The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB
The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB
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.
The STREAM study is an international, multi-centre, parallel-group, open-label, randomised,
 controlled trial in patients with multi-drug resistant tuberculosis (MDR-TB) including
 patients with rifampicin-resistant and isoniazid-sensitive TB.

 Background and Rationale:

 In 2011, World Health Organisation (WHO) guidelines for the treatment for MDR-TB recommended
 an intensive phase of treatment based on at least four drugs known to be effective and given
 for a minimum of 20 months; this is referred to as the WHO 2011 long regimen. Outcomes with
 this approach are generally poor. In the most recent WHO TB surveillance report only 50% of
 MDR-TB patients were successfully treated and a recent meta-analysis reported on average 62%
 successful outcome and a mortality of 11%.

 In 2010, Van Deun et al (2010) reported excellent long-term outcomes in a cohort of over 200
 patients in Bangladesh with MDR-TB who were treated with a regimen given for only nine to 11
 months. Such a regimen, if successful, would represent a considerable advance over current
 practice. Evaluation of this regimen is the objective of Stage 1 of STREAM.

 In 2016, following review of the available data, the WHO MDR TB treatment guidelines were
 modified to recommend a 9-12 month shortened regimen under specific conditions similar to
 Regimen B used in STREAM Stage 1 (referred to as the WHO 2016 short regimen).

 Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity. In a phase II
 trial of patients with MDR-TB time to culture conversion was significantly less in patients
 receiving bedaquiline compared to those receiving an optimised background regimen only
 (Diacon et al (2012). In December 2012 the US Food and Drug Administration (FDA) approved
 bedaquiline as part of the treatment regimen for MDR-TB when other agents are unavailable.
 Stage 2 of STREAM was designed to investigate ways in which Regimen B could be improved
 either by removing the second-line injectable, which is associated with severe drug toxicity,
 or by shortening the regimen to 6 months.

 Treatments that are evaluated within the STREAM trial include:

 Regimen A The locally-used MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment
 guidelines.

 Regimen B is based on the regimen described by Van Deun 2010. At the start of STREAM this
 consisted of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks,
 supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks (intensive
 phase). ); this combination is referred to as Regimen Bmox. With Version 8.0 of the protocol
 Regimen B is modified by replacement of moxifloxacin with levofloxacin (referred to as
 Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen
 refers to either (Bmox or Blev).

 Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol,
 levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide
 for the first 16 weeks (intensive phase).

 Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and
 pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks
 (intensive phase).

 The primary objectives of the STREAM2 trial are:

 To assess whether the proportion of participants with a favourable efficacy outcome at week
 76 on Regimen C is non-inferior to that on Regimen B

 Study Population: Stage 2 will aim to randomise at least 200 patients to each of Regimens B
 and C.

 All patients will be followed up to Week 132. The primary analysis will be based on the data
 accrued to Week 76 and is based on the proportion of patients with a favourable outcome at
 that time point ; the data accrued to Week 132 will be used in secondary analyses.

 Although the STREAM study is an open-label study, wherever possible it will be conducted
 masked to treatment allocation.
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.