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.

IUATLD, Inc

Medical Research Council

Medical Research Council at UCL's web page containing information on the trial 

The International Union Against Tuberculosis and Lung Disease (study sponsor) web page containing information on the trial 

The International Union Against Tuberculosis and Lung Disease (study sponsor) web page containing information on the trial 

Tuberculosis Tuberculosis, Multidrug-Resistant Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Moxifloxacin Levofloxacin Ofloxacin Isoniazid Pyrazinamide Ethambutol Clofazimine Bedaquiline Diarylquinolines	Prothionamide Kanamycin Norgestimate, ethinyl estradiol drug combination Antitubercular Agents Anti-Bacterial Agents Anti-Infective Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Contraceptives, Oral, Combined Contraceptives, Oral Contraceptive Agents, Female Contraceptive Agents