The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB
Condition: MDR-TB
MeSH terms: Tuberculosis; Tuberculosis, Multidrug-Resistant
Intervention: Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline); Moxifloxacin; Clofazimine; Ethambutol; Pyrazinamide; Isoniazid; Prothionamide; Kanamycin; Levofloxacin; Bedaquiline
Intervention description: Drug: Locally-used WHO-approved MDR-TB regimen; Moxifloxacin is an 8-methoxy quinolone, and an anti-bacterial fluoroquinolone; Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine.; Ethambutol is a bacteriostatic that acts against virtually all strains of Mycobacterium tuberculosis and M. bovis and is also active against other mycobacteria such as M. Kansasii.; Pyrazinamide is bactericidal against intracellular mycobacterium tuberculosis. It is a prodrug that is converted into its active form, pyrazinoic acid, by a mycobacterial enzyme, pyrazinamidase, as well as through hepatic metabolism.; Isoniazid is a bactericidal in vitro and in vivo against actively dividing tubercle bacilli. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique constituents of mycobacterial cell wall.; Prothionamide has a bacteriostatic action.; Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.; Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class that acts on the DNA-DNA-gyrase complex and topoisomerase IV. It is the S (-) enantiomer of the racemic active substance ofloxacin.; Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity
Intervention MeSH terms: Moxifloxacin; Levofloxacin; Isoniazid; Pyrazinamide; Ethambutol; Bedaquiline; Clofazimine; Kanamycin; Prothionamide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 588.0
Sex: All
Minimum age: 15 Years
Healthy volunteers: No

Summary:

      Tuberculosis (TB) is a common, infectious, bacterial disease that is spread when an infected
      person transmits their saliva through the air by coughing or sneezing. Despite the
      availability and effectiveness of affordable six-month treatments for tuberculosis (TB), the
      worldwide control of this disease is currently being impacted by the emergence of multidrug
      resistant TB (MDR-TB). MDR-TB refers to TB that is resistant to at least isoniazid and
      rifampicin. These are the two most powerful first-line drugs used to treat pulmonary TB.
      MDR-TB usually develops while a person is taking TB treatment due to either inappropriate
      treatment or failure of patients to comply with their treatment. This strain of
      drug-resistant bacteria can also be spread to other people through the air. With the incident
      rate of MDR-TB on the rise, there is a need to investigate optimal treatment regimens using
      effective drugs.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Consent: Is willing and able to give informed consent to participate in the trial
             treatment and follow-up (signed or witnessed consent if the patient is illiterate). If
             the patient is below the age of consent (according to local regulations), the
             parent/caregiver should be able and willing to give consent, and the patient be
             informed about the study and asked to give positive assent, if feasible

          2. Age: Is aged 18 years or older (Stage 1) or 15 years or older (Stage 2)

          3. AFB or GeneXpert results: Has a positive AFB sputum smear result at screening (at
             least scanty), or a positive GeneXpert result (with a cycle threshold (Ct) value of 25
             or lower) from a test performed at screening or from a test performed within the four
             weeks prior to screening

          4. Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype),
             GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at
             screening or from a test performed within the four weeks prior to screening

          5. 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

          6. 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
             agree to use a barrier method or an intrauterine device unless their partner has had a
             vasectomy; men who have not had a vasectomy must agree to use condoms. In Stage 2
             pre-menopausal women or women whose last menstrual period was within the preceding
             year, who have not been sterilised must agree to use two methods of contraception, for
             example a hormonal method and a barrier method

          7. Resides in the area and expected to remain for the duration of the study.

          8. Has had a chest X-ray that is compatible with a diagnosis of pulmonary TB (if such a
             chest X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not
             required)

          9. Has normal K+, Mg2+ and corrected Ca2+ at screening.

        Exclusion Criteria:

          1. Is infected with a strain of M. tuberculosis resistant to second-line injectables by
             line probe assay (Hain Genotype) from a test performed at screening or from a test
             performed within the four weeks prior to screening

          2. Is infected with a strain of M. tuberculosis resistant to fluoroquinolones by line
             probe assay (Hain Genotype) from a test performed at screening or from a test
             performed within the four weeks prior to screening

          3. Has tuberculous meningitis or bone and joint tuberculosis

          4. Is critically ill, and in the judgment of the investigator, unlikely to survive more
             than 4 months

          5. Is known to be pregnant or breast-feeding

          6. Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule

          7. Is unable to take oral medication

          8. Has AST or ALT more than 5 times the upper limit of normal for Stage 1, and AST or ALT
             more than 3 times the upper limit of normal for Stage 2

          9. Has any condition (social or medical) which in the opinion of the investigator would
             make study participation unsafe

         10. In the investigator's opinion the patient is likely to be eligible for treatment with
             bedaquiline according to local guidelines due to a pre-existing medical condition such
             as hearing loss or renal impairment

         11. Is taking any medications contraindicated with the medicines in any trial regimen

         12. Has a known allergy to any fluoroquinolone antibiotic

         13. Is currently taking part in another trial of a medicinal product

         14. Has a QT or QTcF interval at screening or immediately prior to randomisation of more
             than or equal to 500 ms for Stage 1, and more than or equal to 450 ms for Stage 2

             In addition to the criteria above, for Stage 2 only, a patient will not be eligible
             for randomisation to the study if he/she:

         15. Has experienced one or more of the following risk factors for QT prolongation:

               -  A confirmed prolongation of the QT or QTcF more than or equal to 450 ms in the
                  screening ECG (retesting to reassess eligibility will be allowed once using an
                  unscheduled visit during the screening phase)

               -  Pathological Q-waves (defined as Q-wave more than 40 ms or depth more than
                  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 more than 120 ms

               -  Bradycardia as defined by sinus rate less than 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, hypokalaemia, or
                  hypomagnesemia)

         16. Has received treatment for MDR-TB in the 12 weeks prior to screening, other than the
             maximum permitted treatment specified in Section 5.2.1

         17. 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.

         18. Has an estimated creatinine clearance (CrCl) less than 30 mL/min based on the
             Cockcroft-Gault equation

         19. Is HIV positive and has a CD4 count less than 50 cells/mm3

         20. Has pancreatic amylase elevation more than two times above the upper limit of normal

         21. Has a history of alcohol and/or drug abuse

         22. Has had previous treatment with bedaquiline

         23. Has taken rifampicin in the seven days prior to randomisation

         24. There has been a delay of more than four weeks between the screening consent and
             randomisation

         25. Is an employee or family member of the investigator or study site staff with direct
             involvement in the proposed study.