The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM)

Inclusion Criteria:

• Is willing and able to give informed consent to participate in the trial treatment and follow-up
• Is aged ≥ 18 years
• Has a positive Acid Fast Bacilli (AFB) sputum smear result at screening (at least scanty), unless they are HIV positive in which case a positive GeneXpert result within 4 weeks prior to screening is sufficient
• Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype21), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the 4 weeks prior to screening
• Is willing to have an HIV test and, if positive, is willing to be treated with ART in accordance with the national policies but excluding ART contraindicated for use with bedaquiline
• Is willing to use effective contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must use 2 methods of contraception; men who have not had a vasectomy must agree to use condoms.
• Resides in the area and expected to remain for the duration of the study.
• Has had a chest X-ray at that is compatible with a diagnosis of pulmonary TB.
• Has normal K+, Mg2+ and corrected Ca2+ at screening.

Exclusion Criteria:

• Is infected with a strain of M. tuberculosis resistant to a second-line injectables by line probe assay
• Is infected with a strain of M. tuberculosis resistant to a fluoroquinolone by line probe assay
• Has tuberculous meningitis or bone and joint tuberculosis
• Is critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months
• Is known to be pregnant or breast-feeding
• Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule
• Is unable to take oral medication
• Has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 3 times the upper limit of normal
• Has any condition (social or medical) which in the opinion of the Investigator would make study participation unsafe
• Is taking any medications contraindicated with the medicines in any trial regimen
• Has a known allergy to any fluoroquinolone antibiotic
• Is currently taking part in another trial of a medicinal product
• Has a QT or QTcF interval at screening or immediately prior to randomisation of ≥ 450 ms.

• Has experienced one or more of the following risk factors for QT prolongation:

  • A confirmed prolongation of the QT or QTcF ≥ 450 ms in the screening ECG
  • Pathological Q-waves (defined as Q-wave more than 40 ms or depth > 0.4-0.5 mV)
  • Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome)
  • Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block
  • Evidence of second or third degree heart block
  • Intraventricular conduction delay with QRS duration > 120 ms
  • Bradycardia as defined by sinus rate < 50 bpm
  • Personal or family history of Long QT Syndrome
  • Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia
  • Syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes)
  • Risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, or hypomagnesemia)
• Has received treatment for MDR-TB in the 12 weeks prior to screening.
• Has a history of cirrhosis and classified as Child's B or C at screening or a bilirubin more than 1.5 times upper limit of normal.
• Has an estimated creatinine clearance < 30 mL/min (Cockcraft-Gault equation)
• Is HIV positive and has a CD4 count < 50 cells/mm3
• Has amylase elevation more than 2 times the upper limit of normal
• Has a history of alcohol and/or drug abuse
• Has had previous treatment with bedaquiline
• Has taken rifampicin in the 7 days prior to randomisation
• There has been a delay of more than 4 weeks between the screening consent and randomisation
• Is an employee or family member of the site staff with direct involvement in the study.