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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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STREAM: The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB

Conditions
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MDR-TB

Intervention / Treatment
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* Drug: Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline)
* Drug: Moxifloxacin
* Drug: Clofazimine
* Drug: Ethambutol
* Drug: Pyrazinamide
* Drug: Isoniazid
* Drug: Prothionamide
* Drug: Kanamycin
* Drug: Levofloxacin
* Drug: Bedaquiline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Age: Is aged 18 years or older (Stage 1) or 15 years or older (Stage 2) 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 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 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 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 Resides in the area and expected to remain for the duration of the study. 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) Has normal K+, Mg2+ and corrected Ca2+ at screening. Exclusion Criteria: 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 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 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 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 Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe 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 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 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: 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) 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 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 (CrCl) less than 30 mL/min based on the Cockcroft-Gault equation Is HIV positive and has a CD4 count less than 50 cells/mm3 Has pancreatic amylase elevation more than two times above 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 seven days prior to randomisation There has been a delay of more than four weeks between the screening consent and randomisation Is an employee or family member of the investigator or study site staff with direct involvement in the proposed study.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Regimen A<br>Regimen A locally-used WHO-approved MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines. | Drug: Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline)<br>* Drug: Locally-used WHO-approved MDR-TB regimen<br>|
| Active Comparator: Regimen B<br>Regimen B is based on the regimen described by Van Deun 2010. With Version 8.0 of the protocol Regimen B (Regimen Bmox) is modified by replacement of moxifloxacin with levofloxacin (Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev). Product and dose for [<33 kg, 33-50kg, >50 kg] respectively: Moxifloxacin [400mg, 600mg, 800mg] OR Levofloxacin [750mg, 750mg,1000mg]; Clofazimine [50mg,100mg,100mg]; Ethambutol [800mg,800mg,1200mg]; Pyrazinamide [1000mg,1500mg, 2000mg]; Isoniazid 300mg, 400mg, 600mg]; Prothionamide [250mg,500mg,750mg]; Kanamycin [15mg per kilogram body weight (maximum 1g)]. | Drug: Moxifloxacin<br>* Moxifloxacin is an 8-methoxy quinolone, and an anti-bacterial fluoroquinolone<br>* Other names: Avelox;Drug: Clofazimine<br>* Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine.<br>* Other names: Lamprene;Drug: Ethambutol<br>* 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.<br>* Other names: Myambutol;Drug: Pyrazinamide<br>* 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.<br>* Other names: Zinamide;Drug: Isoniazid<br>* 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.<br>* Other names: Isotamine;Drug: Prothionamide<br>* Prothionamide has a bacteriostatic action.<br>* Other names: Peteha;Drug: Kanamycin<br>* Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.<br>* Other names: Kantrex;Drug: Levofloxacin<br>* 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.<br>* Other names: Levaquin;|
| Experimental: Regimen C<br>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). Product and dose for [<33kg, 33-50kg, >50 kg] respectively: Bedaquiline 400mg once daily for first 14 days/200 mg thrice weekly thereafter; Levofloxacin [750mg, 750mg,1000mg]; Clofazimine [50mg, 100mg, 100mg]; Ethambutol [800mg, 800mg, 1200mg]; Pyrazinamide [1000mg,1500mg, 2000mg]; Isoniazid [300mg, 400mg, 600mg]; Prothionamide [250mg, 500mg,750mg]. | Drug: Clofazimine<br>* Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine.<br>* Other names: Lamprene;Drug: Ethambutol<br>* 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.<br>* Other names: Myambutol;Drug: Pyrazinamide<br>* 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.<br>* Other names: Zinamide;Drug: Isoniazid<br>* 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.<br>* Other names: Isotamine;Drug: Prothionamide<br>* Prothionamide has a bacteriostatic action.<br>* Other names: Peteha;Drug: Levofloxacin<br>* 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.<br>* Other names: Levaquin;Drug: Bedaquiline<br>* Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity<br>* Other names: SIRTURO;|
| Experimental: Regimen D<br>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). Product and dose for [<33kg, 33 to<40kg, 40-50kg, >50-60 kg, >60 kg] respectively: Bedaquiline 400mg once daily for first 14 days/200mg thrice weekly thereafter; Levofloxacin [750mg, 750mg, 750mg, 1000mg, 1000mg]; Clofazimine [50mg, 100mg, 100mg, 100mg, 100mg]; Pyrazinamide [1000mg,1500mg, 1500mg, 2000mg, 2000mg]; Isoniazid [400mg, 500mg, 600mg, 800mg, 900mg]; Kanamycin [15 mg per kilogram body weight (maximum 1g)]. | Drug: Clofazimine<br>* Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine.<br>* Other names: Lamprene;Drug: Pyrazinamide<br>* 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.<br>* Other names: Zinamide;Drug: Isoniazid<br>* 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.<br>* Other names: Isotamine;Drug: Kanamycin<br>* Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.<br>* Other names: Kantrex;Drug: Levofloxacin<br>* 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.<br>* Other names: Levaquin;Drug: Bedaquiline<br>* Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity<br>* Other names: SIRTURO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| STREAM Stage 2 Primary Outcome Measure (the Proportion of Patients With a Favourable Outcome at Week 76) | The primary efficacy outcome of the STREAM Stage 2 comparison is status at Week 76 i.e. the proportion of patients with a favourable outcome at Week 76 | 76 weeks |