Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB With Fluoroquinolone Resistance (endTB-Q)
Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB With Fluoroquinolone Resistance (endTB-Q)
endTB-Q Clinical Trial is a Phase III, randomized, controlled, open-label, non-inferiority,
 multi-country trial evaluating the efficacy and safety of two new, all-oral, shortened
 regimens for multidrug-resistant tuberculosis (MDR-TB) with fluoroquinolone resistance.
This is a Phase III, randomized, controlled, open-label, multi-country trial evaluating the
 efficacy of new combination regimens for treatment of fluoroquinolone-resistant MDR-TB.

 Regimens examined combine newly approved drugs bedaquiline and delamanid with existing drugs
 known to be active against Mycobacterium tuberculosis (linezolid and clofazimine). The study
 will enroll in parallel across 1 experimental and 1 standard-of-care control arms, in a 2:1
 ratio. Randomization will be stratified by extent-of-TB-disease phenotype. In the
 experimental arm, treatment will be for 24 or 39 weeks; duration will be assigned according
 to extent-of-TB-diseasephenotype. In the control arm, treatment will be delivered according
 to WHO guidelines (and local practice); duration will be variable. Trial participation in
 both arms will last at least until Week 73, and up to Week 104.

 Non-inferiority will be established for the experimental arm if the lower bound of the
 one-sided 97.5% confidence interval around the difference in favorable outcome between the
 control and experimental arms is greater than or equal to -12%.
Inclusion Criteria:

 1. Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant to
 rifampin (RIF) and not susceptible to fluoroquinolones, according to a validated rapid
 molecular test.

 2. Is ≥15 years of age;

 3. Is willing to use effective contraception: pre-menopausal women or women whose last
 menstrual period was within the preceding year, who have not been sterilized must
 agree to use two methods of contraception (e.g., a hormonal method and a barrier
 method) unless their partner has had a vasectomy; men who have not had a vasectomy
 must agree to use condoms;

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

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

 Exclusion Criteria:

 1. Has known allergies or hypersensitivity to any of the investigational drugs; 2. Is known
 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, would make study participant
 unsafe; 5. a. Has had exposure (intake of the drug for 30 days or more) in the past five
 years to bedaquiline, delamanid, linezolid, or clofazimine, or has proven or likely
 resistance to bedaquiline, delamanid, linezolid, or clofazimine (e.g., household contact of
 a DR-TB index case who died or experienced treatment failure after treatment containing
 bedaquiline, delamanid, linezolid, or clofazimine or had resistance to one of the listed
 drugs); exposure to other 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 are being
 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 WHO
 definition), who are being considered for a new treatment regimen, and for whom the
 Clinical Advisory Committee (CAC) consultation establishes eligibility.

 6. 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;

 -  Albumin <2.8 g/dL; Unless otherwise specified, Grade 4 result as defined by the MSF
 Severity Scale (Appendix 2) 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 greater than or
 equal to 450 ms. Retesting to reassess eligibility will be allowed using 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 complex
 duration >120 msec on at least one ECG;

 -  Having a pacemaker implant;

 -  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 sinus
 arrhythmia;

 -  Personal history of syncope (i.e. cardiac syncope not including syncope due to
 vasovagal or epileptic causes).

 8. Is currently taking part in another trial of a medicinal product;

 9. Is taking any medication that is contraindicated with the medicines in the trial
 regimen which cannot be stopped (with or without replacement) or requires a wash-out
 period longer than 2 weeks.