Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB With Fluoroquinolone Resistance (endTB-Q)

Inclusion Criteria:

1. Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant torifampin (RIF) and not susceptible to fluoroquinolones, according to a validatedrapid molecular test. Patients with RIF-resistant TB who are unable to toleratefluoroquinolones (history of severe adverse events, allergies, hypersensitivity) arealso eligible, regardless of resistance/susceptibility to fluoroquinolones;

2. Is ≥15 years of age;

3. Is willing to use contraception: pre-menopausal women or women whose last menstrualperiod was within the preceding year, who have not been sterilized must agree to usecontraception unless their partner has had a vasectomy; men who have not had avasectomy must agree to use condoms;

4. Provides informed consent for study participation; additionally a legalrepresentative of patients considered minor per local laws should also provideconsent;

5. Lives in a dwelling that can be located by study staff and expects to remain in thearea for the duration of the study.

Exclusion Criteria:

1. Has known allergies or hypersensitivity to any of the investigational drugs; 2. Isknown to be pregnant or is unwilling or unable to stop breastfeeding an infant; 3.Is unable to comply with treatment or follow-up schedule; 4. Has any condition (social or medical) which, in the opinion of the site principal investigator, wouldmake study participant unsafe; 5. a. Has had exposure (intake of the drug for 30days or more) in the past five years to bedaquiline, delamanid, linezolid, orclofazimine, or has proven or likely resistance to bedaquiline, delamanid,linezolid, or clofazimine (e.g., household contact of a DR-TB index case who died orexperienced treatment failure after treatment containing bedaquiline, delamanid,linezolid, or clofazimine or had resistance to one of the listed drugs); exposure toother anti-TB drugs is not a reason for exclusion.

b. Has received second-line drugs for 15 days or more prior to screening visit date in the current MDR/RR-TB treatment episode. Exceptions include:

1. patients whose treatment has failed according to the WHO definition and who arebeing considered for a new treatment regimen;

2. patients starting a new treatment regimen after having been "lost to follow-up"according to the WHO definition and,

3. patients in whom treatment failure is suspected (but not confirmed according to WHOdefinition), who are being considered for a new treatment regimen, and for whom theClinical Advisory Committee (CAC) consultation establishes eligibility.

4. Has one or more of the following:

• Hemoglobin ≤7.9 g/dL;

• Uncorrectable electrolytes disorders:

• Total Calcium <7.0 mg/dL (1.75 mmol/L);

• Potassium <3.0 mEq/L (3.0 mmol/L) or ≥6.0 mEq/L (6.0 mmol/L);

• Magnesium <0.9 mEq/L (0.45 mmol/L);

• Serum creatinine >3 x ULN;

• Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 x ULN;

• Total bilirubin ≥3 x ULN; Unless otherwise specified, Grade 4 result as definedby the MSF Severity Scale on any of the screening laboratory tests.

7. Has cardiac risk factors defined as:

• An arithmetic average of the two ECGs with highest QTcF intervals of greaterthan or equal to 450 ms. Retesting to reassess eligibility will be allowedusing an unscheduled visit during the screening phase;

• Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome);

• Electrocardiographic evidence of either:

• Complete left bundle branch block or right bundle branch block; OR

• Incomplete left bundle branch block or right bundle branch block and QRS complexduration greater than or equal to 120 msec on at least one ECG; • Having a pacemakerimplant;

• Congestive heart failure;

• Evidence of second or third degree heart block;

• Bradycardia as defined by sinus rate less than 50 bpm;

• Personal or family history of Long QT Syndrome;

• Personal history of arrhythmic cardiac disease, with the exception of sinusarrhythmia;

• Personal history of syncope (i.e. cardiac syncope not including syncope due tovasovagal or epileptic causes).

8. Concurrent participation in another trial of any medication used or beingstudied for TB treatment, as defined in cited documents.
9. Is taking any medication that is contraindicated with the medicines in thetrial regimen which cannot be stopped (with or without replacement) orrequires a wash-out period longer than 2 weeks.