Last updated on March 2019

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


Brief description of study

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.

Detailed Study 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.

Clinical Study Identifier: NCT02409290

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