The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM)
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ClinicalTrials.gov Identifier: NCT02409290 |
Recruitment Status :
Active, not recruiting
First Posted : April 6, 2015
Last Update Posted : October 13, 2022
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Condition or disease | Intervention/treatment | Phase |
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MDR-TB | 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 | Phase 3 |

Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 588 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | STREAM: The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB |
Actual Study Start Date : | April 2016 |
Actual Primary Completion Date : | January 2022 |
Estimated Study Completion Date : | April 2023 |

Arm | Intervention/treatment |
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Active Comparator: Regimen A
Regimen A locally-used WHO-approved MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines.
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Drug: Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline)
Drug: Locally-used WHO-approved MDR-TB regimen |
Active Comparator: Regimen B
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
Moxifloxacin is an 8-methoxy quinolone, and an anti-bacterial fluoroquinolone
Other Name: Avelox Drug: Clofazimine Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-sopropyliminophenazine.
Other Name: Lamprene Drug: Ethambutol 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.
Other Name: Myambutol Drug: Pyrazinamide 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.
Other Name: Zinamide Drug: Isoniazid 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.
Other Names:
Drug: Prothionamide Prothionamide has a bacteriostatic action.
Other Name: Peteha Drug: Kanamycin Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.
Other Name: Kantrex Drug: Levofloxacin 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.
Other Name: Levaquin |
Experimental: Regimen C
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
Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-sopropyliminophenazine.
Other Name: Lamprene Drug: Ethambutol 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.
Other Name: Myambutol Drug: Pyrazinamide 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.
Other Name: Zinamide Drug: Isoniazid 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.
Other Names:
Drug: Prothionamide Prothionamide has a bacteriostatic action.
Other Name: Peteha Drug: Levofloxacin 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.
Other Name: Levaquin Drug: Bedaquiline Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity
Other Name: SIRTURO |
Experimental: Regimen D
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
Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-sopropyliminophenazine.
Other Name: Lamprene Drug: Pyrazinamide 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.
Other Name: Zinamide Drug: Isoniazid 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.
Other Names:
Drug: Kanamycin Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.
Other Name: Kantrex Drug: Levofloxacin 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.
Other Name: Levaquin Drug: Bedaquiline Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity
Other Name: SIRTURO |
- STREAM Stage 2 Primary Outcome Measure (the proportion of patients with a favourable outcome at Week 76) [ Time Frame: 76 weeks ]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

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Ages Eligible for Study: | 15 Years and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
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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:
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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 Cockcraft-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.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02409290
Ethiopia | |
Armauer Hanssen Research Institute | |
Addis Ababa, Ethiopia | |
St. Peter's Tuberculosis Specializes Hospital | |
Addis Ababa, Ethiopia | |
Georgia | |
JSC National Center for Tuberculosis and Lung Diseases | |
Tbilisi, Georgia | |
India | |
BJ Medical College Civil Hospital | |
Ahmedabad, India | |
The National Institute for Research in Tuberculosis | |
Chennai, India | |
Rajan Babu Institute for Pulmonary Medicine and Tuberculosis | |
New Delhi, India | |
Moldova, Republic of | |
Institute of Phthisiopneumology 'Chiril Draganiuc' | |
Chisinau, Moldova, Republic of | |
Mongolia | |
National Centre for Communicable Diseases | |
Ulaanbaatar, Mongolia | |
South Africa | |
King Dinizulu Hospital | |
Durban, South Africa | |
Helen Joseph Hospital | |
Johannesburg, South Africa | |
Doris Goodwin Hospital | |
Pietermaritzburg, South Africa | |
Empilweni TB Hospital | |
Port Elizabeth, South Africa | |
Uganda | |
Makerere University (Mulago Referral Hospital) | |
Kampala, Uganda |
Principal Investigator: | Sarah Meredith, MD | Medical Research Council | |
Principal Investigator: | Andrew Nunn, PhD | Medical Research Council |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | IUATLD, Inc |
ClinicalTrials.gov Identifier: | NCT02409290 |
Other Study ID Numbers: |
78372190/18148631 (Stage 1/2) |
First Posted: | April 6, 2015 Key Record Dates |
Last Update Posted: | October 13, 2022 |
Last Verified: | October 2022 |
Tuberculosis Tuberculosis, Multidrug-Resistant Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Moxifloxacin Levofloxacin Isoniazid Pyrazinamide Ethambutol Bedaquiline Clofazimine |
Kanamycin Prothionamide Anti-Bacterial Agents Anti-Infective Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Anti-Infective Agents, Urinary Renal Agents Cytochrome P-450 CYP1A2 Inhibitors Cytochrome P-450 Enzyme Inhibitors Antitubercular Agents Fatty Acid Synthesis Inhibitors |