Evaluating Newly Approved Drugs for Multidrug-resistant TB

This is a Phase III, randomized, controlled, open-label, non-inferiority, multi-country trial evaluating the efficacy and safety of new combination regimens for MDR-TB treatment.

Regimens examined combine newly approved drugs bedaquiline and/or delamanid with existing drugs known to be active against Mycobacterium tuberculosis (linezolid, clofazimine, moxifloxacin or levofloxacin, and pyrazinamide). The study will enroll in parallel across 5 experimental and 1 standard-of-care control arms. Randomization will be outcome adapted using Bayesian interim analysis of efficacy endpoints. Experimental regimens will contain bedaquiline and/or delamanid and up to 4 companion drugs. Control-arm treatment may contain one of the following (bedaquiline or delamanid) and companion drugs, constructed and delivered according to local standard of care and consistent with WHO guidelines. Trial participation in all arms will last at least until Week 73, and up to Week 104. In the experimental arms, treatment will be for 39 weeks (participants in the experimental arms will be allowed up to 47 weeks to complete the 39-week treatment course) and post-treatment follow up for up to 65 additional weeks. In the control arm, treatment will be delivered according to local standard of care (in consistence with WHO guidance); duration may vary and will be approximately 86 weeks for the conventional regimen and 39-52 weeks for the standardized shorter regimen.

Non-inferiority will be established for any 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

A patient will be eligible for randomization if s/he:

• Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant to rifampin (RIF) and susceptible to fluoroquinolones, diagnosed by validated rapid molecular test;
• 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

A patient will not be eligible for randomization if s/he:

• Has known allergies or hypersensitivity to any of the investigational drugs;
• Is known to be pregnant or is unwilling or unable to stop breast-feeding an infant;
• Is unable to comply with treatment or follow-up schedule;
• Any condition (social or medical) which, in the opinion of the site principal investigator, would make study participant unsafe;
• 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 definition151 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 definition149 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.

• Has one or more of the following:

• Hemoglobin ≤ 7.9 g/dL;
• Uncorrectable electrolytes disorders:
• Calcium < 7.0 mg/dL;
• Potassium < 3.0 or ≥6.0 mEq/L;
• Magnesium < 0.9 mEq/L;
• Serum creatinine > 3 x ULN;
• Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 x ULN;
• Total bilirubin ≥ 1.5 x ULN if accompanied by AST or ALT > ULN or total bilirubin ≥ 2 x ULN when other liver function results are in the normal range;
• Grade 4 result on any of the specified laboratory tests as defined by the MSF Severity Scale.
• Has cardiac risk factors defined as:

• A confirmed QTc interval of greater than or equal to 450 ms. Retesting to reassess eligibility will be allowed once 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 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.