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

This study is currently recruiting participants.
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Verified July 2017 by IUATLD, Inc
Sponsor:
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
IUATLD, Inc
ClinicalTrials.gov Identifier:
NCT02409290
First received: March 31, 2015
Last updated: July 3, 2017
Last verified: July 2017
History of Changes
March 31, 2015
July 3, 2017
April 2016
April 2021   (Final data collection date for primary outcome measure)
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
Same as current
Complete list of historical versions of study NCT02409290 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
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The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB
STREAM: 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.

MDR-TB leads to a considerable reduction in the effectiveness of standard short-length treatments and currently the standard treatments for MDR-TB can last as long as 24 months. With the incident rate of MDR-TB on the rise (511,000 new cases in 2007) and the lengthy duration of current treatments there is a need to investigate whether a shorter-length treatment using effective drugs is a global possibility.

Three short course regimens of drugs will be evaluated alongside the World Health Organisation recommended 24 month regimen for the treatment of MDR-TB.

A total of at least 1155 participants with MDR-TB will be recruited and followed for a total of 132 weeks.

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:

The current recommended treatment approach for MDR-TB is based largely on expert opinion and there is a lack of good evidence on optimal management. The World Health Organisation (WHO) guidelines for the treatment for MDR-TB recommends an intensive phase of treatment based on at least four drugs known to be effective and given for a minimum of 20 months. However, evaluation of the treatment success of such regimens in 9 countries varied from 25% to 73%. 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 months.

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.

Study treatments

The treatments that are evaluated within the STREAM trial stage 2 are:

Regimen A The locally-used World Health Organization (WHO) approved MDR-TB regimen.

Regimen B Regimen B is based on the regimen described by Van Deun et al (2010) which 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 months. In STREAM regimen B consists of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks (intensive phase).

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).

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).

The primary objectives of the STREAM2 trial are:

  1. To assess whether the proportion of patients with a favourable efficacy outcome on Regimen C, the fully oral regimen, is superior to that on Regimen B, the control regimen for Stage 2 at Week 76
  2. To assess whether the proportion of patients with a favourable efficacy outcome on Regimen C, the fully oral regimen, is not inferior to that on Regimen B at Week 76, using a 10% margin of non-inferiority
  3. To assess whether the proportion of patients with a favourable efficacy outcome on Regimen D, the shortened regimen, is not inferior to that on Regimen B at Week 76, using a 10% margin of non-inferiority.

The first primary objective, to assess the superiority of Regimen C over Regimen B, is a requirement of the US FDA; the second and third primary objectives are of programmatic relevance.

Study Population A total of at least 1155 participants with multi-drug resistance tuberculosis (MDR-TB) including patients with rifampicin-resistant and isoniazid-sensitive TB, will be recruited from sites in a number of countries. They will be randomised to either Regimen A, Regimen B, Regimen C, or Regimen D in a ratio 1:2:2:2 (i.e. 165 allocated to Regimen A, 330 allocated to Regimen B, 330 allocated to Regimen C, and 330 allocated to Regimen D).

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.
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
MDR-TB
  • Drug: Regimen A locally-used WHO-approved MDR-TB regimen
    Drug: Locally-used WHO-approved MDR-TB regimen
  • 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:
    • Nydrazid
    • Isotamine
  • 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
  • Drug: Bedaquiline
    Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity
    Other Name: SIRTURO
  • Active Comparator: Regimen A

    Regimen A locally-used WHO-approved MDR-TB regimen

    Regimen A, is the locally-used WHO-approved MDR-TB regimen in a country or site. It will be used in the secondary analysis of the study only.

    Intervention: Drug: Regimen A locally-used WHO-approved MDR-TB regimen
  • Active Comparator: Regimen B

    Product and dose for [<33 kg, 33-50kg, >50 kg] respectively:

    Moxifloxacin [400mg, 600mg, 800mg]; 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)].

    Interventions:
    • Drug: Moxifloxacin
    • Drug: Clofazimine
    • Drug: Ethambutol
    • Drug: Pyrazinamide
    • Drug: Isoniazid
    • Drug: Prothionamide
    • Drug: Kanamycin
  • Experimental: Regimen C

    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].

    Interventions:
    • Drug: Clofazimine
    • Drug: Ethambutol
    • Drug: Pyrazinamide
    • Drug: Isoniazid
    • Drug: Prothionamide
    • Drug: Levofloxacin
    • Drug: Bedaquiline
  • Experimental: Regimen D

    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)].

    Interventions:
    • Drug: Clofazimine
    • Drug: Pyrazinamide
    • Drug: Isoniazid
    • Drug: Kanamycin
    • Drug: Levofloxacin
    • Drug: Bedaquiline

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1155
December 2021
April 2021   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Is willing and able to give informed consent to participate in the trial treatment and follow-up
  • Is aged ≥ 18 years
  • Has a positive Acid Fast Bacilli (AFB) sputum smear result at screening (at least scanty), unless they are HIV positive in which case a positive GeneXpert result within 4 weeks prior to screening is sufficient
  • Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype21), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the 4 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 use 2 methods of contraception; men who have not had a vasectomy must agree to use condoms.
  • Resides in the area and expected to remain for the duration of the study.
  • Has had a chest X-ray at that is compatible with a diagnosis of pulmonary TB.
  • Has normal K+, Mg2+ and corrected Ca2+ at screening.

Exclusion Criteria:

  • Is infected with a strain of M. tuberculosis resistant to a second-line injectables by line probe assay
  • Is infected with a strain of M. tuberculosis resistant to a fluoroquinolone by line probe assay
  • 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 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 3 times the upper limit of normal
  • Has any condition (social or medical) which in the opinion of the Investigator would make study participation unsafe
  • 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 ≥ 450 ms.

  • Has experienced one or more of the following risk factors for QT prolongation:

    • A confirmed prolongation of the QT or QTcF ≥ 450 ms in the screening ECG
    • Pathological Q-waves (defined as Q-wave more than 40 ms or depth > 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 > 120 ms
    • Bradycardia as defined by sinus rate < 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, hypokalemia, or hypomagnesemia)
  • Has received treatment for MDR-TB in the 12 weeks prior to screening.
  • 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 < 30 mL/min (Cockcraft-Gault equation)
  • Is HIV positive and has a CD4 count < 50 cells/mm3
  • Has amylase elevation more than 2 times 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 7 days prior to randomisation
  • There has been a delay of more than 4 weeks between the screening consent and randomisation
  • Is an employee or family member of the site staff with direct involvement in the study.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact: Ira David Rusen, MD 2125005720 irusen@theunion.org
Contact: Meera Gurumurthy, PhD +65 90018835 mgurumurthy@vitalstrategies.org
China,   Ethiopia,   Georgia,   India,   Indonesia,   Moldova, Republic of,   Mongolia,   South Africa,   Uganda,   Vietnam
 
 
NCT02409290
78372190
Yes
Not Provided
Not Provided
IUATLD, Inc
IUATLD, Inc
Medical Research Council
Principal Investigator: Sarah Meredith, MD Medical Research Council
Principal Investigator: Andrew Nunn, PhD Medical Research Council
IUATLD, Inc
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP