Results from Stage 2 of the LSTM partnership STREAM randomized clinical trial, released in The Lancet, show that two new bedaquiline-containing shortened treatment regimens are both safe and effective in treating multi-drug resistant tuberculosis (MDR-TB), and result in lower direct costs to patients. MDR-TB is resistant to two key medicines—isoniazid and rifampicin. Findings were shared at The Union World Conference on Lung Health hosted virtually from Nov. 8-11.
The STREAM clinical trial, carried out by LSTM and global partners including Medical Research Council Clinical Trials Unit at University College London (UCL) and the International Union Against Tuberculosis and Lung Disease (The Union) is the world’s largest clinical trial for multidrug-resistant tuberculosis (MDR-TB). With over 1,000 participants recruited, from eight countries on three continents, the trial was sponsored by Vital Strategies and found all-oral and six-month treatment regimens to be safe and effective. This fills an important gap in evidence on shortened regimens for MDR-TB.
Until 2016, the recommended treatment for MDR-TB typically included 7,200 pills and 240 injections and took up to 24 months to complete. In 2017, STREAM Stage 1 confirmed that a 9-month treatment regimen was as effective as the longer regimen. Now, STREAM Stage 2 has demonstrated that both a fully oral 9-month regimen and a 6-month injection-containing regimen have superior efficacy than the control regimen (the regimen evaluated in STREAM Stage 1). The results ensure decision-makers have the highest quality evidence available to guide their decisions about optimal MDR-TB treatment regimens for their TB programs.
“The impact of new treatments on patient costs and quality of life are as important as those on health system budgets,” said LSTM’s Prof. Bertie Squire. “We found that the all-oral regimen would cost health systems more but would reduce patient direct costs. All treatment regimens improved quality of life, supporting investment in this pervasive disease. Nevertheless, even with the all-oral regimen, a high proportion of patients incurred catastrophic costs. Our data will help countries to reduce the health and economic impact of MDR-TB.”
“In STREAM Stage 2 we generated robust scientific evidence regarding the safety, efficacy, and cost-effectiveness of two shortened regimens for MDR-TB, providing guideline development groups and national TB programs with better information to underpin their decisions about the most appropriate treatments for their populations,” said I.D. Rusen, Senior Vice President, Vital Strategies, and Sponsor for the STREAM trial. “While we are pleased with the performance of the regimens tested in STREAM and the evidence generated, there is still an urgent need to build upon these results and improve the efficacy and safety of MDR-TB regimens available.”
Despite recent advances in the MDR-TB research landscape, treatment guidelines have been based on observational and non-randomized clinical trial data. These results provide randomized clinical trial data to strengthen the evidence-base for treatment recommendations.
Stage 2 evaluated two new regimens – an all-oral 9-month regimen and a 6-month injection-containing regimen (both containing the new anti-tuberculosis drug bedaquiline) compared to a 9-month control regimen studied in Stage 1. Importantly, an in-trial health economics component showed lower direct patient costs for both regimens while also identifying divergent health system costs between the two new regimens.
The global threat of TB has been exacerbated by the COVID-19 pandemic. The recently released WHO Global Tuberculosis Report 2022 highlighted that an estimated 10.6 million people fell ill with TB worldwide in 2021 representing an increase of 4.5% from 2020 and reversing many years of slow decline. The estimated number of new cases of MDR-TB also increased by 3.1% during the same time period, as access to health services and optimal TB diagnosis and management has been severely impacted by the pandemic.
The research builds on the findings from Stage 1 of the STREAM trial, which demonstrated that a 9-month regimen (that contained injections but did not contain bedaquiline) was non-inferior to the 20-24 month regimen recommended in the 2011 WHO guidelines at the time the trial began.
The Results
Fully oral 9-month regimen was more effective than the control regimen
The fully oral 9-month regimen was more effective than the 9-month control regimen; 82.7% of participants receiving the fully oral regimen had a favorable outcome compared to 71.1% receiving the control regimen.
A 6-month regimen was also more effective than the 9-month control regimen
The 6-month regimen – which contained bedaquiline and an injectable medicine for an abbreviated period of two months – was also more effective than the control regimen; 91.0% of participants receiving the 6-month regimen had a favorable outcome compared to 68.5% in concurrent controls.
Professor Andrew Nunn, STREAM co-chief investigator, at the MRC Clinical Trials Unit at UCL said: “It is particularly encouraging to note that the findings in the fully-oral and 6-month regimens are significantly better not only in the combined outcome measure, but also in the TB-associated outcomes, namely significantly fewer failures and relapses.”
A within-trial health economics study led by the Liverpool School of Tropical Medicine found that the fully-oral treatment is more expensive than the control regimen from a health system perspective – largely driven by the cost of the regimen; however, patient direct costs were lower in both study regimens compared to the control regimen. Reducing patient costs is important to eliminate catastrophic costs for TB-affected families, as targeted by the World Health Organization.
Fewer patients experience hearing loss in oral, six-month regimens versus control
Professor Sarah Meredith, co-chief investigator and medical lead for STREAM based at UCL, also noted, “after careful monitoring of all participants in STREAM, we were pleased that no concerning safety signals were identified. In addition, fewer participants experienced severe hearing loss in the all-oral regimen (2%) and the six-month regimen (4%) compared to the control regimen (8%). This is important information, as hearing loss has been a particular concern for patients taking earlier MDR-TB treatments.”
Stage 2 of the trial was conducted in Ethiopia, Georgia, India, Moldova, Mongolia, South Africa and Uganda. In addition to evaluating the efficacy, safety and health economics of new MDR-TB regimens, STREAM has supported a robust program of community engagement, particularly at Stage 2 sites, and encourages use of STREAM data for analyses of important secondary research questions.
STREAM Stage 1 was funded by the United States Agency for International Development (USAID) through the Cooperative Agreement GHN-A-00-08-0004-00. Stage 2 of STREAM was jointly funded by USAID and Janssen Research & Development, LLC. Additional funding for STREAM was provided by the Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union.
From World Health Organization
“The STREAM trial demonstrates the importance of evaluating treatment regimens in clinical trials to fully understand their potential,” said Dr. Tereza Kasaeva, Director, Global Tuberculosis Programme, World Health Organization. “WHO is committed to providing the most up-to-date recommendations to support shorter, more tolerable MDR-TB treatments to improve the quality of life for millions who suffer from TB worldwide. The results from this trial support the current WHO recommendation on the 9-month regimen for treatment of drug-resistant TB.”
From The Union
“These results are very encouraging for the thousands of people affected by MDR-TB. Increased effective treatment options means better choices for people with TB, which ultimately improves treatment outcomes and quality of life,” said Dr. Kobto Koura, Department of Tuberculosis Director, The Union. “We hope these latest findings will contribute to the next international recommendations for the management of MDR-TB.”
From Janssen Pharmaceutica NV, part of the Janssen Pharmaceutical Companies of Johnson & Johnson
“The STREAM Trial underscores the importance of collaborative science in public health to advance critical research that strengthens global public health knowledge and guidance,” said Ruxandra Draghia-Akli, MD, PhD, Global Head of Global Public Health R&D, Janssen Research & Development, LLC. “Janssen is proud to collaborate with organizations across sectors to generate important evidence and information that can further our medicine’s potential to help transform TB treatment for patients in need while maintaining its long-term effectiveness in the face of rising antimicrobial resistance.”
From Brazilian Tuberculosis Research Network (REDE-TBBrazilian)
“Community engagement was a core component of the STREAM trial, and we are proud that all trial sites had an active community advisory board,” said Ezio Távora, CE Coordinator, Brazilian Tuberculosis Research Network (REDE-TB). “The cooperation between the community advisory board, trial researchers and program managers created an unprecedented exchange of knowledge and capacities and strengthened understanding about research in the communities and about the important role communities play in the research process.”
To read the latest research, please visit: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02078-5/fulltext