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

Information source: IUATLD, Inc
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: MDR-TB

Intervention: 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 (Drug)

Phase: Phase 3

Status: Not yet recruiting

Sponsored by: IUATLD, Inc

Official(s) and/or principal investigator(s):
Sarah Meredith, MD, Principal Investigator, Affiliation: Medical Research Council
Andrew Nunn, PhD, Principal Investigator, Affiliation: Medical Research Council

Overall contact:
Ira David Rusen, MD, Phone: 2125005720, Email: IRUSEN@THEUNION.ORG

Summary

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Primary outcome: STREAM Stage 2 Primary Outcome Measure (the proportion of patients with a favourable outcome at Week 76)

Detailed description: 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Ira David Rusen, MD, Phone: 2125005720, Email: IRUSEN@THEUNION.ORG

Additional Information

Medical Research Council at UCL's web page containing information on the trial

The International Union Against Tuberculosis and Lung Disease (study sponsor) web page containing information on the trial

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Last updated: April 3, 2015

Page last updated: August 23, 2015

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