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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.
Verified July 2017 by IUATLD, Inc
Sponsor:
ClinicalTrials.gov Identifier:
NCT02409290
First Posted: April 6, 2015
Last Update Posted: July 5, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
IUATLD, Inc
  Purpose

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.


Condition Intervention Phase
MDR-TB Drug: Regimen A locally-used WHO-approved MDR-TB regimen Drug: Moxifloxacin Drug: Clofazimine Drug: Ethambutol Drug: Pyrazinamide Drug: Isoniazid Drug: Prothionamide Drug: Kanamycin Drug: Levofloxacin Drug: Bedaquiline Phase 3

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by IUATLD, Inc:

Primary Outcome Measures:
  • 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


Estimated Enrollment: 1155
Study Start Date: April 2016
Estimated Study Completion Date: December 2021
Estimated Primary Completion Date: April 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Drug: Regimen A locally-used WHO-approved MDR-TB regimen
Drug: 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)].

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
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].

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: 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

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:
  • Nydrazid
  • Isotamine
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

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

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


Contacts
Contact: Ira David Rusen, MD 2125005720 irusen@theunion.org
Contact: Meera Gurumurthy, PhD +65 90018835 mgurumurthy@vitalstrategies.org

Locations
China
Beijing Chest Hospital Not yet recruiting
Beijing, China
Wuhan Institute for TB control Not yet recruiting
Wuhan, China
Ethiopia
St. Peter's Tuberculosis Specializes Hospital Recruiting
Addis Ababa, Ethiopia
Armauer Hanssen Research Institute Recruiting
Adis Abbaba, Ethiopia
Georgia
JSC National Center for Tuberculosis and Lung Diseases Not yet recruiting
Tbilisi, Georgia
India
BJ Medical College Civil Hospital Not yet recruiting
Ahmedabad, India
The National Institute for Research in Tuberculosis Not yet recruiting
Chennai, India
Indonesia
RSUP Persahabatan Not yet recruiting
Jakarta, Indonesia
Moldova, Republic of
Institute of Phthisiopneumology 'Chiril Draganiuc' Not yet recruiting
Chisinau, Moldova, Republic of
Mongolia
National Centre for Communicable Diseases Recruiting
Ulaanbaatar, Mongolia
South Africa
King Dinizulu Hospital Recruiting
Durban, South Africa
Helen Joseph Hospital Recruiting
Johannesburg, South Africa
Sizwe Tropical Disease Hospital Active, not recruiting
Johannesburg, South Africa
Doris Goodwin Hospital Recruiting
Pietermaritzburg, South Africa
Uganda
Makerere University Not yet recruiting
Kampala, Uganda
Mulago National Referral Hospital Not yet recruiting
Kampala, Uganda
Vietnam
Pham Ngoc Thach Hospital Active, not recruiting
Ho Chi Minh City, Vietnam
Sponsors and Collaborators
IUATLD, Inc
Medical Research Council
Investigators
Principal Investigator: Sarah Meredith, MD Medical Research Council
Principal Investigator: Andrew Nunn, PhD Medical Research Council
  More Information

Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: IUATLD, Inc
ClinicalTrials.gov Identifier: NCT02409290     History of Changes
Other Study ID Numbers: 78372190
First Submitted: March 31, 2015
First Posted: April 6, 2015
Last Update Posted: July 5, 2017
Last Verified: July 2017

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Moxifloxacin
Levofloxacin
Ofloxacin
Isoniazid
Pyrazinamide
Ethambutol
Clofazimine
Bedaquiline
Diarylquinolines
Kanamycin
Prothionamide
Norgestimate, ethinyl estradiol drug combination
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents