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

To evaluate a 9-month fully oral regimen. Initial trial results from Stage 2 of the trial are expected in 2022. Thirteen Stage 2 sites in Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda are participating.

From CT.gov: 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.

The treatments 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.