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

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 country and 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-disease phenotype and treatment response. 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

• 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. Patients with RIF-resistant TB who are unable to tolerate fluoroquinolones (history of severe adverse events, allergies, hypersensitivity) are also eligible, regardless of resistance/susceptibility to fluoroquinolones;
• Is ≥15 years of age;
• Is willing to use contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilized must agree to use contraception unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms;
• Provides informed consent for study participation; additionally a legal representative of patients considered minor per local laws should also provide consent;
• 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

• 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:

• patients whose treatment has failed according to the WHO definition and who are being considered for a new treatment regimen;
• patients starting a new treatment regimen after having been "lost to follow-up" according to the WHO definition and,
• 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.

• 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 defined by the MSF Severity Scale on any of the screening laboratory tests.

• 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 greater than or equal to 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).

• Concurrent participation in another trial of any medication used or being studied for TB treatment, as defined in cited documents.

• 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.