regimen and identify the minimal duration for which it needs to be administered.
 These results will speed the process of moving forward to a confirmatory phase 3 clinical
 trial and increase the likelihood that such a trial is successful.
Inclusion Criteria:

 1. Males and females age ≥12 years. Prior to study procedures, if ≥18 years of age,
 provides informed consent; if <18 years of age, child provides informed assent and has
 a parent or guardian who provides informed consent on the participant's behalf.

 2. Has pulmonary TB based on investigator assessment of all available information (e.g.,
 chest radiograph, sputum smear, culture, molecular testing).

 3. Has a sputum sample that is positive for M. tuberculosis that is rifamycin-resistant
 and fluoroquinolone-susceptible by molecular assay.

 4. Is HIV seropositive or seronegative; HIV serostatus must be assessed at screening if
 either (a) HIV serostatus is unknown, or (b) the last documented negative HIV test was
 more than two (2) months prior to screening.

 5. Willing to attend scheduled follow-up visits and undergo study assessments.

 6. Participants of child-bearing potential must agree either (a) to practice an adequate
 birth control (defined as one of the following oral contraceptives, intrauterine
 devices, contraceptive implants under the skin, contraceptive rings or patches or
 injections, diaphragms with spermicide or condoms with foam) or (b) to abstain from
 heterosexual intercourse during study regimen.

 Exclusion Criteria:

 1. Current MTB isolate is known at screening to be fluoroquinolone-resistant.

 2. History of allergy (hypersensitivity) or intolerability to one or more agents in the
 investigational regimens (i.e., Arms 1 and 2)

 3. History of serotonin syndrome

 4. History of symptomatic ventricular arrhythmia or is taking anti-arrhythmic agents

 5. History of optic neuropathy or peripheral neuropathy

 6. History of Ehlers-Danlos Syndrome, Marfan Syndrome or aortic aneurism

 7. History of prior treatment with delamanid or linezolid for TB for greater than one
 month.

 8. Has at screening received ≥14 days of second-line anti-TB drugs during current TB
 episode

 9. Has at screening a Karnofsky score of ≤40 or, in the opinion of the Investigator, is
 unlikely to survive 76 weeks.

 10. Has at screening laboratory results that meet one or more of the following criteria:

 -  Hemoglobin concentration <7.0 g/dL (<70 g/L)

 -  Platelet count of <80,000/mm3

 -  Absolute neutrophil count (ANC) <2000/ mm3

 -  Serum creatinine >2.0 mg/dL (>177 µmol/L)

 -  Serum ALT >3x upper limit of normal (ULN)

 -  Total bilirubin >3x upper limit of normal (ULN)

 -  Serum albumin <2.8 g/dL (<28 g/L)

 -  For women of childbearing potential, a positive or indeterminate serum pregnancy
 test

 11. For women of childbearing potential, has a positive or indeterminate urine pregnancy
 test on the day of randomization.

 12. Has at screening a mean QTcF >450 msec based on three ECGs.

 13. At screening requires ongoing use of prohibited drugs indicated in section 4.2

 14. At screening, has weight less than 33 Kg.