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

This is an interventional treatment trial for MDR-TB Read More

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 Cockcraft-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.